Diseases doi: 10.3390/diseases14100362

Authors: Emil Aliev Efrat Orenbuch-Harroch Abed Khalaileh Ashraf Imam Matan Joel Cohen Maya Korem

Objectives: Infectious complications, particularly those caused by multidrug-resistant organisms (MDROs), remain a major cause of morbidity and mortality after liver transplantation (LT). While pre-transplant colonization is a recognized risk factor, its prognostic significance relative to post-transplant MDRO status remains unclear. This study evaluated the clinical impact of MDRO presence across the transplant timeline and identified predictors of post-transplant mortality and graft dysfunction. Methods: A retrospective cohort study of 110 adult LT recipients (2018–2024) was conducted at a tertiary center. Patients were stratified by pre-transplant ESBL/MDRO colonization or infection and by post-transplant MDRO status (modeled as a time-dependent exposure). Primary outcomes were one-year all-cause mortality and adverse graft outcomes. Results: Pre-transplant ESBL/MDRO presence (40% of recipients) was not associated with increased one-year mortality or adverse graft outcomes. Conversely, post-transplant MDRO status occurred in 44.5% of patients and was strongly associated with poor outcomes. Post-transplant MDRO colonization or infection was present in 88% (14/16) of non-survivors vs. 37% (35/94) of survivors (p < 0.001). One-year mortality was 47% (9/19) for post-transplant MDRO infection, 17% (5/30) for colonization alone, and 3% (2/61) with no post-transplant MDRO event. In a penalized time-dependent Cox model, post-transplant MDRO acquisition was independently associated with one-year mortality (HR 4.0, 95% CI 1.77–9.03; p < 0.001), confirmed by landmark analysis (HR 3.15, 95% CI 1.08–9.19), whereas pre-transplant status showed no association (p = 0.18). Conclusions: While pre-transplant status did not significantly impact one-year mortality in this cohort, post-transplant MDRO acquisition was independently associated with one-year mortality. Pre-transplant status should guide targeted prophylaxis, whereas the post-transplant period represents the critical window for infection prevention and antimicrobial stewardship interventions.

Diseases doi: 10.3390/diseases14100361

Authors: Zelimkhan Berikkhanov Kseniya Resnina Zakhar Akulov Evgeniy Tarabrin Alexey Shestakov Vadim Razumovsky Aleksey Kotelnikov Andrey Nikolaev Milena Ivanova Sara Nourmahal Sergey Muraviev

Background/Objectives: Acute appendicitis is readily recognised, but its initiating mechanisms remain uncertain. Viral findings are often interpreted without separating direct appendiceal infection, systemic host responses, clinical phenocopies, and virome effects. We examined the evidence for these scenarios and their possible relationship to spontaneous resolution. Methods: A structured narrative synthesis of 82 publications integrated tissue studies, clinical series, epidemiology, microbiome and virome research, natural history, and treatment outcomes. Results: Direct viral injury is documented in rare clinicopathological settings. Available tissue studies argue against frequent direct adenoviral infection. Systemic infection could provoke lymphoid activation, oedema, or early microvascular injury, but this causal sequence has not been demonstrated in humans. Clinical studies document resolution in selected uncomplicated cases, including recovery without antibiotics, without establishing a viral cause. Conclusions: The framework separates observed findings from competing causal hypotheses. A viral prodrome is a candidate research variable whose independent diagnostic and prognostic value remains unestablished. Prospective studies must link infection chronology to local inflammation and subsequent outcomes before such information can guide treatment. Viral symptoms or positive tests cannot justify withholding indicated antibiotics or surgery.

Diseases doi: 10.3390/diseases14100360

Authors: Darya Khalid Mahmood Arivan Mahmood Hama Ahmad Shoeb Hashmi

Background/Objectives: Understanding the biological role of the receptor activator of nuclear factor-κB ligand (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) is vital for clarifying the pathogenesis of gnathic giant cell-containing lesions and directing targeted clinical treatments. Methods: Following PRISMA 2020 guidelines and a registered PROSPERO protocol [CRD420261461026], we searched PubMed, Scopus, and Web of Science databases for human tissue-level or clinical denosumab studies (2003–2026). Quality was appraised using adapted NOS and JBI checklists. A fixed-effect inverse-variance meta-analysis pooled continuous RANK parameters between aggressive and non-aggressive CGCG subtypes. Results: Eleven primary tissue-marker studies (259 specimens; two previously considered studies were excluded as unpublished, non peer-reviewed sources) and 10 non-overlapping clinical cohorts/case reports (58 patients total: 55 from 7 multi-patient cohorts + 3 single-case reports [Hameed, O’Connell, Kawamura]). Mononuclear stromal cells represent the pathogenetic driver, secreting RANKL to recruit RANK-expressing mature giant cells. Meta-analysis (k = 2 studies) showed that raw membrane RANK-positive cell percentages did not differ significantly between aggressive and non-aggressive phenotypes (pooled Hedges’ g = 0.25, 95% CI −0.29–0.80, p = 0.36), while non-aggressive lesions showed a borderline, non-significant trend toward higher staining intensity-distribution (SID) scores (g = 0.55, 95% CI −0.00–1.11, p = 0.0506). Because this 95% CI crosses zero, and only two studies (k = 2) were pooled, this represents a non-significant trend rather than a statistically confirmed difference between aggressive and non-aggressive CGCG; both pooled estimates are, therefore, hypothesis-generating only. In clinical cohorts, denosumab achieved objective clinical and radiological tumor responses in all reported cases, enabling downstaging from disfiguring resection to conservative curettage. However, post-cessation recurrence was frequent, ranging from 37% in adults to 100% in pediatric cohorts, with pediatric patients at risk of rebound hypercalcemia. Conclusions: The RANK/RANKL/OPG axis, driven by RANKL-secreting mononuclear stromal cells, underlies osteolytic activity in gnathic giant cell lesions. Denosumab is an effective neoadjuvant bridge to jaw-preserving surgery but is not curative; a RANKL-independent, OPG-resistant SOFAT pathway has been hypothesized as one possible contributor to treatment failure, although this proposal is derived from a single external study and requires independent validation before any clinical inference is drawn. Close post-treatment metabolic and radiographic surveillance is warranted in pediatric patients. Prospective studies are needed to define optimal weaning protocols.

Diseases doi: 10.3390/diseases14100359

Authors: Gorana Mandić-Stojmenović Vladimir Kostić Ana Marjanović Ivana Novaković Predrag Aleksić Tanja Stojković Elka Stefanova

Background/Objectives: Early-onset dementia (EOD), defined as symptom onset before 65 years of age, is a clinically and genetically heterogeneous group. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are its most common neurodegenerative causes. Methods: We investigated the family history, genetic spectrum, and diagnostic yield of targeted genetic testing in a consecutive Serbian cohort of 130 patients with early-onset AD (EOAD) and 78 with early-onset FTD (EOFTD). Results: Approximately one-third of patients had a positive family history of dementia or another neurodegenerative disorder. Pathogenic or likely pathogenic variants were identified in 3.8% of patients with EOAD, whereas pathogenic or likely pathogenic variants or pathogenic repeat expansions were identified in 9.0% of patients with EOFTD. In EOAD, the diagnostic yield increased to 9.5% in those with a positive family history and, in an exploratory subgroup analysis, was 33.3% in those with symptom onset before 51 years. In EOFTD, the diagnostic yield was 25.0% among those with a positive family history. PSEN1 and APP were the only disease-causing genes identified in EOAD, whereas C9orf72 repeat expansion was the predominant genetic cause of EOFTD, with additional pathogenic variants identified in GRN and VCP. Conclusions: These findings support the clinical value of targeted genetic testing guided by family history, age at onset, and clinical phenotype in patients with EOD. Genetically unresolved familial cases may reflect incomplete assessment of known genetic causes, including genes and variant classes not covered by the targeted testing strategy used in this study.

Diseases doi: 10.3390/diseases14100358

Authors: Rares Voda Sohaib Ahmed Ovidiu Aurelian Budișcă Cătălin-Dumitru Cosma Ovidiu Simion Cotoi Călin Molnar Vladimir Bacârea

Background/Objectives: Systemic inflammatory indices may differ prognostically between resectable and palliative pancreatic cancer. We compared associations of the aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and monocyte-to-lymphocyte ratio (MLR) with overall survival after pancreatic resection or palliative bypass. Methods: This single-center retrospective cohort included 240 patients treated during 2013–2023 (99 resections; 141 palliative bypasses). Indices derived from preoperative blood counts were natural-log transformed, standardized to 1 SD, and entered separately into operative-group-stratified Cox models. Group-specific associations and interactions were estimated. Reconstructed AJCC eighth-edition stage was incorporated only in the resection stratum. Interaction p values were Holm-adjusted. AISI was designated primary and SIRI key secondary. Results: Overall, 215 deaths occurred. Median overall survival was 17.9 months after resection and 5.4 months after palliative bypass. AISI was associated with mortality following bypass (adjusted hazard ratio [HR] per 1-SD increase in ln(AISI), 1.54; 95% confidence interval [CI], 1.28–1.86) but not following resection (HR, 0.97; 95% CI, 0.75–1.25; interaction p = 0.003; Holm-adjusted p = 0.010). SIRI showed corresponding HRs of 1.60 (95% CI, 1.30–1.96) and 0.93 (95% CI, 0.72–1.20), respectively (interaction p = 0.001; Holm-adjusted p = 0.004). Exploratory MLR analysis also showed statistical heterogeneity. SII was associated with mortality following bypass, but its operative-group interaction was not significant. The conventional NLR interaction was also nonsignificant, although model-assumption violations limited its interpretation. The AISI and SIRI findings remained robust in the sensitivity analyses. Conclusions: AISI and SIRI showed statistical heterogeneity in their associations with overall survival between operative groups, with higher values associated with mortality following palliative bypass. These findings do not establish that the operative procedure modifies the underlying biological relationship. The absence of pathological staging in the bypass group leaves potential residual confounding by disease extent. Independent external validation is required before clinical implementation.

Diseases doi: 10.3390/diseases14100357

Authors: Ernur Bekov Olga Ponamareva Ryszhan Bakirova Vilen Molotov-Luchanskiy Yelena Pozdnyakova

Background/Objectives: Thyroid disorders may involve systemic oxidative and carbonyl disturbances, but compartment-specific changes in catalase activity and methylglyoxal concentration across different clinical phenotypes remain unclear. This study aimed to evaluate catalase activity and methylglyoxal concentrations in erythrocytes and plasma across predefined clinical phenotypes representing different combinations of thyroid functional, autoimmune, and structural characteristics and to examine correlations among these variables within and between the erythrocyte and plasma compartments. Methods: This single-center cross-sectional study included 164 participants: 24 controls, 31 patients with hypothyroidism without autoimmune thyroiditis, 30 with autoimmune thyroiditis and hypothyroidism, 42 with euthyroid nontoxic nodular goiter, and 37 with euthyroid autoimmune thyroiditis. Catalase activity and methylglyoxal concentration were measured spectrophotometrically. Results: Erythrocyte catalase activity was higher in all patient groups than in controls. Plasma catalase activity was significantly higher in hypothyroidism without autoimmune thyroiditis and nontoxic nodular goiter, but not in autoimmune thyroiditis with hypothyroidism or euthyroid autoimmune thyroiditis. Erythrocyte MGO concentration was significantly lower in hypothyroidism without autoimmune thyroiditis and nontoxic nodular goiter, whereas autoimmune thyroiditis with hypothyroidism and euthyroid autoimmune thyroiditis did not differ significantly from controls. Plasma MGO concentration did not differ significantly among groups. In patients, catalase activity was not correlated with MGO within either compartment, whereas erythrocyte and plasma MGO concentrations were positively correlated. Conclusions: Thyroid disorders showed nonuniform group-level patterns of catalase activity and MGO concentration across the erythrocyte and plasma compartments. The findings support separate interpretation of erythrocyte and plasma measurements but do not establish distinct phenotype-specific biomarker profiles.

Diseases doi: 10.3390/diseases14100356

Authors: Shuk Yan Mak Jeanny Sui Sum Cheung Ankie Tan Cheung William Ho Cheung Li

Background/Objectives: Sleep disturbance is increasingly recognized as a key contributor to symptom burden and functioning in paediatric oncology, yet comparative evidence across clinical and healthy populations remains limited. This study examined sleep quality and its association with health-related quality of life (HRQoL) in children and adolescents with cancer compared with peers with non-oncological chronic illnesses and healthy controls. Methods: A cross-sectional study was conducted at Hong Kong Children’s Hospital. Participants 6–18 years were recruited by convenience sampling into three groups (oncology, chronic illness, healthy; n = 50 each). Children and adolescents completed the Chinese Pittsburgh Sleep Quality Index (PSQI) and Pediatrics Quality of Life Inventory (PedsQL) 4.0. Group differences were tested using chi-square tests and one-way analysis of variance (ANOVA) with post hoc Tukey comparisons. Pearson correlations and hierarchical multiple linear regression examined PSQI-PedsQL associations. Results: Sleep quality differed significantly across groups (p < 0.001), with the poorest sleep observed in the oncology group. The prevalence of poor sleep (PSQI ≥ 5) was 60.0% in oncology group, compared with 40.0% in those with chronic illness and 30.0% in healthy peers. Mean global PSQI scores were 6.02 ± 3.40 in the oncology group, 4.10 ± 2.60 in the chronic illness group, and 3.30 ± 2.35 in healthy controls, with a significant overall group difference (p < 0.001). Impairments were most pronounced in sleep latency, habitual sleep efficiency, and sleep disturbances. HRQoL was lowest in the oncology group (p < 0.001). Mean PedsQL total scores were 68.98 ± 15.73 in the oncology group, 75.99 ± 14.03 in the chronic illness group, and 85.44 ± 10.26 in healthy controls, respectively, with a significant overall group difference (p < 0.001). Across the full sample, poor sleep quality was independently associated with lower HRQoL after adjustment for demographic and clinical factors (β = −0.271, p = 0.002), with no significant interaction by group. Conclusions: Children and adolescents with cancer reported clinically significant sleep impairment, driven mainly by reduced sleep quality and continuity. Routine sleep screening and targeted supportive interventions may improve HRQoL in paediatric oncology.

Diseases doi: 10.3390/diseases14100355

Authors: Mihai-Codrin Constantinescu Dan-Cristian Moraru Vladimir Poroch Stefana Avadanei-Luca Andrei-Nicolae Gologan Alexandru-Hristo Amarandei Awad Dmour Dragos-Florin Gheuca-Solovastru Bianca-Ana Dmour Delia-Gabriela Ciobanu-Apostol Mihaela Pertea

Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, potentially life-threatening mucocutaneous reactions classified based on body surface area (BSA) involvement: SJS affects less than 10% BSA, SJS/TEN overlap affects 10–30% BSA, and TEN affects more than 30% BSA. The mortality rates range from 4.8–9% for SJS to 14.8–48% for TEN. Treatment remains controversial, with corticosteroids and intravenous immunoglobulin (IVIg) being the most debated therapeutic options. While some studies suggest IVIg may block Fas-mediated keratinocyte apoptosis, meta-analyses have shown conflicting results regarding mortality benefit. Case presentation: We describe two patients from opposite ends of the SJS/TEN spectrum, managed in a burn unit with different therapeutic approaches. The first patient, a 47-year-old man with systemic lupus erythematosus, developed TEN with approximately 35% body surface area involvement, complicated by sepsis and rhabdomyolysis; he was treated with systemic corticosteroids and intravenous immunoglobulin (IVIg, 0.4 g/kg/day for 3 days). The second patient, a 66-year-old woman, developed SJS attributed to amoxicillin–clavulanic acid and was treated with systemic corticosteroids alone. Both patients achieved complete re-epithelialization without major sequelae. Conclusions: These two cases illustrate the clinical heterogeneity of the SJS/TEN spectrum and the central role of early recognition, prompt withdrawal of the culprit drug, transfer to a specialized unit, and multidisciplinary supportive care. Given the substantial differences between the two patients in age, sex, comorbidities, culprit drugs, and disease severity, no comparative or causal inference regarding the relative efficacy of the two treatment strategies can be drawn; no efficacy claim is made for either therapeutic approach; this report is descriptive, and the two cases are presented as contrasting rather than comparable.

Diseases doi: 10.3390/diseases14100354

Authors: Johanna Alcívar Ponce Wilson Alexander Zambrano Vélez Marianela Silva Sánchez Gioryi Sornoza Zavala

Background/Objectives: Immune checkpoint inhibitors have transformed oncology by inducing unexpected and sustained remissions in some patients; however, this atypical survival may be accompanied by significant psychosocial and existential challenges. The objective was to synthesize the available scientific evidence on the psychosocial burden of the ‘Lazarus Effect’, characterized by survivor guilt, identity shift, and discontinuation anxiety. Methods: A systematic review was conducted following the PRISMA2020 guidelines, based on a preregistered protocol on the OSF. Searches were performed in PubMed, Scopus, Web of Science, and APA PsycINFO using PICOS-based eligibility criteria. Seven primary empirical studies were included, and their methodological quality and risk of bias were assessed using the MMAT 2018. Results: Survivor guilt stems interpersonally from peer deaths and intrapersonally from perceived autonomy loss. Identity shift involves transitioning into an “existential limbo,” re-establishing self-identity while off active treatment. Discontinuation anxiety relates to recurrence fears, absence of curative biomarkers, and uncertainty regarding treatment duration. Interactively, these dimensions drive broader psychosocial burden, including social isolation, “scanxiety,” and a discrepancy between physical recovery and emotional vulnerability. Conclusions: Current evidence—limited to seven heterogeneous studies concentrated in high-income settings—indicates exceptional responses to immunotherapy may involve nuanced psychosocial challenges. Given small sample sizes, melanoma overrepresentation, potential report retrieval bias, and non-standardized assessment tools, findings require cautious interpretation. They offer an exploratory foundation for future research rather than definitive clinical conclusions, supporting preliminary psycho-oncological screening during treatment transitions.

Diseases doi: 10.3390/diseases14100353

Authors: Tommaso D’Anna Marcello Trizzino Beatrice Belmonte Claudia Gioè Augusto Orlandi Stefania Zerbo Andrea Cicero Antonina Argo Antonio Cascio

Background: The total urinary protein-to-creatinine ratio (PCr) measures proteinuria but does not establish tubular injury or its recovery. Methods: We examined PCr changes after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in a single-centre retrospective cohort of 364 adults with human immunodeficiency virus (HIV) infection. Paired PCr values were available for 159 patients (43.7%). The primary descriptive endpoint was a PCr reduction below 20%, an operational, nonvalidated threshold. Analyses comprised paired rank-based comparisons, baseline-adjusted regression, threshold and influence sensitivity analyses, and nested cross-validation of ridge logistic regression using three predictor sets. Results: The median paired PCr change was −4.0 mg/g (interquartile range −41.5 to 11.5; signed-rank Benjamini–Hochberg-adjusted q = 0.0098); 99/159 patients (62.3%) had a reduction below 20%. Baseline log(1 + PCr) was positively associated with post-switch log(1 + PCr), while its coefficient in the corresponding change model was exactly one unit lower, illustrating mathematical coupling. The cross-validated area under the curve was 0.709 for baseline PCr alone, 0.475 for the other covariates, and 0.701 for all predictors. Conclusions: PCr changes were heterogeneous, and additional covariates did not improve discrimination over the baseline PCr alone. Missing outcomes, unavailable specimen dates, the absence of tubular-specific biomarkers and the uncontrolled design preclude conclusions about irreversible tubular injury, causal treatment effects or clinical prediction utility.

Diseases doi: 10.3390/diseases14100352

Authors: Marina K. Ibragimova Matvey M. Tsyganov Arina K. Shagabudinova Irina A. Tsydenova Maxim A. Morozovsky Nikolai V. Litviakov

Breast cancer (BC) exhibits considerable metastatic heterogeneity and distinct patterns of organotropism, which contribute to differences in patient outcomes and therapeutic responses. However, the molecular mechanisms underlying this organ specificity remain incompletely understood. Objective: To investigate the genetic landscape of primary breast tumor, surgical specimens, and metastatic lesions and to identify copy number aberration (CNA) regions associated with organ-specific metastatic-site patterns in breast cancer. Materials and methods: The study included paired pretreatment and post-treatment surgical specimens from 50 patients with BC (T1–4N0–3M0) and hematogenous metastases. In addition, three samples (biopsy, surgical specimen, and metastatic lesion) were obtained from four patients with primary metastatic BC (with metastasis to the bones, lungs, liver, and brain). Microarray analysis was performed using high-density CytoScanTM HD Array DNA chips (Affymetrix (USA)). Results: The following CNA regions were associated with organ-specific metastatic-site patterns: bone metastasis was associated with a higher frequency of amplifications in the 14q32.33 region (p = 0.0144); liver metastasis was associated with a higher frequency of amplifications in the 17q23.2 region (p = 0.0042, confirmed by validation on an independent cohort); lung metastasis was associated with a higher frequency of deletions in the 2p13.1 and 19p13.12 regions (p = 0.0449); and brain metastasis was associated with a higher frequency of deletions in the 19q12 region (p = 0.0522) and in the 20q11.22 region (p = 0.0089, confirmed by validation in an independent cohort). Conclusions: Our findings identify CNA regions associated with organ-specific metastatic-site patterns in breast cancer patients.

Diseases doi: 10.3390/diseases14100351

Authors: Diana Iosif Viorel Gherghina Andra Iulia Suceveanu Cristian Ionut Orasanu Marius Dragos Prazaru Iulia Cindea Anca Pantea Stoian Laura Mazilu Alina Doina Nicoara Adrian Paul Suceveanu

Background/Objectives: Severe acute pancreatitis accounts for 20% of acute pancreatitis episodes and carries a substantial mortality risk. The systematic severity of the disease is driven by a massive cytokine release, with Interleukin-17 (IL-17) acting as a crucial modulator of the pro-inflammatory cascade. This study aimed to evaluate the prognostic value of serum IL-17 at admission and correlate it with multi-organ dysfunctions and clinical-biological outcomes in patients with severe acute pancreatitis. Methods: A retrospective analysis was conducted on a cohort of 35 patients with severe acute pancreatitis. Demographic, etiological, and clinical-biological baseline characteristics were extracted. Serum IL-17 levels were determined at admission using the ELISA method, and data were statistically analyzed. Results: Significantly higher levels of IL-17 were observed in patients who developed multi-organ failure. Prognostic thresholds were identified via ROC analysis to predict organ dysfunctions: ≥19.77 pg/mL for neurological dysfunction (AUC = 0.814, p = 0.003) and acute respiratory distress syndrome (AUC = 0.756, p = 0.024); ≥18.45 pg/mL for respiratory (p = 0.004) and cardiovascular dysfunctions (AUC = 0.820, p = 0.002); and ≥19.81 pg/mL for renal dysfunction (AUC = 0.735, p = 0.020). Furthermore, univariate binary logistic regression identified elevated serum IL-17 as a significant prognostic factor for mortality among patients admitted to the intensive care unit (OR = 1.062, p = 0.048). Conclusions: Serum IL-17 at admission functions as a significant prognostic biomarker that reflects the severe systemic pro-inflammatory status in severe acute pancreatitis and mirrors the risk of subsequent organ dysfunctions and mortality. Incorporating IL-17 into initial risk stratification protocols may assist clinicians in timely therapeutic escalation.

