Diseases doi: 10.3390/diseases14050171

Authors: Mălina-Andreea Apostol Simona Trifu Andrei-Gabriel Zanfir Amelia-Damiana Trifu

Objective: We examined the psychological mechanisms underlying cyberchondria by testing whether rumination mediates the association between intolerance of uncertainty and cyberchondria and whether this indirect effect is moderated by prior medical experiences and perceived access to healthcare. Methods and Measures: A cross-sectional design was employed with a non-clinical sample of 96 Romanian adults. Participants completed validated self-report measures of intolerance of uncertainty (IUS-12), rumination (Ruminative Responses Scale), and cyberchondria (Cyberchondria Severity Scale). Additional items assessed medical history and perceived access to healthcare. Moderated mediation analyses with bootstrapped confidence intervals were conducted, controlling for relevant sociodemographic variables. Results: Higher intolerance of uncertainty was associated with higher cyberchondria both directly and indirectly through rumination, which accounted for more than half of the total effect. The rumination–cyberchondria association, and the indirect effect of IU, were significantly stronger among individuals who had experienced a recent acute medical episode, whereas chronic illness did not significantly moderate this pathway. Cyberchondria levels were lowest among participants reporting very good access to healthcare. Conclusions: Cyberchondria appears to arise from the interaction of intolerance of uncertainty, ruminative thinking, and contextual health experiences. Targeting rumination and uncertainty tolerance may be particularly important following acute medical events.

Diseases doi: 10.3390/diseases14050170

Authors: Mouhamad J. Darwich Dalal Ksair Zein Adra Rafaela-Yomn Naji Bushra Sayed Rihab Nasr Zeina Dassouki

Background/Objectives: Cancer patterns in low-resource and crisis-affected settings are poorly characterized, particularly among socioeconomically vulnerable populations. This study aimed to describe cancer distribution, age at diagnosis, and barriers to care among patients presenting to a non-governmental organization (NGO) in Tripoli, Lebanon. Methods: We conducted a retrospective analysis of patients with histopathologically confirmed cancers presenting to a single NGO. Sociodemographic, clinical, and behavioral data were extracted from medical records. Socioeconomic status (SES) was assessed using a validated composite scale. Age-standardized proportions (ASPs) were calculated using GLOBOCAN and WHO standard weights. Barriers to care were categorized into financial, geographic, system-level, and sociocultural domains. Associations were assessed using chi-square tests and regression models. Results: Breast cancer was the most common malignancy (32.0%), followed by colorectal (CRC: 9.8%). A total of 440 patients were included. Colorectal cancer (CRC) was the second-most common malignancy, with 37% of cases occurring before age 50. Breast cancer accounted for nearly half of female cancers. Smoking-related malignancies, particularly bladder and lung cancers, were prominent. Sex differences were cancer-specific, with male sex associated with bladder cancer but not overall cancer distribution. Barriers to care were highly prevalent: 97.3% reported at least one financial barrier, 95.4% system-level barriers, and 72.4% geographic barriers. Low SES was significantly associated with geographic barriers (p < 0.001). Conclusions: Cancer patterns in this vulnerable population are characterized by early-onset disease, a high burden of smoking-related cancers, and pervasive barriers to care. These findings highlight the importance of integrating SES and access-related variables into cancer surveillance systems and support the development of targeted, equity-focused interventions.

Diseases doi: 10.3390/diseases14050169

Authors: Juliana Guarize Claudia Bardoni Cristina Diotti Stefano Maria Donghi Luca Bertolaccini

Background. Robotic-assisted bronchoscopy with the ION™ Endoluminal System facilitates precise access to peripheral pulmonary lesions. However, procedural duration and diagnostic performance remain influenced by patient and lesion-specific factors. To investigate the impact of lesion diameter, radiological appearance, and presence of bronchial signs on procedural duration and diagnostic yield using conventional regression and gradient boosting machine learning models. Methods. In this single-center retrospective cohort study, 189 ION™ Endoluminal System procedures (November 2024–June 2025) were analyzed. Procedural duration and diagnostic yield served as primary outcomes. Predictive modeling included multivariable regression and gradient boosting. Feature importance metrics were extracted. Results. The median lesion diameter was 12.3 mm, with a “strict” diagnostic yield of 87.3%. Gradient boosting regression identified lesion diameter as the primary predictor of procedural time (89.2% importance; test MSE = 865.6). Diagnostic classification achieved an ROC-AUC of 0.68, with lesion diameter (85.8%) and bronchial sign (14.2%) as key predictors. Conclusions. Lesion diameter emerged as the most consistent predictor of procedural efficiency and was associated with diagnostic performance, albeit within the limitations of the dataset. Broader datasets are needed for external validation and generalizability.

Diseases doi: 10.3390/diseases14050168

Authors: Nicholas G. Norwitz David Feldman Adrian Soto-Mota

Background: While reducing LDL cholesterol (LDL-C) remains central focuses of conventional preventive cardiology, substantial heterogeneity exists in the cardiovascular risk associated with even extreme LDL-C elevations, likely depending heavily on the broader metabolic context. Specifically, the lean mass hyper-responder (LMHR) phenotype—characterized by markedly elevated LDL-C with elevated high-density lipoprotein cholesterol (HDL-C) and low triglycerides in the setting of a ketogenic diet—has recently been described, though its long-term risk profile remains poorly defined. Case Presentation: We describe a male in his 30s without any congenital dyslipidemia who adopted a ketogenic diet for the management of ulcerative colitis and who subsequently exhibited a sixfold increase in LDL-C from a baseline of 95 mg/dL to 574 mg/dL, with total cholesterol of up to 705 mg/dL, HDL-C at 124 mg/dL, and triglycerides at 34 mg/dL. Despite maintaining these extreme lipid levels for nearly seven years, he demonstrated no coronary plaque or stenosis on coronary computed tomography angiography (CCTA; CAD-RADS = 0). Additionally, quantification of coronary plaque as assessed by AI-guided quantified analysis by Heartflow® identified 0 mm3 plaque in any vessels, placing him in the lowest percentile for atherosclerotic plaque. Conclusions: This case represents an extreme and extensively characterized example of the LMHR phenotype and highlights the limitations of extrapolating cardiovascular risk from LDL-C levels alone without consideration of broader patient context and the etiology of hypercholesterolemia. While a single case cannot redefine clinical practice, this well-characterized case is consistent with emergent literature on LMHR, and careful study of such individuals may provide valuable insights into lipid metabolism, atherosclerosis biology, and precision cardiovascular risk assessment.

Diseases doi: 10.3390/diseases14050167

Authors: Lavinia-Alexandra Moroianu Cecilia Curis Valeriu Ardeleanu Roxana Elena Bogdan-Goroftei Simona-Dana Mitincu-Caramfil Marius Moroianu Alina Pleșea-Condratovici

Background/Objectives: Evidence linking vitamins D and B12 to psychiatric outcomes remains heterogeneous across designs, populations, phenotypes, exposures, and outcome formats. Methods: We conducted a PRISMA 2020 systematic review and exploratory meta-analysis of nutrient-specific status and supplementation evidence. PubMed/MEDLINE, APA PsycInfo, Cochrane Library, Google Scholar, ClinicalTrials.gov, and ProQuest were searched for human studies published in 2016–2025, with a final update on 1 March 2026. Forty-six studies were included (24 randomized controlled trials, 22 observational studies; N = 69,902), and 44 contributed quantitative data. Effects were harmonized to odds ratios (ORs) for cross-family comparability and pooled using Hartung–Knapp random-effects models; supplementation evidence was additionally interpreted on the standardized mean difference (SMD) scale. Results: Across the main evidence families, pooled estimates showed substantial heterogeneity and limited generalizability. Vitamin D supplementation showed an initial inverse estimate on the secondary harmonized OR scale (OR = 0.439, 95% CI 0.272–0.710) and a clinically interpretable SMD of −0.454 (95% CI −0.718 to −0.189), but heterogeneity was high (I2 = 84.2%) and trim-and-fill attenuated the OR estimate to the null (OR = 0.88, 95% CI 0.48–1.63). Vitamin D status showed a similar pattern (primary OR = 0.615, 95% CI 0.424–0.890; trim-and-fill OR = 0.90, 95% CI 0.54–1.49). Vitamin B12 status was inversely associated with outcomes (OR = 0.310, 95% CI 0.115–0.834), but heterogeneity was extreme (I2 = 94.8%). B12 supplementation evidence was sparse and null. Conclusions: The evidence supports targeted deficiency assessment, not routine supplementation.

Diseases doi: 10.3390/diseases14050166

Authors: Ruzica Kravljanac Kristel Klaassen Vladimir Oparnica Biljana Vucetic Tadic Marina Andjelkovic Anita Skakic Sara Stankovic Maja Stojiljkovic

Alternating hemiplegia of childhood (AHC) represents a severe and complex pediatric neurodevelopmental disorder, predominantly characterized by the occurrence of paroxysmal episodes of transient unilateral or bilateral paresis prior to 18 months of age. It belongs to a group of ultra-rare neurological disorders with a prevalence from 1:100,000 to 1:1,000,000. Even though the majority of AHC patients harbor pathogenic variants in the ATP1A3 gene, recent studies have pinpointed to other causative genes in ATP1A3-negative patients, including RHOBTB2. In this review, we report the case of a patient with a severe phenotype of AHC associated with developmental delay, aphasia and epilepsy, caused by a pathogenic de novo variant in the RHOBTB2 gene. Furthermore, we contribute a literature review on ATP1A3-negative AHC with a special focus on RHOBTB2-related AHC phenotypes, along with an overview of the pathophysiological mechanism of variants affecting residues in the BTB domain of the RHOBTB2 protein. The results of our study indicate that RHOBTB2-related AHC might have a more severe clinical presentation compared to ATP1A3-related AHC. Variants in the RHOBTB2 gene should be considered as disease-causing in patients with early-onset seizures, delayed psychomotor development and alternating hemiplegia of childhood.

Diseases doi: 10.3390/diseases14050165

Authors: Alina Dumitrache (Păunescu) Nicoleta Anca Ionescu (Șuțan) Liliana Cristina Soare Maria Cristina Ponepal Ana Cătălina Țânțu Monica Marilena Țânțu Ileana Monica Baniță Cătălina Gabriela Pisoschi

Background: Chronic hepatitis B and C remain major causes of progressive liver disease, while HBV–HCV coinfection is associated with accelerated fibrosis and hepatocellular injury. Methods: This study evaluated integrated biochemical, histopathological, and immunohistochemical features in patients with chronic hepatitis B (CHB, n = 29), chronic hepatitis C (CHC, n = 15), and CHB+C coinfection (CHB+C, n = 10). Liver biopsies were assessed using Ishak and METAVIR scoring systems, alongside immunohistochemical analysis of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), CD5L, and glial fibrillary acidic protein (GFAP), quantified by H-score. These findings were correlated with biochemical, hematological, and prognostic parameters. Results: Coinfected patients exhibited significantly higher serum ALT, AST, and GGT levels (p ≤ 0.011) and increased CD5L expression (median H-score 197.5 vs. 135 in CHB, p = 0.009), indicating enhanced macrophage-associated inflammatory activity. Although fibrosis stages were comparable across groups, median H-scores for α-SMA, TGF-β1, and GFAP showed a consistent upward trend in CHB+C, suggesting intensified profibrogenic signaling. Principal Component Analysis identified distinct biochemical clusters related to hepatocellular injury, hepatic functional impairment (synthetic and excretory axis), and lipid metabolism. Conclusions: These findings highlight a multidimensional pattern of liver injury in chronic viral hepatitis, with CHB+C coinfection amplifying profibrogenic and hepatocellular markers, both biochemically and histologically.

Diseases doi: 10.3390/diseases14050164

Authors: Maryline Vere Wilma ten Ham-Baloyi Lucy Ochola Opeoluwa Oyedele Lindsey Beyleveld Siphokazi Tili Takafira Mduluza Paula Melariri

Background/Objectives: Intestinal schistosomiasis caused by Schistosoma mansoni is often underestimated in low-transmission settings due to the limited sensitivity of traditional stool microscopy. More sensitive approaches, including antigen detection and molecular diagnostics, are required to detect infections where egg excretion is low or intermittent. This study aimed to determine the prevalence of S. mansoni infection among school-going children in Nelson Mandela Bay (NMB) using a multi-modal diagnostic approach. Methods: This cross-sectional study included 759 schoolchildren aged 5–14 years from 15 primary schools in NMB. Stool samples were analyzed using the Kato–Katz technique to detect S. mansoni eggs, while urine samples were tested using the point-of-care circulating cathodic antigen (POC-CCA) assay for antigen detection. A subset of stool samples from POC-CCA-positive participants (n = 28) was further analyzed using conventional PCR (cPCR), targeting the S. mansoni cox1 gene, for molecular confirmation. Only a single stool specimen was collected per participant. Results: Among the 759 participants (58% male, 42% female), no egg-positive cases were detected. However, POC-CCA testing identified S. mansoni antigen in 3.2% of participants. Of the 28 POC-CCA-positive samples analyzed by cPCR, 9 (32.1%) were PCR-positive, representing molecular confirmation within the antigen-positive subset rather than overall prevalence. Conclusions: Traditional microscopy underestimated S. mansoni prevalence in this low-prevalence setting. Antigen detection combined with molecular diagnostics improved case identification and highlighted ongoing transmission. These findings support the integration of sensitive diagnostic tools into schistosomiasis surveillance and control strategies in South Africa.

Diseases doi: 10.3390/diseases14050163

Authors: Somia A. Nassar

Objectives: This cross-sectional study examined associations of lifestyle factors (physical activity (PA), diet, obesity, and smoking), age groups, and sex with the prevalence of non-communicable diseases (NCDs) in Saudi adults, including the World Health Organization (WHO) core NCDs (type 2 diabetes (T2DM), hypertension (HTN), chronic obstructive pulmonary disease (COPD) and NCD-associated conditions (osteoporosis (OP), chronic kidney disease (CKD)). Methods: A cross-sectional study was conducted across Saudi Arabia involving 2877 participants aged ≥30 years. Data were collected via an electronic survey using a standardized questionnaire. PA was assessed using the International PA Questionnaire (IPAQ-SF), diet using the Alternative Healthy Eating Index (AHEI), and smoking using the WHO Global Adult Tobacco Survey. Results: Prevalence estimates were: OP 22%, diabetes 21.8%, HTN 13.4%, COPD 4.3%, and CKD 5.1%. All conditions were more prevalent among inactive vs. active individuals (e.g., diabetes: 23.5% vs. 18.8%). An unhealthy diet was associated with higher prevalence (e.g., HTN: 16.3% vs. 10.8%). Obesity showed the strongest association with diabetes (37.1% in obese vs. 14.9% in normal-weight). Smoking was associated with higher prevalence (e.g., COPD: 7.9% vs. 3.7%). Women had higher prevalence than men for most conditions (e.g., OP: 23.4% vs. 19.7%), except COPD (5.1% in men vs. 3.8% in women). Prevalence increased with age (e.g., HTN: 7.2% at age 30–40 vs. 17.3% at age > 60). All comparisons were tested using chi-square tests (p < 0.05). Conclusions: The findings underscore an urgent need for targeted public health interventions to promote PA, improve nutrition, combat obesity, and reduce smoking.

Diseases doi: 10.3390/diseases14050162

Authors: Fleischer C. N. Kotey Reuben E. Arhin Nicholas T. K. D. Dayie Emmanuel O. Ampah Abass Abdul-Karim Deric A. Baah Ruth M. Afful Georgina Tetteh-Ocloo Roland T. Kom-Zuta Francis K. M. Tetteh Mary-Magdalene Osei Yvonne N. A. Brew Mame Y. Nyarko Karikari Asafo-Adjei Patience B. Tetteh-Quarcoo Edem M. A. Tette Eric S. Donkor

Background: Streptococcus pneumoniae, also referred to as pneumococcus, is of immense public health significance. In particular, it causes severe invasive diseases among children. This has led to the recommendation of anti-pneumococcal prophylaxis, including the administration of penicillin and pneumococcal conjugate vaccines (PCVs), which have become available in about 90% of the countries in sub-Saharan Africa. Nonetheless, breakthrough disease still occurs. Also, PCVs can cause a shift in the distribution of pneumococcal serotypes, usually towards non-vaccine types. However, in many sub-Saharan African countries where PCVs have been introduced, there are hardly any comprehensive post-vaccination surveillance data on pneumococcus. Aim: To describe the post-vaccination epidemiology of invasive pneumococcal disease (IPD) in Ghana, including the prevalence, serotype distribution and antibiotic resistance. Methods: The study was cross-sectional and involved 14,597 patients recruited at the Korle Bu Teaching Hospital, Greater Accra Regional Hospital, Princess Marie Louise Children’s Hospital, Ho Regional Hospital, Eastern Regional Hospital, and Zonal Public Health and Reference Laboratory, Tamale. Specimens of cerebrospinal fluid (obtained by lumbar puncture) and blood were collected routinely from meningitis patients, while blood specimens were taken from pneumonia patients. These were cultured for S. pneumoniae following standard microbiological methods and subjected to antimicrobial susceptibility testing. The isolates were serotyped by the pneumotest latex agglutination kit, and the results confirmed by Quellung reaction, using serotype-specific antisera. Results: The overall prevalence of IPD was 0.66% (n = 97), varying across syndromes: bloodstream infections (0.53%, n = 38), meningitis (2.45%, n = 43), and pneumonia (0.28%, n = 16). The majority of the cases (56.70%, n = 55) occurred in the 11–20-year-old group. Ten pneumococcal serotypes were identified, with Serotype 1 being predominant (58.76%), followed by Serotypes 23B (11.34%), 33F (9.28%), and 12F (8.24%). Vaccine serotypes accounted for 81.44% of the isolates, while 18.56% were non-vaccine serotypes (23A, 23B, and 38). Antimicrobial resistance was highest against sulphamethoxazole-trimethoprim (52%), ampicillin (51%), and penicillin (46%). No resistance was observed against ciprofloxacin, levofloxacin, and vancomycin. The multidrug resistance proportion was 42.3% (n = 41). Conclusions: Even in the post-vaccination era, vaccine-type IPD remains a significant public health issue in Ghana. The observed serotype distribution and antimicrobial resistance patterns warrant sustained surveillance, more adaptive vaccination policies, and rigorous antibiotic stewardship to effectively mitigate IPD burden.

Diseases doi: 10.3390/diseases14050161

Authors: Mirjana Milinkovic Marija Milovanovic Jelena Milovanovic

Background/Objectives: Acute intravascular hemolysis is associated with the release of labile heme, which contributes to systemic inflammation and organ dysfunction. Galectin-3 (Gal-3) is a known modulator of inflammatory responses. However, its specific role in heme-induced organ injury remains to be fully elucidated. Methods: We used a phenylhydrazine (PHZ)-induced model of acute hemolysis in wild-type (WT) and Gal-3 knockout (KO) mice to investigate the influence of Gal-3 on tissue alterations and the inflammatory response. Results: Despite equivalent levels of hemolysis and anemia in both genotypes, Gal-3 deficiency was associated with reduced injury in the liver, kidneys, and pancreas. In WT mice, Gal-3 was associated with a pro-inflammatory splenic microenvironment. Conversely, Gal-3 KO mice exhibited a shift toward an immunoregulatory phenotype, characterized by an increased frequency of CD4 + CD25 + FoxP3+ regulatory T cells and IL-10+ macrophages. This shift correlated with preserved organ architecture and a more controlled inflammatory profile. Conclusions: Our findings suggest that Gal-3 may act as a mediator of heme-induced systemic inflammation. By influencing the splenic immune microenvironment and promoting a regulatory phenotype, the absence of Gal-3 appears to alleviate multi-organ stress, suggesting its potential as a target for modulating complications during acute hemolytic crises.

