Diseases

16 pages, 1845 KB

Open AccessArticle

Real-World Outcomes of Ambulatory Drug-Susceptible Tuberculosis Management During the COVID-19 Pandemic in Romania

by Ioana Munteanu, Alexandru Stoichiță, Silviu Gabriel Vlasceanu, Mara Balteanu, Oana Andreea Parlițeanu, Traian Constantin Panciu, Adriana Mihaela Iliesiu, Dragos Baiceanu, Ioana-Mădălina Moşteanu, Alexandru-Neculai Pavel and Beatrice Mahler

Diseases 2026, 14(10), 370; https://doi.org/10.3390/diseases14100370 - 6 Oct 2026

Abstract

Background: Romania continues to experience one of the highest tuberculosis (TB) burdens in the European Union/European Economic Area. During the COVID-19 pandemic, reduced inpatient capacity accelerated the use of ambulatory care for patients with drug-susceptible tuberculosis (DS-TB). This study evaluated treatment outcomes, outcome [...] Read more.

Background: Romania continues to experience one of the highest tuberculosis (TB) burdens in the European Union/European Economic Area. During the COVID-19 pandemic, reduced inpatient capacity accelerated the use of ambulatory care for patients with drug-susceptible tuberculosis (DS-TB). This study evaluated treatment outcomes, outcome ascertainment, hospitalization requirements, and factors associated with unfavorable outcomes among patients managed through ambulatory TB services. Methods: We conducted a retrospective observational cohort study of adults with pulmonary or extrapulmonary DS-TB managed through ambulatory tuberculosis dispensaries affiliated with the “Marius Nasta” Institute of Pneumophthisiology, Bucharest, Romania, between January 2020 and December 2022. Treatment outcomes were defined according to World Health Organization criteria. Factors associated with unfavorable outcome were assessed using Firth penalized-likelihood logistic regression. Hospitalization during treatment was analyzed as a secondary outcome. Results: The final cohort comprised 545 patients with DS-TB, with a mean age of 44.8 years and 56.1% being male. Overall, 281 of 545 patients achieved treatment success, corresponding to a WHO-defined treatment-success rate of 51.6%. Twenty-seven patients (5.0%) experienced an unfavorable outcome, while 237 (43.5%) were classified as not evaluated. Among the 308 patients for whom a determinate end-of-treatment outcome was available, 281 (91.2%) achieved treatment success; however, this conditional proportion does not represent the programmatic treatment-success rate for the entire cohort. Conclusions: Structured ambulatory DS-TB care was operationally feasible within this tertiary-care-linked dispensary network during the COVID-19 pandemic. However, the WHO-defined treatment-success rate for the entire cohort was 51.6%, largely reflecting the substantial proportion of patients without an evaluable final outcome. The high proportion of not-evaluated patients represents an important programmatic weakness and limits conclusions regarding the effectiveness of the ambulatory model. Improved outcome ascertainment and continuity of follow-up are essential components of decentralized TB care. Full article

(This article belongs to the Section Respiratory Diseases)

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27 pages, 5960 KB

Open AccessArticle

Male Sex, Early Postoperative C-Reactive Protein and Prolonged Hospital Stay After Lung Resection in Older Patients: A Retrospective Cohort Study

by Yeon Soo Kim and So Hyun Ahn

Diseases 2026, 14(10), 369; https://doi.org/10.3390/diseases14100369 - 6 Oct 2026

Abstract

Background/Objectives: Older patients make up a growing share of the lung-resection workload, and C-reactive protein measured in the first days after operation is used to judge recovery. Whether the same concentration means the same thing in older men and older women is not [...] Read more.