Diseases doi: 10.3390/diseases14090350

Authors: Kingsley Kalu Elizabeth Ayangunna Bushra Shah Gulzar Shah

Background: There is a growing incidence of colorectal cancer and related deaths in the United States, despite screening recommendations. This study analyzed the factors associated with having ever undergone endoscopic colorectal cancer testing among adults aged 45–85 years. Methods: This study analyzed data from the 2023 National Health Interview Survey (N = 17,087 participants). A multivariable logistic regression analysis was conducted to assess the relationship between sociodemographic and healthcare-related factors and the likelihood of having ever (a) undergone a colonoscopy or sigmoidoscopy and (b) taken a fecal immunochemical test (FIT). Results: The majority of the respondents had undergone an endoscopic colorectal exam (66%) vs. FIT (22%) in their lifetime. Compared to respondents aged 45–49 years, those in older age groups (50–85 years) were more likely to have ever undergone an endoscopic colorectal exam or FIT testing. African Americans were more likely to have ever undergone an endoscopic colorectal exam (Adjusted Odds Ratio (AOR) = 1.26, CI = 1.07–1.48), while American Indian/American Native and others (AOR = 1.35, CI = 1.02–1.80) were more likely to have ever undergone a FIT compared to White people. While education and health insurance were associated with having ever undergone an endoscopic colorectal exam, neither was associated with FIT. Compared to married respondents, widowed, separated, or divorced respondents (AOR = 0.88, CI = 0.79–0.98), and unmarried respondents (AOR = 0.70, CI = 0.60–0.82) were less likely to have ever undergone an endoscopic colorectal exam. Conclusions: Variations in factors associated with having ever undergone endoscopic colorectal cancer testing can help to understand disparities in screening uptake better and guide the development of targeted public health interventions to improve colorectal cancer prevention and early detection.

Diseases doi: 10.3390/diseases14090349

Authors: Dean Kaličanin Vanna Žnidar Ivana Listeš Maja Cvek Ana Barić Žižić Marko Vuletić Sanda Sladić Vivian Eneas Micek Vesela Lovrić Torlak Ante Punda Vesna Boraska Perica

Background/Objectives: Vitamin D is an important regulator of immune and inflammatory processes, while its deficiency is frequently observed in Hashimoto’s thyroiditis (HT). The relationship between Vitamin D and systemic inflammation in HT remains insufficiently understood, particularly across different disease stages. Methods: We used the Olink Target 96 Inflammation panel to investigate this association. Inflammatory proteins and serum 25(OH)D levels were measured in 257 HT patients and 173 controls from the CROHT biobank. Participants were categorized as Vitamin D deficient (<20 ng/mL) or non-deficient (≥20 ng/mL), with HT patients further stratified as euthyroid, hypothyroid, or levothyroxine-treated. Associations between 25(OH)D and 92 inflammatory proteins were assessed using multivariable linear regression adjusted for age, sex, BMI, smoking, and season of blood sampling, followed by interaction testing and meta-analysis. Results: Vitamin D deficiency was prevalent in both HT patients and controls. Among Vitamin D-deficient HT patients, higher 25(OH)D levels showed nominal inverse associations with the previously reported HT-associated inflammatory proteins IL-17C, CCL20, and CCL11, as well as with GDNF. Among non-deficient HT patients, a nominal positive association with CD6 was observed. None of these associations or interaction terms remained statistically significant after false discovery rate correction. Conclusions: These findings should therefore be considered exploratory and hypothesis-generating. Nevertheless, the observed Vitamin D status-specific patterns suggest that the relationship with inflammatory profiles in HT may differ according to Vitamin D status and warrant validation in prospective and mechanistic studies.

Diseases doi: 10.3390/diseases14090348

Authors: Paula-Alexandra Popovici Andreea Diana Igna Bianca-Lăcrimioara Petca Timea Claudia Ghitea Mihaela Simona Popoviciu

Background: Diabetes self-management is essential for type 2 diabetes care, but cross-sectional associations may be distorted when questionnaire scores are incorrectly derived or converted into arbitrary categories. We evaluated clinical and sociodemographic correlates of the continuous Diabetes Self-Management Questionnaire (DSMQ) total score in a secondary analysis of an outpatient clinical database. Methods: The analysis included 262 adults with type 2 diabetes recruited between 1 November 2025 and 1 May 2026. DSMQ total and subscale scores were independently recalculated from the 16 item-level responses using the published scoring algorithm. The primary analysis retained the DSMQ score as a continuous outcome. The database provided a participant-level count of documented glucose measurements > 250 mg/dL. This operational count was not treated as a standardized clinical event or severity category; individual measurement timestamps, participant-specific observation duration, and the total number of glucose measurements were unavailable. Results: The recalculated DSMQ score was 5.26 ± 2.35 (median 5.10; interquartile range 3.12–7.08). Among 261 participants with an interpretable sex code, 144 (55.2%) were women. In univariable analyses, lower DSMQ scores were concurrently associated with longer diabetes duration, a higher recorded severe-hyperglycemia count, higher HbA1c, and higher fasting glucose. In the adjusted model (n = 261), the recorded severe-hyperglycemia count remained negatively associated with DSMQ score (adjusted coefficient −0.412 points per recorded episode; 95% confidence interval −0.621 to −0.203; p < 0.001). Individualized versus hospital-based education was not independently associated with the corrected score. A beta-regression sensitivity analysis produced a concordant direction of association (coefficient −0.152 on the logit mean scale; p < 0.001). The linear model explained 17.2% of observed variance (adjusted R2 = 0.136), with an optimism-corrected R2 of 0.099. Conclusions: The recorded severe-hyperglycemia count was a concurrent correlate of lower DSMQ score. Because the study is cross-sectional and glucose-measurement counts were preaggregated without observation-time or monitoring-frequency data, the findings do not establish temporal direction, causality, or individual-level clinical prediction. Item-level score verification and continuous-outcome analysis materially changed the interpretation of the dataset.

Diseases doi: 10.3390/diseases14090347

Authors: Pantelie Nicolcescu Alina Bereanu Ionela Mihai Manuela Arbune Mihai Sava Nicolae Grigore Adrian Hasegan

Background: Fournier’s gangrene (FG) is a severe necrotizing infection requiring urgent resuscitation, empirical broad-spectrum antimicrobials, and radical debridement. We evaluated established severity scores, Sepsis-3-defined organ dysfunction, and malignancy status in a single-center cohort with surgically confirmed FG. Methods: This retrospective observational study analyzed 21 consecutive adult patients treated between 1 January 2019 and 31 January 2025 at a Romanian tertiary referral center. Pre-treatment baseline FGSI, SFGSI, LRINEC, NLR, SOFA, and qSOFA were calculated. All patients received intravenous antimicrobials within 90 min and underwent surgical debridement within 6 h. In-hospital mortality was assessed via ROC curves, Fisher’s exact test, Haldane–Anscombe odds ratios (ORs), and Firth penalized logistic regression. Results: In-hospital mortality was 19.0% (4/21). Admission Sepsis-3 sepsis (SOFA ≥ 2) was present in 7/21 patients (33.3%) and accounted for all four deaths, whereas zero deaths occurred among the 14 patients without organ dysfunction (Fisher’s exact p = 0.006; OR 37.33, 95% CI 1.60–866.90). All nine qSOFA-positive patients without SOFA dysfunction (42.9%) and five patients without organ dysfunction (23.8%) survived. FGSI showed the highest discrimination (AUC 0.934, 95% CI 0.76–1.00), followed by SFGSI (AUC 0.919, 95% CI 0.78–1.00) and LRINEC (AUC 0.860, 95% CI 0.68–0.99); NLR showed poor discrimination (AUC 0.574, 95% CI 0.13–1.00). Metastatic solid malignancy was present in 2/4 non-survivors versus 0/17 survivors (Fisher’s exact p = 0.029; OR 35.00, 95% CI 1.27–961.40). All four non-survivors met Sepsis-3 criteria (two with and two without metastases). Seven patients required ICU admission (all four non-survivors and three survivors). Conclusions: Admission Sepsis-3-defined organ dysfunction was strongly associated with in-hospital mortality. FGSI and SFGSI demonstrated the highest point-estimate discrimination, LRINEC also showed good discrimination, and NLR demonstrated limited standalone discriminative value. Metastatic malignancy occurred exclusively among non-survivors but overlapped with Sepsis-3-defined sepsis. These findings support the combined assessment of Sepsis-3-defined organ dysfunction and established severity scores for early risk stratification, warranting validation in larger cohorts.

Diseases doi: 10.3390/diseases14090346

Authors: Maxence Chicoisneau Christelle Bouchart Matthieu Hein

Background/Objectives: Pancreatic cancer (PC) is characterized by poor survival and a substantial psychological burden. Growing evidence suggests that individuals diagnosed with PC are at an increased risk of suicide. This systematic review aimed to synthesize the available evidence on suicide risk among patients with PC and to identify factors associated with increased vulnerability. Methods: Following the PRISMA 2020 guidelines, a systematic review of the PubMed/MEDLINE and Scopus databases was conducted in August 2026. Of the 1015 records initially identified, 23 studies published between 2010 and July 2026 were included. Eligible studies specifically examined suicide risk among patients with PC using registry-based, administrative, or death certificate data. Risk of bias was assessed using the ROBINS-E tool. Results: Most included studies reported a higher suicide risk among patients with PC compared with the general population and, in many analyses, compared with patients with other cancer types. Large population-based studies generally reported standardized mortality ratios of approximately 2 to 11, although substantially higher estimates were observed in selected populations and specific subgroups. Suicide risk was particularly elevated during the early post-diagnosis period (with several studies identifying the greatest excess risk within the first two months following diagnosis), remained elevated throughout the first year and gradually declined thereafter. Male sex emerged as the most consistently demonstrated risk factor for suicide, while associations with unmarried status were observed across several studies but were derived largely from partially overlapping SEER-based cohorts. Additional evidence suggests a potential role for social vulnerability and poor prognostic factors. Conclusions: Despite the predominantly observational nature of the available evidence, the consistency of the findings highlights the importance of increased awareness of suicide vulnerability among patients with PC and supports consideration of psychosocial assessment and mental health support within routine pancreatic cancer care. Future prospective studies are needed to better characterize high-risk patients and to inform targeted suicide prevention strategies.

Diseases doi: 10.3390/diseases14090345

Authors: H. A. Nati-Castillo Alin Abreu Lomba Juan David Urrea Ospina Jhan S. Saavedra-Torres Sebastián Lozano Ciro Juliana Vela Paz Nelly Johana Alvis Linero Juan S. Izquierdo-Condoy

Thyrotoxic periodic paralysis (TPP) is a reversible but potentially severe complication of thyrotoxicosis characterized by acute muscle weakness and hypokalemia resulting predominantly from intracellular potassium redistribution. Although classically associated with Asian populations, TPP is increasingly recognized in Latin America. We report a 38-year-old Colombian man with recurrent nocturnal proximal quadriparesis, preserved deep tendon reflexes, serum potassium of 2.3 mEq/L, and biochemical thyrotoxicosis secondary to Graves disease. In parallel, we conducted a structured review of published Colombian cases identified through searches of PubMed/MEDLINE, Scopus, Web of Science, SciELO, and Google Scholar from inception through 1 May 2026. Fourteen previously published cases were identified, yielding 15 cases including the index patient. All patients were male, with a mean age of 31.4 ± 7.4 years. Deep tendon reflexes were normal in 4/13 (30.8%) cases in which they were documented, demonstrating that preserved reflexes do not exclude TPP. TSH was suppressed below 0.05 mIU/L in 14/15 (93.3%) patients. Electrocardiographic findings were reported in only 7/15 cases, and antithyroid drug doses in 6/15, highlighting substantial heterogeneity in reporting. All reported patients recovered muscle strength following acute management. TPP should therefore be considered in patients presenting with acute proximal weakness and hypokalemia even when deep tendon reflexes are preserved or overt manifestations of thyrotoxicosis are absent. Standardized reporting of biochemical, electrocardiographic, therapeutic, and follow-up data is needed to improve characterization of TPP in underrepresented populations.

Diseases doi: 10.3390/diseases14090344

Authors: Ariel Torres Paloma González Gisselle Trujillo Martha Fors

Background/Objectives: Drug resistance in tuberculosis remains one of the major challenges to global disease control. Traditionally, its emergence has been attributed to factors such as treatment interruption, poor adherence, and the selective pressure exerted by antimicrobial agents. However, recent advances in bacterial genetics, within-host evolution, cellular persistence, and heteroresistance suggest that relevant biological processes may develop before treatment initiation. The aim of this critical integrative reflection was to explore the biological plausibility that diagnostic delay may act as an amplifying factor for adaptive and evolutionary mechanisms potentially associated with drug resistance in Mycobacterium tuberculosis. Methods: A structured documentary search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Of the 86 documents initially identified, 29 studies were selected using predefined inclusion and exclusion criteria. The evidence was analysed through a conceptual convergence matrix, which enabled the organisation of findings into five analytical categories: diagnostic delay and programmatic determinants; mechanisms of resistance, bacterial adaptation, and clinical implications; persistence and drug tolerance; within-host evolution and genetic diversity; and heteroresistance and resistant subpopulations. In addition, four institutional reports were incorporated to contextualise the issue from a global perspective. Results: The reviewed evidence suggests that extended persistence of infection before diagnosis may favour biological opportunities for bacterial adaptation, the persistence of tolerant subpopulations, the accumulation of genetic diversity, and the emergence of variants with distinct drug susceptibility profiles. Although the available studies do not demonstrate a direct causal relationship, they support the plausibility of an evolutionary trajectory capable of influencing the dynamics of drug resistance. Conclusions: An expanded model of drug resistance in tuberculosis is proposed, in which diagnostic delay does not constitute a direct cause of resistance but rather a potential amplifying factor for biological adaptation and evolutionary change occurring before treatment initiation. This hypothesis generates new avenues for research on the interaction between timely diagnosis, bacterial evolution, and drug resistance.

Diseases doi: 10.3390/diseases14090343

Authors: Juan M. Racosta Jorge Arocha-Perez Da Hee Seo Samin Ayromlou Patricia M. Riccio

Background: Cognitive impairment, particularly reduced information processing speed (IPS), is a clinically meaningful manifestation of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a sensitive, validated measure of IPS widely used in MS research. While vascular and hemodynamic factors are increasingly recognized as contributors to cognitive performance in MS, their relationship with IPS across distinct physiologic challenges remains unexplored. Objective: This pilot study examined IPS and cardiovascular responses in ten people with MS (PwMS), all of whom had relapsing-remitting MS (RRMS), and ten age- and sex-matched healthy participants during four acute physiologic challenges: head-up tilt, head-down tilt, isometric handgrip, and aerobic cycling. Methods: Beat-to-beat blood pressure and heart rate were continuously recorded; IPS was assessed using the oral SDMT. Results: Baseline SDMT scores were lower in PwMS than in healthy participants (p < 0.05). A between-group effect was observed for cycling-related SDMT change (r = 0.49, 95% CI 0.05–0.76; p = 0.03). Despite comparable training impulse (TRIMP)-standardized workloads, systolic blood pressure during cycling was higher in PwMS (p < 0.05), and the cycling-related systolic blood pressure response showed a between-group effect of r = 0.46 (95% CI 0.02–0.75; p = 0.04). In healthy participants, baseline SDMT performance was correlated with resting heart rate and blood pressure, and cycling-related SDMT change was inversely correlated with the blood pressure response. Conclusions: These exploratory findings suggest possible differences in the relationship between cardiovascular measures and IPS during acute physiologic challenges, particularly aerobic exercise. However, the small sample size and wide confidence intervals preclude firm conclusions regarding an exercise-specific effect or differences in cardiovascular–cognitive coupling.

Diseases doi: 10.3390/diseases14090342

Authors: Aladin Altić Nikola Jovanovic Dario Vucic Nikolaos Katsivelos Lydia Giannakou Jongyeob Kim Ali Maaz Una Tonkovic Aleksandar Sič Marko Baralic

Cardiovascular toxicity is an important complication of treatment for hematologic malignancies, but it is often discussed mainly in terms of direct myocardial injury. Endothelial injury may provide a common link between several cardiovascular complications seen in these patients. Endothelial dysfunction may already be present because of the malignancy itself and can be further increased by anticancer treatment, immune activation and haematopoietic stem cell transplantation. Oxidative stress, reduced nitric oxide availability, inflammation, increased vascular permeability and activation of coagulation can shift the endothelium from a protective to a pro-inflammatory and prothrombotic state. These changes could contribute to hypertension, thrombosis, atherosclerotic disease, coronary microvascular dysfunction, arterial stiffness and myocardial dysfunction. The role of endothelial injury is particularly relevant with BCR-ABL inhibitors, proteasome inhibitors, CAR-T-cell therapy, bispecific antibodies and transplantation, although the mechanisms and strength of evidence differ between treatments. Several circulating biomarkers and tools, including angiopoietin-2, von Willebrand factor, soluble thrombomodulin, adhesion molecules and the Endothelial Activation and Stress Index, may help identify endothelial injury, but their clinical roles still remain unclear. This review examines endothelial injury across hematologic malignancies and their treatments and discusses its role in cardiovascular toxicity, current approaches to vascular protection and the main gaps that need to be addressed before endothelial assessment can become part of routine cardio-oncology care.

Diseases doi: 10.3390/diseases14090341

Authors: Saad Al-Fawaeir

Aim: To investigate the association between body mass index (BMI) and gonadotropin secretion, including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the LH/FSH ratio, among women with polycystic ovary syndrome (PCOS), and to compare these parameters with healthy women. Patients and Methods: This comparative cross-sectional analytical study included 400 women aged 18–35 years recruited from outpatient gynecology and endocrinology clinics at private-sector medical centers in Irbid, Jordan, between June 2025 and April 2026. The study included 200 women diagnosed with PCOS according to the Rotterdam criteria and 200 age-comparable healthy controls. The PCOS group was stratified into four BMI categories (<25, 25–<28, 28–<31, and ≥31 kg/m2), with 50 women in each category. Clinical and anthropometric characteristics were assessed, and serum LH and FSH concentrations were measured. The LH/FSH ratio was calculated for each participant. Differences between groups were evaluated using appropriate statistical tests, while one-way analysis of variance was used to compare PCOS subgroups according to BMI. Pearson’s correlation analysis was used to assess associations between BMI and gonadotropin parameters. Results: The mean age was comparable between women with PCOS and healthy controls (26.31 ± 5.36 vs. 26.47 ± 5.16 years; p = 0.23). Women with PCOS had significantly higher BMI than controls (27.85 ± 3.47 vs. 22.81 ± 2.29 kg/m2; p < 0.001). Among women with PCOS, menstrual irregularity, hirsutism, acne, infertility, and polycystic ovarian morphology were observed in 87.5%, 79.5%, 78.5%, 70.0%, and 100%, respectively. Serum LH was significantly higher in women with PCOS than in controls (8.44 ± 2.61 vs. 6.53 ± 1.16 IU/L; p < 0.001), whereas FSH was significantly lower (4.64 ± 0.98 vs. 7.96 ± 1.18 IU/L; p < 0.001), resulting in a higher LH/FSH ratio (1.84 ± 0.50 vs. 0.83 ± 0.20; p < 0.001). Within the PCOS group, LH progressively decreased across increasing BMI categories, from 11.58 ± 1.26 IU/L in women with BMI < 25 kg/m2 to 5.40 ± 1.29 IU/L in those with BMI ≥ 31 kg/m2 (p < 0.001). Similarly, the LH/FSH ratio decreased from 2.46 ± 0.18 to 1.28 ± 0.23 across these BMI categories (p < 0.001), whereas FSH did not differ significantly (p = 0.07). BMI showed strong inverse correlations with LH (r = −0.870, p < 0.001) and the LH/FSH ratio (r = −0.869, p < 0.001), but not with FSH (r = −0.126, p = 0.075). Conclusions: Women with PCOS demonstrated a distinct gonadotropin profile characterized by higher LH and LH/FSH ratio and lower FSH compared with healthy controls. Among women with PCOS, increasing BMI was strongly associated with lower LH concentrations and LH/FSH ratios. These findings highlight the importance of considering BMI when interpreting gonadotropin profiles in PCOS, although prospective studies are required to determine whether changes in body weight directly influence gonadotropin secretion and reproductive outcomes.

Diseases doi: 10.3390/diseases14090340

Authors: Cristina Angelescu Ioana Anca Bădărău Radu Bogdan Mateescu

Background: Choledocholithiasis is a common cause of biliary obstruction and may lead to acute cholangitis, pancreatitis, and other serious complications. Despite the widespread use of endoscopic retrograde cholangiopancreatography (ERCP), data describing the clinical profile and management of patients with choledocholithiasis in Romania remain limited. Objectives: This study aimed to describe demographic characteristics, diagnostic work-up, procedural characteristics of ERCP, microbiological findings, and early clinical outcomes of patients with choledocholithiasis undergoing ERCP at a high-volume tertiary referral center. Methods: We conducted a retrospective, observational, single-center cohort study of adults with confirmed choledocholithiasis who underwent ERCP between January 2021 and September 2025. During the study period, 2514 ERCP procedures were performed at our center for all indications, of which 631 unique patients with choledocholithiasis fulfilled the eligibility criteria and were included in the final cohort. Demographic characteristics, comorbidities, clinical presentation, laboratory findings, imaging results, ERCP-related variables, and early procedural outcomes were analyzed descriptively. Results: The cohort included 631 patients with a median age of 68 years (IQR 56–77), and 59.9% were women. Abdominal pain (59.3%) and jaundice (48.2%) were the most common presenting symptoms. Acute cholangitis was present in 57.7% of patients; among these patients, severity according to the Tokyo Guidelines 2018 was mild in 52.7%, moderate in 10.7%, and severe in 36.6%. Computed tomography was the most frequent imaging modality confirming the diagnosis (42.5%), followed by magnetic resonance cholangiopancreatography (30.7%) and ultrasonography (26.8%). Median common bile duct diameter was 14 mm and median stone diameter was 7.9 mm; multiple stones or sludge were present in 56.7%. Difficult cannulation occurred in 10.8% of patients, mechanical lithotripsy in 19.5%, biliary stent placement in 18.9%, and post-ERCP pancreatitis in 10.8%. Intraprocedural bleeding occurred in 4.9% of patients, while post-ERCP bleeding occurred in 1.9% and no perforations were recorded. In-hospital mortality occurred in 2 patients (0.3%). Bile cultures were obtained in 52 patients (8.3%), of which 37 (71.2%) yielded bacterial growth, with Escherichia coli being the most frequently isolated microorganism. Conclusions: This study provides real-world evidence on the epidemiology, diagnostic evaluation, ERCP management, and early outcomes of choledocholithiasis in a Romanian tertiary referral center.

Diseases doi: 10.3390/diseases14090339

Authors: David R. Axon Stephanie Fenwick

Background/Objectives: Functional limitations are one of many potential clinical consequences for people living with long COVID. However, medical, health, and demographic variables associated with functional limitations in this population have not been fully characterized. The objective of this study was to identify variables associated with having a functional limitation among United States (US) adults with long COVID in a nationally representative dataset. Methods: This was a cross-sectional analysis of US adults in the 2023 Medical Expenditure Panel Survey (MEPS). A multivariable logistic regression model was created to identify factors associated with reporting functional limitations versus no functional limitations in people with MEPS-defined long COVID. Results: In this study, 26% of adults with MEPS-defined long COVID reported functional limitations. Factors that were associated with functional limitations in people with long COVID included non-married status versus married (odds ratio [OR] = 1.8), having 2–4 chronic health conditions versus 0–1 conditions (OR = 2.8), being unemployed versus employed (OR = 3.5), having public health insurance versus uninsured (OR = 5.3), and reporting pain interference versus no pain (little pain interference, OR = 2.3; moderate interference, OR = 8.8; extreme/quite a bit of interference, OR = 16.9). No other associations were found. Conclusions: Functional limitations are common in people experiencing long COVID. Several factors were associated with functional limitations in this population of individuals with long COVID, although whether the functional limitation was caused by long COVID or another problem was unknown. Further research is needed to better understand factors associated with long COVID and to explore the scope and severity of functional limitations in long COVID.

Diseases doi: 10.3390/diseases14090338

Authors: Khaoula Elcadi Oussama Cherkaoui Rhazouani Nissrine Louhab Najib Kissani Mohamed Chraa

Background: In Parkinson’s disease (PD), non-motor symptoms especially anxiety represent a significant and underappreciated burden. Despite the lack of particular validation in this demographic, the Hamilton Anxiety Rating Scale (HAM-A) is widely used in clinical and research contexts. Methods: A cross-sectional study of 200 Parkinson’s disease patients (mean age 62.77 ± 8.32 years; 118 men and 82 females) was conducted. The Hoehn & Yahr (H&Y) scale was used to grade motor severity, whereas the HAM-A was used to measure anxiety. Results: Of the patients, 52.5% of people (n = 105; mean score 13.85 ± 6.09) had anxiety (HAM-A ≥ 14). Age (r = 0.032; p = 0.657), disease duration (r = 0.115; p = 0.105), H&Y stage (r = −0.073; p = 0.305), and sex (p = 0.856) did not significantly correlate with the HAM-A score. Conclusion: Although the HAM-A shows a high incidence of anxiety in Parkinson’s disease (PD), its consistent lack of connection with clinical illness markers raises serious concerns about construct validity, which are probably caused by somatic item overlap. It is best to use disease-specific tools like the GAD-7 or Parkinson Anxiety Scale (PAS).