Diseases doi: 10.3390/diseases14050160

Authors: Dragoș Puia Marius Ivănuță Ovidiu Daniel Bîcă Nicolae Stoican Mihaela Corlade-Andrei Bogdan Doroftei Cătălin Pricop

Background: Renal abscesses represent a serious complication of urinary tract infections, with management decisions often being guided by abscess size and clinical parameters. However, there is no universally accepted size threshold for intervention, and the role of inflammatory markers such as white blood cell count (WBC) and C-reactive protein (CRP) in guiding treatment remains uncertain. We aimed to evaluate the relationship between abscess size, inflammatory markers, and the need for drainage in patients with renal abscesses treated in a tertiary urology clinic. Methods: A retrospective analysis was conducted on 103 adult patients diagnosed with renal abscesses between 2020 and 2025. Patients were categorized into two groups based on abscess size: Group A (<50 mm) and Group B (50 mm). Results: The cohort included 59 females and 44 males, with a mean age of 60.5 years. Computed tomography was used for diagnosis in 55.3% of cases. The most common comorbidities were hypertension (46.6%) and diabetes mellitus (40.8%). Microbiological cultures most frequently identified Escherichia coli (38.3%) and Klebsiella spp. (21.7%). Antibiotic resistance was highest to ampicillin (79.5%), while amikacin (5.8%) and piperacillin/tazobactam (6.2%) showed the lowest resistance rates. Conservative antibiotic therapy was effective in 43 patients (42.7%), whereas 60 patients (58.3%) required percutaneous drainage. Abscess size was associated with invasive intervention, with 88.1% of drained abscesses measuring ≥50 mm compared to 9.1% in the conservatively managed group (p < 0.001). Patients with larger abscesses had significantly lower haemoglobin levels (p = 0.003), while no significant differences were observed in WBC or CRP levels. Conclusions: Abscess size was associated with the need for drainage, supporting its role in clinical decision-making. In contrast, inflammatory markers such as WBC and CRP showed limited value in predicting the need for intervention in this cohort. These findings should be interpreted in the context of the retrospective design.

Diseases doi: 10.3390/diseases14050159

Authors: Isabel Gloor Beatrice Meier Jehona Rexhai Philip Heesen Georg Schelling Bettina Vogel Gabriela Studer Bruno Fuchs on behalf of the Swiss Sarcoma Network on behalf of the Swiss Sarcoma Network

Background: Value-based sarcoma care requires outcome measures that reflect the patient perspective; however, many sarcoma episodes begin with near-normal function and undergo necessary morbidity for oncologic control, making simple “improvement” an unreliable proxy of value. In routine care, patient-reported outcome data are often irregular and incomplete, limiting benchmarking and learning across institutions. We therefore developed a rule-based EQ-5D-5L (index and VAS) traffic-light framework and evaluated its feasibility and benchmarking signal in two institutions. Methods: We performed a retrospective, two-institution cohort analysis of 729 malignant and intermediate episodes, defined using a prespecified histology behavior mapping. PROM evaluation was anchored to a hierarchical T0 (index surgery date; if unavailable, radiotherapy start date; if unavailable, systemic therapy start date where a valid and interpretable start date was available). EQ-5D-5L index and EQ-VAS were assigned to prespecified locked windows: baseline (−90 to +14 days preferred; +15 to +90 days fallback), 12 months (180–365 days; target 270), and 24 months (660–820 days; target 730). A rule-based traffic-light classification was applied at 12 and 24 months (RED if index < 0.75 or VAS < 50; GREEN if index ≥ 0.85 and VAS ≥ 70; otherwise YELLOW). PROM evaluability was defined as the availability of at least one valid EQ-5D-5L index and/or EQ-VAS value within each window. Results: PROM evaluability in locked windows was feasible but incomplete. Baseline PROMs were available for 107/729 episodes (14.7%), 12-month PROMs for 119/729 (16.3%), and 24-month PROMs for 84/729 (11.5%). At 12 months, evaluable episodes included 75 from Institution A and 44 from Institution B; at 24 months, 56 and 28, respectively. Traffic-light outputs showed heterogeneity at both timepoints and clearer cross-institution difference at 24 months than at 12 months. At 12 months, the distribution was predominantly GREEN in both institutions (Institution A: 73.3% GREEN, 9.3% YELLOW, 17.3% RED; Institution B: 65.9% GREEN, 18.2% YELLOW, 15.9% RED; p = 0.373). At 24 months, Institution A maintained a high GREEN proportion with a low RED fraction (76.8% GREEN, 17.9% YELLOW, 5.4% RED), whereas Institution B showed a lower GREEN proportion and higher YELLOW/RED fractions (50.0% GREEN, 25.0% YELLOW, 25.0% RED; p = 0.014). Absolute EQ-5D-5L medians remained high overall, but the follow-up distributions showed a broader lower tail in Institution B. Conclusions: A prespecified EQ-5D-5L (index and VAS) traffic-light framework anchored by hierarchical T0 and evaluated in locked windows yields interpretable patient-perspective benchmarking signals in real-world sarcoma care. The approach was operationally feasible within the evaluable subset and appeared more discriminative at 24 months than at 12 months, while incomplete PROM capture remains a major implementation limitation for representative and reliable network-scale benchmarking and learning.

Diseases doi: 10.3390/diseases14050158

Authors: Shinsuke Imaoka Shohei Minata Taisuke Teroh Kotaro Matsuki Ryotaro Hiramatsu

Background/Objectives: Understanding the available interventions and circumstances under which physical therapy is administered to patients with diabetic foot ulcers is important to provide more evidence regarding physical therapy and associated outcomes in this population. This study aimed to investigate the scope, nature, and extent of literature on physical therapy interventions for adults with diabetic foot ulcers. Methods: Articles on physiotherapy interventions for adults with diabetic foot ulcers published up to 30 June 2024 were included. Relevant articles were identified through searches of PubMed, Scopus, MEDLINE, and the Cochrane Library databases. Opinion articles, study protocols, meeting abstracts, and articles that did not describe physical therapy interventions were excluded. Results: The systematic search identified 13 articles that met the inclusion criteria. Eleven of the 13 articles were specifically related to outpatient physical therapy. Outpatient physiotherapy included unloading gait instruction, ankle stretching instruction, progressive resistance training, and aerobic exercise. In two other cases, exercise instructions were practiced in the early postoperative period of the wound during the hospitalization period. A multidisciplinary approach aimed at improving postoperative activities of daily living was included. The main efficacy indices were the wound reduction rate, plantar pressure reduction, hemodynamics, ankle joint range of motion, walking ability, and other physical function-related parameters. Conclusions: Physiotherapy during outpatient follow-up may contribute to preventing wound deterioration and maintaining physical function in patients with stable DFUs. However, standardized protocols regarding intervention timing, exercise intensity, and wound severity remain unestablished, and interventions should be applied cautiously based on individual clinical conditions.

Diseases doi: 10.3390/diseases14050157

Authors: Oana Mariana Mihailov Loredana Stavăr Matei George Țocu Valerii Luțenco Cosmin George Popovici Raul Mihailov

Background: Tuberculosis (TB) in children is associated not only with infectious burden but also with potential psychological distress, which remains insufficiently explored. The aim of this study was to evaluate the pattern and evolution of depressive symptoms in pediatric TB patients during treatment using a structured screening approach. Methods: We conducted a retrospective observational study including 190 pediatric patients aged 7–18 years diagnosed with tuberculosis between 2019 and 2021. Depressive symptoms were assessed at two time points, namely at diagnosis (T0) and at first follow-up (T1), using a 10-item structured clinical screening tool routinely applied in practice. A threshold of ≥50% affirmative responses was used to identify patients with suspected depressive symptoms. The Children’s Depression Inventory (CDI) was administered to patients with positive screening results, according to standard clinical protocols. Descriptive and comparative analyses were performed to evaluate changes over time. Results: A high proportion of patients screened positive for depressive symptoms at baseline (T0). At follow-up (T1), a reduction in the proportion of patients with suspected depressive symptoms was observed; however, a substantial number of patients continued to report symptoms suggestive of emotional distress. Most symptom changes between T0 and T1 were not statistically significant, with the exception of decreased appetite, which showed a modest improvement. The overall pattern suggests persistence of symptoms in a subset of patients over time. Conclusions: These findings suggest that symptoms indicative of psychological distress are common among pediatric TB patients and may persist during treatment. However, given the use of a non-validated screening tool and the retrospective design, the results should be interpreted with caution. The study highlights the potential value of systematic psychological assessment in this population and supports the need for further research using validated instruments.

Diseases doi: 10.3390/diseases14050156

Authors: Haticegul Tuncer Sevinj Hajiyeva Betul Gungor Serin Muhammed Onur Atakul Ali Can Gunes Taylan Onat Utku Akgor Derman Basaran Zafer Selcuk Tuncer Murat Gultekin

Background/Objectives: Non-ablative local therapies are increasingly used in the conservative management of human papillomavirus (HPV) infection. Coriolus versicolor, an immunomodulatory medicinal mushroom, is one such approach. This study aimed to investigate the effect of a Coriolus versicolor–based vaginal gel on HPV clearance and cervical cytological outcomes. Methods: This retrospective cohort study included 600 women with cervical HPV infection (300 treated with a Coriolus versicolor–based vaginal gel and 300 receiving standard follow-up). Baseline and six-month follow-up assessments included HPV DNA testing and cervical cytology. Results: Baseline demographic characteristics, HPV genotype distribution, infection type, and cytological findings were comparable between the groups. Overall HPV clearance was significantly higher in the treatment group than in the controls (89.3% vs. 44.7%, p < 0.001). Complete clearance of high-risk HPV genotypes, including HPV 16 (77.0% vs. 25.4%, p < 0.001) and HPV 18 (73.9% vs. 18.5%, p = 0.017), was also significantly more frequent among treated women. Cytological normalization occurred more often in the treatment group (88.4% vs. 60.4%, p < 0.001). Multivariable analysis identified use of the vaginal gel as the strongest independent factor associated with HPV clearance (adjusted odds ratio [aOR] = 10.19; 95% confidence interval [CI]: 3.52–29.47; p < 0.001). Conclusions: Treatment with a Coriolus versicolor–based vaginal gel was associated with significantly higher rates of high-risk HPV clearance and cervical cytological normalization. These findings suggest that this therapy may represent an effective adjunct in the conservative management of HPV infection; however, randomized controlled trials are warranted to confirm these results.

Diseases doi: 10.3390/diseases14050155

Authors: Jorge Soria-Cruz Enrique Luna-Ramírez Iván Castillo-Zúñiga Jaime Iván López-Veyna Ma. Angélica Estrada-Ramírez Juan Antonio González-Morales

Background: Dengue fever remains a major public health challenge in Mexico, exhibiting pronounced seasonal behavior and substantial geographic heterogeneity. Using recent epidemiological surveillance data may improve predictive performance and better reflect the current epidemiological context. Objective: The aim of this study was to develop and compare temporal machine learning models for the binary classification of confirmed and negative dengue cases in Mexico using 2025 national surveillance data. Methods: A total of 68,222 suspected dengue cases reported in 2025 were analyzed. The outcome variable was CASE_STATUS, encoded as 0 for negative cases and 1 for confirmed cases. The dataset was divided chronologically into training (January–September), validation (October), and testing (November–December) subsets. Nine machine learning algorithms were evaluated: Random Forest, Bayesian Network, XGBoost, CatBoost, Naïve Bayes, Logistic Regression, Multilayer Perceptron, Support Vector Machine, and LightGBM. Preprocessing included scaling, encoding, age discretization for Bayesian Network, class imbalance treatment, and model-specific feature-importance analyses. Performance was assessed using accuracy, Precision, Recall, F1-score, ROC-AUC, and PR-AUC. Results: Random Forest achieved the best overall performance, with the highest test F1-score (0.7254) and PR-AUC (0.7300) at an optimized threshold of 0.397, together with a high Recall (0.8938). Bayesian Network achieved the highest test accuracy (0.7023) and ROC-AUC (0.7756), although its overall operational balance was less favorable considering class imbalance. Geographic and institutional variables were the most influential predictors across models, whereas comorbidities generally contributed less. Conclusions: Temporal machine learning models are useful for dengue case classification in Mexico, and Random Forest was the most robust approach, balancing sensitivity and overall predictive performance. From an operational perspective, this finding is especially relevant in dengue surveillance, where failure to identify true confirmed cases may have important public health consequences.

Diseases doi: 10.3390/diseases14050154

Authors: Raúl Gómez-Mendoza Eva Juárez-Hernández Vicente Toledo-Coronado César A. Tenorio-Aparicio Javier Sánchez-Zavala Misael Uribe Graciela Castro-Narro Iván López-Méndez

Background/Objectives: In the last decade, the prevalence of metabolic-associated fatty liver disease (17–46%) and non-alcoholic fatty pancreas disease (NAFPD) (16–33%) has increased due to their association with obesity, both predictors of early atherosclerosis and metabolic risk. Computed tomography (CT) has been proposed as a diagnostic method. Currently, the factors associated with NAFPD have not been fully described. The aim of this study is to describe the prevalence and association of NAFPD and liver steatosis in patients with very high cardiovascular risk. Methods: A retrospective evaluation was conducted on the medical records of patients classified as very high cardiovascular risk who had undergone a CT scan. NAFPD was determined by the difference in pancreatic and splenic attenuation (−1.9), while liver steatosis was identified by hepatic attenuation <40. Bivariate and multivariate analyses were performed to determine the independent factors associated with NAFPD. Results: 169 medical records were collected; 68.6% (n = 116) were men, with a median age of 70 [IQR 61–78] years and 25.8 [IQR 23.7–28.7] kg/m2 of body mass index. According to the CT scans, 80.5% (n = 136) presented NAFPD, 24.3% (n = 41) had liver steatosis, and 21.3% (n = 36) had both. In the multivariate analysis, liver steatosis, abnormal levels of aspartate aminotransferase, and being overweight were independent factors associated with NAFPD. Conclusions: In a very high cardiovascular-risk population, the prevalence of NAFPD is high, and it is independently associated with the presence of liver steatosis.

Diseases doi: 10.3390/diseases14050153

Authors: Teresa Smit Ronald Anderson Helen C. Steel Theresa M. Rossouw Bernardo L. Rapoport

Background/objectives: Although informative, current insights into the inflammatory nature of colorectal cancer (CRC) have yet to have a meaningful impact on the prevention of, and development of novel therapies for, the treatment of this prevalent and challenging disease. Accordingly, the current study was focused on identifying putative, key, systemic, mostly pro-inflammatory biomarkers of metastatic CRC (mCRC) prognosis and outcome. Methods: Patients with mCRC (n = 38) and matched healthy controls (n = 30) were recruited to the study. A multiplex magnetic bead array system and an ELISA procedure were used to measure the plasma concentrations of selected cytokines (n = 25) and that of C-reactive protein (CRP) by immunonephelometry. Systemic inflammatory indices (n = 5) were derived from the hematological data. Results: Plasma levels of 17/25 of the cytokine biomarkers and CRP were found to be significantly elevated, while the neutrophil/lymphocyte ratio proved to be the most useful of the various inflammatory indices. Subgroup analysis of the data derived from the group of mCRC patients revealed that the intensity of the systemic inflammatory response was mostly unaffected by tumor location, age, gender, and treatment line. The exception was time to progression, with a shorter time (<120 days) being associated with increased levels of IL-6, IL-8 and TNF-α. Hierarchical cluster analysis of the data revealed a possible association with a small group of four cytokines, comprising IL-1β, IL-13, IL-6/CRP and TGF-β1. Conclusions: This study confirms a strong association of established mCRC with cytokine-driven systemic inflammation. Four of these cytokines, IL-1β/IL-13 IL-6/CRP, and TGF-β1, appear prominent and are possibly indicative of novel targetable therapeutic options.

Diseases doi: 10.3390/diseases14050152

Authors: Muhammad Dahshan Hassan Dahshan Ayhan Basoglu Huseyin Kadikoy

Background/Objectives: Hepatic diseases frequently present with ocular manifestations that aid diagnosis, provide prognostic data, and guide therapy. Despite the clear utility of the liver–eye axis, the literature lacks reviews that categorize these manifestations by etiology. This review evaluates current evidence to identify ocular findings that serve as clinical tools for diagnosis, prognosis, and therapeutic monitoring of hepatic pathologies. Methods: A narrative review was conducted using PubMed and Google Scholar to identify English-language articles addressing ocular manifestations associated with liver disease. The primary search encompassed publications from 2000 to 2025, with inclusion of select foundational works published prior to 2000 when they represented seminal studies establishing diagnostic criteria, pathophysiological mechanisms, or natural history data not superseded by subsequent research. Search terms included combinations of liver, hepatic, hepatitis, cirrhosis, cholestasis, eye, ocular, retina, cornea, sclera, conjunctiva, ophthalmic manifestations, and specific disease names. All study designs were eligible. Society guidelines, systematic reviews, and studies from high-impact journals were prioritized. The final selection comprised 59 references representing the most authoritative sources across the spectrum of hepatic conditions. Results: A spectrum of ocular findings linked to distinct hepatic conditions was identified. Manifestations with established clinicopathologic associations were categorized into congenital and acquired etiologies. Congenital liver pathologies included metabolic disorders (Wilson disease, galactosemia, lysosomal storage disorders) and syndromic/genetic causes (Alagille syndrome, hereditary hemochromatosis). Acquired liver diseases encompassed infectious (hepatitis B/C), drug-induced and iatrogenic (interferon, immune checkpoint inhibitors), nutritional (vitamin A deficiency), neoplastic (metastatic hepatocellular carcinoma), and cirrhotic causes. Conclusions: Specific ocular signs raise clinical suspicion for underlying liver disease and warrant targeted hepatic evaluation. Recognizing these associations facilitates earlier diagnosis and improves outcomes. Systematic screening for these signs is supported in at-risk populations, and prospective validation studies should establish their sensitivity and specificity.

Diseases doi: 10.3390/diseases14050151

Authors: Luca Pecoraro Ilenia Chillura Agnese Bigioni Maria Maddalena Quarta Emiliano Altavilla Enrico Rosati Flavia Indrio

Kidney development in the first 1000 days of life is vulnerable to numerous prenatal, perinatal, and congenital factors. This review aims to analyze the main determinants of early kidney development and to highlight the role of pediatricians in identifying at-risk infants and implementing preventive strategies to reduce the risk of chronic kidney disease (CKD). For at-risk newborns, early assessment of kidney size and function is essential for the timely detection of functional decline. Key risk factors include prenatal exposures, perinatal complications, genetic conditions, and postnatal factors. Early, tailored nephrological follow-up is crucial for preventing CKD and its complications. Determining optimal monitoring intervals through clinical, laboratory, and ultrasound evaluations enables risk stratification, ensuring closer surveillance for the most vulnerable infants during this critical window. This review integrates evidence from experimental, epidemiological, and clinical studies and highlights the importance of early-life interventions in shaping renal health across the lifespan.

Diseases doi: 10.3390/diseases14040150

Authors: Karol Piotr Mirkowski Kalina Aleksandra Hac Zuzanna Kryś Jerzy Leszek

Background: Post-psychotic depression (PPD) is an underestimated but clinically significant affective syndrome that occurs during remission from psychosis, particularly in schizophrenia. Material and Methods: This comprehensive review traces the evolution of this concept over five decades of research, starting from its initial differentiation from primary depression and schizoaffective disorders in the 1970s. Relying on more than thirty studies, we analyze historical definitions, biological and psychosocial mechanisms, diagnostic controversies, and therapeutic implications. Results: Research indicates that PPD develops from multiple contributing factors, including psychological insight, autobiographical disturbances, pharmacological influences, and social losses, rather than simply as a byproduct of psychosis or pharmacological treatment. We discuss the persistence of depressive symptoms after acute remission, their role in suicidal tendencies, and the diagnostic challenges arising from the overlap of negative symptoms and demoralization. Despite its exclusion from current diagnostic standards, PPD continues to affect a significant fraction of patients, particularly those with high insight and early onset. Conclusions: Effective treatment requires a multidimensional, phase-specific approach combining antidepressants, atypical antipsychotics such as lurasidone, and psychological interventions targeting identity, self-esteem, and narrative processing. We argue that PPD should be reintroduced as a distinct clinical unit and incorporated into psychiatric guidelines to reduce diagnostic oversights and improve patient outcomes.