Background/Objectives: Older patients make up a growing share of the lung-resection workload, and C-reactive protein measured in the first days after operation is used to judge recovery. Whether the same concentration means the same thing in older men and older women is not established. Methods: We analysed 724 lung resections in 716 patients from VitalDB, an open perioperative dataset from a Korean tertiary hospital; 313 (43.2%) were aged 65 years or older. The primary outcome was a postoperative stay of 7 days or longer. Older general surgical patients from the same institution served as an age-matched negative control. Results: Among patients aged 65 or older, prolonged stay occurred in 55 of 192 men (28.6%) and 10 of 121 women (8.3%), adjusted odds ratio 3.031 (95% CI 1.425–6.446, p = 0.0040). Median day 1 C-reactive protein was 51.9 mg/L in older men and 27.4 mg/L in older women, adjusted ratio of geometric means 1.825 (1.593–2.090, p = 1.8 × 10⁻¹⁶). C-reactive protein predicted prolonged stay unadjusted (1.594 per doubling, 1.292–1.967) but not once sex entered the model (0.865, 0.691–1.084, p = 0.208), an interval that remains compatible with a modest association in either direction. In 1635 older general surgical patients, neither effect was present (0.863, p = 0.302; 1.238, p = 0.163). The sex-by-age interaction was not significant (p = 0.519). Conclusions: In older patients undergoing lung resection, men mount a larger early inflammatory response than women to comparable operations and are three times as likely to stay a week or longer, an association absent from older general surgical patients at the same institution. In this dataset and with the measured covariates, C-reactive protein on the first postoperative day was not independently associated with prolonged hospital stay after adjustment for sex and the other available factors; with 113 events, this does not establish absence of prognostic value. These data do not derive, validate, or justify sex-specific C-reactive protein thresholds, and none is proposed. Full article

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19 pages, 295 KB

Open AccessArticle

Genetic Polymorphisms in SORL1, CLU, BIN1, and VDR Are Associated with Mild Cognitive Impairment and Dementia in a Russian Population

by Danil Peregud, Olga Pavlova, Konstantin Pavlov, Kira Nebogina, Yana Zorkina, Olga Abramova, Valeriya Ushakova, Aleksandra Ochneva, Eugene Zubkov, Inna Shamakina, Alisa Andryushchenko, Georgy Kostyuk, Anna Morozova, Olga Gurina and Vladimir Chekhonin

Diseases 2026, 14(10), 368; https://doi.org/10.3390/diseases14100368 - 3 Oct 2026

Abstract

Background: Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, and genetic factors may influence progression. This study aimed to identify genetic polymorphisms associated with MCI and dementia in a Russian population. Methods: A total of 280 participants were [...] Read more.

Background: Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, and genetic factors may influence progression. This study aimed to identify genetic polymorphisms associated with MCI and dementia in a Russian population. Methods: A total of 280 participants were enrolled: Controls (n = 84), MCI (n = 94), and Dementia (n = 102). Fifteen single nucleotide polymorphisms in seven candidate genes (TOMM40, SORL1, BIN1, VDR, CLU, CR1, PICALM) were genotyped. Associations were tested using multinomial logistic regression adjusted for age and sex under four genetic models (codominant, dominant, recessive, overdominant). Multiple testing was controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure. Deviation from Hardy–Weinberg equilibrium was observed for three SNPs in the Controls (SORL1 rs1010159, BIN1 rs7561528, rs10200967) and interpreted with caution. Results: Under the primary FDR correction (60 tests per contrast), only BIN1 polymorphisms remained significantly associated with dementia: rs7561528 (overdominant model: OR = 0.318, 95% CI = 0.162–0.624, p = 0.001, q = 0.0035) and rs10200967 (overdominant model: OR = 0.272, 95% CI = 0.136–0.544, p < 0.001, q < 0.007). Under the more conservative exploratory correction (150 tests), these associations were at the threshold of significance (q = 0.050). Conclusions: BIN1 rs7561528 and rs10200967 are associated with reduced odds of dementia in the Russian population. Nominally significant associations with SORL1, CLU, and VDR require replication in larger cohorts. The developed genotyping panel represents a cost-effective research tool for genetic screening; clinical implementation requires validation in larger prospective cohorts. Full article

(This article belongs to the Section Neuro-psychiatric Disorders)

20 pages, 9222 KB

Open AccessArticle

Immune- and Stromal-Associated Tissue-Context Profiles in Pretreatment Triple-Negative Breast Cancer: An Exploratory Institutional Cohort Study

by Valeria Zuccalà, Nicoletta Staropoli, Caterina Labanca, Gabriele Ricciardi, Pietro Tralongo, Vincenzo Fiorentino, Elisabetta Procopio, Maria Renne, Antonio Ieni, Maurizio Martini, Pierfrancesco Tassone and Pierosandro Tagliaferri

Diseases 2026, 14(10), 367; https://doi.org/10.3390/diseases14100367 - 3 Oct 2026

Abstract

Background/Objectives: We examined combinations of immune- and stromal-associated features in pretreatment triple-negative breast cancer (TNBC) biopsies and explored their clinical and germline associations. Methods: This retrospective study included 24 women with nonmetastatic TNBC from a clinically selected BRCA1/BRCA2-tested cohort. Two [...] Read more.