Diseases doi: 10.3390/diseases14090337

Authors: Hung The Dang Thoa Phuong Nguyen Thu Thi Yen Pham Chinh Thi Luu Ha Thi Thu Nguyen Oanh Thi Kieu Nguyen Oanh Thi Phuong Ngo Chinh Thi Tuyet Do Ha Thi Ngoc Bui Quan Hong Duong

Background/Objectives: Occupational pesticide exposure is a recognized hepatotoxic hazard; however, biomonitoring data characterizing liver function among Vietnamese agricultural workers remain scarce. This study compared serum hepatic biomarkers between pesticide-exposed fruit farmers (exposed group) and a non-exposed reference group (unexposed group) in a northern province in Vietnam, and evaluated whether biomarker alteration varied with cumulative exposure duration. Methods: A cross-sectional study using convenience sampling was conducted from April to October 2022 among 150 adults, comprising 100 fruit farmers with ≥1 year of direct occupational pesticide exposure and 50 unexposed controls. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and indirect bilirubin, alpha-fetoprotein (AFP), and glucose were quantified using clinical laboratory assays. Multivariable linear regression models, adjusting for age, sex, and body mass index (BMI), were used to evaluate associations between pesticide exposure duration and biomarker levels. Results: Pesticide-exposed farmers had significantly higher mean concentrations of ALT (28.88 vs. 22.36 U/L, p = 0.002), AFP (3.06 vs. 1.16 ng/mL, p < 0.001), total bilirubin (9.93 vs. 7.74 μmol/L, p < 0.001), and indirect bilirubin (8.40 vs. 5.26 μmol/L, p < 0.001) than unexposed controls. While mean AST did not differ (p = 0.105), the proportion of abnormal AST cases was significantly higher among exposed individuals (23% vs. 8%, p = 0.043). After adjustment for age, sex, and BMI in multivariable linear regression models, prolonged exposure (>10 years) remained modestly associated with higher AFP and bilirubin levels (p < 0.05), while associations with ALT and AST were not statistically evident (p > 0.05). Conclusions: These findings suggest a possible association between occupational pesticide exposure and subclinical hepatic alterations, supporting calls for regular health surveillance and enhanced protective measures among fruit farmers.

Diseases doi: 10.3390/diseases14090336

Authors: Lanxing Fu Yvonne H.-L. Luo Nick Kopsachilis Matteo Capobianco Irene Gattazzo Francesco Cappellani Fabiana D’Esposito Caterina Gagliano Marco Zeppieri

Background: Optical coherence tomography (OCT) has been recognised as a non-invasive imaging modality capable of offering high-resolution visualisation of the corneal tissue. Objective: This review evaluates the role of OCT in chronic corneal disease, focusing on how descriptive imaging has progressed to quantitative imaging biomarkers with translational potential. Methods: A comprehensive review of the published literature on OCT imaging in corneal disease was conducted, emphasising structural features, quantitative parameters, and biomarkers. Results: OCT facilitates detailed visualisation of corneal microstructure, including variations in epithelial thickness, stromal reflectivity patterns, corneal thickness distribution, and interface abnormalities. These morphological observations are converted into quantitative measures that function as imaging biomarkers for disease severity, progression, and therapeutic effectiveness. In conditions such as keratoconus, chronic infectious keratitis, and corneal dystrophies, OCT-derived parameters offer valuable information for phenotyping and longitudinal monitoring. Additionally, advances in automated image analysis and artificial intelligence further increase the potential of OCT for biomarker discovery and evidence-based clinical decision-making. Conclusions: The development and validation of robust OCT-based biomarkers have the potential to enable earlier diagnosis, improved disease monitoring, and personalised treatment strategies. Future research that integrates quantitative imaging, computational analysis, and longitudinal clinical data will be essential to fully realise the translational potential of OCT in corneal disease management.

Diseases doi: 10.3390/diseases14090335

Authors: Giulia Colonna Giulio Nittari Taurino Francesco Pasqualino Sirignano Giovanna Ricci Paolo Bailo

Objectives: To provide a narrative overview of popliteal artery injury (PAI) associated with orthopedic knee surgery, focusing on its mechanisms, risk factors, diagnostic challenges, treatment strategies, and medico-legal appraisal within the Italian civil healthcare liability framework. Methods: A non-systematic literature review was conducted using PubMed, Scopus, and Web of Science, including articles published up to December 2025. Original studies, reviews, case series, and case reports addressing vascular anatomy, mechanisms of injury, diagnosis, treatment, and outcomes were selected. During revision, a separate targeted medico-legal search was conducted in PubMed, Scopus, and Web of Science on 7 September 2026, and Italian statutory, judicial, and deontological sources were examined for the civil healthcare liability analysis. Results: The clinical synthesis included 47 studies. Popliteal artery injury was identified as a rare but serious complication of procedures such as total knee arthroplasty, ligament reconstruction, arthroscopy, osteotomies, and hardware removal. Injury mechanisms included thrombosis, arterial incision, pseudoaneurysm formation, and arteriovenous fistulae. Computed tomography angiography emerged as the preferred imaging modality in uncertain cases, while both open surgical and endovascular treatments showed satisfactory results when performed promptly. Delayed diagnosis was consistently associated with worse functional outcomes and increased risk of limb loss. The targeted medico-legal search found only sparse literature directly addressing PAI; the Italian analysis therefore focused on professional conduct, causal attribution, informed consent, and evidentiary reconstruction rather than treating the adverse event itself as evidence of liability. Conclusions: Although uncommon, PAI remains a potentially limb-threatening complication of knee surgery. Thorough anatomical knowledge, early recognition, and timely vascular intervention remain central to clinical management. Within the Italian civil liability framework, the occurrence of a recognized complication neither establishes nor excludes negligence. Medico-legal appraisal should distinguish the primary vascular event from any additional harm attributable to delayed recognition or treatment and should address informed consent and documentation as separate issues.

Diseases doi: 10.3390/diseases14090334

Authors: Alexander Thomas Mboma Elias Peter Mwakilama Alexander Archippus Kalimbira Duc Minh Cap Tuyen Van Duong Rong-Hong Hsieh

Background: Body mass index (BMI) does not capture abdominal fat distribution and may classify adiposity differently from central-obesity indicators. We quantified discordance between BMI-defined overweight/obesity and waist-to-height ratio (WHtR)-defined central obesity among adults with type 2 diabetes mellitus (T2DM) in Malawi. Methods: This multicenter cross-sectional study included 1356 adults attending diabetes clinics at three tertiary hospitals. Overweight/obesity was BMI ≥ 25 kg/m2. Central obesity was defined by waist circumference (WC ≥ 94/80 cm, men/women), waist-to-hip ratio (WHR ≥ 0.90/0.85), and WHtR ≥ 0.50. BMI and WHtR were cross-classified into four phenotypes, and agreement between the two classifications was summarized using observed agreement and Cohen’s kappa. Logistic and multinomial logistic regression models estimated (adjusted) odds ratios with 95% CIs; sensitivity analyses added study site as a fixed effect and modified Poisson models with robust variance provided adjusted prevalence ratios for the common binary outcomes. Results: Prevalence of BMI-defined overweight/obesity was 60.8%; central obesity was 67.5% (WC), 65.3% (WHR), and 80.1% (WHtR). Cross-classification showed 23.7% had central obesity only and 56.3% had combined overweight/obesity and central obesity; observed agreement between the two classifications was 71.8% and Cohen’s kappa was 0.35 (95% CI 0.30–0.40). Overweight/obesity was associated with older age (aOR 2.95), female sex (aOR 2.19), and physical inactivity (aOR 1.93). WC-defined central obesity was strongly associated with female sex (aOR 10.16), although the corresponding adjusted prevalence ratio was considerably smaller (aPR 2.25). WHR-defined central obesity was associated with older age, and anxiety. WHtR-defined central obesity was associated with older age, female sex, ever-married status, and late-evening eating behavior (aOR 1.36), although the association did not persist when study site was added. The combined phenotype was associated with age, sex, marital status, meal frequency, and physical inactivity. Conclusions: Overweight/obesity and central obesity were highly prevalent, with WHtR identifying the greatest burden and a substantial central-obesity-only phenotype that BMI alone would not detect. Incorporating WHtR alongside BMI may improve anthropometric assessment of adiposity in diabetes care, particularly among older and female patients.

Diseases doi: 10.3390/diseases14090333

Authors: Ivan Shun Fai Lau Hon Chi Yip Philip Wai Yan Chiu Martin Chi Sang Wong Louis Ho Shing Lau

Background: Discrepancies between endoscopic and pathological diagnoses commonly occur. From pre-malignant neoplasms to early gastric cancers (EGC), this inconsistency often leads to significant alteration of management. AI (artificial intelligence) assisted diagnostic tools have the potential to mitigate the differences. From optimizing endoscopic examination through standardizing quality and risk stratification by identifying at-risk populations to enhancing EGC detection and characterization guiding therapeutic interventions, AI-assisted endoscopy has shown potential to overcome current limitations in standard care. Methods: In this state-of-the-art narrative review, we synthesize the current evidence and prevailing paradigm, discuss existing limitations, and outline the future directions of AI-assisted endoscopy in EGC. Results: AI models demonstrate potential in enhancing all steps of the EGC management pathway, from optimizing endoscopy quality, identification of at-risk populations, and lesion detection, lesion characterization, to endoscopic resection guidance and lymph node metastasis prediction. Yet, existing evidence largely remains retrospective, with interventional data demonstrating heterogeneity. The conflicting data largely stems from inherent fundamental limitations of AI research in EGC, such as the lack of standardized objective performance metrics, inconsistent methodologies, and reporting standards. These issues fundamentally hinder generalizability and implementation in routine clinical practice. Conclusions: AI-enhanced endoscopy demonstrates potential to overcome current limitations in EGC management. Despite this promising future, there are obstacles to validation, implementation, and mitigating disparities owing to inherent fundamental issues.

Diseases doi: 10.3390/diseases14090332

Authors: Adriana Gherbon Deiana Roman Marioara Nicula-Neagu Mirela Frandes

Background: Diabetes distress is a key mental health dimension of type 2 diabetes (T2D) and a growing concern as populations age, yet its determinants in older adults remain insufficiently characterized. The independent contributions of demographic and metabolic factors to severe distress and their implications for multidisciplinary screening across the lifespan remain unclear. Methods: In this cross-sectional study, we assessed 453 adults with T2D using the 17-item Diabetes Distress Scale (DDS-17). We categorized participants as experiencing low (<2), moderate (2–2.9), or severe (≥3) distress. We compared categories using the Kruskal–Wallis H test and chi-square tests. Logistic regression models were constructed with severe distress (DDS ≥ 3) as the outcome, adjusting for sex, educational level, and HbA1c. Results: Severe distress was identified in 19 participants (4.2%). Age differed significantly across DDS categories (Kruskal–Wallis H test, p = 0.003), with the severe group being significantly older (72.95 ± 4.38 years). Emotional burden was the dominant subscale across all groups. In multivariable logistic regression, increasing age (aOR = 1.163 per year; 95% CI: 1.055–1.282; p = 0.002) and lower educational level (high school vs. basic: aOR = 0.187; p = 0.020) were independently associated with severe distress, whereas metabolic variables were not independently associated with severe distress. ROC analysis identified age ≥ 70 years as an exploratory, sample-derived cut-off (AUC = 0.726, 95% CI 0.602–0.827; sensitivity 84%, specificity 55%). Results were robust in sensitivity analyses that excluded patients with diabetes duration < 5 years. Conclusions: Severe diabetes distress is more strongly associated with demographic vulnerability than with metabolic burden. Age ≥ 70 years and lower educational attainment may help identify older adults at increased risk of diabetes-related distress, supporting targeted psychological screening strategies in this lifespan stage.

Diseases doi: 10.3390/diseases14090331

Authors: Elisa Mikus Diego Sangiorgi Mariafrancesca Fiorentino Niki Bernardoni Roberto Nerla Simone Calvi Elena Tenti Fausto Castriota Carlo Savini

Objective: Mitral valve repair failure encompasses heterogeneous anatomical patterns requiring redo surgery, yet the factors determining why repaired valves fail through different mechanisms remain poorly understood. We investigated the association of patient characteristics and index repair features with the anatomical mechanisms of failure among patients requiring redo surgery after degenerative mitral valve repair. Methods: We retrospectively reviewed all consecutive patients undergoing redo mitral valve surgery after previous degenerative mitral valve repair between January 2010 and June 2026. To minimize misclassification bias, only patients with complete operative documentation of the index repair and detailed intraoperative information regarding the mechanism of repair failure were included. Operative reports were reviewed to identify the reconstructive techniques used during the initial repair and the anatomical mechanism of failure at reoperation. To account for mutually exclusive clinical outcomes (prolapse recurrence and mitral stenosis), a competing-risks framework was employed. Results: A total of 121 patients constituted the study cohort. Recurrent leaflet prolapse was the most frequent mechanism of repair failure (71.6%) among patients with mitral regurgitation; mitral stenosis was present in 27.3% overall. Leaflet preservation versus resection, implantation of expanded polytetrafluoroethylene (ePTFE) neochordae, edge-to-edge repair, and annuloplasty ring size were not significantly associated with the anatomical mechanism of repair failure. In multivariable analysis, older age at the index operation was independently associated with recurrent prolapse, whereas younger age and female sex independently predicted the development of mitral stenosis. Within this redo cohort, no statistically significant association was observed between the recorded index repair features and the predominant anatomical mechanisms of failure after adjustment for patient characteristics. Conclusions: Among patients requiring redo surgery after degenerative mitral valve repair, the anatomical mechanisms of failure were associated with selected patient characteristics, whereas no significant association was observed with the recorded index repair features. These findings should be interpreted within the context of a selected redo population and do not support conclusions regarding the comparative durability of different repair strategies.

Diseases doi: 10.3390/diseases14090330

Authors: Bartosz Migda Michał Kutyłowski Natalia Madetko-Alster Anna Migda Karol Kutyłowski Piotr Alster

Background: Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) frequently present with overlapping clinical features, creating diagnostic challenges, particularly during the early stages of disease. Structural MRI and peripheral inflammatory biomarkers may provide complementary information for differential diagnosis. Objective: To evaluate the diagnostic performance of automated pallidal volumetry and the neutrophil-to-lymphocyte ratio (NLR), individually and in combination, for distinguishing PSP from PD. Methods: This retrospective case–control study included 12 patients with PSP and 12 patients with PD. Automated brain volumetry was performed using the volBrain 2.0 platform. Total pallidal volume was selected as the primary imaging biomarker based on its established involvement in PSP pathology. NLR was calculated from routine blood counts. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. A combined MRI–blood model was constructed using binary logistic regression. Results: Patients with PSP demonstrated lower normalized pallidal volumes than patients with PD. Pallidal volume showed high diagnostic performance for differentiating PSP from PD (AUC = 0.885), whereas NLR demonstrated only modest discriminatory ability (AUC = 0.715). The combined pallidal volume–NLR model achieved an AUC of 0.903 compared with 0.885 for pallidal volumetry alone, but this difference was not statistically significant (DeLong p = 0.732), and sensitivity, specificity and overall accuracy remained unchanged. Conclusions: Automated pallidal volumetry provided substantially better discrimination between PSP and PD than NLR alone. Although the combined model showed a small numerical increase in AUC, this improvement was not statistically significant and did not alter sensitivity, specificity or overall accuracy. These findings do not demonstrate incremental diagnostic value of NLR beyond pallidal volumetry in this cohort. Larger prospective studies are needed to determine the clinical utility of combined MRI–blood biomarker approaches in PSP.

Diseases doi: 10.3390/diseases14090329

Authors: Igna Andreea Diana Petca Bianca-Lăcrimioara Popovici Paula-Alexandra Timea Claudia Ghitea Roxana Daniela Brata Daniela Florina Trifan Mihaela Simona Popoviciu

Background: Contemporary management of type 2 diabetes mellitus (T2DM) extends beyond glycemic control and requires comprehensive assessment of cardiovascular, renal, metabolic, and anthropometric factors. Nevertheless, clinical status is often summarized predominantly by glycated hemoglobin (HbA1c), potentially overlooking concurrent non-glycemic abnormalities. This study evaluated the prevalence and coexistence of cardiorenal-metabolic abnormalities among patients with HbA1c <7.0% at six months. Methods: This retrospective observational study included adults with T2DM routinely followed in a specialized outpatient diabetes clinic. The primary descriptive analysis included participants with HbA1c <7.0% at the six-month assessment (T1). Seven non-glycemic cardiorenal-metabolic domains were evaluated at T1: LDL cholesterol, HDL cholesterol, triglycerides, body mass index, blood pressure, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio. An unweighted descriptive count of domains outside study-defined analytical thresholds was calculated (range, 0–7). An exploratory Poisson regression model examined associations between selected baseline characteristics and the number of affected domains, excluding baseline variables that directly corresponded to components of the T1 count to minimize mathematical coupling. Results: Among 809 participants, 385 (47.6%) had HbA1c <7.0% at six months and were included in the primary descriptive analysis. Concurrent non-glycemic abnormalities were common, particularly for blood pressure, LDL cholesterol, triglycerides, body mass index, and HDL cholesterol. The median number of domains outside study-defined analytical thresholds was three (IQR 3–4), and only three participants (0.8%) had values within all seven thresholds. In the exploratory multivariable model, none of the evaluated demographic, glycemic, or treatment-related baseline characteristics was independently associated with the number of domains outside study-defined thresholds. Conclusions: HbA1c <7.0% at six months did not necessarily coincide with favorable values across other clinically relevant cardiovascular, metabolic, anthropometric, and kidney-related domains in patients with T2DM. The unweighted domain count provides a descriptive summary of concurrent non-glycemic abnormalities but should not be interpreted as a validated measure of risk, prognosis, or clinical risk stratification. These findings support comprehensive, individualized assessment beyond glycemic status alone.

Diseases doi: 10.3390/diseases14090328

Authors: Aleksandra Dasic Dragan Vasin Maja Stojanovic Dragana Jovanovic Anja Kisic Ana Marija Tomic Rada Miskovic

Sarcoidosis and granulomatosis with polyangiitis (GPA) are the most common non-infectious causes of granulomatous lung disease. However, they can sometimes be difficult to distinguish due to overlapping clinical, radiological, and histopathological features. A 54-year-old man was considered to have sarcoidosis in 2018. Treatment with glucocorticoids led to improvement, but the patient self-discontinued it in 2021. In January 2022, he was readmitted due to recurrent cough and fatigue, who then developed purpuric lesions on the lower extremities, renal impairment, and abnormal results for liver function tests. Chest computed tomography showed lymphadenopathy, consolidations, and nodular lesions. Liver and spleen lesions were detected on abdominal ultrasound, and liver biopsy was performed revealing necrotizing granulomas. Strongly positive proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) together with clinical, radiological, and histopathological findings supported the diagnosis of GPA. Treatment with methylprednisolone and cyclophosphamide led to clinical and partial laboratory improvement. Unfortunately, the patient died suddenly, reportedly in association with massive hemoptysis. Ongoing reassessment during the disease course is essential for accurate diagnosis and optimal management. This case highlights the diagnostic challenges posed by overlapping features of sarcoidosis and GPA, and the rare presence of hepatic necrotizing granulomas with concurrent radiologically suspected granulomatous splenic involvement. The limited data reported in the literature make this case particularly unique and diagnostically significant.

Diseases doi: 10.3390/diseases14090327

Authors: Natalia Zaporojan Ramona Hodișan Claudiu Zaporojan Andreea Atena Zaha Andrei Nicolae Csep Dana Carmen Zaha

Background/Objectives: The rapid diagnosis of tuberculous pleural effusion (TPE) presents significant challenges for clinicians due to its paucibacillary nature. Routine biochemical markers may complement microbiological and molecular tests, especially in resource-limited settings. The objective of this study was to evaluate the diagnostic performance of pleural fluid adenosine deaminase (ADA), lactate dehydrogenase (LDH), total protein (TP), and the ADA/LDH and ADA/TP ratios for tuberculous pleural effusion, using Löwenstein–Jensen culture and Xpert MTB/RIF as microbiological reference standards Methods: We conducted a retrospective study (2016–2024) including 325 consecutive patients investigated for suspected TPE in a tertiary hospital. ADA, TP and LDH were measured, and additional ratio-based indices (ADA/TP, ADA/LDH) were calculated for 325 pleural fluid (PF) samples. Löwenstein–Jensen (LJ) culture (with MPT64 confirmation) and GeneXpert MTB/RIF (Xpert MTB/RIF) were used as separate microbiological reference standards. Sensitivity (Se), specificity (Sp), and areas under the ROC curve (AUC) were estimated, and optimal thresholds were determined using the Youden index. Results: Among 325 pleural fluid samples, 23 (7.1%) were culture-positive. Xpert MTB/RIF was performed in 73/325 patients (22.5%), with Mycobacterium tuberculosis detected in 19/73 (26.0%) tested samples. In PF, ADA provided the best performance against culture, with Se of 100%. Correlation analysis in PF showed a moderate positive association between TP and LDH (p < 0.0001). Conclusions: Among routine biochemical markers, PF ADA shows high NPV. Integrating these rapid, low-cost tests alongside LJ culture and Xpert MTB/RIF may streamline the diagnostic pathway for TPE.

Diseases doi: 10.3390/diseases14090326

Authors: Diana A. Grigoryan Maria A. Gordukova Elena V. Galeeva Irina E. Turina Ekaterina V. Ligskaya Oleg B. Kovalev Alina D. Matsvay

Background/Objectives: Acute respiratory viral infections (ARVIs) are the leading cause of pediatric morbidity and exhibit considerable clinical heterogeneity. The analysis of clinical and etiological associations, as well as the identification of factors linked to severe ARVI cases, is essential for effective epidemiological surveillance. Methods: A retrospective, single-center observational study was conducted including 1362 non-COVID-19 pediatric cases of acute respiratory infections (ARIs), registered between 2021 and 2024. Viral pathogens were detected using real-time PCR for broad-spectrum screening of respiratory viruses. Results: Viral etiology was established in approximately 50% of cases. The most frequently detected pathogen was Human rhinovirus (HRV) (35.6%), followed by Respiratory syncytial virus (RSV) and Human adenovirus (HAdV). Despite its predominance, HRV did not demonstrate nosological specificity. The strongest associations with lower respiratory tract infections were identified for RSV (OR = 3.2) and Human bocavirus (HBoV; OR = 2.4), predominantly within the pneumonia category. RSV was also associated with bronchitis/bronchiolitis (OR = 1.8). Significant associations with upper respiratory tract infections were established for Influenza viruses (OR = 10.4) and HAdV, including nasopharyngitis (OR = 3.88) and acute tonsillitis (OR = 3.9). HAdV additionally demonstrated an association with otitis media (OR = 5.1). Severe disease was registered in 52.3% of all clinical observations and occurred most frequently among young children, particularly in cases associated with respiratory syncytial virus (RSV >80%), as well as with human bocavirus (HBoV) and Human metapneumovirus (HMPV) (~55–59%). Co-infections were not associated with increased disease severity compared with monoinfections (OR = 1.1). Conclusions: The obtained results highlight the contribution of specific etiological agents to severe respiratory infections in children. These findings support the prioritization of such pathogens in clinical diagnostics, including the design of diagnostic algorithms and the selection of patient management strategies in pediatric populations.