Diseases doi: 10.3390/diseases14040149

Authors: Konstantina Chalakatevaki Georgios Kokkotis Maria Gazouli Stratigoula Sakellariou Ioannis Vamvakaris Alexandros Chatzidakis Gerasimos Gerasimatos Maria Kalogirou Kanellos Koustenis Dimitra Lazou Afroditi Orfanidou Maria Palatianou Evgenia Papathanasiou Andreas Psistakis Christos Sotiropoulos Evaggelia Anagnostopoulou Konstantinos Argyriou Matina-Lydia Chatzinikolaou Kalliopi Foteinogiannopoulou Olga Giouleme Andreas Kapsoritakis Pantelis Karatzas Konstantinos Karmiris Nikolaos Kiriakos Ioannis Koutroubakis Christos Liatsos Aikaterini Mantaka Gerasimos Mantzaris Panagiotis Markopoulos Georgios Michalopoulos Spiros Michopoulos Dimitrios Polymeros Konstantinos Soufleris Georgios Theocharis Angeliki Theodoropoulou Eftychia Tsironi Maria Tzouvala Nikos Viazis Eirini Zacharopoulou Evanthia Zampeli Giorgos Bamias

Background/Objectives: Ustekinumab has been approved for the treatment of moderate to severe ulcerative colitis. Real-world data regarding its efficacy and the discovery of predictive factors of response need to be studied further. We aimed to evaluate the efficacy and identify predictors of response to induction treatment with ustekinumab in patients with ulcerative colitis. Methods: This is a multicenter, prospective cohort study. Clinical response (CR) at week 16 was the primary endpoint, and steroid-free clinical remission (SFCRem) and endoscopic response were the secondary endpoints. Baseline histology, mucosal gene expression, and pharmacokinetics were studied for their effect on response to treatment. Results: We included 123 patients (mean age = 50.3 years). CR was recorded in 70.8% (75/106), SFCRem in 48% (59/123), endoscopic improvement in 71.4% (40/56), and mucosal healing in 28.6% (16/56). Higher PRO-stool frequency (OR = 0.49, p = 0.027), concomitant use of 5-ASA (OR = 3.69, p = 0.021), platelet number of ≥284 × 109/L (OR = 6.52, p = 0.001) at baseline, and a drop in the total count of platelets by 108/L (OR = 1.23, p = 0.022) at week 8 were independently associated with CR. Elevated trough levels of ustekinumab at week 16 were associated with a higher probability of endoscopic improvement (median difference = 3784 ng/mL, p = 0.013), with an optimal cut-off value of 3500 ng/mL (AUC = 0.82, 95% CI: 0.66–0.96). Increased mucosal mRNA expression for IL-23 (p = 0.007) and IL-23R (p = 0.031) at baseline was associated with increased probability of CR. Higher continuous Geboes scores at baseline were associated with a lower probability of CR (OR = 0.80, p = 0.045), with an optimal cut-off value of 14 (AUC = 0.75, 95% CI: 0.57–0.93). Conclusions: Clinical, laboratory, and molecular markers may identify patients with ulcerative colitis who are more likely to respond to ustekinumab.

Diseases doi: 10.3390/diseases14040148

Authors: Marta La Milia Mario Capasso Tommaso Pessarelli Guido Manfredi Arnaldo Amato

Background/Objectives: Despite substantial progress in understanding its pathophysiology and risk factors, gastric cancer remains a significant global health burden. Advances in endoscopic technology have improved the potential for early detection, yet variability in clinical practice persists. In this comprehensive narrative review, we summarize the most recent epidemiological trends in gastric pre-neoplastic and neoplastic lesions and critically appraise current evidence on optimizing endoscopic techniques and strategies for the detection of early gastric neoplasia, with an emphasis on emerging innovations. Methods: The relevant literature on epidemiology, risk factors, pathophysiology, and endoscopic management of GC was selectively reviewed based on the authors’ expertise and appraisal of contemporary evidence. Results: Marked global disparities persist in GC incidence, mortality, and stage at diagnosis. Interval GC—including missed lesions and so-called “true” interval cancers—remains a clinically relevant challenge and is frequently identified at advanced stages. These gaps are partly attributable to inconsistent quality in diagnostic esophagogastroduodenoscopy (EGD). High-quality EGD relies on adequate mucosal inspection time, systematic photodocumentation, optimal gastric preparation, and the use of standardized terminology, including mucosal visibility scores. Routine integration of chromoendoscopy and magnification techniques further enhances detection rates. Looking ahead, artificial intelligence holds promise as a transformative adjunct to standardize and augment real-time lesion recognition and quality assurance. Conclusions: High-quality endoscopic evaluation, coupled with tailored surveillance strategies, enables earlier detection of pre-neoplastic lesions and early gastric cancer, improving clinical outcomes. Future priorities include broadening access to high-quality endoscopy, harmonizing performance standards, and promoting continuous training alongside technological integration.

Diseases doi: 10.3390/diseases14040147

Authors: Irini Gergianaki Foteini Anastasiou Sophia Papadakis Marilena Anastasaki Manolis Linardakis Juan Mendive Leen J. M. Heyens Ger Koek Jean Muris Christos Lionis

Objectives: The objective of this study was to investigate metabolic dysfunction-associated steatotic liver disease (MASLD)-related awareness, health literacy (HL), and illness perception among patients at risk of MASLD in European primary care settings. Methods: Participants aged ≥50 years with either obesity, metabolic syndrome (MetS), or type 2 diabetes mellitus (T2DM), and attending general practices (GPs) in Greece, Spain, or The Netherlands were included in the study. The participants completed surveys to collect data on their socio-demographic characteristics and health habits, including the European Health Literacy Survey (HLS-E-Q16), the Brief Illness Perception Questionnaire [B-IPQ], and the Public Awareness of NAFLD Questionnaire. Results: Overall, 234 patients participated in the study (mean age: 66.5 ± 9.5 years; 45.7% were male). Among the participants, 64.5%, 66.2%, and 59.8% had a diagnosis of diabetes, obesity, and MetS, respectively. Almost one-third (27.9%) had never heard about MASLD or discussed MASLD with their GP. Twelve percent (12.1%) had never heard about cirrhosis, and 20.5% were unaware that liver disorders may cause serious health problems. Overall, 43.6% of the patients had a sufficient level of HL (score >13) with a mean score of 11.5 ± 3.3. Illness perception (B-IPQ score) was low at 41.6 ± 11.6. Significantly higher B-IPQ scores were documented for female compared to male respondents (43.1 vs. 39.8; p < 0.01). Multivariate analysis found that knowledge about MASLD was associated with higher HLS-E-Q16 (p = 0.017) and B-IPQ (p = 0.028) scores. Conclusions: Despite being at risk, a significant proportion of the study participants were unaware of MASLD, its risk factors, and their personal susceptibility. This study underscores the importance of enhancing patient HL and promoting prevention and risk reduction, particularly among high-risk patient populations.

Diseases doi: 10.3390/diseases14040146

Authors: Fabiola Menco Contreras Karina Pastor-Sierra Nany Castilla Herrera

Introduction: Cow’s milk protein allergy (CMPA) is one of the most common food allergies in early infancy and poses important clinical and economic challenges for affected children, their families, and healthcare systems. In Latin America, variability in diagnostic and therapeutic approaches remains substantial. Objective: We aim to systematically review the available evidence on CMPA, with emphasis on clinical characteristics, diagnosis, management, and economic impact, and to provide a complementary cost analysis of specialized formulas in the Colombian context. Methods: A systematic review was conducted according to PRISMA guidelines to synthesize current evidence on CMPA in pediatric populations. Studies published between 2010 and 2023 were screened using predefined eligibility criteria, and 46 studies were included in the qualitative synthesis. A complementary cost analysis was also performed to estimate the six-month costs associated with specialized infant formulas in Colombia, based on average age-specific formula consumption and standardized 2025 market prices. Results: The reviewed evidence confirms that CMPA is a heterogeneous condition with variable clinical manifestations and persistent diagnostic challenges, particularly in non-IgE-mediated presentations. Elimination of cow’s milk protein followed by oral food challenge remains the reference diagnostic approach. Breastfeeding with maternal dairy exclusion is consistently recommended as the preferred first-line strategy, whereas extensively hydrolyzed and amino-acid-based formulas are used when breastfeeding is not feasible or is insufficient. Estimated six-month costs ranged from COP 4,337,640 to COP 14,480,700 (approximately USD 1100–3600), depending on formula type. Conclusions: CMPA requires early recognition, careful clinical evaluation, individualized nutritional management, and improved access to effective and affordable treatment strategies.

Diseases doi: 10.3390/diseases14040145

Authors: Maxim Rantsev Alexey Sarapultsev Valeriy Chereshnev

Background/Objectives: Acute pancreatitis (AP) lacks disease-modifying pharmacotherapy. Neuroimmune, serotonergic, and redox-regulated pathways may modulate inflammatory amplification and acinar injury, although pharmacovigilance data link some psychotropic drug classes to AP risk. This review synthesized controlled rodent studies evaluating neuromodulatory interventions with serotonergic, stress-axis, or ferroptosis-linked targets in experimental AP. Methods: PubMed, Scopus, eLIBRARY.ru, and Elicit were searched in January 2026, supplemented by Google Scholar audit and citation chasing. Eligible studies were controlled in vivo rodent experiments using validated AP models with quantitative outcomes. Intervention timing was classified a priori as a primary analytic variable. Risk of bias was assessed with SYRCLE. A prespecified audit showed that no subset met the criteria for quantitative pooling because of heterogeneity in model class, compounds, timing, outcome definitions, units, and sampling timepoints. Mechanism-stratified qualitative synthesis was therefore performed. The protocol was registered on OSF (doi: 10.17605/OSF.IO/CZXDJ). Results: Nine studies (1992–2023) yielded 410 outcome rows across three mechanistic strands. Serotonergic modulation (5-HT2/5-HT2A-focused; six studies) reduced serum amylase/lipase (−37% to −65% vs. disease controls) and histological injury, with receptor-selectivity data supporting 5-HT2A-mediated mechanisms. Stress-axis modulation with thiadiazine L-17 reduced 7-day mortality in two severe models (from 50–70% to 30%). Olanzapine attenuated ferroptosis-linked injury via off-target antioxidant activity independent of serotonergic receptors. All interventions were prophylactic, peri-induction, or very early post-induction; no delayed therapeutic-window studies were identified. Most SYRCLE domains were unclear, particularly allocation concealment and blinding-related procedures. Conclusions: Neuromodulatory pathways modulate experimental AP in rodents, but evidentiary strength differs across mechanistic strands. Inference is constrained by absent therapeutic-window testing, heterogeneous endpoints, and reporting deficits. The findings support mechanism-level target prioritization rather than clinical repurposing.

Diseases doi: 10.3390/diseases14040144

Authors: Wei Xiong Fei Tang Beck Graefe Ana Raquel Calzada Bichili Duncan Ryan Joseph Bonner Arlette Perry

Background/Objectives: Cardiovascular disease is the leading cause of adult deaths globally and has recently been reported to be on the rise in younger adult women. The present study examined the impact of physical and lifestyle predictors of vascular health in 125 apparently healthy premenopausal East Asian volunteers. Methods: Vascular health outcomes included carotid–femoral pulse wave velocity (cfPWV), central augmentation index (cAIx), and mean arterial pressure (MAP). Body composition/anthropometric predictors included total adiposity, visceral adipose tissue (VAT) and skeletal muscle mass (SMM), as well as body mass index (BMI) and waist circumference (WC). Lifestyle predictors included the International Physical Activity Questionnaire (IPAQ) and dietary recall. Multivariate linear regression was used to identify independent predictors of combined vascular health and individual vascular outcome variables. The analysis for independent vascular outcomes was repeated after age stratification (<35 years versus ≥35 years). Results: VAT showed a significant multivariate effect on combined vascular health outcomes (p = 0.002) and independently contributed to cfPWV (p = 0.013). WC positively predicted cAIx (p = 0.010) while SMM was inversely related to cAIx (p = 0.024). BMI positively predicted MAP (p = 0.039) in the multivariate analysis. After age adjustment however, only BMI emerged as a significant independent predictor of both cfPWV (p = 0.040) and MAP (p = 0.024). Furthermore, WC remained positively associated with cAIx (p = 0.042) while SMM remained inversely related to cAIx (p = 0.038). After age stratification, IPAQ was inversely related to cfPWV while BMI was positively associated with MAP (p = 0.035) in women < 35 years only. However, in older women, total adiposity (p = 0.040) and total cholesterol (p = 0.011) were both positively, while SMM (p = 0.046) was negatively associated with cAIx. Conclusions: With the exception of age, VAT was the single best predictor of general vascular health in East Asian women. Independent of age, however, BMI, WC, and SMM significantly contributed to independent vascular outcome measures and in combination with age, substantially add to the prediction of vascular risk. Furthermore, stratifying younger versus older premenopausal women resulted in different associations with independent vascular outcome measures demonstrating that across a large age range of premenopausal women, it is important to consider age in the evaluation of vascular health.

Diseases doi: 10.3390/diseases14040143

Authors: Mohammad Aljarba Mishari Alanezi Majed A. Alali Azzam Alotaibi Faisal Alkhunein Khalid Alqahtani

Background/Objective: The parotid gland is the largest salivary gland, and tumors arising from it exhibit wide histopathological diversity. Management approaches vary according to tumor characteristics and carry a risk of postoperative complications, particularly facial nerve injury. However, local data remain limited. This study aimed to describe the clinicopathological characteristics, surgical approaches, and postoperative outcomes of patients undergoing parotidectomy. Method: A retrospective cohort study was conducted at a high-volume tertiary center in Saudi Arabia. All consecutive patients who underwent parotidectomy between June 2015 and January 2025 were included. Demographic data, histopathological diagnoses, surgical procedures and postoperative complications were extracted from electronic medical records. Statistical analyses were performed using SPSS version 26, with A p-value of <0.05 considered statistically significant. Results: A total of 154 patients were included, with a mean age of 45.2 ± 12.6 years; 61% were male. Benign lesions constituted 87% of cases, with pleomorphic adenoma being the most common histopathological diagnosis. Malignancies accounted for 13% of cases, most frequently mucoepidermoid carcinoma. The most common postoperative complications were facial nerve palsy, followed by sensory numbness. Conclusions: The majority of parotid gland tumors in this cohort were benign, with pleomorphic adenoma as the most common histological subtype. Facial nerve palsy and sensory disturbances were the most common postoperative complications. These findings provide valuable local data on parotid gland lesions in Saudi Arabia and support current surgical management practices.

Diseases doi: 10.3390/diseases14040142

Authors: Lesly Adelis Valdivia Quispe Lucio Velasco Lopez Daysi Zulema Díaz Obregón Alexis German Murillo Carrasco Joel de León Delgado Luis Lloja Lozano Jhon Wilfredo Pando Mayta Anthony Brayan Rivera Prado Kelly Geraldine Yparraguirre Salcedo Víctor Hugo Carbajal Zegarra Claudio Willbert Ramírez Atencio

Background/Objectives: Chemically induced hepatotoxicity is widely used in experimental research to model liver disease pathophysiology and to support preclinical studies. Thioacetamide (TAA) is a well-established hepatotoxic agent in conventional laboratory rodents; however, its effects in synanthropic rats—characterized by genetic heterogeneity and chronic environmental exposure—remain poorly defined. This study aimed to establish and characterize a preclinical model of TAA-induced hepatotoxicity in synanthropic rats and to assess its relevance for experimental liver disease research. Methods: Female synanthropic rats representing four phenotypic variants (albino, mottled, black, and brown; total n = 132) were housed under controlled conditions and assigned to control or TAA-treated groups. TAA was administered intraperitoneally at doses ranging from 200 to 300 mg/kg. Clinical parameters, including body weight and vital signs, were periodically monitored. Hematological profiles and serum biochemical markers of liver function were analyzed. Hepatic injury was evaluated by histopathological examination using hematoxylin–eosin staining. Statistical analyses were performed using R software, with p ≤ 0.05 considered statistically significant. Results: TAA-treated rats developed consistent clinical manifestations of hepatotoxicity, including progressive weight loss and reduced activity. Biochemical analyses revealed significant increases in serum transaminases, gamma-glutamyl transferase, and alkaline phosphatase, accompanied by alterations in hematological parameters. Histological evaluation demonstrated dose-dependent liver injury characterized by centrilobular necrosis, inflammatory infiltration, hepatocellular degeneration, and architectural disruption across all synanthropic rat variants. Conclusions: Synanthropic rats exhibit reproducible biochemical, hematological, and histopathological features of TAA-induced liver injury comparable to those reported in conventional laboratory strains. This model represents a robust preclinical approach for studying chemically induced hepatotoxicity and may provide enhanced translational relevance due to its genetic and environmental heterogeneity.

Diseases doi: 10.3390/diseases14040141

Authors: Agnessa Kozak Jana Wischnat Corinna Rademacher Andreas Gonschorek Ingo Schmehl Susann Seddigh Andrea Fürst Kai Wohlfarth Lynn Engel Jakob Wefers Kerrin Kobes Olaf Kleinmüller Majid Essa Martin Tegenthoff Albert Nienhaus Peter Schwenkreis

Background/Objectives: Persistent symptoms following SARS-CoV-2 infection pose a substantial burden in occupational settings. This study aimed to characterize symptoms following work-related SARS-CoV-2 infection and to assess their associations with sociodemographic and clinical factors. Methods: Data were obtained from a multicenter clinical registry of insured individuals referred for persistent symptoms 12 weeks after laboratory-confirmed work-related SARS-CoV-2 infection. Participants were assessed within a standardized post-COVID diagnostic program at six specialized clinics for occupational accident insurance in Germany. Persistent symptoms reported by ≥50% of participants were analyzed using generalized linear mixed models with random intercepts for center. Results: A total of 1511 participants (76.7% women; median age 54 years) were included, with a median interval of 16 months between infection and assessment. On average, participants reported ten persistent symptoms. The most frequent complaints were limited physical capacity (95.6%), concentration difficulties (78.8%), dyspnea (70.5%), exhaustion/tiredness (68.9%), and memory difficulties (67.5%). Individuals reporting more than ten acute symptoms had increased odds of persistent complaints (ORs between 2.1 and 4.66). Hospitalization was independently associated with persistent dyspnea (OR 1.62; 95%CI 1.17–2.25). Reinfections were linked to exhaustion and cognitive fatigue. Compared with Omicron, wild-type infection was associated with higher odds of concentration difficulties (OR 1.65; 95%CI 1.17–2.33). Comorbidities demonstrated symptom-specific associations. Conclusions: Among individuals with work-related SARS-CoV-2 infection, limited physical capacity and cognitive impairments were the most frequently reported symptoms, and higher acute symptom burden was strongly associated with the development of persistent symptoms. These findings support course-oriented evaluation and symptom-specific approaches in occupational disease assessment and management.