Background/Objectives: We examined combinations of immune- and stromal-associated features in pretreatment triple-negative breast cancer (TNBC) biopsies and explored their clinical and germline associations. Methods: This retrospective study included 24 women with nonmetastatic TNBC from a clinically selected BRCA1/BRCA2-tested cohort. Two pathologists, blinded to clinical and germline data, jointly assessed stromal tumor-infiltrating lymphocytes (sTILs), programmed death-ligand 1 (PD-L1), CD68/CD163-positive macrophages, and CD117/tryptase-positive mast cells. Profiles were assigned before unblinding. A second blinded joint sTIL assessment provided continuous estimates for subsequent hierarchical clustering; profile assignments remained unchanged. Results: Profiles I–III comprised seven, 13, and four tumors, respectively. Profile I combined higher sTILs and PD-L1 with a CD68-high/CD163-low pattern and rare mast cells. Profile II showed lower sTILs and PD-L1, a CD68-low/CD163-high pattern, and dense mast-cell hotspots; Profile III had minimal sTILs, low macrophage counts, and no mast cells detected in evaluated fields. Clustering reproduced these assignments. All four patients with pathogenic/likely pathogenic germline BRCA1/BRCA2 variants were in Profile I (adjusted p = 0.030); omitting one positive case at a time increased the adjusted p value to 0.068. Seven of 16 neoadjuvant-treated patients achieved pathologic complete response. Five posttreatment recurrences and seven deaths were recorded; exploratory comparisons of pathologic complete response and overall survival were inconclusive. Conclusions: These profiles describe different combinations of lymphocytic infiltration, PD-L1 expression, macrophage counts, and mast-cell hotspots. The profiles and the exploratory BRCA1/BRCA2 finding require validation in larger, independent cohorts before clinical use. Full article

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15 pages, 764 KB

Open AccessSystematic Review

Therapeutic Exercise for Chronic Whiplash-Associated Disorders: A Systematic Review of Randomized Controlled Trials on Pain, Disability, and Kinesiophobia

by Rosario Ferlito, Giuseppe Lanza, Gianluca Testa, Vito Pavone, Fabio Manfrè and Salvatore Giunta

Diseases 2026, 14(10), 366; https://doi.org/10.3390/diseases14100366 - 2 Oct 2026

Abstract

Background/Objectives: Chronic whiplash-associated disorders (WAD) are a common cause of persistent neck pain and disability. Therapeutic exercise is widely used, but its effectiveness remains uncertain. This systematic review evaluated the effects of therapeutic exercise, alone or combined with other interventions, on pain, neck-related [...] Read more.

Background/Objectives: Chronic whiplash-associated disorders (WAD) are a common cause of persistent neck pain and disability. Therapeutic exercise is widely used, but its effectiveness remains uncertain. This systematic review evaluated the effects of therapeutic exercise, alone or combined with other interventions, on pain, neck-related disability, and kinesiophobia in adults with chronic WAD. Methods: PubMed, PEDro, and the Cochrane Library were searched from inception to December 2025 for randomized controlled trials (RCTs) including adults with chronic WAD (>3 months). Eligible studies compared exercise-based interventions with minimal intervention, usual care, or other active treatments. Primary outcomes were pain and neck-related disability, with kinesiophobia as a secondary outcome. Methodological quality was assessed using the PEDro scale, risk of bias using Cochrane RoB 2, and certainty of evidence using GRADE. Due to heterogeneity, findings were synthesized without meta-analysis using SWiM principles. Results: Six reports representing five independent RCT cohorts (up to 635 unique participants) were included. Interventions included neck-specific exercise, home-based programmes, multimodal rehabilitation, and exercise combined with manual therapy. Exercise generally produced greater short- to medium-term improvements in pain and disability than minimal intervention or advice, whereas comparisons with other active treatments were heterogeneous and statistically inconclusive. Effects on kinesiophobia were inconsistent. PEDro scores ranged from 7–9/10. RoB 2 indicated predominantly some concerns. GRADE certainty was low for pain and disability and very low for kinesiophobia. Conclusions: Therapeutic exercise may improve pain and disability compared with minimal interventions, but evidence certainty is low. Its superiority over other active treatments and effects on kinesiophobia remain uncertain. Full article