Diseases doi: 10.3390/diseases14090325

Authors: Ban AbdulWahid Kanna Suha Saeed Azeez

Background: Therapeutic drug monitoring (TDM) has emerged as an important strategy for optimizing anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). However, data regarding anti-TNF pharmacokinetics and immunogenicity from Middle Eastern populations remain limited. This study evaluated the associations between serum anti-TNF trough concentrations, anti-drug antibody (ADAb) levels, and therapeutic response among Iraqi patients with IBD receiving infliximab or adalimumab therapy. Methods: This cross-sectional observational study included 80 patients with Crohn’s disease or ulcerative colitis receiving maintenance infliximab or adalimumab therapy at a tertiary Gastroenterology Center in Iraq. Patients were categorized as responders or non-responders according to clinical disease activity indices and biochemical assessment. Serum trough levels of infliximab and adalimumab, as well as ADAb concentrations, were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Responders had significantly higher serum trough concentrations than non-responders for both infliximab [3.75 µg/mL (IQR: 3.40–4.15) vs. 1.05 µg/mL (IQR: 0.92–1.12), p < 0.001] and adalimumab [6.32 µg/mL (IQR: 5.67–7.15) vs. 3.30 µg/mL (IQR: 2.70–4.26), p < 0.001]. Adalimumab-treated non-responders had significantly higher ADAb levels compared with responders (p = 0.047). Conclusions: Favorable therapeutic outcomes in Iraqi IBD patients treated with anti-TNF agents were associated with adequate serum trough levels and low ADAb levels. Reactive therapeutic drug monitoring may provide clinically valuable pharmacokinetic information capable of guiding individualized treatment optimization and identifying mechanisms of treatment failure in patients receiving infliximab or adalimumab therapy.

Diseases doi: 10.3390/diseases14090324

Authors: Aleksandar Rakić Lazar Nejković Dejan Oprić Ana Đorđević Marija Rakić Aleksandar Jurišić Danilo Obradović

Background/Objectives: Uterine leiomyosarcoma (uLMS) shares clinical and radiological similarities with benign uterine leiomyoma (LM), while validated discriminatory markers remain scarce. We compared cyclin E1 (CCNE1) expression in uLMS and LM tissue samples. Methods: This retrospective case-control study included 61 patients (16 uLMS, 45 LM) treated at a single institution (2017–2023). Of 22 eligible uLMS cases, six were excluded because suitable tissue was unavailable and they had significantly higher FIGO stages than the included cases. CCNE1 immunoreactivity was assessed using an adapted Allred score in five non-overlapping high-power fields selected from regions of highest expression. Two blinded pathologists independently scored each field, and the patient-level median was used for primary analysis. Results: The median CCNE1 Allred score was 6 (IQR 5–6) in uLMS versus 2 (IQR 0–3) in LM (p < 0.001), with excellent interobserver agreement (ICC 0.94). The AUC was 0.941 (95% CI 0.875–0.990). A data-derived cut-off ≥4 yielded 93.8% sensitivity and 84.4% specificity. A conservative minimum-expression analysis yielded an AUC of 0.882. Postmenopausal status was strongly associated with uLMS but was nearly completely confounded with the diagnostic group (12/16 uLMS vs. 0/45 LM). A premenopausal-only analysis was directionally consistent but underpowered. Clinical symptoms and tumor size did not differ between the groups. Conclusions: CCNE1 immunoexpression was substantially higher in uLMS than LM, with excellent reproducibility. Diagnostic-performance estimates remain exploratory and were influenced by tumor-region sampling, menopausal imbalance, and under-representation of advanced-stage uLMS. Independent multicenter validation, particularly in premenopausal and advanced-stage disease, is required before clinical application.

Diseases doi: 10.3390/diseases14090323

Authors: Epameinondas Koumpis Maria Nasiou Georgios Monastiriotis Dimitrios Leonardos Vasileios Georgoulis Elisavet Apostolidou Alexandra Papoudou-Bai Panagiotis Kanavaros Eleftheria Hatzimichael

Background/Objectives: Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is a gamma-2 herpesvirus implicated in a distinctive group of lymphoproliferative disorders (LPDs) and lymphomas. In some of these entities, lesional cells are concurrently infected with Epstein–Barr virus (EBV), a gamma-1 herpesvirus, raising important questions regarding viral cooperation in lymphomagenesis. This narrative review summarizes the clinicopathological spectrum and biological significance of HHV-8/EBV co-positive lymphoproliferations. Methods: We provide a narrative synthesis of the biology of HHV-8 and EBV, including latent, abortive lytic, and productive lytic infection programmes and viral mechanisms involved in cell-cycle deregulation, apoptosis inhibition, immune evasion, and B-cell transformation. Major HHV-8-associated lymphoproliferative entities are reviewed within the current WHO-HAEM5 and International Consensus Classification frameworks, with particular attention to patterns of EBV co-infection and diagnostically atypical or overlapping lesions. Results: Primary effusion lymphoma, including its extracavitary presentation, is frequently EBV-positive, whereas HHV-8-positive germinotropic lymphoproliferative disorder is characteristically HHV-8/EBV dual-positive. In contrast, HHV-8-positive lesional cells in multicentric Castleman disease and HHV-8-positive diffuse large B-cell lymphoma are typically EBV-negative. True dual positivity requires demonstration of HHV-8 latency-associated nuclear antigen and EBV-encoded RNA within the same morphologically defined lesional cell population. Rare atypical cases show overlapping clinicopathological features among established entities. Conclusions: HHV-8/EBV co-positive lymphoproliferations comprise a biologically and diagnostically heterogeneous group. Although unusual overlapping cases suggest potential relationships among HHV-8-associated disorders, current evidence does not support a single continuous disease spectrum or a uniform mechanism of HHV-8/EBV cooperation.

Diseases doi: 10.3390/diseases14090322

Authors: Roberta Modica Michele Coletta Elio Benevento Alessia Liccardi Roberto Minotta Gianfranco Di Iasi Massimo Di Nola Roberta Pia Bertenni Annamaria Colao

Background/Objectives: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary syndrome characterized by primary hyperparathyroidism, duodeno-pancreatic and pituitary neuroendocrine tumors. Adrenal lesions are acknowledged manifestations of MEN1, but their functional characterization remains limited. Mild autonomous cortisol secretion (MACS) is associated with cardiometabolic risk and skeletal involvement in sporadic adrenal incidentaloma, significantly impacting patient morbidity, but data in MEN1 are lacking. The aims of the study were to estimate the prevalence of MACS in adult patients with MEN1 and radiological evidence of adrenal involvement, and to evaluate the associated biochemical, cardiometabolic, and skeletal features. Methods: This retrospective single-center observational study included adult patients with clinical, familial, or genetic MEN1 and adrenal involvement. MACS was defined as serum cortisol >1.8 µg/dL after a 1 mg overnight dexamethasone suppression test in the absence of overt Cushing syndrome. Cardiometabolic and skeletal characteristics were compared according to MACS status. Results: Among 101 MEN1 patients, 38 had adrenal involvement and 22 underwent complete hormonal evaluation. MACS was identified in 15 of the 22 patients (68.2%). Patients with MACS had significantly lower baseline ACTH concentrations and showed a trend toward a higher prevalence of metabolic syndrome. No significant differences were observed in osteoporosis or fracture prevalence. Conclusions: This is the first study specifically evaluating the prevalence of MACS in MEN1 patients with adrenal lesions. MACS appears to be more common than in sporadic adrenal incidentalomas and may represent an important factor for improving clinical characterization and tailoring patient management. Larger prospective studies are needed to define the optimal follow-up strategy.

Diseases doi: 10.3390/diseases14090321

Authors: Paula López-González María Antonia Padial Vilchez María Teresa Palomeque Rodríguez María Galicia Dávila-Fernández Virginia Bellido Linares Emilio Funes Vera Conchita Cordobés Durán Ana Montoro Ferrer Estefanía Moreno Mata Victoria Villalobos Violán Laura Ortega-Martín Aída Gómez-Cardenosa

Background/Objectives: To evaluate the tolerability and effectiveness of subcutaneous immunotherapy (SCIT) with a glutaraldehyde-polymerized undiluted mixture of grass and olive pollen in adults and children with allergic respiratory disease in routine clinical practice. Methods: Observational, ambispective, controlled multicenter study including patients ≥ 5 years with allergic rhinitis/rhinoconjunctivitis +/− asthma due to olive and grass pollen. Patients initiating SCIT with Olea europaea/grass pollens undiluted mixtures were included in the O&G group, and those continuing symptomatic treatment in the untreated (UT) group. Safety (primary objective) was assessed as the incidence of adverse reactions. Effectiveness variables (symptoms, control, and medication use) were compared during the pollen season before and after AIT; patients and investigators reported perceived satisfaction. Results: We included 218 patients in the O&G group (children, 23.4%; adolescents, 13.8%; adults, 62.8%) with a mean (SD) age of 26.5 (15.6) years, and 94 in the UT group. At the time of evaluation, patients had received treatment for a mean (SD) of 10.6 (2.5) months. Seventeen patients (7.8%) experienced 18 adverse reactions in total, all local (12 in adults, 6 in children; mean overall rate: 0.8%). Rhinitis frequency shifted from predominantly persistent to intermittent (−64.6% in persistent) (p < 0.0001), with significantly improved intensity and control overall and across age groups in the O&G group but not in the UT group. Patients with asthma symptoms decreased by −46.6% (p < 0.0001), along with improved asthma classification, treatment steps, and control overall (O&G group), and across most age groups. Changes in conjunctivitis symptoms followed a similar trend. Symptomatic medication use significantly decreased overall (O&G group) and across specific age groups. Patients and investigators perceived decreased symptoms and medication use after AIT. Conclusions: SCIT with a glutaraldehyde-polymerized undiluted allergen mixture of olive/grass pollen extract demonstrated safety and effectiveness to treat allergic rhinitis and asthma in adults and children in a real-world setting.

Diseases doi: 10.3390/diseases14090320

Authors: Georgios S. Markopoulos Yannis V. Simos Konstantinos I. Tsamis Lampros Lakkas Eleftheria Hatzimichael Eleni Kapsali Dimitrios Peschos Leonidas Benetatos

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy in which B-cell receptor signaling, microenvironmental interactions, genomic lesions, and epigenetic deregulation cooperate to shape disease behavior. The imprinted DLK1-DIO3 locus at chromosome 14q32 contains the largest human miRNA cluster and has been implicated in cancer-related regulatory networks; however, its contribution to CLL remains incompletely defined. Methods: In the present study, we investigated the potential involvement of DLK1-DIO3 miRNAs in CLL biology by integrating public transcriptomic datasets with miRNA-centered pathway analysis. GSE70830 was used as a discovery dataset and GSE66117 as a supportive validation cohort to identify genes consistently downregulated in CLL compared with normal B cells. Results: The analyses identified 1236 and 2145 downregulated genes, respectively, and their intersection yielded a 345-gene consensus set. The overlap was significantly greater than expected by chance (odds ratio 2.33; p = 1.55 × 10−31). This set was used as gene-filter input for DIANA-miRPath v3.0 analysis of the DLK1-DIO3 miRNA cluster, identifying eight KEGG pathways mainly involving B-cell receptor/NF-κB signaling, cell adhesion, leukocyte transendothelial migration, and glycan-related processes. DIANA-miRPath v4.0 provided pathway-centered refinement. GSE216258 miRNA analysis did not show generalized locus-wide upregulation, while a GSE12366 sensitivity analysis showed that 32 of the 345 genes overlapped the strongest naïve-memory B-cell differentiation signatures. The absence of uniform locus-wide upregulation suggests that these data do not establish a direct link between DLK1-DIO3 activation and generalized repression of the 345-gene set. Future studies are needed to identify gene- and pathway-specific effects. Conclusions: Overall, our findings support an association between DLK1-DIO3 miRNA target/pathway annotations and CLL-relevant transcriptional programs, providing a hypothesis-generating framework that warrants further experimental validation.

Diseases doi: 10.3390/diseases14090319

Authors: Krupa Arun Navalkar José Garnacho-Montero María Luisa Cantón-Bulnes José Luís García-Garmendia Ángel Estella Adela Fernández-Galilea Isidro Blanco Maria Antonia Estecha-Foncea Marina Gordillo-Resina Jorge Rodríguez-Gómez Juan Jesús Pineda-Capitán Carmen Martínez-Fernández Ana Escoresca-Ortega Rosario Amaya-Villar Juan Mora-Ordóñez Sara González-Soto Antonio Gutierrez-Pizarraya Robert Balk Russell R. Miller John P. Burke Gourang Patel Jorge P. Parada Marcus J. Schultz Brendon P. Scicluna Emily Blodget Santhi Kumar Dayle Sampson Thomas D. Yager Roy F. Davis Silvia Cermelli Richard B. Brandon

Background: Accurate early identification of sepsis remains a major clinical challenge due to its heterogeneous presentation and overlap of clinical signs with the non-infectious systemic inflammatory response syndrome (SIRS). Timely differentiation is crucial for improving patient outcomes, meeting sepsis bundle requirements and reducing inappropriate antimicrobial use. We hypothesized that clinical–laboratory data available within the first three hours of patient presentation could be used to identify patients with sepsis at a clinically useful level of diagnostic accuracy, in lieu of traditional microbiology results which would not become available until at least 12–24 h. Data from two independent studies were used to quantify the diagnostic value of demographic, vital, clinical–laboratory, and microbiological data available at three time points for distinguishing retrospectively diagnosed critically ill patients with either sepsis or non-infectious SIRS. A particular focus of this work was an assessment of the utility of SeptiCyte RAPID (Immunexpress Inc., Seattle, WA, USA) as an aid to sepsis diagnosis, producing actionable data within one hour. Methods: Data from two independent study cohorts were analyzed. The “510(k) cohort” consisted of 419 adult patients in intensive care (ICU) (MARS, VENUS, and NEPTUNE studies). The “Andalusian cohort” consisted of 353 ICU patients from the PANGEA study. Logistic regression models, selected by a greedy search algorithm and validated by repeated cross-validation, were used to determine the contributions of different variables to diagnostic accuracy. Diagnostic performance was quantified by the area under the receiver operating characteristic curve (AUC). Results: For the 510(k) cohort, a baseline AUC of 0.69–0.73 was observed using five to seven vital and demographic variables assessed immediately upon presentation (time T1). The addition of clinical–laboratory variables, in particular SeptiCyte RAPID, within one to three hours post-presentation (time T2) increased the AUC to 0.85–0.86. Finally, the addition of microbiological data 12–24 h post-presentation (time T3) further improved the AUC to 0.90–0.91. Similar results were obtained for the Andalusian cohort. AUC values at the three time points were as follows: At time T1, AUC = 0.67 based solely on vital signs and demographics; at time T2, AUC = 0.87 based on vitals + demographics + SeptiCyte RAPID ± other clinical–laboratory data; at time T3, AUC = 0.93 based on vitals + demographics + SeptiCyte RAPID ± other clinical–laboratory data + microbiology results. For both cohorts, the most significant variables included temperature, mean arterial pressure, respiratory rate, suspected infection site, SeptiCyte RAPID, procalcitonin, confirmed bacterial infection and positive blood culture confirmation. In summary, the AUC for diagnosing sepsis rose progressively from T1 (510(k) 0.69–0.73; Andalusian 0.67) to T2 (510(k) 0.85–0.86; Andalusian 0.87) with the addition of SeptiCyte RAPID to T3 (510(k) 0.90–0.91; Andalusian 0.93) as more clinical information became available over time. Conclusions: The accuracy of identification of sepsis increases markedly as demographics and vital signs are supplemented with clinical–laboratory information, and ultimately with microbiological culture results. The AUC improves in the shortest time within the first three hours when laboratory data, and particularly SeptiCyte RAPID results, become available. Integrating rapid host response testing with SeptiCyte RAPID into time-based diagnostic frameworks may enhance early sepsis recognition, improve antimicrobial stewardship, and support guideline-driven clinical decisions.

Diseases doi: 10.3390/diseases14090318

Authors: Gustavo A. Hernández-Fuentes Mario A. Alcalá-Pérez Uriel Díaz-Llerenas Marcos E. Guerrero-Verduzco Nancy A. Reyes-Méndez Laura A. Larios-Gómez Dalila G. Virgen-Aguilar Jessica C. Romero-Michel Verónica M. Guzmán-Sandoval Fabian Rojas-Larios Pedro J. Flores-Moreno Osval A. Montesinos-López Marina Delgado-Machuca Iván Delgado-Enciso

Background/Objectives: Acute collective emotional events may coincide with variation across multiple dimensions of mental health and health-related behaviors. This study compared mental health outcomes and recent alcohol consumption between assessments conducted before and after a major international sporting event and explored factors associated with psychological and behavioral outcomes among young adults. Methods: An observational study was conducted among 146 adult students in western Mexico who participated in assessments surrounding the 2026 FIFA World Cup match between Mexico and England. Assessments were conducted approximately 10 h before kick-off and 11 h after completion of the match. Because individual responses could not be linked across assessment periods, comparisons were analyzed as repeated cross-sectional marginal comparisons rather than paired longitudinal analyses. Psychological outcomes were assessed using standardized instruments, and recent alcohol consumption was defined as alcohol use during the eight hours preceding each assessment. Results: Anxiety-related symptom scores were lower at the post-event assessment, whereas depressive-related symptoms remained relatively stable. Emotional well-being was also lower at the post-event assessment, while recent alcohol consumption during the eight hours preceding the assessment was substantially more frequent post-event than pre-event (41.1% vs. 0.7%). The small difference observed in sexual-attitude scores was considered exploratory. Post-event multivariable analyses identified several factors associated with psychological outcomes and recent alcohol consumption; these associations were interpreted as cross-sectional. Conclusions: Psychological and behavioral outcomes exhibited distinct patterns between assessment periods surrounding the sporting event. Given the observational design, inability to link individual responses, and presence of unmeasured co-occurring exposures, these differences should not be interpreted as within-participant changes or as effects attributable specifically to the match.

Diseases doi: 10.3390/diseases14090317

Authors: Daisuke Asaoka Tsutomu Takeda Yasuhisa Jimbo Eiji Kamba Yusuke Nomoto Osamu Nomura Daiki Abe Kumiko Ueda Hiroya Ueyama Hiroyuki Isayama Mariko Hojo Akihito Nagahara

Background/Objectives: Functional constipation is common in older adults and impairs quality of life. Evidence for multi-strain orally disintegrating (OD) probiotic formulations in this population remains limited. Methods: In this single-center, open-label, single-arm pre–post study, adults aged 65–90 years meeting the Rome IV criteria for functional constipation were administered an OD tablet containing Bacillus subtilis TO-A, Enterococcus faecium T-110, and Clostridium butyricum TO-A for 8 weeks. The primary endpoint was change in the defecation score based on a modified Bristol Stool Form Scale. Secondary endpoints included stool frequency, straining, JPAC-QOL, the modified Constipation Scoring System, Izumo Scale, Dietary Variety Score (DVS), selected metabolic/nutritional variables, and exploratory gut microbiota analyses. Results: Fifty participants provided consent, and 49 were included in the full analysis set; 45 participants completed the 8-week intervention and were included in the paired primary endpoint analysis. The defecation score showed a nominally significant change toward normalization of stool form at week 8 (IQR: −1.0, 7.0; 95%CI: −9.6, −4.2). Stool frequency did not change significantly, whereas constipation-related quality of life and symptom burden significantly changed. DVS increased modestly, and HbA1c decreased slightly; however, these secondary findings should be interpreted as exploratory because no adjustment for multiplicity was performed. Four patients withdrew from this study: one was due to death, but a causal relationship with the study drug was not confirmed. Two gastrointestinal adverse events could have been related to the study product. Exploratory subgroup analyses suggested a larger change in participants not receiving acid-suppressive therapy. Conclusions: The three-strain OD probiotic tablet was associated with changes in stool form and constipation-related symptom burden in older adults with functional constipation. Because this was a single-arm, open-label study without multiplicity adjustment for secondary endpoints, the findings should be regarded as exploratory and hypothesis-generating. Given the absence of a control group, causal efficacy cannot be inferred, and placebo effects, natural symptom fluctuation, or other time-varying confounders cannot be excluded; therefore, the most robust conclusion is that the preparation appeared safe and well tolerated for over 8 weeks in this population.

Diseases doi: 10.3390/diseases14090316

Authors: Erik Shorabaev Amankeldi Sadanov Baiken Baimakhanova Irina Ratnikova Gulzakira Xetayeva Sholpan Akhelova Aknur Turgumbayeva

Background/Objectives: Probiotic preparations have attracted increasing attention because of their potential to modulate the gut microbiota and improve health outcomes in a wide range of gastrointestinal and extraintestinal diseases. However, their efficacy and safety are strain-specific and remain inconsistent across many clinical indications. The aim of this review was to evaluate current evidence regarding the efficacy, safety, mechanisms of action, and clinical applications of probiotic preparations. Methods: A narrative literature review was conducted using the PubMed, Scopus, and Web of Science databases to identify publications addressing the efficacy, safety, and clinical applications of probiotic preparations. The literature search was last updated in July 2026. No publication-year restrictions were applied; the studies included in this review were published between 2000 and 2026. Priority was given to systematic reviews, meta-analyses, randomized controlled trials, international clinical practice guidelines, and mechanistic studies. Results: The reviewed evidence indicates that probiotics may contribute to intestinal homeostasis through modulation of the gut microbiota, enhancement of intestinal barrier function, and regulation of immune responses. The strongest evidence supports the use of selected probiotic strains for the prevention of antibiotic-associated diarrhea, whereas evidence for the prevention of necrotizing enterocolitis is generally favorable but depends on the specific probiotic preparation, product quality, and clinical setting. Evidence for most other gastrointestinal and extraintestinal disorders remains heterogeneous and strain-specific. Although probiotics generally exhibit a favorable safety profile, rare infectious complications have been reported in high-risk patients. Conclusions: Current evidence indicates that the efficacy and safety of probiotics depend on the specific strain, clinical indication, and patient characteristics. Further high-quality, strain-specific clinical studies are needed to optimize their use in medical practice.

Diseases doi: 10.3390/diseases14090315

Authors: Dan Boitor Mihai Surcel Cristina Ioana Rotar Gheorghe Cruciat Georgiana Nemeti Andreea Florian Daniel Muresan Mihaela Oancea

Cognitive tunnelling poses significant risks in OB/GYN, where rapid clinical deterioration and time-pressured decision-making are common. This critical review synthesized evidence from a comprehensive literature search across multiple databases, yielding 414 unique papers examining cognitive tunnelling mechanisms, patient safety consequences, and mitigation strategies in obstetric and gynecological contexts. Medicolegal analysis reveals that cognitive tunnelling contributes to malpractice exposure and that adoption of structured safety programs addresses root causes and strengthens the clinical record for forensic review. Mitigation strategies were critically evaluated: metacognition and individual cognitive forcing strategies such as DECLARE (Differential, Examine, Consider, List, Assess, Review, Evaluate) and Pivot-and-Cluster show theoretical promise but depend on intact executive capacity that is depleted under the very conditions that precipitate tunnelling; debriefing demonstrates consistent improvements in team situational awareness and latent threat identification but requires organizational just culture and psychological safety; and hierarchical closed-loop communication systems provide the strongest evidence of reducing preventable adverse events by distributing attentional load across teams, though authority gradients risk suppressing junior-staff dissent. Despite growing recognition, significant knowledge gaps remain regarding measurement methodologies, obstetric-specific research, intervention effectiveness, and the integration of emerging artificial intelligence technologies. Addressing cognitive tunneling through quality studies with patient-centered outcomes and validated measures is essential for reducing medical errors and enhancing patient safety in women’s healthcare.