Diseases doi: 10.3390/diseases14040140

Authors: Rooban Sivakumar Arul Senghor Kadalangudi Aravaanan Vinodhini Vellore Mohanakrishnan Janardhanan Kumar

Background: Early vascular aging (EVA) is a common complication of type 2 diabetes mellitus. Early identification is crucial in middle-aged individuals with T2DM, as vascular stiffness can occur gradually for years before cardiovascular disease. However, EVA is rarely considered in routine care. Adropin is a vasoprotective peptide that may counter-regulate endothelin-1 (ET-1). Therefore, this study aims to examine the association between circulating adropin, ET-1, oxLDL, MMP-2, VEGFA, and EVA. Methods: This observational study included 300 adults aged 25–55 years (150 T2DM; 150 age/sex-matched controls). ePWV was calculated from age and mean blood pressure. EVA was classified using a residual-based, age-specific ePWV threshold derived from controls. Associations were tested using correlation and logistic regression. ROC and decision curve analyses were performed to evaluate diagnostic performance and clinical utility. Results: EVA prevalence was 38.6% overall, occurring in 7.3% of controls and increasing across T2DM with good and poor glycemic control (56.1% and 80.95%, respectively, p < 0.001). Compared with normal vascular aging, EVA showed lower adropin and higher ET-1, oxLDL and MMP-2, with lower VEGFA (all p < 0.05). In fully adjusted models, adropin (OR 0.991 per pg/mL; p < 0.001) and ET-1 (OR 1.017 per pg/mL, p = 0.005) remained independently associated with EVA. A combined adropin + ET-1 predictor improved discrimination (AUC 0.901, 95% CI 0.868–0.934), at a predicted-probability cutoff of 0.607, 78.7% sensitivity and 87.0% specificity. Conclusions: In middle-aged T2DM, EVA was associated with lower adropin and higher ET-1 in T2DM. These findings support an association between these biomarkers and the EVA phenotype.

Diseases doi: 10.3390/diseases14040139

Authors: Yusef Muhana Alenezi Rana Awad S. Alanazi Danah Ashwi S. AlShalikhi Rimas Naif A. Alanazi Aryam Meshal S. Alanazi Sarah Ahmed S. Alanazi Renad Abdulrahman O. Alanazi Noor Awad S. Alanazi Baraah Abu Alsel Fathia Ahmed Mersal Safya E. Esmaeel Manal S. Fawzy

Background/Objectives: Nonalcoholic fatty liver disease (NAFLD), also referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects roughly one-quarter of the global population and represents a major public health concern. Despite its rising prevalence and potential for serious complications, NAFLD remains underrecognized and poorly understood in many communities. This study aimed to assess knowledge of NAFLD and its determinants among adults in the Northern Border Region of Saudi Arabia. Methods: A descriptive, population-based cross-sectional study was conducted using a previously validated online questionnaire adapted from published NAFLD awareness instruments, administered to adults residing in the Northern Border Region of Saudi Arabia. Data were analyzed using Python (statsmodels, version 0.14), and non-parametric tests, correlation analyses, and multivariable linear regression were used to examine NAFLD knowledge and its associated determinants. Results: A total of 1016 adults (mean age 34.7 ± 11.8 years) were included in the analysis. The mean NAFLD knowledge score was 14.6 ± 8.3 out of 30 (48.7% correct responses), with a median of 16 (interquartile range 8–21). Overall, 59.2% of participants had poor knowledge, 26.8% had moderate knowledge, and 14% had good knowledge. In bivariate analyses, educational level (χ2 = 15.62, p < 0.001), family history of liver disease (p = 0.001), body weight category (p = 0.003), and smoking status (p = 0.007) were significantly associated with NAFLD knowledge. In multivariable linear regression, university education (B = 2.783, 95% CI 0.627–4.940, p = 0.011) was an independent positive predictor of higher knowledge scores. Current smoking (B = −1.857, 95% CI −3.477 to −0.237, p = 0.025), private-sector employment (B = −1.934, 95% CI −3.867 to −0.001, p = 0.050), and overweight status (B = −4.119, 95% CI −7.337 to −0.901, p = 0.012) were independently associated with lower knowledge scores. The final model explained 2.2% of the variance in knowledge (adjusted R2 = 0.022). Conclusions: This study demonstrates generally low levels of NAFLD knowledge among adults in the Northern Border Region of Saudi Arabia, with only a minority achieving good knowledge scores. The findings underscore the need for targeted health promotion initiatives, educational interventions, and public campaigns to improve awareness of NAFLD and to support its prevention and management.

Diseases doi: 10.3390/diseases14040138

Authors: Magdalena Stocker Johanna Felber Patricia Bäck

Background/Objectives: Atypical skull base osteomyelitis (ASBO) is a rare disease, typically involving the basisphenoid and basiocciput. Diagnosis consists of clinical examination, imaging methods such as PET-CT scans and MRI, microbiological testing, and possibly native tissue samples. Long-term intravenous antibiotic therapy is the treatment of choice. Methods/Case Report: We present a case of ASBO of the clivus initially suspected to be a malignant lesion due to malignant melanoma in the patient’s history. Several tissue biopsies were taken, and microbiological testing of native tissue biopsies in combination with PET-CT and MRI imaging led to the diagnosis of ASBO. The patient received long-term antibiotic therapy with meropenem and drastically improved in his overall health. Discussion and Conclusions: This case highlights the challenges encountered in the diagnosis and management of ASBO, especially with relevant possible differential diagnoses.

Diseases doi: 10.3390/diseases14040137

Authors: Sneha Krishnamoorthi Rupachandra Saravanakumar Vivek Kumar

Protein glycation is a nonenzymatic modification that links sugar chemistry to molecular aging and chronic disease. Sequential reactions involving Schiff bases, Amadori products, and reactive α dicarbonyl intermediates generate advanced glycation end products (AGEs) that irreversibly alter protein structure and function. AGEs also act as ligands for the receptor for advanced glycation end products (RAGE), initiating oxidative stress, inflammation, and tissue remodeling. This review synthesizes the molecular pathways of AGE formation, their structural diversity, and the biological factors influencing glycation kinetics. Advances in analytical detection methods—including fluorescence spectroscopy, LC–MS/MS, and immunochemical approaches—are highlighted for their role in monitoring AGE accumulation. Particular attention is given to the contribution of glycation to diabetes, cardiovascular disease, neurodegeneration, and cancer, alongside emerging therapeutic strategies to limit AGE formation or block AGE–RAGE signaling. Glycation thus represents a central mechanism in human disease pathogenesis and an emerging therapeutic frontier.

Diseases doi: 10.3390/diseases14040136

Authors: Olga Alexatou Konstantinos Papadimitriou Exakousti-Petroula Angelakou Sousana K. Papadopoulou Myrsini Pappa Apostolia Ntovoli Aspasia Serdari Konstantina Apostolidou Theophanis Vorvolakos Constantinos Giaginis

Background and Objectives: Rates of obesity have been consistently increasing in recent years across all age groups, with a notable rise among young people. Obesity represents a persistent inflammatory condition and a key contributor to various chronic health problems, such as cardiovascular disorders, metabolic abnormalities, cancer, and psychological conditions. The move from high school to university is a transitional phase accompanied by specific pressures that can affect both body weight control and mental health in students. This cross-sectional investigation aimed to investigate potential associations between excess weight and the presence of depressive and anxiety symptoms in university populations. Methods: This cross-sectional analysis included 5298 students enrolled at universities across ten geographic areas of Greece. Participants filled out questionnaires concerning demographic information and lifestyle behaviors. Levels of depression and anxiety were measured using the Beck Depression Inventory (BDI-II) and the short form of the State Anxiety Inventory (STAI-6), respectively. Measurements of height and body weight were obtained to compute Body Mass Index (BMI). Results: The presence of overweight or obesity among students was significantly and independently related to female sex, urban residence, living independently, tobacco use, and lower academic performance (p = 0.0103, p = 0.0102, p = 0.0203, p = 0.0075, and p = 0.0168, respectively). Individuals reporting insufficient physical activity had 85% higher odds of being overweight or obese (p = 0.0068). Similarly, participants experiencing depressive or anxious symptomatology had more than double odds of excess body weight compared with those without such symptoms (p = 0.0015 and p = 0.0012, respectively). Furthermore, poor Mediterranean diet adherence was linked to more than a twofold increase in the odds of overweight or obesity (p = 0.0005). Conclusions: These findings offer considerable evidence that symptoms of depression and anxiety may serve as significant contributors to the development of overweight and obesity among university students. Additional longitudinal studies are strongly encouraged to substantiate these observations.

Diseases doi: 10.3390/diseases14040135

Authors: Austin A. Kohler David H. Shuler Leke O. Adeleye Andrew R. Moore Nicole Peritore A. Maleah Winkler

Background/Objectives: Dietary approaches to combating risk factors for cardiovascular disease are valuable, especially for individuals in high-stress occupations like first responders. The purpose of this pilot randomized control trial was to determine the effect of regular peanut butter (PB) supplementation on blood pressure and primary measures of body composition (body fat %, fat mass, and lean mass) in firefighters. Methods: Full-time firefighters (N = 40; 1 woman) were randomly assigned to a control group or a peanut butter group for 7 weeks. Participants in the peanut butter group consumed one serving of peanut butter before bed at least 5 days per week for the intervention period. Participants in the control group continued with their usual diet. Indices of body composition and blood pressure were collected before and after the intervention period and compared using mixed-factorial ANOVAs (α = 0.05). Results: No interaction effects between group and time were observed for blood pressure variables (p = 0.619–0.650). Similarly, the changes among the PB group over time in percent body fat (Δ = −0.53 ± 1.74%), fat mass (Δ = −0.73 ± 2.21 kg), and lean body mass (Δ = 0.04 ± 1.65 kg) were not significantly different than the changes over time in the control group (p ≥ 0.067 for all). Conclusions: Seven-week PB supplementation did not affect male firefighter body composition or blood pressure; however, future studies should investigate longer durations with sophisticated dietary recall methods. ClinicalTrials.gov Identifier: NCT06364202.

Diseases doi: 10.3390/diseases14040134

Authors: Elpida Stratou Georgia-Nektaria Porfyri Stavros Antonopoulos Afroditi Biziou Aikaterini Kalogeropoulou Katerina Theodorou Kalliopi Kalogeropoulou Aikaterini Kyriaki Timotheou Maria Kapouralou Aikaterini Gamvroula Maria Saridi

Background/Objectives: The COVID-19 pandemic posed significant challenges to quality of life, particularly for individuals living with chronic physical and/or mental conditions. Psychological factors such as fear of COVID-19, psychological distress, and resilience may be associated with quality-of-life outcomes during prolonged public health crises. This study aimed to examine quality of life and its psychological correlates among individuals with chronic conditions during the later phases and aftermath of the COVID-19 pandemic crisis. Methods: A cross-sectional study was conducted among 293 adults with chronic physical and/or mental conditions attending the General Hospital of Argolida, Greece. Participants completed validated self-report measures assessing quality of life (MVQOLI), fear of COVID-19 (FCV-19S), depression, anxiety, and stress (DASS-21), and psychological resilience (CD-RISC-25). Descriptive statistics, Spearman correlation analyses, and multivariable regression models were used to examine associations and identify factors associated with quality-of-life domains. Results: Higher levels of fear of COVID-19 and depressive symptoms were significantly associated with poorer quality of life across multiple domains. Depressive symptoms showed consistent negative associations with functional, interpersonal, transcendent, and overall quality-of-life scores. In contrast, psychological resilience was positively associated with interpersonal, transcendent, and overall quality of life. Regression analyses showed that depressive symptoms were negatively associated with overall quality of life, while resilience was independently associated with better quality-of-life outcomes. Conclusions: Psychological distress, particularly depressive symptoms and fear related to COVID-19, was associated with lower quality of life among individuals with chronic conditions during the later phases and aftermath of the COVID-19 crisis. Psychological resilience was positively associated with better quality-of-life outcomes, underscoring its relevance for supporting well-being during and after public health crises.

Diseases doi: 10.3390/diseases14040133

Authors: Juan Manuel Bello-López Dulce Milagros Razo Blanco-Hernández Andres Emmanuel Nolasco-Rojas Emilio Mariano Durán-Manuel Víctor Hugo Gutiérrez-Muñoz Carol Vivian Moncayo-Coello Jesus Alberto Meléndez-Ordoñez José Alberto Díaz-Quiñonez Magnolia del Carmen Ramírez-Hernández Adolfo López-Ornelas María Concepción Tamayo-Ordóñez Yahaira de Jesús Tamayo-Ordóñez Francisco Alberto Tamayo-Ordóñez Benito Hernández-Castellanos Luis Gustavo Zárate-Sánchez Oscar Sosa-Hernández Julio César Castañeda-Ortega Claudia Camelia Calzada-Mendoza Alejandro Cárdenas-Cantero Clemente Cruz-Cruz Miguel Ángel Loyola-Cruz

The increasing burden of dengue represents a growing global public health concern. Among the factors associated with rising dengue incidence, climate change, particularly increasing temperatures, has been frequently highlighted, alongside other environmental, biological, and social determinants. The emergence of dengue in previously non-endemic areas and its sustained increase in incidence have become increasingly common in recent decades. Objective: The aim of this study was to describe national dengue case trends in Mexico from 1990 to 2023 and to assess their association with temperature over the same period using a descriptive, retrospective analysis of epidemiological surveillance and temperature data. Methods: Epidemiological data on confirmed dengue cases and incidence were obtained from the Morbidity Yearbook of the General Directorate of Epidemiology (DGE) of the Mexican Ministry of Health. These data were used to construct epidemic curves and to analyze the geographic distribution of incidence using quartiles. Temperature data were derived from the national annual mean calculated from monthly reports issued by the National Water Commission (CONAGUA). Associations between temperature and dengue cases and incidence were explored over the study period. Results: Temporal analysis revealed a significant increase in both dengue cases and incidence in Mexico, with a positive association with temperature during the same period. Quartile-based geographic analysis showed that state-level classifications remained relatively stable across periods, with several states clustering within or tending toward the group considered endemic. Conclusions: The results of this study show an increase in cases and incidence of dengue over time, as well as a positive association between cases/incidence of dengue in Mexico and the increase in the national average temperature during the study period; however, due to its descriptive and retrospective design, causal inference is not possible. Dengue transmission is inherently multifactorial, and the observed trends likely reflect the combined influence of climatic conditions, historical expansion of transmission cycles, vector establishment, and unmeasured socio-epidemiological factors. The absence of entomological indicators, additional climatic variables, and spatially or seasonally disaggregated analyses limits the ability to capture localized dynamics. Overall, temperature should be interpreted as a contributing factor within a complex system rather than as the sole driver of dengue trends, underscoring the need for integrated surveillance and control strategies in both endemic and non-endemic regions.

Diseases doi: 10.3390/diseases14040132

Authors: Siphosihle Conham Ncomeka Sineke Ntandazo Dlatu Lindiwe Modest Faye Mojisola Clara Hosu Teke Apalata

Background: Drug-resistant tuberculosis remains a major challenge in resource-limited settings, particularly in rural regions of the Eastern Cape Province, where limited laboratory infrastructure, constrained access to advanced molecular diagnostics, shortages of specialized healthcare personnel, and prolonged diagnostic turnaround times can delay appropriate treatment initiation. This study examined whether routinely detectable genomic resistance markers could be integrated with parsimonious machine learning approaches to support early risk stratification for isoniazid (INH) and/or rifampicin (RIF) resistance and multidrug-resistant tuberculosis (MDR-TB). Methods: We conducted a retrospective analysis of clinical, demographic, and genomic data from 207 Mycobacterium tuberculosis isolates representing 207 unique patients. Resistance was classified as INH and/or RIF resistance or MDR-TB (concurrent resistance to both drugs). Predictors included age, sex, and canonical resistance-associated mutations (katG S315T, inhA −15C>T, and rpoB codon substitutions). Logistic regression was used to estimate adjusted odds ratios (aORs), while Random Forest models were applied to assess non-linear feature importance. Internal validation was performed using 10-fold cross-validation. A systems network analysis mapped the integration of model-derived risk bands into Clinical Governance structures and Community-Engaged Education pathways, including interventions delivered by Community Health Workers (CHWs). Results: INH and/or RIF resistance was identified in 58.9% of isolates, with 21.7% classified as MDR-TB. The most frequently detected mutations were katG S315T (29.0%) and rpoB S450L (26.6%). Logistic regression identified rpoB S450L (aOR 4.20; 95% CI: 2.10–8.45) and katG S315T (aOR 2.85; 95% CI: 1.40–5.80) as the strongest independent predictors, while age and sex were not statistically significant. Models demonstrated strong internal discrimination (AUCs of 0.96 for INH and/or RIF resistance and 0.99 for MDR-TB). Risk stratification categorized 18% of patients as high risk. Scenario-based modelling suggested that prioritizing high-risk patients for reflex Line Probe Assay testing could reduce the median time to appropriate treatment from 14 to 3 days and may reduce progression from isoniazid-resistant TB to MDR-TB under specified operational assumptions. Conclusions: Mutation-informed predictive modelling demonstrates strong internally validated discrimination and provides a structured framework for risk-stratified intervention. Integrating probability-based risk thresholds within Clinical Governance systems and community-level support structures, including CHW-led adherence and education strategies, may support earlier treatment optimization in high-burden rural settings. External validation and prospective implementation studies are required before broader programmatic adoption.

Diseases doi: 10.3390/diseases14040131

Authors: Alexandru Marius Petrusan Catalin Vladut Ionut Feier Calin Muntean Vasile Gaborean Andrei Stefan Petrusan Dragos Stefan Morariu Ionut Flaviu Faur Alaviana Monique Faur Patriciu Achimas-Cadariu

Background/Objectives: High-grade serous ovarian cancer (HGSOC) represents the most aggressive subtype of epithelial ovarian cancer and is frequently diagnosed at advanced stages. Increasing evidence suggests that systemic inflammation plays an important role in tumor progression and clinical outcomes. This study aimed to evaluate the association between preoperative systemic inflammatory indices and tumor burden, perioperative outcomes, and recurrence risk in patients with HGSOC undergoing primary debulking surgery. Methods: We conducted a retrospective study including 125 patients with histopathologically confirmed HGSOC who underwent primary debulking surgery between January 2020 and December 2025. Preoperative hematological parameters obtained within 24 h before surgery were used to calculate inflammatory indices including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). Associations between inflammatory markers, clinicopathological characteristics, perioperative outcomes, and recurrence were analyzed using non-parametric tests and logistic regression models. Results: The mean patient age was 53.66 ± 9.14 years, and most patients presented with advanced disease (FIGO III–IV: 70.4%). Patients with T3 tumors showed significantly higher monocyte (0.66 vs. 0.50 × 109/L, p = 0.003), neutrophil (5.43 vs. 4.99 × 109/L, p = 0.042), and platelet counts (325 vs. 280 × 109/L, p = 0.006) and lower lymphocyte counts (1.79 vs. 1.96 × 109/L, p = 0.009). Composite inflammatory indices were also increased in advanced disease, including PLR (177 vs. 153, p = 0.009), AISI (492 vs. 341, p = 0.002), and SIRI (1.65 vs. 1.18, p = 0.018). Patients requiring postoperative blood transfusion had higher neutrophil counts (7.65 vs. 4.97 × 109/L, p < 0.001) and elevated SIRI (2.56 vs. 1.55, p < 0.001). Patients with recurrence had significantly higher platelet counts (339 vs. 293 × 109/L, p = 0.001) and SII values (2849 vs. 2586, p = 0.012). In multivariate analysis, SII remained independently associated with recurrence (OR 1.022 per 100-unit increase; 95% CI 1.002–1.043; p = 0.033) together with advanced FIGO stages (OR 2.863; 95% CI 1.011–8.104; p = 0.048). Conclusions: Preoperative systemic inflammatory markers are significantly associated with tumor burden, surgical outcomes, and recurrence risk in HGSOC. An elevated SII appears to be an independent predictor of recurrence and may represent a practical biomarker for improving preoperative risk stratification and postoperative surveillance.