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17 pages, 1262 KB

Open AccessArticle

Exploratory Comparison of Routine Inflammatory Biomarkers in Nasopharyngeal Carcinoma and Benign Adenoid-Associated Pathology

by Darius Radu Roman, Carmen Delia Nistor Cseppento, Dana Carmen Zaha, Timea Claudia Ghitea, Alexia Manole, Dana Zdremtan, Alexandru Chioreanu and Felicia Manole

Diseases 2026, 14(10), 365; https://doi.org/10.3390/diseases14100365 - 2 Oct 2026

Abstract

Background: Nasopharyngeal carcinoma (NPC) may be accompanied by systemic inflammatory changes, but routine inflammatory markers are nonspecific and have not been validated as diagnostic tests for NPC. Methods: This exploratory retrospective comparison screened 178 adults and included 72 eligible records (36 histopathologically confirmed [...] Read more.

Background: Nasopharyngeal carcinoma (NPC) may be accompanied by systemic inflammatory changes, but routine inflammatory markers are nonspecific and have not been validated as diagnostic tests for NPC. Methods: This exploratory retrospective comparison screened 178 adults and included 72 eligible records (36 histopathologically confirmed NPC and 36 histologically confirmed benign adenoid-associated pathology); 106 records were excluded because of incomplete endoscopic or laboratory records (n = 41), hematological malignancy (n = 15), severe hepatic failure (n = 11), or a documented systemic inflammatory condition unrelated to the nasopharyngeal presentation (n = 39). CRP, erythrocyte sedimentation rate (ESR), leukocyte count, selected biochemical variables, and an investigator-derived loco-regional clinical/endoscopic severity score were compared. Prespecified sensitivity analyses included age- and sex-adjusted rank regression, restriction to the overlapping age range (39–52 years), group-stratified correlations, and partial rank correlations adjusted for diagnostic group, age, and sex. Results: The NPC group was younger than the benign group (38.1 ± 7.6 vs. 56.1 ± 8.3 years; p < 0.001). CRP, ESR, leukocyte count, uric acid, and the loco-regional score were higher in the NPC group (all p < 0.01). The principal differences persisted in the overlapping-age subset (NPC n = 17; benign n = 16; all p < 0.001) and in age- and sex-adjusted rank analyses. Pooled correlations were attenuated or changed after stratification and covariate adjustment, indicating that part of the pooled association reflected between-group separation. Exploratory ROC AUCs were 1.000 for CRP, leukocyte count, and the loco-regional score and 0.948 for ESR; these values were derived and evaluated in the same selected cohort. In separate Firth models adjusted for age and sex, CRP, leukocyte count, and the loco-regional score remained associated with NPC, whereas ESR did not (p = 0.200). Conclusions: The study identifies marked between-group differences in this selected retrospective cohort but does not establish diagnostic biomarkers or clinical cut-offs. Independent prospective evaluation, standardized sampling, and fuller control of inflammatory and tumor-related confounding are required. Full article

13 pages, 582 KB

Open AccessArticle

Testing Continuous Age as an Effect Modifier of the Association Between Diminished Ikigai and Psychological Distress in Two Long-Term Disaster Contexts in Japan

by Tetsushi Omori and Michiko Iwai

Diseases 2026, 14(10), 364; https://doi.org/10.3390/diseases14100364 - 2 Oct 2026

Abstract

Background/Objectives: Mental-health research often represents chronological age as a threshold or adjustment variable, although psychosocial associations may vary across adulthood. We tested whether continuous age modified the association between a context-specific single-item indicator of diminished ikigai and psychological distress in two Japanese communities [...] Read more.

Background/Objectives: Mental-health research often represents chronological age as a threshold or adjustment variable, although psychosocial associations may vary across adulthood. We tested whether continuous age modified the association between a context-specific single-item indicator of diminished ikigai and psychological distress in two Japanese communities with long-term disaster consequences. The ikigai indicators differed by context and were not treated as equivalent multidimensional measures. Methods: Secondary cross-sectional analyses used Miyakejima 2020/21 (N = 158; complete-case n = 147) and Okuma 2024 (N = 134; 111 valid 28-item General Health Questionnaire (GHQ-28) classifications; complete-case n = 110). Age-by-ikigai interactions were primary; fixed <65/≥65 analyses and robustness checks were secondary or exploratory. Results: In Miyakejima, the estimated interaction odds ratio (OR) was 2.00 per 10 years (95% confidence interval [CI] [1.03, 3.91], p = 0.042; likelihood-ratio p = 0.029), with substantial uncertainty at age extremes; the threshold interaction was unsupported. In Okuma, low/absent ikigai was associated with GHQ-28 high-risk status (OR = 12.94, 95% CI [4.96, 33.8], p < 0.001), while age modification was not detected (interaction OR = 0.88, 95% CI [0.44, 1.76], p = 0.711). The historical Miyakejima reanalysis also did not provide detectable evidence of corresponding modification. Conclusions: Within these context-specific samples, continuous-age modelling yielded preliminary evidence of heterogeneity in Miyakejima not captured by a 65-year threshold. Larger longitudinal studies should evaluate this signal’s precision and transferability. Full article