Diseases doi: 10.3390/diseases14090314

Authors: Evgeniya Klein Daria Velina Irina Stanislavovna Kolesnikova Valeriy Vladimirovich Polunovskiy Nina Vitalievna Panteleeva Dmitry Alexandrovich Kulikov Alla Nikolaevna Stolyarova Igor Nikitin

Background: Subclinical disordered eating behaviors (DEBs) are common among young women and are thought to result from complex interactions between psychological, dietary, and genetic factors. While chronic stress and unhealthy dietary habits have been implicated in the development of DEBs, the independent and interactive contributions of perceived stress, added sugar intake, and genetic susceptibility remain insufficiently understood. This pilot study investigated these associations using a two-stage case–control design. Methods: A total of 100 female university students (18–27 years) completed the Dutch Eating Behavior Questionnaire (DEBQ) during the first stage of the study. Based on DEBQ scores, 20 participants with the highest risk of DEBs and 20 with the lowest risk were selected for the second stage, forming case and control groups. Perceived stress was assessed using the Perceived Stress Scale (PSS-14), and added sugar intake was estimated using a semi-quantitative food frequency questionnaire (FFQ). Participants were also genotyped for four candidate polymorphisms (5-HTTLPR, rs6295, rs6265, and rs1800497). Group differences, correlation analyses, binary logistic regression models adjusted for BMI, and gene–environment interaction analyses were performed. Results: Perceived stress emerged as the strongest and most consistent predictor of belonging to the upper DEBQ quintile, with each one-point increase on the PSS-14 associated with a 44% increase in the odds of high-risk status after adjustment for BMI (OR = 1.44; 95% CI: 1.120–1.853; p = 0.004). Added sugar consumption did not withstand correction for multiple comparisons (p = 0.030, Bonferroni-adjusted α = 0.025). No significant main effects or gene–environment interactions were detected for any of the investigated polymorphisms or the cumulative genetic risk score. Conclusions: These preliminary findings highlight perceived stress as the important modifiable risk factor for subclinical disordered eating behaviors in young women, suggesting that stress-reduction and emotional regulation interventions may be more effective than dietary approaches in this population. However, the lack of significant associations for the genetic variants studied should be interpreted with caution given the limited sample size and statistical power. Replication in larger, longitudinal cohorts is warranted to confirm these findings and explore developmental trajectories.

Diseases doi: 10.3390/diseases14090313

Authors: Claudia Lucia Toma Ștefania Florina Oprea Ștefan Dumitrache-Rujinski Ionela Nicoleta Belaconi Daniela Jipa-Dună Cristian Cojocaru Alexandra Maria Cristea Camelia Cristina Diaconu Dragos Cosmin Zaharia

Background: Immunotherapy and targeted therapy have gained ground over conventional chemotherapy in treating various cancers. While pulmonary toxicity associated with these agents is rare, it represents a significant factor in both mortality and morbidity and may influence the overall success of cancer treatment. This case series report adds to the emerging evidence of cancer therapy-induced pneumonitis features and corticotherapy outcomes. Patients and methods: This single-center, retrospective case series analyzed 12 consecutive cases of patients undergoing immunotherapy (four receiving nivolumab, four receiving pembrolizumab) or targeted therapy (three receiving obinutuzumab, one receiving abemaciclib) for cancer (seven with lung cancer, three with non-Hodgkin lymphoma, one with breast cancer, one with renal cancer) who developed pneumonitis during their follow-up. Results: The interval from oncological treatment initiation to pneumonitis onset ranged from 6 to 48 months (median = 18.5), and in four patients it occurred after discontinuation of oncologic therapy. In most patients, the diagnosis was established with high probability based only on the clinical presentation, radiologic pattern, and concomitant oncologic therapy. Bronchoscopy with bronchoalveolar lavage analysis was performed in eight of the 12 patients, particularly when onset followed treatment discontinuation. The main symptom was dyspnea (10/12 cases), and three of 12 patients had respiratory failure (SpO2 ≤ 88%). The CTCAE severity grades were: one mild, seven moderate, three severe, and one life-threatening. The CT scan showed different patterns (7 OP, 4 NSIP-like, and 1 HP). Eleven patients received oral methylprednisolone (0.40 to 0.82 mg/kg) for 5 to 16 weeks. Two patients continued oncologic treatment, and six discontinued. Pneumonitis improved or resolved in 11 of the 12 patients; one patient deteriorated after reintroduction of immunotherapy and subsequently died from cancer-related complications. Conclusions: Immunotherapy- and targeted therapy-induced pneumonitis can express various features and severities, and prompt recognition and diagnosis based on clinical, radiologic and contextual elements are mandatory. In this small, heterogeneous series the individualized corticosteroid regimens used were followed by favorable outcomes. Our observations suggest that, in selected clinically improving patients, follow-up may rely only on clinical assessment and chest X-ray, and extensive tests may be reserved for non-responsive cases.

Diseases doi: 10.3390/diseases14090312

Authors: Shayna Xueli Lin Di Zhang Khee Ling Choo Qinghua Tan Puja Sharda Nur Kalimallah Khairul Anwar Xin Yi Hannah Luah Zongwen Wee Priscilla Chiam Pei Sze Angela Koh Fang Yung Sueziani Bte Zainudin Ling-Jun Chen

Aims: International diabetes guidelines recommend inpatient glycaemic management protocols for bolus enteral feeding in people with diabetes to improve clinical outcomes. This study aims to evaluate before and after hospital-wide implementation of an inpatient bolus enteral feeding protocol: (1) the incidence of hyperglycaemia (>13.9 mmol/L) and hypoglycaemia (<4.0 mmol/L), (2) medication prescribing practices and capillary blood glucose monitoring and (3) health care professionals’ knowledge and confidence levels. Methods: We implemented an inpatient glycaemic management protocol for bolus enteral feeding developed by a multidisciplinary team of diabetes nurse educators and endocrinologists and approved by the institutional medical board in July 2024. This before-and-after quality improvement study was conducted over 3 months across eight inpatient wards. Adult inpatients were consecutively enrolled if they met the inclusion criteria: (1) a documented diagnosis of diabetes mellitus, (2) receiving bolus enteral feeding and (3) treatment with glucose-lowering medication. Patients listed as critically ill were excluded. Nurses working in the pilot wards were also recruited. Before implementing the protocol, diabetes nurse educators trained inpatient nurses on understanding and executing the protocol for administering capillary blood glucose monitoring and medications for patients with diabetes on enteral feeding. Nurses’ pre- and post-knowledge levels and perceived confidence were assessed using a structured questionnaire. Electronic medical records were reviewed to evaluate the incidence rates of hypoglycaemia and hyperglycaemia before and during the 3 months following protocol implementation. We also assessed adherence to protocol-recommended capillary blood glucose monitoring frequencies based on the diabetes medication regimen. Results: A total of 31 patients were observed during the 6-week baseline period and 28 patients following protocol implementation. A total of 192 clinical care episodes were audited, comprising 78 in the pre-intervention phase and 114 in the post-intervention phase. The incidence of hyperglycaemia decreased from 43.6% to 10.5%, while hypoglycaemia decreased from 3.8% to 2.6%. After adjusting for protocol adoption rates, protocol implementation was associated with significantly lower odds of hyperglycaemia (odds ratio [OR] 0.22, 95% CI [0.07, 0.65], p = 0.006). A significant increase in appropriate nursing practices was observed post-intervention (p < 0.001). Adoption of the protocol by nurses decreased the odds of hyperglycaemia by 70% (p = 0.014). Nurses’ knowledge scores improved significantly from baseline to 3 months post-implementation (p < 0.001). Conclusions: Implementation of a standardised inpatient glycaemic management protocol for PWD receiving bolus enteral feeding was associated with reduced rates of hyperglycaemia and hypoglycaemia. Larger-scale studies are warranted to evaluate the effectiveness and sustainability of wider implementation in improving clinical outcomes.

Diseases doi: 10.3390/diseases14090310

Authors: Maria Letizia Salvetat Francesco Pellegrini Marco Zeppieri Matteo Capobianco Alessandro Avitabile Ludovica Cannizaro Giuseppe Gagliano Francesco Cappellani Caterina Gagliano

Background: Age-related macular degeneration (AMD) represents a leading cause of irreversible vision loss worldwide, driven by intricate interactions among oxidative stress, low-degree chronic inflammation, and macular pigment depletion in aging retinas. Lutein, a component of the macular pigment, has attracted significant attention in AMD management for its antioxidant and blue-light filtering properties. Its oral supplementation, however, although showing potential in slowing AMD progression, requires daily intake and results in variable macular absorption. Trans-scleral iontophoresis (TSI) is a non-invasive technique using low-intensity electric currents to deliver charged molecules into biological tissues and represents an innovative method to deliver lutein into the retina. Methods: The present narrative review synthesizes and discusses the results of lutein supplementation in AMD patients; the ocular iontophoresis basal principles, efficacy, safety and limitations in treating different ophthalmic pathologies; and the evolving clinical evidence supporting lutein TSI in the AMD management. Results: Ex-vivo studies have shown that lutein TSI may provide efficient, localized, rapid, and sustained retinal supplementation of macular pigment, overcoming oral intake limitations. Recent preliminary clinical studies have demonstrated that this technique is well-tolerated and effective in enhancing macular pigment optical density and improving some visual functions in AMD patients. Conclusions: Ex-vivo and pilot clinical studies highlight the capacity of TSI to deliver lutein inside the retina, overcoming physiological barriers that may limit the efficacy of lutein oral administration. The demonstration of the efficacy of the procedure in preserving/improving visual functions and delaying disease progression in AMD patients requires further long-term randomized controlled clinical studies.

Diseases doi: 10.3390/diseases14090311

Authors: Shinichi Watanabe Takayasu Koike Kenji Tsujimoto Ryoma Tahara Tomohiko Kamo Katsuyoshi Suzuki Keisuke Suzuki

Objective: Exercise therapy is recommended for patients with peripheral arterial disease (PAD) to improve walking capacity and functional outcomes. However, rehabilitation programmes after lower-limb revascularisation remain poorly defined. We aimed to map the existing literature on exercise-based rehabilitation following lower-limb revascularisation in patients with PAD and summarise key intervention features and reported outcomes. Data Sources: PubMed/MEDLINE, Embase, the Physiotherapy Evidence Database (PEDro), and the Cochrane Central Register of Controlled Trials were systematically searched from inception to identify relevant studies. Review Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). Studies involving adult patients with PAD or chronic limb-threatening ischaemia who underwent lower-limb revascularisation and participated in postoperative exercise or rehabilitation programmes were included. Two reviewers independently screened studies and extracted data on study characteristics, intervention components, and outcomes. Findings were synthesised descriptively and presented in tables and narrative summaries. Results: Fourteen studies were included. Rehabilitation programmes showed substantial heterogeneity in exercise modality, timing of initiation, intensity, supervision, and duration. Walking-based exercise was the most commonly reported modality. Sessions typically lasted 20–60 min. Exercise frequency ranged from daily inpatient mobilisation or 6 days/week during early rehabilitation to two to five sessions/week in outpatient or home-based programmes, and programme length ranged from inpatient-only rehabilitation to 12 months. The most frequently reported outcomes were measures of walking capacity, including treadmill walking distance and the 6 min walk test. In contrast, limb-related outcomes (e.g., wound healing, limb salvage, and reintervention) and safety outcomes were less frequently reported. Conclusions: Exercise-based rehabilitation after lower-limb revascularisation in patients with PAD demonstrates considerable variability in programme characteristics and outcome measures. Although most studies focus on walking performance, key outcomes—particularly limb-related events and safety—remain underreported. Future research should establish standardised postoperative rehabilitation protocols and evaluate a broader range of clinically relevant outcomes, especially in patients with chronic limb-threatening ischaemia.

Diseases doi: 10.3390/diseases14090309

Authors: Lavinia-Alexandra Moroianu Laurentiu Dragus Stefan Rosca Magdalena Rusu Negraia Valeriu Ardeleanu Rares Nicolae Vadana Ionelia State Georgel Mihu Madalina Nicoleta Matei Simona Dana Mitincu Caramfil

Background/Objectives: Oral structural and functional impairment and depressive outcomes frequently coexist in older adults, but the strength and interpretation of their association remain uncertain. This systematic review and meta-analysis evaluated whether poorer oral status or function is associated with depressive outcomes in older populations. Methods: Six databases were searched for observational studies published from 1 January 2016 to 5 January 2026, with an update on 19 April 2026. Eligible studies examined oral impairment as the exposure and depressive outcomes as the endpoint in older adults. Risk of bias was assessed using Newcastle–Ottawa criteria and certainty using GRADE. Comparable adjusted odds ratios (ORs) were pooled using random-effects meta-analysis with restricted maximum likelihood and Hartung–Knapp adjustment; non-comparable metrics were synthesized separately. Results: Thirty studies were included; fifteen contributed to the primary OR meta-analysis. In the primary model, poorer oral status or function was associated with higher odds of adverse depressive outcomes (OR = 1.61, 95% CI: 1.31–1.99), although between-study heterogeneity was substantial (I2 = 88.1%). In the trim-and-fill sensitivity analysis, the pooled estimate decreased to OR = 1.29 (95% CI: 0.99–1.69; p = 0.0584) and no longer reached conventional statistical significance. The certainty of the primary evidence was very low. Conclusions: Poorer oral structural or functional status is associated with worse depressive outcomes in older adults, but the magnitude is heterogeneous and sensitive to small-study-effect assumptions. The evidence remains observational and of very low certainty and should be interpreted as hypothesis-generating rather than causal or treatment evidence.

Diseases doi: 10.3390/diseases14090308

Authors: Raphael Omena Wanderley Carmina Silva dos Santos Karine Ferreira Agra Francisco Pirauá Alves Gonçalves Douglas Tenório Paes Gabriel Borges de Brito Gabriele Maria de Oliveira Lucena Lucas de Carvalho Carriço José Roberto da Silva Junior Eduardo Jorge da Fonseca Lima

Background/Objectives: Severe acute respiratory syndrome (SARS) remains an important cause of hospitalization and mortality, particularly among vulnerable populations. Understanding the factors associated with previous hospitalization may support more effective prevention and vaccination strategies. This study aimed to analyze the epidemiological profile of previous hospitalization among patients with SARS in the state of Pernambuco, Brazil. Methods: A quantitative, retrospective, cross-sectional study was conducted using data from the Influenza Epidemiological Surveillance System (SIVEP-Gripe), including 79,852 adult patients (≥18 years) notified with SARS in Pernambuco between 2021 and 2024. Sociodemographic, clinical, and vaccination-related variables were analyzed to identify factors associated with previous hospitalization. Results: The prevalence of previous hospital admission (readmission history) was 6.6%. Patients with previous hospitalization had a significantly higher median age compared to those without previous hospitalization (66 vs. 63 years; p < 0.001). The prevalence of previous hospitalization was higher among individuals with chronic comorbidities, particularly hematologic diseases (prevalence ratio [PR] = 1.95; 95% confidence interval [CI]: 1.51–2.51; p < 0.001) and asthma (PR = 1.67; 95% CI: 1.42–1.96; p < 0.001). Influenza vaccination was associated with a lower prevalence of previous SARS hospitalization (PR = 1.29; 95% CI: 1.03–1.61; p = 0.023). In contrast, COVID-19 vaccination status showed no significant association with previous hospitalization. A history of previous SARS hospitalization was associated with a higher prevalence of death in subsequent hospitalizations (PR = 1.09; 95% CI: 1.01–1.18; p = 0.022). Conclusions: Older adults and individuals with chronic comorbidities showed a higher prevalence of previous SARS hospitalization in Pernambuco. The findings show an association between influenza vaccination and a lower prevalence of previous SARS hospitalization and highlight the importance of post-discharge follow-up and epidemiological surveillance.

Diseases doi: 10.3390/diseases14090307

Authors: MiaSara Pérez-Salvá Carolyn M. Ruiz-Pérez Alondra Veloz-Bonilla Rocío K. Rivera-Valentín

Background/Objectives: Pediatric solid tumors (PST) are a biologically distinct group of malignancies whose developmental origins and molecular drivers differ substantially from those of adult cancers, with direct implications for therapeutic strategy and clinical outcome. This review synthesizes current evidence on molecular pathogenesis, tumor microenvironment biology, and the structural conditions that shape access to care across select PST. Methods: A narrative review of peer-reviewed literature was conducted primarily using PubMed, supplemented by Google Scholar, covering publications from 2000 to 2025. Tumor types were selected based on their prevalence in the pediatric population and the availability of evidence addressing both molecular features and health disparities. Body: Across eight tumor types (neuroblastoma, Ewing sarcoma, pediatric brain tumors, rhabdomyosarcoma, Wilms tumor, retinoblastoma, osteosarcoma, and chondrosarcoma), recurrent molecular alterations including MYCN amplification, EWS-FLI1 fusions, PAX-FOXO1 rearrangements and IDH 1/2 mutations emerge as central determinants of disease behavior and eligibility for treatment. The tumor microenvironment manifests as a shared mediator of immune exclusion and therapeutic resistance across tumor types, with, but not limited to, tumor-associated macrophages, myeloid-derived suppressor cells, and checkpoint molecule expression, identified as recurrent features influencing treatment response. Immunotherapeutic strategies have shown variable efficacy across PST, with the most consistent clinical benefit established in neuroblastoma. A critical and underappreciated pattern stands out across tumor types: children carrying the most aggressive molecular subtypes are disproportionately those with the least access to therapies those subtypes demand, emphasizing an overlap of biological and structural disadvantage that is also amplified in low- and middle-income countries, where late-stage presentation, treatment abandonment and limited access to molecular diagnostics compound the biological disadvantage. Conclusions: Within the eight PST reviewed, the most aggressive molecular subtypes and the greatest structural disadvantages converge in the same children; those carrying MYCN amplification, PAX-FOXO1 fusions, or EWS-FLI1 fusions are disproportionately those with the least access to the therapies their biology demands. Genomic and immunologic advances will only reach their full clinical potential when paired with inclusive trial data, diversified genomic databases, and most importantly, equitable access to biomarker-specialized therapies across all populations.

Diseases doi: 10.3390/diseases14090306

Authors: Erkan Topkan Efsun Somay Sibel Bascil Duriye Ozturk Ugur Selek

Background/Objectives: To evaluate the prognostic significance of the novel hemoglobin–albumin–C-reactive protein (HARP) index in patients with locally advanced nasopharyngeal carcinoma (LANPC) treated with definitive concurrent chemoradiotherapy (CCRT). Methods: This retrospective study included 248 patients with LANPC treated with definitive CCRT between 2011 and 2020. The HARP index [hemoglobin × (albumin ÷ C-reactive protein)] was calculated using pretreatment laboratory values. Prognostic associations between HARP and survival outcomes were evaluated using continuous and categorical Cox regression analyses, restricted cubic spline modeling, receiver operating characteristic analyses, and bootstrap-based internal validation. Results: Lower pretreatment HARP values were independently associated with inferior progression-free survival (PFS) and overall survival (OS). In continuous Cox analyses, increasing HARP values were associated with reduced risks of mortality and disease progression (both p < 0.001). ROC analysis identified 3.2 as the exploratory cut-off value for clinical stratification. Patients with HARP ≥ 3.2 (n = 112) had significantly better outcomes than those with HARP < 3.2 (n = 136). Median PFS and OS were not reached in the high-HARP group, whereas they were 47.0 and 72.0 months, respectively, in the low-HARP group. Low HARP values were associated with inferior PFS (HR, 3.86; p < 0.001) and OS (HR, 3.06; p < 0.001). Bootstrap internal validation demonstrated stable model discrimination with minimal optimism. Conclusions: The novel HARP index is an independently associated and internally validated prognostic biomarker in patients with LANPC treated with definitive CCRT. HARP may provide a practical tool for improved risk stratification, pending prospective external validation.

Diseases doi: 10.3390/diseases14090305

Authors: Olatunde Michael Oni Tim A. D. Smith

Background: Patient-specific targeted radionuclide therapy (TRT) requires consideration not only of administered activity but also of the spatial distribution of radiopharmaceutical uptake and radionuclide-specific energy deposition. This study developed a voxel-based computational workplan to compare 177Lu, 161Tb and 90Y, together with hybrid radionuclide models, using patient-specific PSMA PET-derived tumour activity distributions. Methods: PSMA PET/CT data from 20 patients with prostate cancer, comprising 10 18F-PSMA and 10 68Ga-PSMA examinations, were processed to obtain 2285 quality-filtered lesions. Radionuclide-specific dose-point kernels (DPKs) were generated in water using OpenGATE and applied to voxel-wise lesion activity distributions to reconstruct absorbed-dose maps. Kernel characteristics were evaluated using radial energy-containment metrics, and 177Lu, representing 161Tb simulations, was subjected to grid-convergence testing and external comparison with a published DPK. Lesion dosimetry was assessed using Dmean, D90, D95, equivalent uniform dose (EUD) and tumour control probability (TCP), with uncertainty quantified using patient-cluster bootstrap confidence intervals. Kinetic sensitivity and diagnostic tracer subgroup analyses were additionally performed. Results: The study showed that 161Tb produced the highest median lesion-level Dmean, D90, D95 and EUD at 182.79, 136.28, 132.07 and 148.53 Gy, respectively, with a median TCP of 0.981. Corresponding values for 177Lu were 141.33, 105.42, 102.10 and 114.78 Gy (TCP 0.930), while 90Y produced lower local dose metrics but the broadest radial dose distribution, consistent with its longer-range β-particle crossfire. 161Tb remained the highest-ranking radionuclide across the investigated kinetic cases and within both diagnostic tracer subgroups. Hybrid 161Tb/90Y kernels provided a controllable compromise between localised energy deposition and extended crossfire; a 70:30 model increased central dose localisation while retaining an R90 and R95 of 6 and 7 mm, respectively. Grid-convergence and published-DPK comparisons supported the numerical adequacy of the kernel methodology. Radionuclide emission characteristics substantially influence the transformation of heterogeneous tumour uptake into spatial absorbed-dose distributions. Within this model, 161Tb provided the strongest overall lesion-level dosimetric performance, whereas the extended range of 90Y may offer complementary crossfire for selected bulky or heterogeneous lesions. Conclusions: The findings support phenotype-informed radionuclide comparison and provide a computational basis for investigating hybrid strategies. However, the absolute dose estimates and proposed radionuclide combinations remain model-based and require validation using serial therapeutic imaging, heterogeneous patient-specific dosimetry and normal-organ dose constraints before clinical translation.

Diseases doi: 10.3390/diseases14080304

Authors: Ariel Torres Paloma González Martha Fors Gisselle Trujillo

Background: Elite HIV controllers exhibit persistent immune activation despite sustained viral suppression, a phenomenon that challenges the traditional view of immunological equilibrium. In parallel, autoimmune diseases are characterised by chronic inflammation driven by dysregulated immune responses. Objective: This study aimed to analyse the potential pathophysiological convergence between both conditions and to identify a shared inflammatory axis with possible translational implications. Methods: A critical narrative and integrative reflection was conducted using a purposive, concept-driven selection of evidence from PubMed/MEDLINE, Scopus, and Web of Science. A total of 43 sources were included: 28 studies informing mechanistic findings (14 on elite HIV controllers and 14 on autoimmune diseases), 12 addressing modulatory strategies (pharmacological and lifestyle-based), and 3 providing contextual frameworks. Results: Both conditions demonstrate sustained activation of innate immunity, characterised by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF, type I interferons), increased inflammatory biomarkers (e.g., sCD14, IP-10), and activation of pathways such as NLRP3 inflammasome and NF-κB signalling. Collectively, these findings suggest convergence towards a potential shared inflammatory axis mediated by the inflammasome–interferon pathway, which may contribute to persistent systemic inflammation and tissue damage. Evidence from pharmacological and non-pharmacological interventions suggests that components of this axis may be susceptible to modulation. Conclusions: The observed convergence supports a conceptual model of shared innate inflammatory activation across both conditions. Rather than implying a unified therapeutic approach, the findings suggest a framework of convergent modulation targeting the inflammasome–interferon axis. This hypothesis warrants further investigation to determine its clinical and translational relevance.