Diseases doi: 10.3390/diseases14040130

Authors: Ming-Hsin Yeh Mei-Chun Lin Hui-Ju Tsai Yi-Chou Liu Tzu-Min Wang Wei-Shan Hung Chih-Peng Lin Ching-Hsing Liang Chih-Jen Tseng

Background/Objectives: Breast cancer (BC) is the most commonly diagnosed cancer in women, and metastasis is the leading cause of BC-related death. Circulating tumor cells (CTCs) are a prerequisite for metastasis. This study examined the diagnostic and prognostic value of CTCs for assessing metastatic risk and recurrence in BC. Methods: The Chiline CATCH® Circulating Target Cell Enrichment System, an automated negative selection platform, was used to enrich and enumerate CTCs from the peripheral blood of patients with BC. Epithelial cell adhesion molecule (EpCAM) and cell-surface Vimentin (CSV) were used as markers for CTC identification. Results: CSV+ CTC counts, but not EpCAM+ CTC counts, were increased in patients with BC at higher metastatic risk. A cut-off of >4.5 CSV+-CTCs/2 mL blood yielded a sensitivity of 0.56 and specificity of 0.92 for identifying patients at high metastatic risk. CSV+-CTCs outperformed conventional serum tumor markers, including cancer antigen 15-3 (CA 15-3), cancer antigen 125 (CA 125), and carcinoembryonic antigen (CEA), in identifying patients with high metastatic risk, and their combined use further improved risk stratification. An elevated CSV+-CTC count (≥5 cells/2 mL blood) was significantly associated with worse progression-free survival in patients with BC. Conclusions: These findings suggest that CSV+-CTCs may serve as a biomarker for metastatic risk stratification and recurrence monitoring in BC when measured using an automated negative selection platform.

Diseases doi: 10.3390/diseases14040129

Authors: Yuma Terada Takafumi Yayama Akira Nakamura Kanji Mori Narihito Kodama Tomohiro Mimura Kosei Ando Kosuke Kumagai Yoshinori Takemura Shinji Imai

Background: Malignant lymphoma is the most common hematological malignancy; however, primary central nervous system lymphoma accounts for only a small percentage of non-Hodgkin lymphoma (NHL). Among these, primary cauda equina lymphoma (CEL) is extremely uncommon. Its rarity and atypical clinical presentation often make diagnosis challenging. Case Presentation: An 80-year-old man presented with progressive gait disturbance, lower-extremity weakness, and numbness. MRI revealed diffuse swelling and homogeneous gadolinium enhancement of the cauda equina at T12–L1; additionally, CSF cytology identified malignant lymphocytes. Open biopsy confirmed a diagnosis of diffuse large B-cell lymphoma. At diagnosis, the patient was classified as Ann Arbor stage IV, and the clinical parameters corresponded to a high-risk International Prognostic Index (IPI) category. The patient received five courses of immunochemotherapy with rituximab, methotrexate, vincristine, and procarbazine (R-MPV), resulting in marked radiological improvement and functional recovery, achieving a complete response. However, consolidation therapy was discontinued as the patient did not wish to continue. Unfortunately, intracranial relapse occurred four months later, and the patient ultimately succumbed to infectious complications. Only 29 cases of primary CEL have been reported. For all cases, a biopsy with histopathological examination is required for a definitive diagnosis. Currently, combined chemotherapy and radiotherapy are considered the standard treatment. This case was diagnosed through nerve biopsy with cauda equina at T12 to L1 levels, and immunochemotherapy successfully reduced the lesion while improving lower extremity function. Conclusions: Despite the considerable burden on patients, nerve biopsy is necessary for primary CEL to obtain a diagnosis and an early therapeutic approach for both neurological and vital prognoses.

Diseases doi: 10.3390/diseases14040128

Authors: Hasibul Islam Shahad Saif Khandker Anwara Khatun Ehsan Suez Alif Hasan Pranto Dewan Zubaer Islam Rahima Begum Md. Nizam Uddin Md. Ashraful Hasan Md. Shah Alam A. N. M. Mamun-Or-Rashid

Background: Chronic kidney disease (CKD) represents an escalating global health burden, fundamentally altering morbidity and mortality trajectories across the world, particularly as it advances into end-stage renal disease (ESRD). Beyond the primary decline in renal filtration and excretion, a wide spectrum of endocrine and metabolic derangements frequently accompanies kidney failure, with thyroid dysfunction emerging as a critical complication. Methods: The current study was designed to rigorously evaluate the nuanced association between thyroid hormone dynamics—specifically thyrotropin (TSH), triiodothyronine (T3), and thyroxine (T4)—and renal status in three distinct cohorts: individuals with suspected thyroid issues but normal renal function (NPs), non-dialysis kidney disease patients (NDKPs), and patients undergoing maintenance hemodialysis (DPs). Data were collected from a clinical setting in Bangladesh, involving 161 subjects. Results: The results demonstrated that patients in the DP cohort exhibited slightly elevated thyroid hormone levels relative to those in the NDKP cohort. Specifically, within the subgroups of patients exhibiting normal or sub-reference hormonal levels, dialysis patients maintained higher concentrations than their non-dialysis counterparts. Demographic stratification further revealed that males, females, and individuals younger than 45 years were more likely to demonstrate restorative hormonal profiles in the DP group than in the NDKP group. Conclusions: These collective outcomes suggest that renal replacement therapy, specifically hemodialysis, may serve to stabilize or improve thyroid function in ESRD patients by potentially mitigating the suppressive effects of uremic toxins and normalizing homeostatic feedback loops.

Diseases doi: 10.3390/diseases14040127

Authors: Aleksandra Sosin Tetiana Tkachuk Aleksandra Furtak Magdalena Janeczko Karol Stożek Teofila Książek Helena Poławska Damian Loska Sebastian Wardak Jerzy Starzyk Dominika Januś

Background: Short stature is a frequent clinical problem with a broad differential diagnosis. Emerging evidence indicates that pathogenic variants in the ACAN gene represent an underrecognized cause of growth failure and are often misclassified as idiopathic short stature. Case presentation: We report two pediatric patients harboring pathogenic ACAN gene variants, both presenting with short stature and distinctive facial dysmorphism. The first patient, a 15-year-old boy, exhibited short stature, advanced bone age, and a characteristic facial gestalt, including ptosis, hypertelorism, down-slanting palpebral fissures, and fleshy auricles, features not previously described in association with aggrecanopathy. Genetic analysis revealed a novel heterozygous frameshift variant, c.5677_5684del (p.Glu1893TrpfsTer8), in exon 12 of the ACAN gene. The second patient, a 5.5-year-old girl, presented with short stature, mild facial dysmorphism (down-slanting palpebral fissures and retracted mandible), and feeding difficulties. Copy number variation analysis identified a heterozygous deletion encompassing exons 15–19 of the ACAN gene. In both patients, the endocrine evaluation was unremarkable, and no chronic systemic disease was identified. The genetic findings were concordant with the clinical phenotype, confirming aggrecanopathy as the underlying cause of growth failure. Conclusions: These cases further delineate the phenotypic spectrum of ACAN-related short stature and underscore the diagnostic value of genetic testing in children with unexplained or idiopathic growth failure. Importantly, we expand the dysmorphological phenotype of aggrecanopathy by describing previously unreported facial features, which may facilitate earlier clinical recognition and diagnosis. The timely identification of pathogenic variants in the ACAN gene may have significant implications for patient management and long-term outcomes.

Diseases doi: 10.3390/diseases14040126

Authors: Petros Bozidis Christos Kittas Alexandra Myari Konstantinos Patras Konstantina Gartzonika

Background/Objectives: This retrospective study investigates the prevalence and distribution of HCV genotypes among 233 genotyped patients from the Epirus region of Northwestern Greece from 2014 to 2024. Methods: Genotypes were detected by molecular diagnostic assays, and their association with demographic parameters and viral load was analyzed. Results: The most prevalent subtype was 3a (50.2%), especially among younger and male patients, followed by subtypes 1b and 1a. A statistically significant association was found between genotype and both age and sex, while genotype distribution did not significantly differ by national origin. Furthermore, subtype 6c-I was found only in a non-native case, suggesting a possible introduction of this rare strain. Viral load showed no significant difference by sex, genotype, or age group. A notable decline in HCV cases was documented during the COVID-19 pandemic, underscoring the impact of the public health crisis on HCV diagnosis. Despite the decreasing need for genotyping in the direct-acting antiviral (DAA) era, our findings support the continued molecular surveillance of circulating HCV strains. Conclusions: This is the first study to longitudinally assess HCV genotype dynamics over a full decade (2014–2024) in the Epirus region of Northwestern Greece, capturing trends during the COVID-19 era and documenting the emergence of rare genotypes. It contributes to the evolving knowledge of HCV epidemiology in Southeastern Europe.

Diseases doi: 10.3390/diseases14040125

Authors: Paweł Muszyński Małgorzata Chlabicz Joanna Kruszyńska Katarzyna Wilk-Śledziewska Piotr Kazberuk Dominika Musiałowska Monika Groth Kinga Dudzińska

Despite the availability of numerous lipid-lowering agents, the treatment of lipid disorders remains a public health challenge. A substantial portion of patients, especially those with severe dyslipidemia or familial hypercholesterolemia (FH), fail to achieve the LDL-C goal. The leading causes of suboptimal LDL-C control include underprescription and poor adherence; however, in rare cases, it may result from an unusual biological response to treatment. In the presented case, a 78-year-old female with a history of transient ischemic attack and myocardial infarction was diagnosed with a heterozygous variant of FH and true statin intolerance following trials of simvastatin, rosuvastatin and pitavastatin. Initially, inclisiran was added to ezetimibe, leading to an unexpected increase in LDL-C. Due to the patient’s refusal of another statin re-challenge and the unavailability of bempedoic acid, nutraceuticals were introduced. After 6 months, inclisiran was discontinued because only a 22% reduction in LDL-C was achieved, likely attributable to the nutraceutical’s effect. Another PCSK9 inhibitor, evolocumab, was subsequently initiated. Shortly after the treatment onset, the patient complained of paraesthesia in the upper extremities and discontinued therapy. LDL-C levels increased by 7% after one month of treatment with evolocumab. The patient refused treatment with lipid apheresis. Possible causes of poor response to PCSK9 inhibitors include elevated lipoprotein(a) and FH.

Diseases doi: 10.3390/diseases14040124

Authors: Constantin Popazu Cristiana Voineag Ionica Grigore Cristina Șerban Mădălin Guliciuc Dragoș Voicu Alexandra Toma

Background: Continuous glucose monitoring (CGM) systems have significantly improved glycemic management in patients with type 1 diabetes mellitus and are generally considered safe. However, transcutaneous sensor insertion disrupts the skin barrier and, in susceptible individuals, may contribute to infectious complications. Severe soft tissue infections occurring in temporal association with CGM use are exceedingly rare. Case Presentation: We report a fatal case of necrotizing soft tissue infection in a 54-year-old male with long-standing type 1 diabetes mellitus occurring in temporal association with CGM use. The patient initially developed localized inflammation at a prior sensor insertion site that failed to fully resolve. Over subsequent weeks, he experienced progressive systemic symptoms and worsening local findings, culminating in advanced necrotizing infection. Despite emergency surgical debridement, broad-spectrum antimicrobial therapy, and intensive care support, the clinical course was complicated by septic shock and multiorgan failure, resulting in death. Discussion: This case highlights the role of patient-specific vulnerability, persistent insertion-site inflammation, and delayed clinical recognition in the progression from localized skin changes to life-threatening infection. Importantly, this report does not establish a direct causal relationship between CGM use and necrotizing soft tissue infection but underscores the need for heightened vigilance in high-risk individuals. Conclusions: Although CGM systems have a favorable safety profile, careful inspection of insertion sites, avoidance of sensor reapplication over incompletely healed tissue, and early evaluation of persistent or progressive symptoms are essential to minimize the risk of severe outcomes in susceptible patients.

Diseases doi: 10.3390/diseases14040123

Authors: Nicoleta Sgavardea Ovidiu Bedreag Greeshmasree Kambam Tamara Mirela Porosnicu Ciprian Gîndac Claudiu Barsac Cristian Oancea Patricia Hogea Alexandru Crisan Voichita Elena Lazureanu

Background and Objectives: Severe COVID-19 frequently fulfills Sepsis-3 criteria and is characterized by thrombo-inflammation and endothelial injury. We evaluated whether a bedside endothelial activation index (EAI = D-dimer/fibrinogen) identifies biologically distinct phenotypes and relates to interleukin-6 (IL-6) response after therapeutic plasma exchange (TPE), and whether baseline IL-6 predicts a ≥50% IL-6 reduction. Methods: Retrospective single-center ICU cohort of adults with SARS-CoV-2 infection, sepsis-related organ dysfunction, and ≥1 TPE session (n = 51). Patients were stratified by median EAI (low vs. high). Outcomes included peri-procedural biomarker/physiology changes (post–baseline), IL-6 responder status (≥50% reduction), correlations with IL-6 reduction (%), and multivariable predictors of response. Results: Compared with low EAI (n = 25), high EAI (n = 26) had higher baseline D-dimer (6.2 vs. 2.2 µg/mL) and lower fibrinogen (2.9 vs. 7.1 g/L) (both p < 0.001). Low EAI showed larger CRP decreases (ΔCRP −84.0 vs. −2.3 mg/L; p = 0.001) and larger fibrinogen falls (Δ −3.1 vs. −0.4 g/L; p < 0.001), while high EAI had larger D-dimer decreases (Δ −2.5 vs. −0.6 µg/mL; p = 0.004) and a modest SOFA improvement (Δ −0.3 vs. +0.1; p = 0.026). IL-6 responders (n = 20) had higher baseline IL-6 than non-responders (365.2 vs. 47.1 pg/mL; p < 0.001). Baseline IL-6 independently predicted response (per doubling: OR 1.94, 95% CI 1.27–2.95; p = 0.002), while age reduced odds (OR 0.91/year, 95% CI 0.84–0.99; p = 0.032). IL-6 reduction correlated with ΔCRP (ρ = −0.41; p = 0.003) and ΔPaO2/FiO2 (ρ = 0.37; p = 0.01). Conclusions: EAI stratifies distinct thrombo-inflammatory patterns around TPE, while baseline IL-6 is the dominant predictor of achieving large IL-6 reductions. To emphasize the novelty and clarify the study objective, this exploratory analysis used a phenotype-stratified framework to test whether a simple bedside endothelial activation index could enrich biological response assessment to adjunctive TPE. The prespecified primary outcome was achievement of a ≥50% IL-6 reduction after completion of the TPE course; secondary outcomes included peri-procedural biomarker, oxygenation, SOFA, and ICU endpoints.

Diseases doi: 10.3390/diseases14040122

Authors: Hiroyuki Kamide Shingo Kato Naofumi Yasuda Shungo Sawamura Yoshinobu Ishiwata Nobuyuki Horita Ryusuke Sekii Tomohiro Oshima Zenjiro Sekikawa Daisuke Utsunomiya

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly employed in patients with hemorrhagic shock and cardiovascular collapse; however, its impact on mortality remains controversial. Differences in geographic regions and patient populations may influence clinical outcomes. Methods: We conducted a systematic review and meta-analysis of observational studies comparing mortality between patients receiving REBOA and those managed without REBOA. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analyses were performed according to propensity score (PS) matching, trauma versus non-trauma populations, and geographic regions. Results: A total of 10 studies involving 18,611 patients were included. Overall, REBOA was not associated with a significant reduction in mortality compared with non-REBOA (pooled OR = 0.52, 95% CI: 0.19–1.39, p = 0.19). In PS-matched studies, the pooled OR was 0.82 (95% CI: 0.34–1.98, p = 0.66), whereas in non-PS-matched studies it was 0.40 (95% CI: 0.12–1.26, p = 0.12). Geographic analyses revealed no significant mortality benefit in either Western studies (OR = 0.47, 95% CI: 0.12–1.89; p = 0.29) or non-Western studies (OR = 0.60, 95% CI: 0.11–3.38; p = 0.56). No survival benefit was observed among trauma patients (OR = 0.57, 95% CI: 0.20–1.61; p = 0.29), whereas a significant reduction in mortality was observed in non-trauma patients (OR = 0.21, 95% CI: 0.05–0.88; p = 0.03). Conclusions: In this systematic review and meta-analysis, REBOA was not associated with a significant reduction in mortality in the overall population or in trauma patients. However, in a single small non-trauma study (n = 53), REBOA was associated with significantly reduced mortality; this finding is exploratory and requires confirmation in larger prospective studies. These findings suggest that the clinical benefit of REBOA may depend on patient population and underlying etiology of hemorrhage.

Diseases doi: 10.3390/diseases14040121

Authors: Elisa Abreu Rolando Pinho Fernando Magro Maria Manuela Estevinho

Objectives: Strictures are a major complication of Crohn’s disease (CD) affecting up to 20% of patients at diagnosis. Endoscopic balloon dilation (EBD) is the first-line endoscopic approach; however, it entails complications and a need for reintervention. Endoscopic stricturotomy (ESt) and stricturoplasty (ESTx) are promising alternatives. This review aims to provide an up-to-date and comprehensive assessment of their efficacy and safety in CD-associated strictures. Methods: A literature search was performed until August 2025. Primary outcomes were clinical and technical success. Secondary outcomes included adverse events, additional endoscopic or surgical treatments, medication escalation, emergency department visits and hospitalization following intervention. A minimum of four studies were required for meta-analysis, and pooled estimates were calculated using random-effects meta-analysis. Study quality was assessed using CASP checklist. Results: Fifteen studies including 1050 IBD patients (470 CD) were included. Strictures were short (0.9–2.4 cm) and some had prior EBD (7.8–57.1%) or surgery (3.6–91%). Technical success of ESt ranged from 88% to 100% and clinical success from 50% to 96%. The bleeding rate was up to 11.8%, but perforation rate was mostly <2%. The need for additional intervention, endoscopic (18.2–66.6%) or surgical (0–18.2%), varied considerably. Additionally, ESTx’s technical success ranged from 91.7% to 100% whereas clinical success ranged from 71.4% to 91%, with bleeding ranging from 5.2% to 8.8% and perforation from 0% to 3.4%. Similarly, the need for additional endoscopic procedures (7.1–57.1%) and surgery (9.5–25%) varied considerably. Conclusions: ESt and ESTx are safe and effective for managing CD-related strictures, particularly when short, straight, accessible, fibrotic, anastomotic, or refractory to EBD.

Diseases doi: 10.3390/diseases14040120

Authors: Sergiu Costescu Adrian Ratiu Bogdan Cerbu Oana Cristina Costescu Cosmin Citu Aniko Maria Manea Zoran Laurentiu Popa

Background and Objectives: Very preterm infants are vulnerable to late-onset infection and prolonged NICU exposure, with potential downstream effects on caregiver health. We evaluated neonatal outcomes and caregiver psychosocial status across culture-confirmed infection phenotypes. Methods: We investigated a single-center prospective cohort (March 2023–December 2025) of 87 preterm infants assigned to one of three groups: no proven infection (n = 44), bacterial sepsis (n = 31), or candidemia (n = 12). Neonatal outcomes included a composite adverse endpoint (death or major morbidity) and resource utilization. Caregivers completed the SF-36, WHOQOL-BREF, HADS, PHQ-9, GAD-7, and Body Image Scale near discharge. Results: Candidemia occurred later than bacterial sepsis (day of life 17.8 ± 4.8 vs. 10.1 ± 3.9; p < 0.001) and had a longer time to effective therapy (23.3 ± 9.5 vs. 13.3 ± 5.3 h; p = 0.004). The composite adverse outcome was 27.3% in the no-infection group versus 54.8% in the bacterial group and 58.3% in the candidemia group (p = 0.025); ROP requiring treatment increased from 4.5% to 29.0% and 25.0% (p = 0.012). Length of stay rose from 39.7 ± 10.2 to 50.1 ± 11.9 and 60.9 ± 13.1 days (p < 0.001), and ventilation days from 15.7 ± 7.6 to 23.3 ± 7.5 and 34.2 ± 10.4 (p < 0.001). Caregiver SF-36 mental health (MCS) scores decreased from 44.7 ± 7.5 to 38.5 ± 6.0 and 36.7 ± 6.4 (p < 0.001), while PHQ-9 scores increased from 9.4 ± 3.9 to 11.6 ± 3.3 and 15.5 ± 4.6 (p < 0.001); NICU burden correlated with PHQ-9 scores (r = 0.52, p < 0.001). Conclusions: Culture-confirmed infection, particularly candidemia, was associated with higher neonatal morbidity, markedly greater resource use, and substantial caregiver distress at discharge.