(This article belongs to the Special Issue Mental Health Across the Lifespan: Integrating Multidisciplinary Perspectives)

14 pages, 3566 KB

Open AccessArticle

Immunophenotypic Features of CD68 and CD163 Distribution in Oral Squamous Cell Carcinoma of Tongue and Lip

by Grigory Demyashkin, Andrey Kostin, Maya Epifanova, Alexandr Epifanov, Ekaterina Blinova, Anton Kasianov, Vladimir Shchekin, Dibakhan Tsomartova, Matvey Vadyukhin, Petr Shegai and Andrei Kaprin

Diseases 2026, 14(10), 363; https://doi.org/10.3390/diseases14100363 - 2 Oct 2026

Abstract

Background and Objectives: Oral squamous cell carcinoma (OSCC) belongs to a broad group of malignant neoplasms of the head and neck. It is known that components of the tumor microenvironment (TME) influence tumor progression. Similar patterns are being actively investigated in OSCC. In [...] Read more.

Background and Objectives: Oral squamous cell carcinoma (OSCC) belongs to a broad group of malignant neoplasms of the head and neck. It is known that components of the tumor microenvironment (TME) influence tumor progression. Similar patterns are being actively investigated in OSCC. In particular, a high density of CD68⁺ macrophages is associated with longer survival, whereas an abundance of M2 macrophages (CD163⁺) correlates with metastasis and an unfavorable prognosis. The present study compares the density and spatial distribution of CD68⁺ and CD163⁺ macrophages between intratumoral and peritumoral compartments in OSCC of the tongue and lip. Materials and Methods: Data from 112 patients with a verified OSCC diagnosis were included in this study. For the comparative morphological analysis, two core groups were formed: (a) Group I (n = 84), patients with Squamous Cell Carcinoma (pT1) of the tongue; (b) Group II (n = 28), patients with Squamous Cell Carcinoma (pT1) of the lip. Immunohistochemistry was performed according to standard protocols. Results: Tongue OSCC was characterized by the predominant accumulation of both CD68⁺ and CD163⁺ macrophages in the peritumoral stroma compared with the intratumoral zones (34.2 ± 8.1 vs. 48.1 ± 6.4 cells/mm²). In contrast, in lip OSCC, a higher density of CD68⁺ macrophages was observed in the intratumoral compartment, whereas the number of CD163⁺ macrophages remained considerably lower in both the intratumoral (51.1 ± 4.3 vs. 9.4 ± 2.1 cells/mm²) and peritumoral stroma of the tumor. Conclusions: These findings demonstrate that tongue and lip OSCC harbor distinct patterns of macrophage distribution and polarization, underscoring the role of the immune microenvironment in the biological heterogeneity of OSCC and warranting further investigation into macrophage subtype-specific prognostic markers. Full article

16 pages, 609 KB

Open AccessArticle

The Impact of Pre- Versus Post-Transplant Multidrug-Resistant Organism Colonization on Liver Transplant Outcomes: A Retrospective Cohort Study

by Emil Aliev, Efrat Orenbuch-Harroch, Abed Khalaileh, Ashraf Imam, Matan Joel Cohen and Maya Korem

Diseases 2026, 14(10), 362; https://doi.org/10.3390/diseases14100362 - 1 Oct 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Infectious Disease)

19 pages, 4459 KB

Open AccessReview

Viral Signals in Acute Appendicitis: Direct Tissue Infection, Systemic Triggers, and the Unresolved Biology of Spontaneous Resolution

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

Diseases 2026, 14(10), 361; https://doi.org/10.3390/diseases14100361 - 1 Oct 2026

Abstract

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 [...] Read more.