Diseases doi: 10.3390/diseases14080303

Authors: Arkadeep Dhali Jyotirmoy Biswas Ali Shan Hafeez Sajjad Ahmed Khan Saikat Mandal

Background: U.S. mortality trends involving pancreatic cancer and pulmonary embolism (PE) and whether PE is becoming increasingly represented among pancreatic cancer deaths remain incompletely characterized. Methods: We analyzed CDC WONDER Multiple Cause of Death data for adults aged ≥ 25 years from 1999 through 2024. Deaths were included in the primary analysis when pancreatic cancer and PE were both recorded as underlying or contributing causes. Age-adjusted mortality rates (AAMRs) were evaluated using Joinpoint Regression Program version 6.0.1. Forecasting and additional weighted log-linear and segmented regression analyses were performed in R version 4.5. Additional analyses evaluated race/ethnicity, the proportion of pancreatic cancer underlying-cause deaths with PE recorded, and sensitivity to the COVID-19 years. Results: Overall, 18,243 deaths involved both pancreatic cancer and PE. The AAMR increased from 0.19 per 100,000 in 1999 to 0.55 in 2024. Mortality increased by 2.65% annually during 1999–2016 and by 8.54% annually during 2016–2024, with a significantly steeper post-2016 slope (p < 0.001). Rates were consistently higher among males and non-Hispanic Black individuals. Hispanic or Latino mortality increased significantly during 2011–2024, whereas estimates for Asian or Pacific Islander individuals were too sparse or frequently suppressed to support reliable longitudinal trend analysis. Among deaths with pancreatic cancer as the underlying cause, the proportion with PE recorded increased from 1.00% in 1999 to 2.85% in 2024, with significantly faster growth after 2016 (p < 0.001). Excluding 2020–2021 did not materially alter the post-2016 increase. Conclusions: Mortality involving pancreatic cancer and PE increased substantially in the United States, and PE was recorded in a growing proportion of pancreatic cancer deaths. These death-certificate data identify an increasing population-level burden but cannot establish causality or demonstrate the effectiveness of specific clinical interventions.

Diseases doi: 10.3390/diseases14080302

Authors: Maedeh Mirasheh Zahra Shahabinia Afrooz Mazidimoradi Leila Allahqoli Hamid Salehiniya Do-Youn Lee

Background: Human papillomavirus (HPV) is the most common sexually transmitted infection and the primary etiological agent of cervical cancer. Despite the high global disease burden, the Middle East and North Africa (MENA) region faces substantial challenges in HPV prevention and control. This narrative review aimed to synthesize existing evidence on the prevalence, genotypic distribution, awareness, vaccination status, clinical outcomes, and the role of HPV in non-cervical malignancies in the MENA region. Methods: PubMed, Web of Science, Scopus, and Google Scholar were searched, and 122 studies were included. Findings were synthesized qualitatively and descriptively. Cohort studies, systematic reviews, and meta-analyses were prioritized to support inferences about associations and potential causal relationships. Results: HPV prevalence in the general female population of the MENA region ranged from 4.7% to 53.3%, exceeding 90% in high-risk groups and patients with malignancies. The most common genotypes were HPV16 and HPV18; however, distribution patterns varied across populations. Key risk factors included younger age, multiple sexual partners, early age at first sexual intercourse, smoking, and alcohol consumption. General awareness was low to moderate, and vaccination coverage was very low in most countries. Barriers included lack of knowledge, fear of side effects, religious concerns, and social stigma. Evidence also indicates an association between HPV and non-cervical malignancies (head and neck, esophageal, gastric, breast, and thyroid cancers), with HPV DNA detected in tumor tissues. Conclusions: HPV poses a significant public health challenge in the MENA region, characterized by high prevalence, genotypic diversity, limited knowledge and awareness, and unsatisfactory vaccination coverage. Expanding screening and vaccination through financial support, culturally and religiously appropriate education, and longitudinal studies to monitor genotypic changes and associations with other malignancies are essential measures to reduce the burden of HPV-related diseases in the region.

Diseases doi: 10.3390/diseases14080301

Authors: Corina Porr Valentin-Cristian Iovin Anca Vidrighin Emi Marinela Preda Gabriela Mariana Iancu Dana M. Harris Cosmina Diaconu

Background/Objectives: Leptin is a pleiotropic adipokine linking energy metabolism with innate and adaptive immunity. Its relationship with clinical severity across distinct airway disease phenotypes remains insufficiently characterized. This study examined serum leptin concentrations in adults with allergic rhinitis, non-allergic asthma, and allergic asthma associated with allergic rhinitis. Methods: This single-center retrospective observational study analyzed fully anonymized clinical and laboratory data from 88 adults: patients with allergic rhinitis (n = 31), non-allergic asthma (n = 15), or allergic asthma with allergic rhinitis (n = 22) and healthy controls (n = 20). Serum leptin was measured using a quantitative sandwich enzyme-linked immunosorbent assay. Disease severity was classified using the Allergic Rhinitis and its Impact on Asthma and Global Initiative for Asthma frameworks applicable during the study period. Statistical analyses were performed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY, USA), and available original statistical outputs were summarized using retained t statistics and two-sided p values. Results: Stage-specific mean serum leptin concentrations were heterogeneous and non-monotonic. Statistically significant relationships between leptin concentration and disease stage were reported for allergic rhinitis (t = 2.844; p = 0.008), non-allergic asthma (t = 4.240; p = 0.001), and allergic asthma with allergic rhinitis (t = 2.700; p = 0.013). In the allergic rhinitis subgroup, 64.5% of participants had normal weight, 32.3% were overweight, and 3.2% had grade II obesity; weight category was not significantly related to rhinitis stage. Conclusions: The retained analyses indicate statistically significant relationships between serum leptin concentration and clinical disease stage across the investigated airway phenotypes. However, the stage-specific descriptive means were heterogeneous and non-monotonic and therefore do not support a uniform progressive increase in leptin with increasing disease severity. Because complete model outputs and covariate-adjusted estimates were unavailable, these findings should be regarded as exploratory and require prospective validation with appropriate adjustment for adiposity and other relevant metabolic confounders.

Diseases doi: 10.3390/diseases14080300

Authors: Apostolos Andronikou Dimitra Psalla Rafail Ioannidis Apostolos Papalois Stavros Iliadis Konstantina Dinaki Apostolos Kamparoudis

Purpose: Intestinal ischemia–reperfusion injury (IRI) remains a major clinical challenge associated with substantial morbidity. Although the biological functions of insulin-like growth factor-I (IGF-I) have been extensively investigated, evidence regarding the direct administration of exogenous recombinant IGF-I in experimental intestinal IRI remains limited. This study evaluated the histological effects of recombinant IGF-I administered at different time points in a rat model of intestinal IRI. Methods: Male Wistar rats underwent 45 min of superior mesenteric artery occlusion followed by 3 h of reperfusion. Animals were allocated to five groups: Sham, untreated Control, and three IGF-I-treated groups receiving intraperitoneal recombinant IGF-I before ischemia, during ischemia, or at reperfusion. Histological injury was assessed using the Chiu grading system (0–5). Data were analyzed using non-parametric statistical methods. Results: Forty-five rats were included in the final analysis. Untreated controls demonstrated the greatest mucosal injury (median Chiu score: 4, IQR: 3–4), whereas Sham-operated animals exhibited minimal injury (median: 0, IQR: 0–1). All IGF-I-treated groups demonstrated lower median histological injury scores (median: 2), with the lowest median observed in the reperfusion group (IQR: 1–3). However, none of the individual comparisons with untreated controls remained statistically significant after Bonferroni correction. A post hoc exploratory pooled analysis demonstrated a similar histological pattern but likewise did not show a statistically significant difference between pooled IGF-I-treated animals and controls after adjustment for multiple comparisons. Conclusions: In this experimental rat model, exogenous recombinant IGF-I administration was consistently associated with lower histological injury scores than untreated ischemia–reperfusion controls, although a definitive treatment effect could not be established. These findings provide additional experimental evidence regarding the histological effects of recombinant IGF-I in intestinal ischemia–reperfusion injury and support further investigation in larger experimental studies incorporating quantitative histological, molecular, and functional endpoints.

Diseases doi: 10.3390/diseases14080299

Authors: Mohamed Thabit Ahmed Bashir A. Yousef Gonen Ozsarlak-Sozer Tahir Yagdi Sanem Nalbantgil Emine Nur Ozbek Elmoiz Babekir Khalid A. Ateyyah Mohammed Ahmed Zahrani Sultan Almuallem Alaa Mousli Mohammed Basendowah

Objectives: The aim of this study was to determine whether direct evidence shows that contemporary guideline-directed heart failure (HF) pharmacotherapies influence cardiac remodeling through hydrogen sulfide (H2S) signaling, and to define the resulting evidence gap. Design: A systematic review was conducted according to PRISMA 2020. Registration: PROSPERO CRD420251238589. Data Sources: MEDLINE (PubMed), Web of Science, Scopus, and the Cochrane Library; searches were initiated in March 2025, covered publications from January 2007 onward, and were last updated in November 2025. Eligibility Criteria: Primary studies had to include (A) an HF or cardiac-remodeling model, (B) an HF-relevant pharmacological intervention, (C) direct assessment or manipulation of H2S biology, and (D) at least one cardiac-remodeling endpoint. Results: Of the 40,796 unique records screened, 50 reports underwent full-text assessment and 14 unique studies were included. No study demonstrated that the remodeling benefits of ACE inhibitors, ARBs, ARNIs, beta-blockers, MRAs, hydralazine/isosorbide dinitrate, or SGLT2 inhibitors are mediated by endogenous H2S signaling. Doiron et al. evaluated empagliflozin with or without the H2S donor SG1002 in experimental HFpEF; the combination improved several outcomes beyond empagliflozin alone, but this adjunctive design does not establish H2S mediation of empagliflozin action. Most eligible evidence concerned exogenous H2S donors in animal models and reported improvements in fibrosis, hypertrophy, oxidative stress, mitochondrial injury, and cardiac function. The overall certainty was low because of preclinical predominance, heterogeneous models and H2S assays, donor-specific pharmacology, and incompletely reported randomization and blinding. Conclusions: The principal finding is negative but clinically important: direct evidence that H2S mediates established HF pharmacotherapy is currently absent. H2S remains a promising experimental therapeutic candidate rather than an established shared mechanism or clinically validated treatment target.

Diseases doi: 10.3390/diseases14080298

Authors: Thitinat Duangchan Moltira Promkan Susan D. Kraner Nurdina Charong

Background: Red blood cell (RBC) antibody screening in blood donors is a key component of transfusion safety. However, reported prevalence and antibody specificities vary widely across studies, and a consolidated global estimate remains limited. This study aimed to quantify the prevalence of RBC antibody detection among blood donors, identify factors associated with variation in reported prevalence, and summarize antibody specificities. Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidelines. PubMed, MEDLINE, Embase, Scopus, and Google Scholar were searched from inception to 27 August 2025 for observational studies reporting RBC antibody detection in blood donors. Methodological quality was assessed using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data. Pooled prevalence estimates were synthesized using random-effects models. Subgroup analyses, meta-regression, leave-one-out sensitivity analyses, and publication-bias assessments were performed. Associations between ABO blood group and RBC antibody detection were summarized using pooled odds ratios. The review protocol was registered in PROSPERO (CRD420251181987). Results: Forty-one studies comprising 43 reports and 3,561,088 blood donors from 18 countries were included. The pooled prevalence of RBC antibody detection was 0.2% (95% CI: 0.2–0.3%), with substantial between-study heterogeneity (I2: 99.61%) and a 95% prediction interval of 0.0–1.4%. Prevalence was higher in female donors than in male donors (0.5% vs. 0.1%). Publication year was inversely associated with reported prevalence, although temporal and methodological effects could not be separated. An exploratory analysis based on six studies showed higher estimated odds of antibody detection among blood group AB donors (OR: 1.20, 95% CI: 1.07–1.34). Among clinically significant antibodies, Rh and Kell specificities were predominated. Anti-Mia was prominent in Southeast Asian populations. Conclusions: RBC antibody detection among blood donors was uncommon overall but varied considerably across settings. Interpretation is limited by substantial methodological heterogeneity, uneven geographic representation, and incomplete reporting of donor characteristics. The pooled estimate should be interpreted as an international benchmark rather than a uniform prevalence applicable to individual blood services. This large-scale synthesis may inform context-specific donor antibody screening, confirmatory testing, component management, and hemovigilance policies.

Diseases doi: 10.3390/diseases14080297

Authors: Haytham A. Sheerah Ahmed Arafa Rola A. Jalloun Mudi H. Alharbi Haneen N. Molla Amnah N. Yamani Sahar A. Alqadi Abdullah A. Asiri Norah F. Saleh Yazeed M. Alsaedi Banan H. Mekwar Anas Almofarreh

Background and Objectives: Diet is a potential modifiable risk factor for ulcerative colitis (UC). This study examined the associations of individual dietary components and combined dietary profiles with UC. Methods and Study Design: This case–control study included 157 patients with UC and 395 controls. Dietary consumption frequencies were converted into ordinal scores ranging from 1 to 4. Participants were additionally classified into four dietary profiles based on combined levels of risk-promoting and protective food consumption. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher consumption of fast food (OR = 5.30, 95% CI: 3.65, 7.70), carbonated soft drinks (OR = 9.37, 95% CI: 5.78, 15.18), and spicy food (OR = 1.56, 95% CI: 1.21, 2.01) was positively associated with UC. Dairy consumption was inversely associated with UC (OR = 0.52, 95% CI: 0.33, 0.82). In sex-stratified analyses, vegetable consumption was inversely associated with UC among women only. Compared with participants with high risk-promoting/low protective food consumption, those with low risk-promoting/low protective food consumption (OR = 0.07, 95% CI: 0.02, 0.21) and those with low risk-promoting/high protective food consumption (OR = 0.08, 95% CI: 0.03, 0.17) had substantially lower odds of UC. The high risk-promoting/high protective food consumption was not associated with UC. Conclusions: Frequent consumption of fast food, carbonated soft drinks, and spicy food was associated with higher odds of UC, whereas dairy consumption was associated with lower odds. Lower consumption of risk-promoting foods, irrespective of protective food consumption, was associated with substantially lower odds of UC. Prospective studies are needed to confirm these associations.

Diseases doi: 10.3390/diseases14080296

Authors: Christian D’Elia Edda Russo Giada Santagata Viola Svelti Serena Guiducci Mariangela Manfredi Maria Infantino Francesca Li Gobbi Maurizio Benucci

Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease frequently associated with obesity and metabolic comorbidities. Increasing evidence suggests that obesity is associated with systemic inflammation, insulin resistance, and adverse clinical outcomes; however, the immunometabolic profile associated with obesity in PsA has not been fully characterized. Objective: To investigate the relationship between obesity, inflammatory biomarkers, cytokine profiles, metabolic parameters, insulin resistance, and disease-related characteristics in patients with PsA. Methods: In this monocentric cross-sectional study, 224 consecutive patients fulfilling the Classification Criteria for Psoriatic Arthritis (CASPAR) for PsA were evaluated. Clinical, inflammatory, metabolic, and cytokine-related variables were analyzed within an integrated immunometabolic framework. Patients were stratified according to obesity status based on body mass index (BMI ≥ 30 kg/m2). Correlation analyses, multivariable regression analyses, and exploratory machine-learning approaches were applied to identify multidimensional patterns associated with obesity. Adjusted multivariable regression analyses were performed to account for available demographic, clinical, comorbidity-related, and therapeutic covariates. Results: Ninety-four patients (42.0%) were classified as obese and 130 (58.0%) as non-obese. Compared with non-obese patients, obese individuals exhibited significantly higher levels of C-reactive protein (CRP; 0.31 vs. 0.13 mg/dL, p < 0.001), erythrocyte sedimentation rate (ESR; 15.0 vs. 10.0 mm/h, p = 0.006), serum amyloid A (SAA; 7.7 vs. 6.4 mg/L, p = 0.008), insulin (8.0 vs. 6.1 μU/mL, p < 0.001), glycated hemoglobin (HbA1c; 38.0 vs. 37.0 mmol/mol, p = 0.003), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR; 1.29 vs. 1.21, p = 0.007), triglycerides (106.0 vs. 85.0 mg/dL, p = 0.019), and Health Assessment Questionnaire (HAQ) scores (p < 0.001). Obese patients also showed a higher prevalence of hypertension (18.1% vs. 6.9%, p = 0.018). BMI was positively correlated with several inflammatory, metabolic, and disease-related variables, including CRP (ρ = 0.383), interleukin-6 (IL-6; ρ = 0.295), insulin (ρ = 0.289), ESR (ρ = 0.245), SAA (ρ = 0.228), HbA1c (ρ = 0.199), HAQ score (ρ = 0.351), and Disease Activity Index for Psoriatic Arthritis (DAPSA) score (ρ = 0.183), while showing an inverse correlation with high-density lipoprotein cholesterol (HDL-C) (ρ = −0.189). After adjustment for age, sex, disease duration, DAPSA, hypertension, type 2 diabetes mellitus, and current therapy class, obesity remained associated with higher CRP and fasting insulin levels and with greater odds of belonging to a higher HAQ category. Machine-learning analyses identified inflammatory biomarkers, insulin resistance indices, and lipid-related parameters as the most informative features associated with obesity-related phenotypes. Conclusions: Obesity in PsA was associated with a broader immunometabolic phenotype characterized by increased inflammatory burden, metabolic dysfunction, and worse functional outcomes. These findings support the integration of metabolic and cardiovascular assessment into routine rheumatology practice and highlight obesity as an important marker of increased immunometabolic and clinical burden in PsA. Although the cross-sectional design precludes causal inference, the observed associations may help identify patients requiring closer metabolic and cardiovascular assessment.

Diseases doi: 10.3390/diseases14080295

Authors: Yin Yin Bashir Rahaf AL-Huneiti Anfal AL-Dalaeen Firas S. Azzeh

Background: Obesity is a chronic, multifactorial disease that demands personalized and sustainable management approaches. Digital health technologies, such as artificial intelligence, wearable devices, mobile health apps, and virtual reality (VR), may support obesity care by providing enhanced behavioral monitoring, personalized feedback, and patient engagement. Objective: This critical narrative review discusses the current evidence on artificial intelligence, wearable technologies, and VR in the context of precision nutrition and obesity management and their possible clinical applications and limitations. Method: A critical narrative review was conducted using peer-reviewed literature published between 2019 and 2026 and identified through PubMed and Google Scholar. Search terms included combinations of “precision nutrition,” “personalized nutrition,” “obesity,” “weight management,” “metabolic health,” “digital health,” “artificial intelligence,” “machine learning,” “mobile health,” “wearable devices,” and “omics” using Boolean operators. Evidence from randomized controlled trials, systematic reviews, meta-analyses, and key conceptual studies was critically synthesized due to substantial heterogeneity in interventions and outcomes. Result: Wearables and mobile applications can enable continuous self-monitoring of physical activity, dietary intake, sleep, and physiological measures. Artificial intelligence may improve dietary personalization, risk prediction, glycemic control, and adaptive feedback. VR offers an immersive way to tackle behavioral and cognitive mechanisms related to overeating such as cravings, food cue reactivity, and inhibitory control. However, the evidence is heterogeneous, with many studies limited by short follow-up periods, small samples, variable adherence, and insufficient clinical validation. Conclusions: Artificial intelligence, wearable technologies, and VR are promising tools for precision obesity management, but their long-term clinical effectiveness remains uncertain. Future research should prioritize adequately powered trials, longer follow-up, standardized outcomes, transparent algorithms, ethical data governance, and integration with multidisciplinary nutrition and obesity care.

Diseases doi: 10.3390/diseases14080294

Authors: Victor Ivanovich Seledtsov

Inflammation can either encourage or suppress tumor growth, thus having a two-sided effect on cancer development. This depends on the balance between pro-tumor and anti-tumor immune responses within the tumor microenvironment (TME). Pro-tumor inflammation, driven by specific immune cells, enhances blood flow and nutrient supply to tumors, promoting the activation of dormant cancer cells (DCCs). Conversely, antitumor inflammation hinders blood flow and can force active cancer cells into a state of dormancy. Tumors actively shift this balance towards pro-tumor inflammation to create a favorable environment for growth. Therefore, anti-inflammatory therapy may be an integral part of comprehensive cancer immunotherapy. This review explores how different anti-inflammatory medications, such as glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, anti-leukotrienes, statins, drugs that block pro-inflammatory cytokines, agents that inhibit oxidative phosphorylation, antioxidant vitamins, anti-angiogenic drugs, and low-dose chemotherapy, can be used to combat cancer. Granulocyte counts and erythrocyte sedimentation rate (ESR) can be used to assess inflammation levels and the effectiveness of anti-inflammatory treatments. We advocate for a paradigm shift in cancer treatment, moving away from aggressive tumor destruction, which triggers uncontrolled tumor regeneration, toward long-term immunological control of tumor growth while preserving the patient’s overall health.

Diseases doi: 10.3390/diseases14080293

Authors: Erik Shorabaev Amankeldi Sadanov Baiken Baimakhanova Saltanat Orasymbet Irina Ratnikova Bakhytzhan Kerimzhanova Zhanar Assilova Zaure Datkhayeva Aknur Turgumbayeva

Background/Objectives: Intestinal diseases are a major global health problem due to their high prevalence, chronic course, and significant impact on quality of life. Increasing attention has been given to the extra-skeletal effects of vitamin D, particularly its role in immune regulation, maintenance of intestinal barrier integrity, and modulation of the gut microbiota. The aim of this review was to evaluate current evidence regarding the role of vitamin D in immune regulation, intestinal barrier function, and the pathogenic mechanisms of intestinal diseases, including inflammatory and functional gastrointestinal disorders. Methods: A structured narrative review was conducted using the PubMed, Scopus, and Web of Science databases to identify publications addressing the role of vitamin D in intestinal diseases. The literature search was updated in May 2026 and included studies published between 2004 and 2026. The aim of this review was to summarize current evidence on the effects of vitamin D on immune regulation, intestinal barrier integrity, gut microbiota, and their clinical relevance in intestinal diseases. Results: The included studies demonstrated that vitamin D plays an important role in maintaining intestinal homeostasis through regulation of innate and adaptive immune responses, preservation of epithelial barrier integrity, and modulation of gut microbiota composition. Vitamin D deficiency was associated with impaired VDR-dependent signalling, increased intestinal permeability, dysbiosis, and enhanced pro-inflammatory immune responses, which may contribute to the development and progression of inflammatory bowel disease, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, and celiac disease. Conclusions: Current evidence supports the important role of vitamin D in immune regulation, intestinal barrier protection, and maintenance of gut microbial balance. Further clinical studies are required to better understand its therapeutic potential in intestinal diseases.

Diseases doi: 10.3390/diseases14080292

Authors: Theodoros A. Voulgaris Dimitrios I. Ziogas Ioannis Stasinos Eleni Koukoulioti Eleni Koukouvaidou Antonios Vezakis Ioannis S. Papanikolaou

The Functional Lumen Imaging Probe (EndoFLIP®) system is an impedance-based technology providing real-time measurements of cross-sectional area (CSA) and intraballoon pressure across a luminal segment. Initially developed for esophagogastric junction (EGJ) evaluation in achalasia, the application of EndoFLIP has subsequently expanded to the assessment of both sphincteric and non-sphincteric regions throughout the gastrointestinal tract in a variety of clinical conditions, including eosinophilic esophagitis (EoE), post-fundoplication states, and gastroparesis. Its unique ability to be utilized in both the diagnostic and therapeutic settings, including the assessment of treatment response, makes it a valuable tool in the overall management of gastrointestinal motility disorders. The present review extends beyond a simple overview of EndoFLIP applications by providing a comprehensive evaluation of its performance in comparison with other diagnostic modalities, as well as the current knowledge gaps regarding its use. Study limitations and procedure-related aspects requiring further investigation are critically discussed, with the aim of supporting and guiding future research in this field.