Diseases doi: 10.3390/diseases14040119

Authors: Jongkonnee Thanasai Chaimongkhon Chanthot Anchalee Chittamma Supphachoke Khemla Atthaphong Phongphithakchai Moragot Chatatikun Jitbanjong Tangpong Sa-ngob Laklaeng Wiyada Kwanhian Klangbud

Background: Procalcitonin (PCT) is a biomarker of bacterial infection and sepsis severity, but its role in melioidosis remains unclear. This study aimed to synthesize available evidence on serum PCT levels in culture-confirmed melioidosis and explore associations with disease severity and mortality. Methods: We conducted a systematic review following PRISMA guidelines and registered the protocol with PROSPERO (CRD420251166979). PubMed, Embase, and Scopus were searched up to 30 October 2025. Observational studies reporting serum PCT levels in microbiologically confirmed melioidosis were included. Study quality was assessed using the Newcastle–Ottawa Scale (NOS) for observational studies. Random-effects models were used to calculate pooled mean PCT levels, with heterogeneity assessed by I2. Sensitivity analyses were performed to explore the influence of historical and small-sample studies. Results: Seven studies comprising 284 patients with culture-confirmed melioidosis were included. The pooled mean PCT level was 14.46 ng/mL (95% CI: 4.59–24.33), with substantial heterogeneity (I2 = 87.7%). Sensitivity analyses excluding the oldest study and the smallest sample size reduced heterogeneity but retained consistently elevated PCT levels across cohorts. Higher PCT concentrations were consistently observed among patients with septic shock, bacteremia, and fatal outcomes, although variability in definitions precluded quantitative synthesis of prognostic effect sizes. These findings were based on heterogeneous study-level comparisons and could not be synthesized quantitatively. Conclusions: PCT is markedly elevated in melioidosis and reflects the severity of systemic infection, supporting its potential role as an adjunctive biomarker for early risk stratification. However, substantial heterogeneity and limited sample sizes prevent the establishment of a melioidosis-specific prognostic threshold. Standardized, prospective, multicenter studies are required to clarify the independent prognostic value of PCT in melioidosis management. This study establishes a pooled estimate of serum PCT levels in melioidosis and demonstrates that these values are comparable to those observed in severe bacterial sepsis, supporting its interpretation as a marker of systemic inflammatory burden rather than a disease-specific biomarker.

Diseases doi: 10.3390/diseases14040118

Authors: Daniela Alves Pereira Priscila Rezeck Nunes Marcelo Rizzatti Luizon Valéria Cristina Sandrim

Preeclampsia (PE) is a leading cause of maternal and perinatal complications and is classified by early or late onset according to the gestational age. The complex pathogenesis of PE involves placental ischemia, oxidative stress, angiogenic imbalance, and inflammation, all of which contribute to impaired placentation and widespread maternal endothelial dysfunction. These mechanisms drive hypertension, multi-organ involvement, and increased long-term cardiovascular risk. Parallel research highlighted the role of the NLRP3 inflammasome, a multiprotein complex that, upon activation, increases the gene expression, processing, and release of the pro-inflammatory cytokines IL-1β and IL-18. The NLRP3 pathway is markedly upregulated in placentas from pregnant women with PE, where endogenous danger signals stimulate inflammasome activation and amplify inflammation. Increasing evidence indicates that microRNAs (miRNAs) help regulate inflammatory processes, including the NLRP3 inflammasome, thereby affecting placental function and maternal adaptation. Although several immunoregulatory miRNAs may influence NLRP3 activity, their specific contribution to inflammasome regulation in PE remains insufficiently understood. Understanding these interactions could reveal new therapeutic targets for PE. In this narrative review, we explore the interconnected roles of endothelial dysfunction, inflammasome activation, and miRNA-mediated regulation in the pathogenesis of PE.

Diseases doi: 10.3390/diseases14040117

Authors: Austin M. Breaux Garret R. Miller Harrison D. Cooper Kristin Nicole Bembenick Aishwarya Reddy Shahab Ahmadzadeh Sahar Shekoohi Alan D. Kaye

Volatile anesthetics have steadily become more popular in intensive care units for sedation for reasons related to their beneficial pharmacokinetic and pharmacodynamic properties. Common anesthetics such as isoflurane and sevoflurane rapidly reach sedative levels in the body, but they are also rapidly eliminated, allowing for quick recovery. These agents have minimal impact on the liver and kidneys, which makes them attractive options when compared to other agents including opioids, benzodiazepines, ketamine, and propofol. Use of delivery systems like AnaConDa® (Anaesthetic Conserving Device; Sedana Medical AB, Danderyd, Sweden) has enabled providers to easily use these agents in the Intensive Care Unit (ICU). In this regard, they have recently provided additional beneficial consideration during intravenous drug shortages seen during the COVID-19 pandemic and at other times. These agents have shown organ-protective effects in the kidneys and lungs, which may even reduce the total time spent in the ICU. Pharmacodynamically, these anesthetics mediate their effects through central nervous system ion channels to exert analgesic and anxiolytic actions, thereby minimizing effects in the kidneys and lungs. These agents are primarily eliminated via exhalation, which makes them potential options for those with liver or kidney failure. This narrative review examines current efficacy and risks of using volatile anesthetics for sedation in the ICU setting and clinical roles for the future.

Diseases doi: 10.3390/diseases14040116

Authors: Yi Yuan Zhou Robert W. Maitta

Thrombocytopenia is a frequent complication of patients presenting emergently across the world for a wide array of etiologies. From patients who develop thrombocytopenia due to invasive neoplastic disease affecting the bone marrow to patients who develop immune complications secondary to the formation of auto-antibody responses that drive patients’ platelet counts lower or even cause infection, these patients stress the clearest need for prompt tests to discern the more likely thrombocytopenic-inducing cause. It is in this setting that looking at other platelet variables easily obtainable from modern hematology analyzers has gained traction. One of the elements found in extended platelet profiles are immature platelets (youngest and newly released platelets), also known as reticulated platelets, which are readily measurable from a complete blood count. One of the advantages of obtaining these counts is that they represent the immediate response of the bone marrow to the thrombocytopenia and, depending on etiology inducing the thrombocytopenia, they also provide information on the marrow’s response to therapeutic approaches. It is in this context that this review will present information of how these relatively novel platelet parameters can be used in clinical practice and how they can be a rapid gauge of the body’s response to disease processes leading to platelet losses. Thrombocytopenias resulting from infection (sepsis, viremia), autoantibody formation (immune thrombocytopenia and immune-mediated thrombotic thrombocytopenic purpura), immune dysregulation (systemic lupus erythematosus), and iatrogenic (drug-induced) will be discussed and used to explain how these young platelet measurements can provide valuable clinical information.

Diseases doi: 10.3390/diseases14030115

Authors: Calogero Velluto Giovan Giuseppe Mazzella Michele Inverso Maria Ilaria Borruto Andrea Perna Riccardo Totti Laura Scaramuzzo Luca Proietti

Background: Oxygen–ozone (O2–O3) therapy is a minimally invasive treatment for discogenic lumbar pain. Although rare, spinal infections—specifically spondylodiscitis—have been reported following intradiscal injections. To date, Lactobacillus iners has not been described as a causative agent in this context. Case Presentation: A 55-year-old immunocompetent woman presented with progressive lumbosciatica and elevated inflammatory markers three months after intradiscal O2–O3 therapy. MRI revealed L4–L5 spondylodiscitis with paravertebral involvement. Surgical biopsy confirmed L. iners as the pathogen. She underwent decompression and received targeted intravenous antibiotics, achieving full clinical and radiological recovery. Methods: A systematic literature review was performed using PubMed, MEDLINE, and Scopus to identify reports of spondylodiscitis following oxygen–ozone therapy. Six cases were included based on predefined inclusion criteria. Results: The 8 identified cases involved a range of pathogens, including Staphylococcus aureus, Streptococcus beta-haemolyticus, Escherichia coli, Achromobacter xylosoxidans, Mycobacterium abscessus, and Streptococcus intermedius, and one culture-negative infection. Clinical presentations varied from radiculopathy to sepsis. Management strategies encompassed both conservative (antibiotics alone) and surgical approaches, depending on neurological status and abscess formation. Outcomes were favorable in all cases except one fatality. Conclusions: This report is the first to describe L. iners spondylodiscitis in an immunocompetent patient following O2–O3 therapy. Clinicians should vigilantly evaluate post-infiltration spinal infections, maintain a low threshold for imaging and biopsy, and implement pathogen-targeted antibiotic regimens, with surgical intervention as needed.

Diseases doi: 10.3390/diseases14030114

Authors: Daciana Grujic Teodora Hoinoiu Catalin-Alexandru Pirvu Mihai Iliescu-Glaja Simona Cerbu Silviu Cristian Suciu Daniel Pit Cristina Marinela Oprean Horia Cristian

Background/Objectives: Phyllodes tumors are rare fibroepithelial neoplasms of the breast, accounting for less than 1% of all breast tumors and approximately 2–3% of breast fibroepithelial tumors. They can be benign, borderline, or malignant, depending on cellular atypia and stromal invasion. Although most display local behavior, malignant forms can metastasize hematogenously, most frequently to the lungs, bones, and liver, with lymph node metastases being exceptional. Case Presentation: We analyzed the case of a 47-year-old woman with a phyllodes breast tumor weighing approximately 5 kg. The tumor evolved slowly over five years, followed by accelerated growth, cutaneous necrosis, superinfection, and severe anemia. Total mastectomy was performed, and histopathological examination confirmed the diagnosis of a malignant phyllodes tumor. Five months after surgery and adjuvant radiotherapy, the patient developed laterocervical metastases with thyroid invasion and life-threatening tracheal compression, an extremely rare presentation for this type of tumor in adults. Discussion/Conclusions: This case illustrates the aggressive and unpredictable behavior of malignant phyllodes tumors and underscores the necessity of careful oncological monitoring and a multidisciplinary approach, given their potential for dissemination to unusual locations.

Diseases doi: 10.3390/diseases14030113

Authors: Tatjana Zekić Nataša Katalinić Filip Blažić Nada Starčević Čizmarević Aleksandar Čubranić

Background/Objectives: This observational study investigated associations between human leukocyte antigen (HLA) polymorphisms and imaging-defined hepatic steatosis (non-alcoholic fatty liver disease—NAFLD) and liver fibrosis in patients with rheumatoid arthritis (RA). Methods: Steatosis was assessed by transient elastography (FibroScan) and defined as controlled attenuation parameter (CAP) ≥ 275 dB/m; fibrosis was defined as liver stiffness measurement ≥ 8 kPa. We tested 11 frequent HLA alleles (HLA-A*02, HLA-B*07, HLA-B*08, HLA-B*27, HLA-B*35, HLA-B*44, HLA-B*51, HLA-DRB1*11, HLA-DRB1*14, HLA-DRB1*15, and HLA-DRB1*16). Associations were evaluated using multivariable logistic regression (individual and omnibus models) adjusted for age, body mass index (BMI), triglycerides, and glucose. Results: A total of 176 patients with rheumatoid arthritis were enrolled. NAFLD/steatosis was present in 35.2% of patients (n = 62), and fibrosis in 10.8% (n = 19). No HLA allele was significantly associated with steatosis or fibrosis after correction for multiple testing. BMI and triglycerides were independently associated with steatosis (BMI OR 1.22, 95% CI 1.12–1.34; triglycerides OR 1.48, 95% CI 1.04–2.18). For fibrosis, HLA-DRB1*15 showed the strongest trend-level association (OR ~2.6–2.9) but did not remain significant after correcting for multiple testing. Conclusions: In this RA cohort, metabolic factors (particularly BMI and triglycerides) were the dominant predictors of CAP-defined steatosis. No robust association between the tested HLA markers and steatosis or fibrosis was identified. Trend-level signals—most notably HLA-DRB1*15 for fibrosis—should be considered hypothesis-generating and warrant replication in larger, adequately powered cohorts.

Diseases doi: 10.3390/diseases14030112

Authors: Aisulu Gainutdin Alexander Nersesov Komori Atsumasa Aigul Raissova Saltanat Madenova Laura Yerdaliyeva Dinara Suleimenova Balday Issenova

Background/Objectives: Primary biliary cholangitis (PBC) is a chronic immune-mediated cholestatic liver disease with increasing global prevalence. However, data on this disease from Central Asia are lacking. We aimed to describe the clinical, serological, and treatment characteristics of PBC patients in Kazakhstan. Methods: This study was a multicenter, retrospective, observational study including adults diagnosed with PBC between 2014 and 2022 across seven hepatology centers in Kazakhstan. Clinical presentation, laboratory parameters, autoimmune comorbidities, liver disease severity, and ursodeoxycholic acid (UDCA) treatment response were assessed. Biochemical response at 1 year was evaluated using Paris-1 and Barcelona criteria. Results: A total of 230 patients were included; 93.9% were female and 91.3% were of Asian ethnicity, with a median age at diagnosis of 53 years. Cirrhosis was present at diagnosis in 50.2% of the patients. PBC with autoimmune hepatitis (AIH) features was identified in 56.1% of the patients and was associated with higher rates of cirrhosis, portal hypertension complications, antinuclear antibody (ANA) positivity, and higher elastography indices compared with isolated PBC. Overall, approximately 55% of the patients achieved a biochemical response to UDCA at 1 year, with similar response rates between patients with PBC and those with PBC with AIH features. Conclusions: This first comprehensive study of PBC in Kazakhstan demonstrates late disease presentation with a high burden of cirrhosis and frequent AIH features. Despite advanced disease, about half of the patients achieved biochemical remission on UDCA. These findings underscore the need for earlier diagnosis and optimized management strategies for PBC in Kazakhstan and similar settings in Central Asia.

Diseases doi: 10.3390/diseases14030111

Authors: Djilali Batouche Djamila Djahida Batouche Zoheir Zakaria Addou Souhila Fatima Bouchama Rabia Okbani Siham Simerabet Nadia Faiza Benatta Soulef Saadi-Ouslim Miloud Lahmer

Background: Pediatric kidney failure, whether acute or chronic, constitutes a major public health issue because of its impact on survival, linear growth, neurocognitive development, and long-term quality of life. While high-income countries have markedly improved outcomes through early diagnosis, advanced dialysis technologies, and kidney transplantation, management remains limited in low- and middle-income countries, particularly in the Maghreb region. Objective: This review aims to provide an updated synthesis of pediatric kidney failure, with emphasis on renal replacement therapy modalities and the specific challenges encountered in resource-limited contexts, particularly in Algeria. Methods and Content: We successively address the pathophysiological and clinical bases of pediatric acute kidney injury and chronic kidney disease, followed by a discussion of available therapeutic strategies: peritoneal dialysis, intermittent hemodialysis, continuous renal replacement therapy, and pediatric kidney transplantation. Particular attention is given to organizational constraints, actual availability of modalities, limited access to consumables and immunosuppressive therapies, and the specificities of pediatric kidney care in the Maghreb region in comparison with international recommendations. Perspectives: Improving outcomes for children with kidney failure in Maghreb countries requires a multidimensional approach integrating early screening, strengthening peritoneal dialysis programs, structured development of pediatric kidney transplantation, and enhanced regional and international collaboration. Reinforcing local research capacity and participation in international registries are essential steps toward reducing disparities in care and adapting global guidelines to local realities.

Diseases doi: 10.3390/diseases14030110

Authors: Luca Degli Esposti Stefania Mazzoni Maria Cappuccilli Franco Maggiolo Sergio Lo Caputo Silvia Nozza Lucia Taramasso Anna Marra Mario Pittorru

Background/Objectives: Among the antiretroviral therapies (ARTs) recently introduced for people living with HIV (PLWH), the fixed-dose combination of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) became reimbursable in Italy in June 2019. Methods: This study evaluated drug utilization, healthcare resource consumption and direct costs among ART-naïve adults initiating B/F/TAF or other non-bictegravir-based regimens, identified from June 2019 to September 2022 within administrative databases of healthcare entities covering approximately nine million citizens. Baseline clinical characteristics at first ART prescription were compared across B/F/TAF-treated patients, those receiving other ART regimens, and non-HIV controls, while treatment outcomes during follow-up were evaluated among PLWH receiving B/F/TAF or other ARTs; healthcare consumption and costs were assessed after propensity score matching within the PLWH cohorts only. Results: Overall, 374 individuals initiated B/F/TAF and 5576 other ARTs. Patients treated with B/F/TAF showed greater adherence and persistence, with multivariate analyses confirming a lower risk of discontinuation or switching (HR = 0.66, 95% CI 0.57–0.76, p < 0.001) and a higher likelihood of adherence (HR = 2.40, 95% CI 1.58–3.64, p < 0.001). After matching, the B/F/TAF group exhibited lower 12-month consumption of non-HIV medications, fewer non-HIV hospitalizations, and reduced total healthcare costs, particularly for non-HIV drug prescriptions compared to other ART users. Conclusions: Overall, B/F/TAF was associated with better treatment continuity and meaningful cost savings.

Diseases doi: 10.3390/diseases14030109

Authors: Aleksandar Ristic Marija Rovcanin Ana Tomic Aleksandar Rakic Nebojsa Zecevic Svetlana Jankovic

Intravascular lymphoma (IVL) is an uncommon subtype of non-Hodgkin’s extranodal lymphoma, distinguished by the proliferation of neoplastic cells within the lumen of small- to medium-sized arteries, with various organs recorded as impacted. The objective of this study was to evaluate the current literature about IVL and its involvement in the female genital tract, including an overview of diagnostic methods, imaging, and pathological features, selected therapy modalities, and outcomes in patients afflicted by this malignancy. We performed a narrative review with a systematic identification and presentation of published cases of IVL affecting the female genital tract. A literature search was carried out across PubMed, Scopus, and Web of Science for relevant studies presenting data on IVL affecting the female genital tract. Case reports and series that met predefined inclusion and exclusion criteria specified by the modified PECOS (“Population,” “Exposure,” “Comparison,” “Outcomes,” and “Study design”) framework were included. Patients most commonly presented with abnormal vaginal bleeding, pelvic pain, and B symptoms. Fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT), often performed alongside abnormal laboratory findings such as elevated lactate dehydrogenase (LDH), played a key role in raising suspicion for hematologic involvement of the female genital tract and guiding biopsy. Most cases represented B-cell intravascular lymphoma and were treated with Rituximab plus (CHOPR-CHOP) based chemotherapy, frequently combined with hysterectomy.

Diseases doi: 10.3390/diseases14030108

Authors: Anthony Brayan Rivera Prado Luis Lloja Lozano Daysi Zulema Diaz Obregón Víctor Hugo Carbajal Zegarra Joel De León Delgado Jhon Wilfredo Pando Mayta Alexis German Murillo Carrasco Kelly Geraldine Yparraguirre Salcedo Claudio Willbert Ramirez Atencio

Background: Chronic liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition and architectural remodeling, which may ultimately lead to cirrhosis and liver failure. Although mesenchymal stem cells (MSCs) exhibit antifibrotic and immunomodulatory properties, their therapeutic effects in established chronic liver fibrosis remain incompletely defined. This study aimed to evaluate the biochemical, hematological, and histopathological effects of MSC therapy in a chronic thioacetamide-induced liver fibrosis model. Methods: A controlled preclinical experimental study was conducted using rats with liver fibrosis induced by intraperitoneal thioacetamide administration for 24 weeks. Animals were allocated into three groups: control, untreated fibrosis, and fibrosis treated with MSCs derived from human umbilical cord tissue after fibrosis establishment. Serum biochemical markers, hematological parameters, and liver histopathology were assessed. Fibrosis severity was evaluated using hematoxylin–eosin and Masson’s trichrome staining and graded according to the METAVIR scoring system. Results: Thioacetamide exposure induced chronic liver injury characterized by marked elevations in serum transaminases, reduced albumin and total protein levels, hematological alterations, and early-to-intermediate fibrosis stages (METAVIR F1–F2). MSC-treated animals exhibited approximately 40–45% reductions in transaminase levels, partial recovery of hepatic synthetic function, and attenuation of hematological alterations. Histopathological analysis demonstrated a reduction in fibrotic burden and limitation of fibrogenic progression within METAVIR F1–F2 stages. Conclusions: MSC therapy partially mitigates biochemical, hematological, and histopathological alterations associated with chronic thioacetamide-induced liver fibrosis, supporting its potential as a modulatory strategy to attenuate fibrogenic progression and stabilize liver function rather than as a curative intervention.