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. Full article

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20 pages, 2272 KB

Open AccessSystematic Review

RANK/RANKL/OPG Axis Expression and Response to Anti-RANKL Therapy in Gnathic Giant Cell Lesions: A Systematic Review and Meta-Analysis

by Darya Khalid Mahmood, Arivan Mahmood Hama and Ahmad Shoeb Hashmi

Diseases 2026, 14(10), 360; https://doi.org/10.3390/diseases14100360 - 1 Oct 2026

Abstract

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 [...] Read more.

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. Full article

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18 pages, 428 KB

Open AccessArticle

Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer’s Disease and Frontotemporal Dementia: A Serbian Memory Clinic

by Gorana Mandić-Stojmenović, Vladimir Kostić, Ana Marjanović, Ivana Novaković, Predrag Aleksić, Tanja Stojković and Elka Stefanova

Diseases 2026, 14(10), 359; https://doi.org/10.3390/diseases14100359 - 29 Sep 2026

Abstract

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 [...] Read more.

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. Full article

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23 pages, 1013 KB

Open AccessArticle

Differential Prognostic Associations of Monocyte-Containing and Traditional Systemic Inflammatory Indices with Overall Survival After Resection or Palliative Bypass for Pancreatic Cancer: A Retrospective Cohort Study

by Rares Voda, Sohaib Ahmed, Ovidiu Aurelian Budișcă, Cătălin-Dumitru Cosma, Ovidiu Simion Cotoi, Călin Molnar and Vladimir Bacârea

Diseases 2026, 14(10), 358; https://doi.org/10.3390/diseases14100358 - 28 Sep 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Section Oncology)

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24 pages, 1199 KB

Open AccessArticle

Catalase Activity and Methylglyoxal Concentration in Plasma and Erythrocytes Across Different Clinical Phenotypes of Thyroid Disease: A Cross-Sectional Study

by Ernur Bekov, Olga Ponamareva, Ryszhan Bakirova, Vilen Molotov-Luchanskiy and Yelena Pozdnyakova

Diseases 2026, 14(10), 357; https://doi.org/10.3390/diseases14100357 - 26 Sep 2026

Abstract

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 [...] Read more.

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. Full article

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16 pages, 485 KB

Open AccessArticle

Sleep Disturbances and Health-Related Quality of Life in Paediatric Oncology: A Comparative Study with Non-Oncological Chronic Illness and Healthy Peers

by Shuk Yan Mak, Jeanny Sui Sum Cheung, Ankie Tan Cheung and William Ho Cheung Li

Diseases 2026, 14(10), 356; https://doi.org/10.3390/diseases14100356 - 26 Sep 2026

Abstract

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 [...] Read more.

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. Full article

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20 pages, 3177 KB

Open AccessCase Report

The Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis Spectrum: A Report of Two Contrasting Cases Managed in a Burn Unit

by 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 and Mihaela Pertea

Diseases 2026, 14(10), 355; https://doi.org/10.3390/diseases14100355 - 25 Sep 2026

Abstract

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 [...] Read more.

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. Full article

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22 pages, 753 KB

Open AccessSystematic Review

The Psychosocial Burden of the ‘Lazarus Effect’: A Systematic Review of Survivor Guilt, Identity Shift, and Discontinuation Anxiety in Exceptional Responders to Cancer Immunotherapy

by Johanna Alcívar Ponce, Wilson Alexander Zambrano Vélez, Marianela Silva Sánchez and Gioryi Sornoza Zavala

Diseases 2026, 14(10), 354; https://doi.org/10.3390/diseases14100354 - 25 Sep 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Mental Health—Management and Care, Multidisciplinary Approaches and Perspectives)

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21 pages, 1316 KB

Open AccessArticle

Assessing Renal Outcomes After Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People with HIV: Proteinuria Changes and Limits of Causal Attribution

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

Diseases 2026, 14(10), 353; https://doi.org/10.3390/diseases14100353 - 24 Sep 2026

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Topic HIV Prevention and Treatment: A Guide to Health and Safety)

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17 pages, 4239 KB

Open AccessArticle

Association of DNA Copy Number Aberrations with Organ-Specific Metastasis in Luminal B HER2-Negative Breast Cancer

by Marina K. Ibragimova, Matvey M. Tsyganov, Arina K. Shagabudinova, Irina A. Tsydenova, Maxim A. Morozovsky and Nikolai V. Litviakov

Diseases 2026, 14(10), 352; https://doi.org/10.3390/diseases14100352 - 23 Sep 2026

Abstract

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, [...] Read more.

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 CytoScan^TM 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. Full article

(This article belongs to the Section Oncology)

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