Diseases doi: 10.3390/diseases14080291

Authors: Naomi Gerzvolf Mieres Kauanna Oliveira Nathália Carolina Barreiro Marques Nicole Milagritos Cardoso Azorza Helena Hiemisch Lobo Borba Roberto Pontarolo Marcel Henrique Marcondes Sari Juliana Sartori Bonini Jéssica Brandão Reolon Raul Edison Luna Lazo Luana Mota Ferreira

Background/Objectives: Melanoma remains one of the most aggressive skin cancers worldwide, with rising incidence and persistent therapeutic challenges, particularly in advanced diseases. Drug repositioning has emerged as a cost- and time-efficient strategy for identifying adjunctive treatments, and antihypertensive medications have attracted attention for their potential off-target antitumor and immunomodulatory effects. This scoping review aimed to map and critically appraise the evidence on the repositioning of antihypertensive drugs for melanoma management. Methods: The review followed the JBI methodology, and the results were reported in accordance with the PRISMA-ScR guidelines. Searches were conducted in July 2025 and updated in May 2026 in PubMed, Scopus, and Web of Science. For Methodological Quality and Risk-of-bias assessment, the SYRCLE Risk of Bias tool was employed for animal studies. Results: This review included 37 studies. β-Blockers, particularly propranolol, were the most frequently investigated agents (n = 21). Several studies reported antiproliferative, pro-apoptotic, antiangiogenic, and immunomodulatory effects; however, these findings were not uniform. Absent direct antiproliferative effects, biphasic dose responses, lack of angiogenic effects, and outcomes dependent on drug concentration, treatment schedule, and experimental model were also reported. Agents targeting the renin–angiotensin system and calcium channels similarly produced heterogeneous and context-dependent findings. The animal studies frequently presented high or unclear risk of bias, particularly because of incomplete reporting of randomization, allocation concealment, and blinding. No formal methodological quality assessment was performed for the in vitro studies. Conclusions: Antihypertensive agents, particularly β-blockers, show promising but heterogeneous preclinical signals in melanoma. However, the available evidence is not sufficient to establish reproducible efficacy or translational validity. Standardized and methodologically rigorous preclinical studies are required before these agents can be considered for clinical investigation as adjunctive melanoma therapies.

Diseases doi: 10.3390/diseases14080290

Authors: Manuela Arbune Pantelie Nicolcescu Anamaria Ciubara Pompiliu Mircea Bogdan Constantin-Marinel Vlase Anca-Adriana Arbune

Background/Objectives: Neuroinflammation is increasingly recognized as a key mechanism linking infectious diseases with psychiatric disorders through interactions between peripheral immune activation, metabolic pathways, and brain network alterations. This review aimed to synthesize current evidence on the neuroimmune mechanisms and biomarkers underlying infection-associated psychiatric disorders. Methods: A narrative literature review structured according to the SANRA (Scale for the Assessment of Narrative Review Articles) criteria was conducted using the Web of Science Core Collection, PubMed/MEDLINE, Scopus and PsycINFO databases. Boolean search strategies identified studies investigating neuroinflammatory biomarkers, neuroimmune mechanisms, and psychiatric outcomes associated with infectious diseases. The search (January 2022–30 June 2026) included 76 studies in the final qualitative analyses. Results: The reviewed evidence consistently identified inflammatory cytokines and chemokines, complement proteins, blood–brain barrier markers, glial activation biomarkers, neuroaxonal injury markers, kynurenine pathway metabolites, neurotrophic factors, and neuroimaging markers as complementary indicators of infection-induced neuroimmune dysfunction. Across diverse bacterial, viral, parasitic, and systemic infections, these mechanisms converged on peripheral immune activation, blood–brain barrier disruption, microglial activation, kynurenine pathway dysregulation, impaired neurotrophic signaling, synaptic dysfunction, and altered brain network connectivity, contributing to depression, anxiety, psychosis, cognitive impairment, and fatigue. Based on these findings, a unified neuroimmune model integrating peripheral and central mechanisms is proposed. Conclusions: Neuroinflammation emerges as a shared biological pathway linking infections with transdiagnostic psychiatric phenotypes. Although no single biomarker currently demonstrates sufficient diagnostic specificity, integrated multimodal biomarker panels may improve biological stratification, facilitate earlier identification of high-risk patients, and support the development of mechanism-based precision approaches—including candidate anti-inflammatory pharmacological strategies currently under clinical investigation—for infection-associated psychiatric disorders.

Diseases doi: 10.3390/diseases14080289

Authors: Luz María González Huerta Miguel Ángel Fonseca Sánchez Marcela Esquivel Velázquez Jaime Toral López

Neurodevelopmental disorder, speech impairment, and dysmorphic facies (NEDSID) is an autosomal dominant condition primarily driven by SETD1A haploinsufficiency. While most documented cases are sporadic, genomic mechanisms underlying intrafamilial phenotypic heterogeneity remain poorly understood. This study presents a comprehensive clinical, neurophysiological, and molecular characterization of a two-generation Mexican family segregating a novel heterozygous missense SETD1A variant. Whole-exome sequencing (WES) identified a c.1604G>A (p.Gly535Glu) substitution localized within the critical Functional Location on SETD1A (FLOS) domain, which was validated via automated Sanger sequencing across all family members and 100 ethnically matched controls. The proband exhibited a moderate NEDSID phenotype, including global developmental delay, macrocephaly, borderline IQ (79) with pronounced information-processing deficits, and abnormal EEG sharp waves. Conversely, first-degree relatives carrying the identical variant presented with mild, non-intellectually disabling phenotypes characterized primarily by isolated psychiatric disorders (bipolar disorder, depression) and minimal dysmorphism. Structural 3D modeling and multi-algorithmic in silico profiling confirmed high evolutionary conservation and a deleterious impact (CADD: 22.2, SIFT: 0.00, GERP: 2.924), classifying the variant as a Variant of Uncertain Significance (VUS)/Likely Pathogenic according to ACMG/AMP criteria (PM2, PP1, PP3, PP4). Furthermore, epigenetic dysregulation and chromatin remodeling defects increasingly link these histone-modifier variants to broader psychiatric landscapes. Emerging transcriptomic profiling confirms that dosage-sensitive COMPASS complex disruptions alter downstream neurodevelopmental gene cascades. Our findings present observational evidence of intrafamilial clinical variability in a single pedigree with a SETD1A missense alteration, supporting the hypothesis that non-catalytic domain substitutions may contribute to diverse neurodevelopmental outcomes.

Diseases doi: 10.3390/diseases14080288

Authors: Alejandro Castañeda-López Fernando Suárez-Sánchez Fengyang Huang Miguel Cruz Adrián Hernández-Díazcouder

Coffee is one of the most widely consumed beverages worldwide. Coffee and its bioactive compounds, including caffeine, chlorogenic acid, and caffeic acid, have attracted increasing attention because of their potential health benefits. Evidence from pediatric and adult populations supports a positive association between fructose intake from sugar-sweetened beverages and the increasing prevalence of obesity and other non-communicable diseases. In this context, coffee consumption may represent a potential protective dietary factor against high fructose intake-induced metabolic alterations, including obesity, type 2 diabetes, liver disease, cardiovascular disease, and alterations in gut microbiota composition. Therefore, this review summarizes current evidence on the potential role of coffee consumption and coffee-derived bioactive compounds in modulating fructose-induced metabolic alterations and discusses the mechanisms involved. However, current evidence from human studies remains limited, and the clinical relevance of the beneficial effects observed in experimental models requires confirmation through well-designed clinical trials.

Diseases doi: 10.3390/diseases14080287

Authors: Artur Rebelo Sara Seyedinia Nepomuk Sochor Jessica Döbereiner Matthias Sommerer Ulrich Ronellenfitsch Johannes Klose Andreas Odparlik Alexander Heinzel Jörg Kleeff

Introduction: Delayed gastric emptying (DGE) is a common complication after pancreatoduodenectomy, occurring in up to two-thirds of patients. Although rarely life-threatening, DGE prolongs hospitalization and increases healthcare costs. The International Study Group of Pancreatic Surgery (ISGPS) definition enables retrospective grading but lacks objective physiological assessment. This pilot study evaluated the feasibility and clinical relevance of standardized postoperative gastric scintigraphy. Methods: Six patients undergoing pancreatoduodenectomy between January and May 2025 received one or two standardized liquid gastric emptying scintigraphies on postoperative days (POD) 4–6 and 10–13. Quantitative analysis included half-emptying time (T½) and residual activity (RA%) at 30 and 60 min. Findings were correlated with ISGPS-defined DGE. Results: Eleven scintigraphic examinations were performed. Clinically relevant ISGPS Grade B/C DGE occurred in two patients and was associated with persistently elevated RA% at 60 min and prolonged T½ on early scintigraphy. Two additional patients showed scintigraphic abnormalities without meeting clinical DGE criteria, without confirmed outcome-level consequences. Conclusions: Standardized gastric scintigraphy may provide an objective and reproducible method for evaluating DGE after pancreatoduodenectomy and may complement clinically based ISGPS definitions.

Diseases doi: 10.3390/diseases14080286

Authors: Ali Abduwani Abdullah Al Lawati Ruai Al Abri Reem Al Mayyahi Hoor Al Barhi Shatha Al Hussaini Moath Shummo Hanan Al Lawati Nawaf Al-Muqaimi Srijit Das

Background: Complex wounds present significant reconstructive challenges owing to impaired healing, infections, and tissue loss. Skin grafting remains a widely used reconstructive technique; however, outcome data from the Gulf region are limited to a few studies. This study aimed to evaluate early graft outcomes and complications following skin graft reconstruction for complex wounds at a tertiary hospital. Methods: A retrospective, hospital-based study was conducted at Sultan Qaboos University Hospital (SQUH), including all patients who underwent split-thickness or full-thickness skin grafting between 2023 and 2025. Demographic, clinical, surgical, and wound-related data were collected. The main outcomes were graft take on postoperative days 5–7, time to complete re-epithelialization, and the occurrence of postoperative complications. Results: A total of 50 patients were included; 72% were males, with a median age of 45.5 years. Diabetes mellitus was present in 34% of patients. Trauma (28%) and infection/necrotizing causes (22%) were the most common etiologies of wounds. Complete graft take (>90%) was achieved in 90% of the patients, whereas 10% had partial graft take. The median time to complete re-epithelialization was 13 days. Complications were infrequent and minor, including postoperative infection (8%), hypertrophic scar formation (6%), and wound dehiscence (2%). No significant differences in healing time were observed between the diabetic and non-diabetic patients. Conclusions: In this descriptive institutional cohort, a combined protocol of wound-bed preparation, skin graft reconstruction, and postoperative NPWT-assisted stabilization was associated with favorable early graft take and fewer complications. These findings should be interpreted cautiously because of wound heterogeneity, unavailable wound size measurements, and limited subgroup sizes. Larger prospective studies are needed to evaluate the predictors of graft success.

Diseases doi: 10.3390/diseases14080285

Authors: Bozhidar Krastev Natalia Spasova Georgi Dimitrov Elena Kinova Assen Goudev

Background: Cancer-associated thrombosis is a clinically important complication of malignancy. The systemic immune–inflammation index (SII), calculated from platelet, neutrophil, and lymphocyte counts, may reflect the inflammatory background of cancer, but its value in matched heterogeneous cancer cohorts remains unclear. Objective: To evaluate whether SII is associated with thrombotic status and recorded all-cause mortality in patients with solid cancers. Methods: This retrospective matched cohort study was derived from 2020 consecutive adult patients hospitalized with solid malignancies between September 2023 and December 2025 at the Oncology Clinic of University Hospital “Tsaritsa Yoanna—ISUL”, Sofia, Bulgaria. Patients with documented thrombosis were matched 1:2 to non-thrombotic controls using a nearest propensity-score approach, with preference for exact matching on sex and cancer type. The final cohort included 110 thrombotic patients and 220 matched controls. SII was analyzed in relation to thrombotic status and recorded all-cause mortality using logistic regression. Results: Thrombotic patients and controls were well balanced for matching variables. Mortality was similar between groups: 29.1% versus 28.2%. SII did not differ significantly between thrombotic patients and controls: 772 (516–1471) versus 783 (501–1292), p = 0.655, and showed poor discrimination for thrombotic status, with an AUC of 0.515. In the overall matched cohort, higher SII was associated with recorded all-cause mortality after adjustment for thrombotic status, age, sex, cancer type, stage, and metastatic disease: OR 1.31 per 1000-unit increase, 95% CI 1.05–1.64, p = 0.016. The association was numerically stronger among thrombotic patients, but interaction testing was not statistically significant. Conclusions: SII was not associated with thrombotic status in this matched cancer cohort. Higher SII was associated with recorded all-cause mortality, suggesting that SII may better reflect systemic inflammatory burden than cancer-associated thrombosis itself.

Diseases doi: 10.3390/diseases14080284

Authors: Ahmed Bishara Huma Saeed Layan Akkielah Noor BuMurah David K. Driman Michael Silverman Reza Rahimi Shahmirzadi

Background: Malakoplakia is a rare chronic granulomatous inflammatory disorder characterized by defective macrophage phagolysosomal activity and accumulation of Michaelis–Gutmann bodies on histopathology. It occurs predominantly in immunocompromised individuals and may mimic infectious, inflammatory, or neoplastic processes, creating significant diagnostic challenges. We describe four cases of malakoplakia occurring in distinct immunocompromised states and review the published literature to better characterize its clinical spectrum, management, and outcomes. Methods: We conducted a retrospective case series of four patients diagnosed with histologically confirmed malakoplakia at our institution. Cases occurred in the setting of liver transplantation, kidney transplantation, relapsed acute myeloid leukemia, and ulcerative colitis treated with immunosuppressive therapy. A literature review was performed using PubMed and Google Scholar to identify published cases of malakoplakia in immunocompromised hosts. Demographic, clinical, microbiological, therapeutic, and outcome data were extracted and analyzed descriptively. Results: Four patients with malakoplakia involving the gastrointestinal tract or renal allograft were identified. Clinical presentations ranged from incidental endoscopic findings and tumor-like colonic masses to recurrent bacteremia and graft dysfunction. Histopathologic examination demonstrated characteristic Michaelis–Gutmann bodies in all cases. Management included antimicrobial therapy, observation, and surgical intervention when necessary. Two patients achieved complete clinical and histologic resolution, one required transplant nephrectomy because of persistent allograft infection, and one died from progressive acute myeloid leukemia. Combined with 48 cases identified in the literature, 52 patients were analyzed. The gastrointestinal tract was the most frequently affected site (76.9%), followed by the genitourinary tract (19.2%). Malignancy (32.7%), solid-organ transplantation (26.9%), and autoimmune disease (21.2%) were the most common underlying conditions. Conclusions: Malakoplakia should be considered in the differential diagnosis of mass lesions, persistent infections, and inflammatory lesions in immunocompromised patients, particularly those with malignancy or receiving immunosuppressive therapy. Early histopathologic diagnosis is essential to distinguish malakoplakia from malignancy and guide appropriate management. Our findings highlight the heterogeneous clinical manifestations and outcomes of this uncommon condition and emphasize the importance of multidisciplinary evaluation in affected patients.

Diseases doi: 10.3390/diseases14080283

Authors: Yuji Shimizu Asuka Oyama Yuko Noguchi Mutsumi Matsuu-Matsuyama Koichiro Hamada Shin-Ya Kawashiri Hirotomo Yamanashi Seiko Nakamichi Yasuhiro Nagata Takahiro Maeda Naomi Hayashida

Background/Objectives: Subclinical hypothyroidism (SCH) has been reported to be associated with chronic kidney disease (CKD). Anti–thyroid peroxidase antibody (TPO-Ab) positivity, a known cause of autoimmune thyroid disease, has been reported to be positively associated with SCH with hypertension, but not with SCH without hypertension. Therefore, hypertension status might indicate latent thyroid damage among individuals with SCH. This distinction suggests that categorizing SCH by hypertension status could be useful for evaluating its association with CKD. Methods: A cross-sectional study of 1479 Japanese aged 40–69 years, all of whom had thyroid hormone levels (free triiodothyronine and free thyroxine) within the normal range, was conducted to evaluate the association between CKD and SCH categorized by hypertension status. Results: No significant association between SCH without hypertension and CKD was observed. However, a significant positive association between SCH with hypertension and CKD was identified. The potential confounders-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 0.96 (0.39, 2.38) for SCH without hypertension and 2.76 (1.37, 5.59) for SCH with hypertension. Conclusions: Although further investigation is warranted, categorizing SCH by hypertension status may be useful for understanding the association between SCH and CKD. These findings may help clarify the biological significance of SCH in the development of CKD.

Diseases doi: 10.3390/diseases14080282

Authors: Seth Greenspan Michele Branigan Naomi Nguyen Saba Gulzar Stephen Probst Meng Wang

Alpha-gal syndrome (AGS) is an acquired allergy characterized as a delayed hypersensitivity reaction to the galactose-alpha-1,3-galactose carbohydrate, which is present on mammalian meat. AGS can cause severe anaphylactic reactions and has been implicated in intraoperative reactions to medications or surgical products that are derived from mammalian meat. This narrative review will describe the current literature on alpha-gal etiology, epidemiology, and perioperative management. Additionally, our institution is present in Suffolk County, New York, US, a highly endemic area, and we share our centers’ recommendations for managing AGS patients from their initial preoperative presentation throughout the perioperative period. We propose a detailed pathway for detection, preparedness, and intraoperative management of AGS patients undergoing elective surgery as well as alternative management suggestions for AGS patients undergoing emergency surgery.

Diseases doi: 10.3390/diseases14080281

Authors: Aleksandra Hejnosz Bartosz Migda Natalia Madetko-Alster Dagmara Otto-Ślusarczyk Piotr Alster

Background/Objectives: Evidence suggests that inflammation contributes to the pathogenesis of neurodegenerative disorders. The utility of blood-derived inflammatory biomarkers in differentiating neurodegenerative disorders remains incompletely understood. The aim of this study was to compare peripheral inflammatory markers in patients with essential tremor (ET), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and control participants. Methods: This retrospective study included 44 patients with ET, 47 with PD, 44 with PSP, and 45 control participants. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were calculated from routine complete blood counts. Between-group comparisons were performed using the Kruskal–Wallis test, with a Holm correction across the six indices. The effect sizes were also estimated. Results: The PLR was the only inflammatory marker that significantly differentiated the analyzed groups (p = 0.045), with the highest value observed in PSP patients and the lowest in ET patients. A post hoc analysis indicated different PLR values in PSP than in ET patients (Cliff’s delta = 0.336, small-to-moderate effect). However, the overall association did not remain statistically significant after Holm correction across the six indices (adjusted p = 0.268), and the diagnostic group was not independently associated with PLR after adjustment for age and sex. No statistically significant differences were observed for the NLR, MLR, SII, SIRI, or AISI. Nevertheless, PSP patients consistently exhibited the highest median values of the NLR, SII, and AISI, whereas ET patients generally showed lower inflammatory marker levels. Conclusions: PLR was the only inflammatory marker that significantly differentiated the analyzed groups and was the highest among patients with PSP. The observed trends suggest a tendency toward greater peripheral immune activation in PSP compared with PD and ET. Larger prospective studies incorporating both inflammatory and neurodegenerative biomarkers are warranted to validate these findings.

Diseases doi: 10.3390/diseases14080280

Authors: Ciro Gargiulo Isacco Van Hung Pham Huong Thien Pham Kieu Cao Diem Nguyen Toai Cong Tran Thach Huy Le Felicita Jirillo Emilio Jirillo Luigi Santacroce

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, also known clinically as gastric MALT lymphoma (GML) or MALToma, is an indolent B-cell neoplasm strongly associated with chronic Helicobacter pylori (H. pylori) infection. While early-stage disease is based on persistent antigenic stimulation and chronic inflammation, the metabolic and molecular transitions that drive monoclonal B-cell autonomy remain poorly understood. Importantly, H. pylori maintain this long-term colonization by defusing the host’s innate immunity; specifically, its lipid A portion features unique elongated acyl chains, composed of 16–18 carbon atoms, that fail to bind to and activate host TLR4/MD2 receptors, resulting in exceptionally weak endotoxic potency. Persistent colonization relies on key oncoproteins, particularly cytotoxin-associated gene A (CagA) and vacuolar cytotoxin A (VacA), which orchestrate early inflammatory infiltration (neutrophils, Th1, Th2 and Th17 cells) before shifting the microenvironment toward a suppressive regulatory T cell (Treg) phenotype. In this study, we propose a new critical step in the oncogenesis of gastric metastasis: chronic mitochondrial and immunometabolic adaptation within the gastric microenvironment. We claim that H. pylori act not only as a trigger for infection but also as a chronic driver of mitochondrial adaptation to oxidative stress and hypoxia, which subsequently results in defective mitophagy. CagA- and VacA-mediated mitochondrial damage induces reactive oxygen species (ROS) and functional hypoxia, stabilizing HIF-1α to force a glycolytic metabolic shift, while incomplete mitophagy rescues metabolically altered, apoptosis-resistant clones to drive monoclonal B-cell expansion. Within this ecological-microenvironmental framework, the predominantly cytoplasmic sequestration of BCL10 and the NF-κB subunit p65 observed in GML is reinterpreted not as evidence of signaling inactivity, but as a dynamically regulated adaptive state. This configuration is orchestrated by mitochondrial stress responses that enable adaptation to the chronic microenvironmental pressures imposed by H. pylori, acting in concert with the metabolic programs governed by MYC, NRF2, and BCL2. Overall, this review outlines the multi-step pathogenesis of H. pylori-mediated GML, highlighting how mitochondrial dysfunction and metabolic remodeling drive the transition from chronic infection to malignant transformation.

Diseases doi: 10.3390/diseases14080279

Authors: Giuseppe Losurdo Francesco Squeo Angela Marotti Antonio Giangaspero Enzo Ierardi Mariabeatrice Principi

Background: Celiac disease (CD) is an immune-mediated enteropathy associated with extra-intestinal manifestations. Sleep disorders may be frequent in CD patients. We aimed to investigate the quality of sleep in CD patients and to assess its relationship with clinical and biochemical parameters. Methods: We included patients with a proven diagnosis of CD under a gluten free diet at least twelve months prior to enrolment. All the participants completed the Sleep Scale from the Medical Outcomes Study (MOS sleep scale) and the Sleep Problems Index II was calculated. A high SLP9 score indicated a bad quality of sleep and values >20 revealed sleep disturbance. Moreover, blood samples were collected and demographic and clinical data were recorded from each subject. Linear logistic regression was used for uni- and multivariate analyses; the b coefficient and 95% confidence intervals (CI) were calculated. Results: We enrolled 53 patients, with the mean age being 42.75 ± 11.19 and 84.9% being females. The average hours of sleep per night were 6.47 ± 1.11. The mean SLP9 was 37.44 ± 20.65. Forty patients (75.5%) showed sleep disturbance, and 81.1% of patients had vitamin D insufficiency. According to univariate analysis, high SLP9 values (worse sleep) were inversely related to the number of sleep hours (b = −0.38, 95%CI: −11.8 to −2.2, p = 0.005) and to vitamin D levels (b = −0.57, 95%CI: −2.7 to −0.46, p = 0.009). In multivariate analysis only serum levels of vitamin D were inversely related to SLP9 (b = −0.47, 95%CI −12.8 to −0.43, p = 0.05). Conclusions: Low serum levels of vitamin D are independently associated with poor sleep quality in celiac patients. These findings need to be confirmed in future experimental and clinical studies.

Diseases doi: 10.3390/diseases14080278

Authors: Merita Hashani Arjeta Podrimaj-Bytyqi

Background/Objective: Melanoma is an aggressive skin malignancy characterized by significant molecular heterogeneity. Among the molecular alterations identified in melanoma, BRAF mutations represent one of the most common genetic abnormalities and play an important role in activating the MAPK signaling pathway. BRAF mutation status has become clinically important because of its prognostic significance and implications for targeted therapy. This study aimed to evaluate the frequency of BRAF mutations and their associations with demographic, histopathological, and clinicopathological characteristics in melanoma patients at the only referral center for BRAF testing in Kosova, the Institute of Pathology, University Clinical Center of Kosova (UCCK). Methods: This retrospective study included 127 melanoma patients. Descriptive statistics, frequency analysis, Spearman’s correlation and multivariable binary logistic regression analyses were performed to evaluate associations between BRAF mutation status and clinicopathological variables, including age, gender, Breslow thickness, histological type, ulceration, and anatomical localization. Results: BRAF mutation was identified in 76 of 127 melanoma patients (59.8%). The BRAF V600E/V600E2/V600D variants represented the predominant molecular subtype (75%). BRAF-positive melanoma was more frequently observed in younger patients and was significantly associated with increased Breslow thickness, nodular melanoma, ulceration, and trunk localization. Conclusions: BRAF mutations were highly prevalent in melanoma patients from Kosova and were associated with clinicopathological features of a more aggressive disease. The findings establish an important baseline for molecular epidemiology in the country and support the integration of routine BRAF testing into personalized melanoma management and future regional research.