Diseases doi: 10.3390/diseases14030107

Authors: Aigerim Turekulova Nurzhamal Dzhardemaliyeva Heike Rabe Mukhtar Kulimbet

Background/Objectives: Delayed umbilical cord clamping (DCC) is widely recommended for neonatal benefit; however, concerns persist among professionals that DCC may increase the risk of postpartum hemorrhage. There is a higher risk of postpartum hemorrhage in women with hypertensive disorders of pregnancy (HDP). We aimed to evaluate the association between umbilical cord clamping timing and maternal blood loss in term pregnancies, including those complicated by HDP. Methods: We conducted a cross-sectional study of women delivering at three major hospitals in Almaty, Kazakhstan (August 2020–March 2021). The primary outcome was maternal blood loss. Secondary outcomes included hemoglobin (Hb) and red blood cell (RBC) change from pre-delivery to discharge. Multivariable models were adjusted for maternal age, parity and hypertension category. Results: Two hundred and seven women were analyzed (early cord clamping ≤ 60 (ECC) n = 21; delayed cord clamping 60–119 s (DCC60s) n = 161; delayed cord clamping ≥ 120 s (DCC120s) n = 25). Baseline characteristics were similar across groups except for hypertension distribution. Median blood loss did not differ significantly (255–260 mL; p = 0.9128). Adjusted models confirmed no association between clamping category and blood loss (RoM: ECC vs. DCC60s 0.97; 95% CI 0.93–1.01; DCC120s vs. DCC60s 1.01; 95% CI 0.96–1.07). Conclusions: Among term births in Almaty, including HDP-affected pregnancies, delayed umbilical cord clamping was not associated with increased maternal blood loss or hematologic decline. These findings indicate that DCC does not appear to increase maternal bleeding risk in high-risk obstetric populations and are broadly in line with current international recommendations. Further prospective research is warranted to evaluate specific subgroups, including severe preeclampsia.

Diseases doi: 10.3390/diseases14030106

Authors: Syed Faisal Ali Julia Natche Mahendrakumar Achlaram Chaudhari Hassan Abbasi Sammy Dawoud Hany Dawoud Amna Shoaib Hersh Tilokani Harleen Kaur Chela Arsal Zafar

Background: Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis, marked by rapid renal function decline and poor prognosis. Although clinical predictors of HRS outcomes have been extensively studied, less is known about how demographic factors influence mortality patterns. Methods: This analysis utilized CDC WONDER data to assess U.S. mortality trends for hepatorenal syndrome (HRS) in adults aged ≥25 years from 1999 to 2024. We calculated crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 100,000 and analyzed temporal trends using Joinpoint regression to determine the annual percentage change (APC) and average annual percentage change (AAPC). Results: From 1999 to 2024, 118,894 HRS-associated deaths were recorded. The overall AAMR decreased significantly from 2.43 in 1999 to 2.12 in 2024, with an AAPC of (AAPC −0.69% [95% CI: −0.90% to −0.51%]). Males consistently exhibited higher AAMRs than females (Males: 2.62 vs. Females: 1.63 in 2024). When stratified by race, the highest AAMR in 2024 was observed among non-Hispanic (NH) American Indian or Alaska Native populations (11.02), followed by Hispanic or Latino (2.58), NH White (2.23), NH Black or African American (1.30), and NH Asian or Pacific Islander populations (0.72). Regionally, the highest mortality was observed in the West, followed by the Midwest, South, and Northeast (2.88, 2.00, 1.92, and 1.53, respectively, in 2024). Rural areas (2.44) consistently exhibited higher AAMRs than urban areas (1.91) throughout the study period. Conclusions: HRS-related mortality has decreased modestly in the U.S over the last 26 years, yet significant inequities remain across population subgroups and regions. Mortality is disproportionately higher among males, NH American Indian or Alaska Native individuals, and residents of rural and western areas, highlighting the continued necessity for focused public health strategies.

Diseases doi: 10.3390/diseases14030105

Authors: Matteo Capobianco Marco Zeppieri Federico Visalli Francesco Pellegrini Leandro Inferrera Rosa Giglio Irene Gattazzo Francesco Cappellani Fabiana D’Esposito Caterina Gagliano

Background/Objectives: Rosacea is a chronic inflammatory dermatosis that may involve the eye, causing surface and adnexal damage that can precede cutaneous signs. Detecting subclinical ocular changes is clinically important because early ocular surface dysfunction may be missed on routine examination yet progress to corneal complications, allowing earlier preventive management when identified. We prospectively evaluated subclinical ocular alterations in cutaneous rosacea using a combined, fully non-invasive high-tech imaging workflow—tear film interferometry, infrared meibography, and exploratory retinal optical coherence tomography angiography (OCT-A)—including patients without clinically evident ocular involvement. Methods: Sixteen patients with cutaneous rosacea (mean age 44.3 ± 11.2 years; 4 males, 12 females) were enrolled and divided into: Group 1—rosacea with clinically evident ocular involvement (n = 11); Group 2—rosacea without clinical ocular involvement (n = 5). Six age-matched healthy subjects served as controls (Group 3). All underwent LipiView II® interferometry and meibography to quantify lipid-layer thickness (LLT, nm) and meibomian gland (MG) loss score (1 = normal–4 = severe), plus retinal OCT-A (Optovue Inc., Fremont, CA, USA). ANOVA with post hoc Tukey test assessed inter-group differences. Results: OCT-A showed no significant alterations in superficial or deep retinal plexuses across groups (p > 0.05). Conversely, LLT was significantly reduced in both rosacea groups vs. controls (OD: 45.5 ± 21.4 nm and 67.4 ± 10.1 nm vs. 92.7 ± 8.2 nm; OS: 40.4 ± 15.3 nm and 66.4 ± 10.1 nm vs. 96.0 ± 6.7 nm; p < 0.001). MG score was markedly higher (worse) in rosacea (OD: 3.63 ± 0.50 and 3.20 ± 0.83 vs. 1.83 ± 0.75; OS: 3.45 ± 0.68 and 3.40 ± 0.54 vs. 1.66 ± 0.81; p < 0.001). Ocular symptoms were reported by 85% of patients yet slit-lamp examination revealed surface alterations in 58% of asymptomatic cases. Conclusions: Tear film interferometry and meibography detect early ocular surface impairment in rosacea—even in the absence of clinical signs—while retinal microvasculature appears unaffected. Routine ophthalmologic screening of all rosacea patients could enable prompt treatment of subclinical dysfunction, potentially preventing corneal complications. Retinal OCTA metrics were not significantly different in this small pilot cohort, and these negative findings should be interpreted cautiously pending larger studies.

Diseases doi: 10.3390/diseases14030104

Authors: Elisabeth Emanuel Graae Louise Faaborg Rikke Fredslund Andersen Lars Ulrik Fokdal Caroline Brenner Thomsen

Background/Objectives: Platinum resistant ovarian cancer represents a treatment challenge due to lack of efficient treatments and the absence of prognostic biomarkers. The circulating tumor DNA (ctDNA), methylated homebox A9 (meth-HOXA9), has been suggested as a biomarker for ovarian cancer, and might have a clinical impact in terms of predicting progression and supporting clinical decision making. Hence, this study investigated the prognostic value of meth-HOXA9 in platinum resistant recurrent ovarian cancer (PR-ROC) treated with bevacizumab and tocotrienol. Methods: Twenty patients with platin-resistant recurrent ovarian cancer were prospectively enrolled in this non-randomized phase II study. The treatment consisted of bevacizumab (Avastin) 10 mg/kg intravenously every three weeks and tocotrienol (Traptol) capsules 300 mg orally three times daily as a continuous treatment. The Level of meth-HOXA9 was measured at baseline and every three weeks. Results: The overall survival (OS) in the cohort was 7.5 months (95% CI 3.0–10.0), and the progression free survival was 4 months (95% CI 1.4–6.6). Comparing meth-HOXA9 ctDNA levels at baseline, there was no statistic significant difference in OS (p = 0.23). Conclusions: Treatment was well tolerated in this heavily pretreated cohort of PR-ROC patients with expected poor prognostic outcomes, with a few individuals showing extraordinary response in terms of progression free survival. The study was not powered to reproduce evidence of potential of meth-HOXA9 as a prognostic biomarker in PR-ROC.

Diseases doi: 10.3390/diseases14030103

Authors: Dimitrios E. Magouliotis Vasiliki Androutsopoulou Andrew Xanthopoulos Noah Sicouri Bo Yang

Aortic valve disease is increasingly recognized as a chronic, progressive condition in which the initial valve intervention exerts a decisive influence on all subsequent therapeutic options. The persistence of prosthesis–patient mismatch (PPM), often driven by implantation of small surgical prostheses (≤21–23 mm), is associated with higher residual transvalvular gradients, attenuated left ventricular reverse remodeling, inferior long-term survival, and compromised outcomes following valve-in-valve (ViV) transcatheter procedures. Accumulating clinical and imaging evidence indicates that aortic annular enlargement (AAE), particularly using contemporary Y-incision and extended “roof” reconstruction techniques, can safely and reproducibly expand the annulus, sinuses of Valsalva, and sinotubular junction, thereby permitting implantation of larger prostheses and substantially reducing the risk of PPM. Insights from computational fluid dynamics further demonstrate that annular and root enlargement favorably alters postoperative flow dynamics, resulting in lower peak velocities, reduced pressure gradients, and more physiologic flow patterns in both primary surgical valve replacement and simulated ViV settings. From a lifetime management perspective, valve diameter optimization emerges as a critical determinant of both immediate hemodynamic performance and future procedural feasibility. Surgical programs that adopt a systematic approach to anatomic assessment, valve sizing strategy, PPM surveillance, and ViV preparedness may achieve meaningful improvements in short- and long-term outcomes. This review integrates anatomic, operative, hemodynamic, and quality-oriented evidence to support consideration of valve upsizing as a central principle in contemporary aortic valve replacement.

Diseases doi: 10.3390/diseases14030102

Authors: Tiago Lima Sandra Trigo Eduarda Silveira Gabriela Jorge da Silva Sara Domingues

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Despite the availability of effective treatments and advances in diagnostic methods, TB remains the leading cause of death from infectious disease globally, with its incidence tending to increase. Pregnant women constitute a population group with particular characteristics, as the diagnosis and treatment of certain conditions can be challenging. Early diagnosis and monitoring of TB by a multidisciplinary team are crucial to guide treatment and reduce complications. Congenital TB, although uncommon, is a serious complication that should be assessed in neonates, especially when the mother has previously been diagnosed with the disease. First-line anti-TB drugs are considered safe during pregnancy and lactation. In contrast, second-line drugs have a less well-established safety profile during breastfeeding, and the available evidence regarding their excretion in breast milk remains limited; therefore, their use requires individualised risk-benefit assessment. Data on this specific population group are limited, as physiological changes during pregnancy alter the pharmacokinetics/pharmacodynamics (PK/PD) of drugs and the inclusion of pregnant women in clinical trials remains contentious. Routine TB screening in prenatal care, particularly in high-prevalence regions, is crucial to improving maternal and neonatal outcomes. This narrative review was based on a structured search of PubMed, Scopus, and Web of Science (January 2000–June 2025), using the keywords tuberculosis, Mycobacterium tuberculosis, pregnancy, and breastfeeding. Eligible articles included original studies, reviews, and international guidelines.

Diseases doi: 10.3390/diseases14030101

Authors: Natasa Stanisavljevic Ljudmila Stojanovich Aleksandra Djokovic Violeta Dopsaj Neda Milinkovic Dusica Mrdaković Olivera Markovic Marija Zdravkovic Dragomir Marisavljevic

Background: Anemia is common among patients with antiphospholipid syndrome (APS). It can persist alone (primary APS—pAPS) or with another associated disease (secondary APS—sAPS), predominantly systemic lupus erythematosus (SLE). There are no systematic reviews addressing the type of anemia (iron deficiency without anemia—IDWA, iron deficiency—IDA, and anemia of chronic disease—ACD) in these patients. Objectives: This study aimed to assess the type of anemia and to compare the usefulness of common diagnostic anemia parameters and their mutual relations. Methods: A cross-sectional study involving 163 patients was conducted at the University Clinical Center Bezanijska kosa from June 2022 to June 2024, including 79 patients with pAPS, 47 with sAPS and 37 patients diagnosed with SLE. We compared the usefulness of iron metabolism markers (serum iron—Fe; total iron-binding capacity—TIBC; ferritin; hepcidin) in the presence of inflammatory markers such as high-sensitivity (hsCRP) and IL6 in determining the type of anemia. Results: The most common types were IDA (61.9%) and IDWA (64.3%) in pAPS patients. In contrast, ACD was equally distributed across the three groups, with prevalences of 32%, 32%, and 36% (pAPS, sAPS, and SLE, respectively). A higher frequency of thrombosis was significantly associated with a high ferritin level ≥100 (p = 0.017) and high IL6 levels (p = 0.033) as well as fetal losses (p = 0.034 and p = 0.019, respectively). The logistic regression model identified ferritin as the only significant predictor of IDA (p = 0.023). For IDWA, both ferritin (p = 0.017) and hepcidin (p = 0.038) were significant predictors of this type of iron depletion. IL-6 levels were significantly correlated with ferritin and hsCRP levels (p = 0.004 and p = 0.007, respectively). In contrast, hepcidin did not show a statistically significant correlation with inflammatory markers. A total of 40% of patients with IDA had hepcidin levels below 10, and 48% of those with ACD had hepcidin levels above 10 (p = 0.036). Conclusions: It was found that iron deficiency anemia was the most common form in pAPS, while anemia of chronic disease was equally present across all patient groups. Ferritin emerged as an independent marker for identifying iron deficiency anemia in APS patients. Although hepcidin reflects a low-inflammatory state in APS, it proved to be a more valuable tool than ferritin in distinguishing the type of anemia, especially when ferritin levels were inconclusive. Clinical manifestations in APS patients correlated with inflammatory markers. Liver function or any drug used alone or in combination had no impact on anemia type.

Diseases doi: 10.3390/diseases14030100

Authors: Ageliki A. Karatza Eirini Kostopoulou Sotirios Fouzas Nikolaos Antonakopoulos Xenophon Sinopidis Dimitra Kritikou Alexandra Efthymiadou Gabriel Dimitriou Dionysios Chrysis

Background: Fetal Growth Retardation (FGR) is considered a risk factor for atherosclerosis and coronary artery disease in adulthood. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is reported to be elevated in atherosclerosis. Objectives: In this case-control study, we investigated whether FGR affects postnatal OPG serum concentrations and the possible association between OPG levels and aortic intima–media thickness (aIMT), an index of preclinical atherosclerosis. Methods: We studied 30 infants with FGR and 30 appropriate for gestational age (AGA) infants matched for gestational age and sex. Quantitative determination of plasma OPG was performed via enzyme immunoassay on the second (DOL2) and fifth (DOL5) day of life. aIMT was measured in the distal abdominal aorta and adjusted for aortic lumen diameter. Results: Infants with FGR had significantly higher OPG levels on both DOL2 and DOL5 as compared to controls (DOL2: 5.4 ± 1.0 pmol/L vs. 4.6 ± 1.0 pmol/L, p = 0.002 and DOL5: 5.1 ± 0.8 pmol/L vs. 3.9 ± 0.7 pmol/L, p < 0.001). Between DOL2 and DOL5, OPG concentrations did not change significantly in infants with FGR (difference 0.3 ± 0.2 pmol/L, p = 0.087) but decreased slightly in controls (difference 0.7 ± 0.3 pmol/L, p = 0.003). FGR was also associated with increased aIMT (0.11 ± 0.03 vs. 0.06 ± 0.02, p < 0.001). There was a positive correlation between OPG and aIMT on DOL2 (r = 0.494, p < 0.001), which became stronger on DOL5 (r = 0.791, p < 0.001). Conclusions: We report significantly increased concentrations of OPG in infants with FGR and a positive correlation with aIMT. Follow-up studies with repeat OPG and aIMT measurements may be indicated to evaluate whether these findings represent a permanent effect of FGR on the offspring.

Diseases doi: 10.3390/diseases14030099

Authors: Abraham Chorbajian Ira Glassman Akhila Swarna Manvita Mareboina Po-En Chen Jammal Abu-Khazneh Jiayan Tan Surbi Dayal Kian Yazdan Bianca Urness Vishwanath Venketaraman

Background/Objectives: Mycobacterial infections and autoimmune diseases affect many worldwide, and growing evidence suggests that there is a bidirectional relationship. This review examines mechanisms by which various autoimmune diseases predispose patients to mycobacterial infections, and vice versa. Methods: We conducted a PubMed/MEDLINE search using the keywords “mycobacterium” and the names of the autoimmune conditions to identify relevant papers. Results: Rheumatoid arthritis therapies, especially TNF-α inhibitors, raise tuberculosis (TB) and non-tuberculous mycobacteria (NTM) risk. Type 1 diabetes features impaired cell-mediated immunity and macrophage dysfunction, with evidence for Mycobacterium avium subspecies paratuberculosis (MAP) mimicry involving HSP65–GAD65. In systemic lupus erythematosus, immune dysregulation plus corticosteroids and cytotoxins elevates TB and NTM risk, amplified in endemic settings. In multiple sclerosis, heightened TLR2/4/9 signaling agents that inhibit pyrimidine synthesis may increase IL-10 and reduce antimycobacterial immunity. Crohn’s disease shows genetic susceptibility (e.g., NOD2 variants) and MAP detection, supporting impaired clearance of intracellular mycobacteria. Conclusions: Overall, evidence supports a bidirectional relationship: mycobacterial antigens can initiate or amplify autoimmunity via molecular mimicry and chronic stimulation, while autoimmune biology and iatrogenic immunosuppression increase susceptibility to infection. Implications include latent TB screening before immunosuppression, attention to local epidemiology, and vigilance for NTM. Research priorities include prospective cohorts, mechanistic studies of mimicry and NOD2–TLR pathways, safety registries, and trials of screening and prophylaxis.

Diseases doi: 10.3390/diseases14030098

Authors: Maria Carmina Pau Elisabetta Zinellu Barbara Piras Alice Nardi Maria Roberta Lacana Chiara Scala Angelo Zinellu Arduino A. Mangoni Ciriaco Carru Alessandro G. Fois Gaetano Caramori Pietro Pirina

Background: Silicosis is a progressive fibrotic lung disease caused by chronic inhalation of crystalline silica. Increasing evidence indicates that oxidative stress plays a central role in linking silica exposure to inflammation, tissue injury, and fibrosis. We conducted a systematic review to critically appraise the current evidence on the imbalance between oxidant and antioxidant markers in patients with silicosis compared with unexposed healthy controls. Methods: A systematic literature search was conducted in PubMed, Scopus, and Google Scholar from their inception to 30 November 2025. Eligible studies assessed oxidative stress biomarkers in biological samples from patients with silicosis and non-exposed controls. Results: Malondialdehyde (MDA) and Superoxide Dismutase (SOD) were the most frequently assessed oxidative and antioxidant markers, respectively, with MDA significantly increased and SOD decreased in patients with silicosis, highlighting amplified lipid peroxidation and impaired antioxidant defense. In addition, elevated levels of other oxidant molecules confirmed the presence of lipid, nitrosative, and DNA oxidative damage. Overall, antioxidant defenses were compromised, although some markers appeared to vary with disease stage. Conclusions: This review highlights the central role of oxidative stress in the pathogenesis and progression of silicosis. Future studies with larger cohorts and a broader range of biomarkers are needed to better understand oxidative imbalance and its potential utility for monitoring disease progression and assessing severity in this population.