Diseases doi: 10.3390/diseases14080277

Authors: Irena Gencheva-Angelova Radka Nuneva-Doncheva

Background: In our recent research, we established a strong and statistically significant association between the highest quartile of lipoprotein(a) [Lp(a)] and mildly reduced estimated glomerular filtration rate (eGFR). Comparisons with similar studies were hindered by varying Lp(a) analytical methods and different eGFR equations. We analyzed how replacing the diagnostic standard CKD-EPI 2021 equation with alternatives (CKD-EPI 2009, CKD-MDRD, CKD-EKFC) affects predictive models under comprehensive demographic and clinical confounder adjustments. Methods: We calculated eGFR for 310 adults using the four equations. Creatinine and Lp(a) were measured via IFCC-recommended methods. The cohort was divided into a main (eGFR 60–80 mL/min/1.73 m2) and a control group (eGFR > 80 mL/min/1.73 m2). Multivariable logistic regression and Area Under the Curve (AUC) metrics evaluated model performance. Results: Alternative equations systematically underestimated eGFR, artificially increasing the reduced filtration group. After full multivariable adjustment, only CKD-EPI 2021 preserved the independent association between the highest Lp(a) quartile and mildly decreased eGFR (OR = 2.65, p = 0.008), achieving an AUC of 0.732. Conversely, CKD-EPI 2009 lost significance; CKD-MDRD exhibited mathematical instability from control group depletion, and EKFC showed severe over-adjustment when demographic covariates were included. Conclusions: Older equations and the age-embedded EKFC equation may influence regression models, potentially obscuring the true biomarker associations. CKD-EPI 2021 demonstrated the highest precision, successfully isolating physiological aging and suggesting an independent association between high Lp(a) and mildly reduced eGFR, irrespective of metabolic and vascular confounders.

Diseases doi: 10.3390/diseases14080276

Authors: Raghad Saeed Asiri Khaled Abdulwahab Amer Leen Abdulmohsin Sarhan Najla Ahmad Jahash Riham Hamoud Alharbi

Chronic spontaneous urticaria (CSU) is a mast cell-driven disorder defined by recurrent wheals, angioedema, or both, persisting for longer than six weeks without an identifiable external trigger. Second-generation H1-antihistamines remain first-line therapy, yet a large share of patients stay symptomatic after the dose is raised up to fourfold, and for more than a decade, omalizumab was the only targeted option for those who failed antihistamines. This began to change in 2025, when the interleukin-4 receptor alpha (IL-4Rα) antagonist dupilumab and the oral, covalent Bruton tyrosine kinase (BTK) inhibitor remibrutinib were approved for antihistamine-refractory CSU within months of one another, while the anti-KIT monoclonal antibody barzolvolimab, which depletes mast cells, advanced into the largest phase 3 program the disease has seen. This narrative review outlines the guideline framework that still anchors CSU care, appraises the pivotal efficacy and safety data for omalizumab, dupilumab, remibrutinib, and barzolvolimab, and considers how these mechanistically distinct agents might be positioned and sequenced. The widening choice makes individualized, mechanism-informed treatment a realistic goal, but it also sharpens unresolved questions about patient selection, optimal treatment duration in a naturally remitting disease, and the long-term safety of newer oral and mast cell-depleting approaches.

Diseases doi: 10.3390/diseases14080275

Authors: Elisabeth A. Mates Alexandrea Kilgore-Gomez Claire Phibbs

Background: Thiamine deficiency (TD) causes thiamine deficiency disorders (TDDs) which are frequently overlooked in food-secure countries such as the United States (U.S.). Lack of awareness and the absence of validated, rapidly available biomarkers perpetuate underdiagnosis. Our objective was to determine prevalence of TD in hospitalized U.S. veterans without alcohol use disorder (AUD) and describe clinical characteristics of TDDs. A secondary objective was to evaluate the utility of plasma and whole-blood thiamine biomarkers in identifying thiamine-responsive disorders (TRDs). Methods: Newly hospitalized veterans without AUD were recruited. Fasting plasma and whole-blood thiamine were obtained. Interview, physical exam, and chart review were completed to assess clinical signs of TD. Participants were invited to return after thiamine repletion and changes in symptoms and exam findings were noted. Results: A total of 286 participants were enrolled: 261 had plasma thiamine results, 259 had whole-blood thiamine results, 179 completed interviews, 164 completed initial examination, and 60 returned for reexamination after repletion. A majority (86.59%) had potential signs or symptoms of TDDs, 26.44% had low plasma thiamine, 2.70% had low whole-blood thiamine, and 97.92% with low plasma thiamine had clinical signs of TDDs and many experienced multiple TD syndromes. Those with low plasma thiamine who returned after repletion showed improvements in cognitive scores (p = 0.0093) and motor strength (p = 0.0417), and most reported symptom improvement. Whole-blood thiamine missed many cases of TRDs. Conclusions: TD affects one quarter of hospitalized veterans without AUD. Low plasma thiamine identifies TRDs more frequently than low whole-blood thiamine. Using clinical criteria alone to diagnose TDDs overestimates cases and biomarker confirmation appears necessary.

Diseases doi: 10.3390/diseases14080274

Authors: Alessandra Pizzo Marco Zeppieri Filippo Marano Alessandro Vasco Corrado Pizzo Antonio M. Vicari Fabiana D’Esposito Caterina Gagliano Francesco Cappellani

Cocaine-induced ocular toxicity is an increasingly acknowledged but often underestimated clinical condition that includes a wide range of eye-related symptoms. The extensive recreational use of cocaine, together with its powerful sympathomimetic and vasoconstrictive effects, leads to various ocular problems that can impact all anatomical components of the eye. This narrative review aims to deliver a thorough and current synthesis of the existing research on the epidemiology, pathophysiology, clinical symptoms, and therapy of cocaine-related ocular illness. Evidence suggests that cocaine-induced ocular damage involves vascular, local toxic, neuronal, and immunological processes. Reported manifestations in the literature include the ocular surface, optic nerve, posterior segment, orbit, and adnexal tissues. Novel imaging techniques have revealed subclinical retinal microvascular changes in chronic users, suggesting a continuum from initial vascular dysregulation to manifest ischemic injury. Notwithstanding increased awareness, the existing evidence is constrained by heterogeneity, small sample sizes, and a prevalence of case reports. A comprehensive understanding of the pathophysiological mechanisms and long-term ocular effects is crucial for enhancing diagnostic precision, directing management, and informing preventive measures. Enhanced multidisciplinary collaboration between ophthalmologists and addiction experts is essential to tackle this intricate and dynamic clinical dilemma.

Diseases doi: 10.3390/diseases14080273

Authors: Maedeh Mirasheh Zahra Shahabinia Afrooz Mazidimoradi Toktam Soleimani Leila Allahqoli Hamid Salehiniya

Environmental exposure to pesticides is considered a risk factor for gynecological cancers, contributing to their onset and progression through various mechanisms. This narrative review investigates the role of different pesticides in the development and progression of ovarian, endometrial, and cervical cancers, and provides a comprehensive synthesis of epidemiological findings along with molecular mechanisms, highlighting carcinogenic pathways, conflicting findings, and potential therapeutic implications. Relevant epidemiological and experimental studies published between 2000 and 2025 were identified through searches of major scientific databases. Various pesticides, particularly organochlorines, contribute to gynecological cancers through mechanisms such as estrogen mimicry, DNA damage, oxidative stress, increased pro-inflammatory cytokines, and disruption of cellular signaling pathways. However, most studies found no significant association between certain pesticides, such as Triazines and Atrazine, and gynecological cancers. Furthermore, some pesticides, like Carbendazim, exhibit a dual role; while carcinogenic, they can also serve therapeutic purposes in cancer treatment when utilized with nanotechnology. Overall, pesticide exposure is a significant factor in the development and progression of women’s cancers, although the strength of the evidence varies across pesticide classes. Despite numerous studies, contradictory findings necessitate further research to clarify causal relationships.

Diseases doi: 10.3390/diseases14080272

Authors: Karim Chamari Wissem Dhahbi Sumaia AlMadhoun James England Mohammad Mansi Hala Al Ali Jallal Toufiq Khalifa Alkuwari

Background/Objectives: Substance use disorders (SUDs) remain a major public health challenge, with high relapse rates despite established pharmacological and behavioral treatments. This scoping review maps evidence on structured exercise interventions as therapeutic approaches in SUD treatment, focusing on direct clinical outcomes, substance-specific effects, and implementation strategies. Methods: Following PRISMA-ScR and JBI guidance, searches of PubMed, Scopus, PsycINFO, and SPORTDiscus identified human studies published from 2000 to 31 December 2024 that evaluated supervised exercise interventions in adults with SUDs. Results: Evidence from randomized trials and recent network meta-analyses indicates clinically relevant benefits for abstinence, craving reduction, mood symptoms, cognitive function, treatment retention, and withdrawal management. Moderate-to-vigorous aerobic exercise delivered three to four times weekly for at least 12 weeks, at approximately 180 MET-minutes per week, appears particularly effective, while combined aerobic and muscle-performance protocols may yield broader benefits. Conclusions: Exercise interventions show strong potential as adjuncts to SUD care. Implementation should incorporate individualized prescription, substance-specific safety screening, cardiovascular and psychiatric monitoring, and multidisciplinary coordination. Further long-term randomized trials, mechanistic studies, and cost-effectiveness evaluations are needed.

Diseases doi: 10.3390/diseases14080271

Authors: Michał Kutyłowski Piotr Alster Natalia Madetko-Alster Bartosz Migda

Background/Objectives: Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) share several clinical manifestations, which may complicate differential diagnosis. The aim of this study was to evaluate whether automated volumetric measurements of the pallidum and ventral diencephalon can differentiate PSP from PD. Methods: Thirty-two patients were included, comprising 20 patients with PD and 12 patients with PSP. All participants underwent 3-T brain magnetic resonance imaging. Automated segmentation and volumetric analysis were performed using the vol2Brain pipeline. Absolute and normalized volumes of the pallidum and ventral diencephalon were compared between groups. Receiver operating characteristic (ROC) analysis was used to assess diagnostic performance. Results: Patients with PSP demonstrated lower pallidal and ventral diencephalic volumes than patients with PD. Differences were observed for both absolute and normalized volumetric measurements (all p ≤ 0.002). Total pallidal volume showed the highest diagnostic performance, with an area under the ROC curve (AUC) of 0.958, sensitivity of 85%, and specificity of 100%. Total ventral diencephalon volume also differentiated PSP from PD, yielding an AUC of 0.829, seNsitivity of 70%, and specificity of 92%. Conclusions: Pallidal and ventral diencephalic volumes differed between patients with PSP and PD. Automated measurements of pallidal and ventral diencephalic volumes may complement conventional MRI findings in patients with parkinsonian syndromes. Further studies are needed to validate these findings in larger cohorts.

Diseases doi: 10.3390/diseases14080270

Authors: Emmanuel U. Azu Gulzar H. Shah Toktam Naderimoghaddam Lili Yu

Background/Objectives: Multimorbidity is increasingly recognized as a major contributor to mortality worldwide, yet its underlying patterns and prognostic implications remain poorly understood in the United States. This study identified distinct multimorbidity patterns and examined their association with all-cause mortality in a nationally representative sample of U.S. adults. Methods: We conducted a retrospective cohort study using data from the 2004 National Health Interview Survey linked to the National Death Index through 2019 (n = 28,598). Latent class analysis identified unobserved multimorbidity classes based on patterns of co-occurring physician-diagnosed chronic conditions, and Cox proportional hazards models were fitted to estimate mortality risk while accounting for complex survey design. Six distinct multimorbidity classes were identified, reflecting cardiometabolic, respiratory, cardiovascular, and inflammatory disease profiles. Results: Compared with the Low Multimorbidity group, all other classes were associated with increased mortality risk. In fully adjusted analyses, the Severe Cardiopulmonary–Metabolic (HR 3.71, 95% CI 2.99–4.60) and Advanced Cardiovascular (HR 2.81, 95% CI 2.52–3.14) classes showed the highest risks. Intermediate risks were observed in the Cardiometabolic–Arthritis (HR 2.45, 95% CI 2.13–2.81) and Respiratory–Musculoskeletal (HR 1.39, 95% CI 1.22–1.58) classes, while the Inflammatory Pain–Airway class showed a more modest increase. Subgroup analyses suggested stronger relative effects among younger adults and women in the most severe classes. Conclusions: The study findings highlight the heterogeneous nature of multimorbidity and suggest that specific disease clusters carry substantially different mortality risks. Recognizing these patterns may improve risk stratification and support more targeted, patient-centered care strategies.

Diseases doi: 10.3390/diseases14080269

Authors: Denisa-Catalina Dragomir Adelaida-Sorana Trifu Amelia-Damiana Trifu

Background: Subclinical eating-disorder tendencies may reflect early psychological vulnerability before the development of clinically diagnosed eating disorders. Body image concerns, perceived social support, and control-related beliefs are established correlates of eating pathology. However, their joint pattern across several eating-disorder tendency profiles has received less attention in Romanian nonclinical adult samples. Objective: We examined differences in perceived social support, locus of control, and body image concerns among participants with and without subclinical tendencies associated with anorexia, bulimia, and binge eating. We investigated the association between locus of control and body image concerns. Methods: A cross-sectional quantitative design was used. The sample included 108 participants who completed online self-report measures assessing perceived social support, eating-disorder tendencies, body image concerns, and locus of control. Independent-samples t-tests and Welch tests were used for group comparisons. Bonferroni correction was applied within families of comparisons. Effect sizes were reported using Hedges’ g. Pearson correlation and simple linear regression were used to examine the association between locus of control and body image concerns. Results: Body image concerns were significantly higher among participants with anorexic, binge-eating, and bulimic tendencies. Perceived social support was lower among participants with binge-eating and bulimic tendencies, but not among those with anorexic tendencies. Locus of control differed significantly only in the exploratory bulimia comparison after correction. External locus of control was positively associated with body image concerns and explained a small but significant proportion of variance. Conclusions: Body image concerns emerged as the most consistent correlate of subclinical eating-disorder tendencies. The findings support the relevance of body image, interpersonal resources, and control-related beliefs in early eating-disorder vulnerability.

Diseases doi: 10.3390/diseases14080268

Authors: Vasile Calin Arcas Iulian Roman-Filip Doru Florian Cornel Moga Adriana Saceleanu Anca Maria Fratila Lucia Nicola Fratila Corina Roman-Filip

Background: Multiple sclerosis and periodontal disease are chronic inflammatory conditions that may share immune-mediated mechanisms, including cytokine activation, oral dysbiosis, oxidative stress, and systemic inflammatory burden. This systematic review aimed to synthesize recent evidence on common inflammatory pathways linking periodontal disease and multiple sclerosis. Methods: The review was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Cochrane Library, and Scopus were searched for English-language studies published between June 2020 and June 2026. Eligible studies addressed multiple sclerosis, periodontal disease, oral microbiome alterations, systemic inflammation, or neuroinflammatory outcomes. Study selection and data extraction were performed independently by three reviewers. Risk of bias was assessed using AMSTAR 2, the Newcastle–Ottawa Scale, and the Joanna Briggs Institute checklist, according to study design. Results: Seventeen studies were included in the qualitative synthesis. The main shared mechanisms were cytokine-mediated inflammation involving TNF-α, IL-1β, IL-6, and IL-17; NF-κB signaling; Th17/Treg imbalance; blood–brain barrier disruption; oxidative stress; matrix metalloproteinase activity; complement activation; and oral–gut–brain axis dysregulation. The evidence suggests that periodontal inflammation may contribute to systemic immune activation and may amplify neuroinflammatory processes in multiple sclerosis. Conclusions: Current evidence supports a biologically possible association between periodontal disease and multiple sclerosis through shared inflammatory and microbial pathways. However, causality remains unproven, and further longitudinal and interventional studies are needed.

Diseases doi: 10.3390/diseases14080267

Authors: Ariel Torres Paloma González Martha Fors Gisselle Trujillo

Background: Tuberculosis remains a major public health challenge in Latin America, where social inequalities, fragmented health systems, and barriers to care continue to undermine disease control. Although effective treatment is available, treatment abandonment and loss to follow-up remain persistent obstacles to successful outcomes. Methods: A structured critical analysis of the contemporary literature on tuberculosis treatment abandonment and retention in care was conducted using a narrative evidence synthesis approach. Forty scientific documents published between 2018 and 2026 were included. Of these, 23 Latin American studies informed the results synthesis, while 13 international studies supported the comparative critical reflection. Results: Findings were organised into five domains: social vulnerability, clinical complexity, health system barriers, priority populations, and protective factors and innovation. The evidence indicates that treatment abandonment is not an isolated individual behaviour, but a phenomenon associated with the convergence of social, clinical, and institutional determinants across the care trajectory. Poverty, migration, drug resistance, incarceration, weak follow-up systems, and fragmented care were repeatedly associated with discontinuity, whereas social support, active follow-up, digital tools, and economic measures were linked to improved adherence and retention in care. Conclusions: From a biopsychosocial perspective, treatment abandonment should be understood as a systemic and preventable failure across the tuberculosis care continuum. The proposed Latin American Integrated Model for Retention in Tuberculosis Care (MILERTB) offers an anticipatory, equity-oriented, and person-centred framework to strengthen retention in care and guide future implementation research.

Diseases doi: 10.3390/diseases14080266

Authors: Bouchra Nour El Houda Baiski Zoulikha Mokrani Sara Mimi Atmani Fatma Zohra Ider Nabila Lakri Fatma Zohra Souid Samia Chaib Assia Galleze

Objective: Axonal injury is a key determinant in irreversible disability in multiple sclerosis (MS). Reliable biomarkers of neuroaxonal damage are essential for improving diagnosis, monitoring disease progression, and evaluating treatment response. This study investigated the relationship between phosphorylated neurofilament heavy chain (pNF-H), clinical characteristics, and conventional cerebrospinal fluid (CSF) and serum biomarkers in Algerian patients with MS. Methods: A total of 102 participants were enrolled. Clinical, immunological, and biochemical parameters were assessed, including the Expanded Disability Status Scale (EDSS), oligoclonal bands (OCBs), IgG index, albumin quotient, and pNF-H concentrations in paired CSF and serum samples. Results: OCBs were detected in 85.5% of patients, and 65.21% exhibited intrathecal immunoglobulin synthesis, with a median IgG index of 0.87. Patients with progressive MS were significantly older and more disabled than those with relapsing–remitting MS (age: p = 0.01; EDSS: p = 0.0007). OCB-positive patients had significantly higher IgG index values (p = 0.0004), but OCB status was not associated with age, EDSS, or albumin quotient. EDSS correlated positively with age (p = 0.0007), albumin quotient (p = 0.01), and IgG index (p = 0.001). Both CSF and serum pNF-H levels were significantly elevated in MS patients compared with NSDs group (p < 0.001). Increased pNF-H concentrations were associated with progressive disease and greater disability (EDSS ≥ 5). Conclusions: Elevated pNF-H levels in CSF and serum are associated with disease severity and progressive MS, supporting their potential as complementary biomarkers of neuroaxonal damage and clinical disability in routine MS assessment.

Diseases doi: 10.3390/diseases14080265

Authors: Christian Spiegel Riham Shanti Friederike Weschenfelder Michelle Mueller Spiegel Maik Neumann Mark Lenz Wolfram Weschenfelder

Background: Wound complications and unplanned revision surgery remain common after soft tissue sarcoma (STS) resection. Established risk models focus on patient- and tumour-related factors, while the role of operative and perioperative variables is less well defined. Methods: This retrospective single-centre study included 95 patients undergoing STS resection between 2021 and 2025. Associations with unplanned revision surgery were evaluated using univariate and exploratory multivariable logistic regression analyses. Receiver operating characteristic (ROC) analysis assessed the discriminatory performance of postoperative drainage output. Results: Unplanned revision surgery occurred in 23 patients (24%). On univariate analysis, several intraoperative and postoperative variables were associated with revision, whereas most patient- and tumour-related factors were not statistically significant. In multivariable analysis, intraoperative crystalloid administration was the only intraoperative factor associated with unplanned revision (OR 1.45 per 500 mL, 95% CI 1.05–2.02; p = 0.026). Among postoperative parameters, drainage output remained associated with revision (OR 1.45 per 100 mL, 95% CI 1.15–1.82; p = 0.005). In patients without planned secondary reconstruction, drainage output showed good exploratory discriminatory performance (AUC 0.927), with a cutoff of 925 mL providing high specificity (94.4%) with acceptable sensitivity (75%). Conclusions: In this cohort, unplanned revision was more frequently associated with markers of surgical complexity, including higher intraoperative crystalloid administration, and the early postoperative course, particularly drainage output. Drainage output appears to reflect an evolving complication rather than an independent predictor and may serve as an early clinical warning signal. Findings are hypothesis-generated and require external validation.

Diseases doi: 10.3390/diseases14070264

Authors: Camilla Laureti Dario Benelli Federica Zoccali Gabriele Riccardi Mattia Umberto Di Michele Stefano Venarubea Christian Barbato Antonio Minni Carla Petrella

Background: Bacteria colonizing the nasal cavity contribute to mucosal homeostasis, and altered sinonasal bacterial communities have been associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Whether routine, culture-based microbiology can distinguish the cultivable bacterial profile of CRSwNP patients from that of controls remains unclear. Methods: In this single-center observational pilot study, middle-meatus swabs from 30 patients with CRSwNP and 30 controls were cultured on four media, and isolates were identified with the VITEK 2 system. For each species, presence or absence per subject was compared between groups using Fisher’s exact test with Benjamini–Hochberg correction for multiple comparisons; the number of cultivable species per subject was compared with the Mann–Whitney test. Results: The two groups were comparable in age and sex. Patients yielded more cultivable bacterial species per subject than controls (mean 4.4 vs. 2.9; Mann–Whitney p < 0.001). Several species were numerically more frequent in patients (e.g., Staphylococcus hominis, S. lugdunensis) and others in controls (e.g., S. epidermidis, S. aureus), but no individual species difference remained significant after correction. Conclusions: Using routine culture, CRSwNP was characterized chiefly by a higher number of cultivable bacterial species, whereas individual species differences were not statistically robust. These hypothesis-generating findings warrant confirmation in larger, sequencing-based studies.

Diseases doi: 10.3390/diseases14070263

Authors: Ana De Maya-Martínez Omar Cauli María del Carmen Giménez-Espert Cristina Buigues

Background: Healthcare-associated infections (HAIs) remain a major preventable challenge in healthcare systems worldwide. Nursing students play a key role in infection prevention during clinical training; therefore, adequate education in hand hygiene (HH), standard precautions (SPs), and infection prevention and control (IPC) is essential. This systematic review aimed to evaluate nursing students’ knowledge of HAI prevention according to international recommendations and to identify factors associated with higher knowledge levels. Methods: A systematic review was conducted following Joanna Briggs Institute methodology and PRISMA guidelines. Searches were performed in MEDLINE (PubMed), CINAHL, Cochrane Library, Embase, Scopus, and Web of Science. Observational studies assessing nursing students’ knowledge of HH, SPs, or IPC were included. Methodological quality was assessed using the Joanna Briggs Institute critical appraisal checklist for analytical cross-sectional studies. Results: Fifty-two studies involving 13,912 nursing students across five continents were included. Most studies focused on HH, followed by SPs and IPC. The WHO Five Moments for Hand Hygiene (14 of 26 (53.8%)) was the most frequently used instrument for HH assessment, while the Compliance with Standard Precautions Scale (5/11 (45.5%)) was the most used for SPs. Regarding IPC, most studies (5/7 (71.4%)) evaluated it by study-specific questionnaires developed/adapted by the researchers. Higher knowledge and compliance levels were generally associated with advanced academic year, prior training, positive attitudes, and supportive clinical environments. However, substantial heterogeneity was identified across study designs, assessment instruments, outcome measures, and methodological quality. Conclusions: Continued and updated education in HH, SPs, and IPC appears essential for improving nursing students’ knowledge and preventive practices. Greater standardization of assessment methods is needed to improve comparability across studies.