Diseases doi: 10.3390/diseases14030097

Authors: Fangfei Wang Jinhao Li Xin Zhao Shaocheng Lyu Qiang He

Objectives: The TNM staging system for distal cholangiocarcinoma (dCCA) has limited accuracy due to its anatomical basis. This study developed a prognostic model integrating inflammatory-nutritional markers and tumor biomarkers to improve risk stratification. Methods: We analyzed 208 dCCA patients undergoing pancreaticoduodenectomy (2017–2024). Independent prognostic factors for overall survival (OS) were identified via Cox regression, including tumor marker (corrected CA19-9) and host status markers (PLR, CAR, and PNI). A nomogram was constructed and evaluated using calibration, ROC, and DCA. Patients were risk-stratified using the model’s score. Results: Four independent factors were identified: corrected CA19-9 (HR = 2.438), PLR (HR = 2.041), CAR (HR = 2.477), and PNI (HR = 0.415). The nomogram showed excellent discrimination for 1-, 3-, and 5-year OS (AUC: 0.847, 0.824, 0.858), good calibration, and clinical utility per DCA. Risk stratification significantly distinguished high-risk (n = 110) from low-risk (n = 98) groups (log-rank p < 0.0001). Discussion: This multidimensional model (tumor burden, inflammation, nutrition) outperforms TNM staging, highlighting host systemic status. Despite its single-center retrospective design, it shows promise for personalized risk assessment. Conclusion: The CINS (Cholangiocarcinoma Inflammation–Nutrition Score) accurately predicts prognosis and effectively risk-stratifies dCCA patients, aiding personalized treatment planning.

Diseases doi: 10.3390/diseases14030096

Authors: Zamza Khairullina Saulesh Kurmangaliyeva Rustam Yussupov Elmira Kelimberdiyeva Liliya Tryfonyuk Nasriddin Shapambayev Aizat Seidakhmetova Talgat Medetbekov Anton Tkachenko

A compelling body of evidence links pesticide exposure to human diseases. The liver plays a central role in the detoxification of pesticides, suggesting intense pesticide–liver cell interactions. A growing body of studies highlighted in this review supports the contribution of pesticides of various chemical classes to the development of non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), liver cirrhosis, viral hepatitis, hepatocellular carcinoma, etc., via disrupting lipid and carbohydrate metabolism and redox homeostasis, promoting endoplasmic reticulum stress and mitochondrial dysfunction, as well as stimulating apoptosis, fibrosis, and inflammation. In this review, we systematically illustrated an underappreciated mechanism of pesticide-induced overall and hepatic toxicity, i.e., the ability to induce non-apoptotic regulated cell death (RCD) pathways such as ferroptosis, necroptosis, and pyroptosis. Our analysis indicates that pesticides are implicated in driving liver diseases by inducing ferroptosis, necroptosis, and pyroptosis. Non-apoptotic RCDs mediate pesticide-induced liver steatosis and fibrosis. Furthermore, these cell death modalities fuel inflammation through the promotion of pro-inflammatory cytokine production and the generation of damage-associated molecular patterns. Understanding of deeper mechanisms of pesticide-induced effects on the non-apoptotic cell death machinery and subsequent immunogenic effects in liver pathology might help develop novel preventive strategies to reduce liver damage.

Diseases doi: 10.3390/diseases14030095

Authors: Elisabeth A. Mates Kellie Watkins Christopher Sanchez Nicolas Fiore Claire Phibbs

Background: Micronutrient deficiencies (MiDs) can increase medical complexity in hospitalized adults, but the prevalence in those without alcohol use disorder (AUD) is unknown. Our objectives were to prospectively determine the prevalence of thiamine, cobalamin, folate, magnesium, and cholecalciferol deficiencies in hospitalized veterans without AUD. Methods: Newly hospitalized veterans without AUD were recruited. Plasma thiamine, cholecalciferol, cyanocobalamin, folate, magnesium, C-reactive protein, albumin, and prealbumin were obtained. Interviews, physical exams, and medical record reviews were completed to assess clinical signs of MiDs, food insecurity, malnutrition, and hospitalization metrics. Pearson chi-square, Fisher’s exact, and logistic regression evaluated relationships among MiDs, malnutrition, food insecurity, demographics, and hospitalization metrics. Results: A total of 206 participants were enrolled, and 183 had partial results while 155 had complete results. The prevalences of deficiencies were 31.32% for magnesium, 27.07% for thiamine, 25.27% for cholecalciferol, 4.40% for cyanocobalamin, and 0.55% for folate. Malnutrition was reported by 50.60% of participants, and 56.00% reported food insecurity. Of those with biomarker MiDs, signs and symptoms were found in 97.92% with thiamine, 85.96% with magnesium, 67.39% with cholecalciferol, and 37.5% with cyanocobalamin deficiency. Cholecalciferol deficiency was associated with thiamine deficiency (p = 0.011, OR 3.180, CI 1.556–6.529), food insecurity (p = 0.0073, OR 2.690, CI 1.289–5.662), and longer length of hospital stay (p = 0.0401, IRR 1.295). All other associations were not statistically significant. Conclusions: In this exploratory pilot study, MiDs affected more than half of hospitalized veterans without AUD and were frequently associated with clinical signs and symptoms. TD affected one quarter of participants. Cholecalciferol deficiency was associated with longer hospital stays.

Diseases doi: 10.3390/diseases14030094

Authors: Young Joo Han

Background: Severe infectious diseases remain a preventable cause of adolescent mortality worldwide, yet global evidence focused on adolescence as a distinct life-course stage—and its vulnerability to health system disruption—remains limited. We examined long-term mortality rate trends, cause composition, and COVID-19–related changes among adolescents compared with late childhood. Methods: We analyzed Global Burden of Disease 2023 mortality estimates from 1990 to 2023 for six acute severe infectious causes: lower respiratory infections, meningitis, encephalitis, diarrhoeal diseases, typhoid/paratyphoid fever, and COVID-19. Analyses focused on adolescents aged 10–19 years, with children aged 5–9 years as a comparator. Mortality rates (per 100,000 population) were the primary metric. Trends were quantified using estimated annual percentage change (EAPC), and pre-COVID, COVID peak, and post-COVID periods were compared across Socio-demographic Index (SDI) categories. Results: From 1990 to 2023, mortality rates declined globally across all age groups; however, reductions among adolescents were consistently slower than those among children aged 5–9 years (EAPC −2.27% vs. −3.55% per year). Diarrhoeal diseases and typhoid/paratyphoid fever exhibited the steepest long-term declines, whereas lower respiratory infections and meningitis demonstrated slower reductions and maintained a substantial share of adolescent mortality risk. During the COVID-19 peak, mortality rates modestly increased among adolescents, while children continued their gradual decline. Mortality rates remained highest in low-SDI settings. Conclusions: Despite substantial global progress, severe infectious diseases continue to impose significant and inequitable mortality risk among adolescents. The persistence of a concentrated cause profile and the amplification of mortality during system disruption underscore adolescence as a vulnerable life-course stage requiring sustained prevention and resilient acute care systems.

Diseases doi: 10.3390/diseases14030092

Authors: Enas Khdeda Nora Naumann-Bartsch Nawres Khdeda Giulia Cramer Laura S. Hildebrand Paula Schiller Paul Julian Wagner Franziska Fahrmeier Ulrike Hüffmeier Stefanie Corradini Luitpold V. Distel Lukas C. F. Kuhlmann

Background/Objectives: DNA polymerase ε (Pol ε), encoded by POLE1, plays a pivotal role in high-fidelity DNA replication and in coordinating DNA repair. While pathogenic exonuclease-domain variants are well established in cancer, biallelic POLE1 variants remain largely unexplored in non-malignant human cells. Methods: Here, we analyzed primary fibroblasts derived from a skin biopsy of a compound-heterozygous patient carrying two POLE1 variants. Western blot analysis confirmed detectable Pol ε protein levels, indicating preserved protein expression despite the underlying variants. Results: Nevertheless, functional alterations were observed across multiple independent assays. Compared with healthy control fibroblasts, this patient-derived Pol ε fibroblast line exhibited reduced clonogenic survival following ionizing radiation. Surviving fractions were consistently lower across radiation doses from 2 to 4 Gy, with an approximately twofold reduction at 2 Gy and progressively greater differences at higher doses. The isoeffect dose corresponding to 10% survival was reduced relative to pooled control fibroblasts. In addition, chromosomal breakage was increased, supporting altered processing of radiation-induced DNA damage in this cellular model. Live-cell imaging and senescence assays revealed delayed proliferation and an increased proportion of senescent or senescence-like cells under baseline and genotoxic stress conditions, including enhanced senescence-associated β-galactosidase activity. Flow-cytometric analysis demonstrated S phase accumulation and G2/M arrest, consistent with replication stress and cell-cycle perturbation. Immunofluorescence staining revealed increased γH2AX foci, consistent with persistent DNA double strand breaks. RAD51 foci formation was not reduced; instead, increased RAD51 recruitment was observed under combined cisplatin and irradiation treatment, arguing against a primary defect in RAD51-mediated homologous recombination. POLE1-variant fibroblasts also showed impaired proliferative recovery, reduced wound closure, increased γH2AX accumulation following cisplatin exposure, suggesting heightened susceptibility to DNA crosslinking stress. Conclusions: Collectively, these findings provide the first functional characterization of a patient-derived POLE1-variant fibroblast cell line and indicate that altered Pol ε function may influence cellular responses to genotoxic stress. While based on primary fibroblasts from a single compound-heterozygous patient, validation in additional patient-derived or isogenic models will be required to determine the broader relevance of these findings.

Diseases doi: 10.3390/diseases14030093

Authors: Vitaliy V. Suvorov Davlet B. Sayitkuliev

The development of sternal infection in neonates after cardiac defect correction using median sternotomy is a serious complication, increasing the length of hospital stay, mortality, and treatment costs. One effective method for preventing this complication is the local administration of antibiotics to the wound. The objective of this study was to evaluate the effect of local antibiotic application on renal and hepatic function in the postoperative period. Methods: A retrospective analysis of the treatment of 130 newborns with congenital heart defects (CHDs) was conducted. A local antibiotic (vancomycin, 0.5–1 g) was administered to the wound during sternotomy closure to prevent sternal infection. Liver and kidney function were assessed based on changes in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine levels preoperatively and at 1 and 3 days postoperatively. Data were analyzed using repeated-measures analysis of variance (ANOVA) and Friedman’s chi-square test. Results: In total, local vancomycin was administered to the wound during sternotomy closure in 130 newborns after the correction of CHDs. Thirty-three patients were excluded from the study because intraoperative signs of acute kidney injury were noted. Thus, 97 newborns were included in the study and there were no cases of sternal infection in this cohort of patients. According to the results from the statistical data analysis, the preoperative ALT level was lower (Md = 19.2) than the postoperative ALT level on the first day (Md = 23, p = 0.076). On the third day of postoperative observation, after the local application of vancomycin, the ALT level increased slightly, but remained within the normal range (Md = 26, p < 0.001). The AST level on the first day was higher (Md = 43.2) than the preoperative AST level (Md = 39, p = 0.002). However, on the third day after surgery, the AST level decreased (Md = 36.4, p = 0.059) and remained within the normal range. The differences in the dynamics of ALT levels on the third day and AST on the first day after surgery were statistically significant. These levels corresponded to normal levels, leading to the conclusion that the local application of vancomycin has no effect on the levels of AST and ALT. On the first day after surgery, creatinine values were lower (M = 58.3) than before (M = 62.3, p = 0.073). On the third day of postoperative observation, the creatinine values were lower than before surgery (M = 56.8, p = 0.009). Creatinine levels decreased after the local application of vancomycin. Conclusions: The use of vancomycin locally in the wound intraoperatively in newborns after CHD repair did not result in a clinically significant increase in ALT, AST, or creatinine in the blood plasma in the early postoperative period, proving that there were no negative effects on renal and hepatic function during three postoperative days.

Diseases doi: 10.3390/diseases14030091

Authors: Maja Djordjevic Milosevic Anita Skakic Marina Andjelkovic Angelica Maria Delgado-Vega Håkan Thonberg Kristel Klaassen Jovana Komazec Bozica Kecman Nikola Jocic Erik Björck Anna Lindstrand Maja Stojiljkovic

Background/Objectives: Hypoparathyroidism (HPT) is a disorder caused by the insufficient production of parathyroid hormone (PTH). Its main features include decreased serum calcium, increased serum phosphorus, and abnormal bone modeling. In children, HPT is most commonly due to genetic disorders. Among rare genetic syndromes that can include HPT in their clinical spectrum is Kenny–Caffey syndrome (KCS) type 2. Conventional therapy for HPT primarily consists of oral calcium and active vitamin D metabolites. The major limitation of conventional therapy is hypercalciuria with an increased risk of nephrocalcinosis. However, a subset of patients fails to achieve the desired therapeutic response to conventional treatment; the reasons for this remain incompletely understood in some cases. The failure to achieve therapeutic targets and persistent hypercalciuria are the main indications for considering therapy with recombinant human parathyroid hormone (rhPTH). Methods: In addition to the review of the literature on rhPTH use in pediatric hypoparathyroidism, the first application of rhPTH in the treatment of genetically caused HPT in a child with Kenny–Caffey syndrome type 2 (KCS2) was described. Results: In this paper, we present a two-month-old infant who received rhPTH for 14 months. A heterozygous de novo p.Ser541Pro variant in the FAM111A gene was identified through whole-genome sequencing, indicating a diagnosis of KCS2. A biological mechanism linking FAM111A protein function with a more profound disruption of parathyroid development or function was proposed, suggesting that rhPTH therapy may be particularly beneficial in KCS2 cases. Conclusions: This is the first reported use of rhPTH in a child in Serbia and the first reported use in KCS type 2. By reviewing the literature, we analyzed the conditions in which rhPTH has been used, dosing approaches and durations, requirements for concomitant conventional therapy during rhPTH treatment, and the effects of rhPTH on calciuria. We provide an overview of rhPTH use in children. Additionally, based on the pathogenic genetic variant responsible for KCS2 in our patient, we propose possible etiologic explanations. This work aims to encourage a consideration of rhPTH use in children following its official approval.

Diseases doi: 10.3390/diseases14030090

Authors: Marian-Vlad Lăpădat Claudia Georgeta Iacobescu Ion Daniel Baboi Maria Nedelcu Lavinia Alice Bălăceanu Valeria Ioana Grigorescu Ion Dina

Liver cirrhosis represents the end stage of chronic liver disease arising from diverse etiologies and is characterized by persistent hepatic injury, architectural distortion, extensive fibrosis, and nodular regeneration. While decompensated cirrhosis is commonly associated with overt, life-threatening complications such as hepatic encephalopathy, hepatorenal syndrome and gastrointestinal bleeding, less apparent manifestations—including sarcopenia and metabolic disturbances—have emerged as major determinants of prognosis. Sarcopenia, defined by the progressive loss of skeletal muscle mass and function, is highly prevalent in cirrhotic patients and is closely linked to frailty, increased morbidity, mortality, and adverse liver transplantation outcomes. Increasing data support the role of gastrointestinal dysfunction in the pathogenesis of sarcopenia in liver cirrhosis. In chronic liver disease, intestinal dysfunction is exacerbated by portal hypertension, which promotes increased intestinal permeability and bacterial translocation. Furthermore, gut dysbiosis, a key feature of advanced liver disease, contributes to impaired digestion, malabsorption of macro- and micronutrients, increased intestinal permeability, malnutrition and systemic inflammation. These alterations promote negative energy balance, reduce muscle protein synthesis and enhance muscle catabolism, thereby accelerating muscle wasting. Despite increasing recognition of the individual roles of gut dysbiosis, malabsorption, and sarcopenia in cirrhosis, their complex interrelationship has not been comprehensively addressed. This narrative review synthesizes current evidence on the interplay between gut dysbiosis, malabsorption and sarcopenia in patients with liver cirrhosis. We discuss underlying pathophysiological mechanisms, clinical implications and potential therapeutic strategies, while highlighting existing knowledge gaps and future research directions. Improved understanding of the gut-liver-muscle axis may offer novel opportunities for early intervention and optimization of outcomes in this high-risk patient population.

Diseases doi: 10.3390/diseases14030089

Authors: Sophie Marie Pätzold Julia Christina Gross

Background: Extracellular vesicles (EVs) play an important role in tumor progression and intercellular communication, yet the contribution of specific cancer-related genes to EV secretion remains incompletely defined. Methods: To address this, we performed an siRNA-based loss-of-function screen targeting 30 frequently altered (proto-)oncogenes and tumor suppressor genes in the colorectal carcinoma cell line HCT-116 to assess their impact on EV release. EVs were isolated by sequential ultracentrifugation to obtain P14 and P100 fractions pelleting at 14,000× g or 100,000× g, respectively, and were characterized by nanoparticle tracking analysis, EV marker expression, and total protein quantification. Cell viability was assessed to control for potential apoptosis-related effects. Results: With few exceptions, knockdown of the investigated genes led to an increase in EV secretion. Silencing of KRAS and BRAF resulted in significantly elevated P14 EV levels, increased EV marker expression, and higher total protein content, while KRAS knockdown was additionally associated with a shift toward larger particle sizes. Downregulation of CTNNB1 increased P14 and decreased P100 EV secretion, whereas CDH1 knockdown reduced P14 EV levels and slightly increased P100 EVs. No general distinction between tumor suppressor genes and (proto-)oncogenes regarding their effects on EV secretion was observed, and cell viability was not significantly altered under the experimental conditions. Conclusions: These findings suggest that components of the Ras/Raf/MAPK and Wnt signaling pathways may contribute to the regulation of EV secretion in colorectal cancer cells.

Diseases doi: 10.3390/diseases14030088

Authors: Precious Patrick Edet Amal K. Mitra Melissa Dennis Md S. Zaman

Background: Microplastics and nanoplastics (MNPs) are ubiquitous environmental contaminants from plastic degradation, leading to human exposure through ingestion, inhalation, and dermal contact. While emerging evidence suggests potential health effects, comprehensive human-specific data remain limited. Objective: To systematically review evidence on MNP exposure and health impacts across human organ systems. Methods: Following PRISMA guidelines, we searched Embase, Environment Complete, MEDLINE, and Scopus for peer-reviewed English-language studies published between 2020 and 2025 that reported MNP exposure in adult human populations and addressed at least one organ system. Thirty studies met inclusion criteria, and all clinical studies were assessed for risk of bias using the Newcastle–Ottawa Scale (NOS) Results: Clinical studies consistently detected MNPs in human blood, thrombi, feces, and respiratory and reproductive tissues. Higher MNP burdens correlated with increased disease severity across cardiovascular, gastrointestinal, respiratory, musculoskeletal, and reproductive systems. In vitro studies using human-derived cell lines demonstrated that MNPs penetrate cells and disrupt cellular processes, inducing oxidative stress, cytotoxicity, mitochondrial dysfunction, inflammation, DNA damage, and apoptosis. Toxic effects were size-, polymer-, and concentration-dependent, with smaller particles exhibiting greater cellular uptake and toxicity. Conclusions: Human MNP exposure is widespread and associated with adverse biological effects across multiple organ systems. Further interdisciplinary research is needed to establish causal relationships and inform risk assessment and regulatory frameworks for plastic-associated contaminants. Other: This research received no external funding. The research protocol was registered with PROSPERO (Registration ID number CRD420261284559).

Diseases doi: 10.3390/diseases14030087

Authors: Marius Moroianu Ramona-Oana Roșca Laura-Carmen Cristescu-Budala Valeriu Ardeleanu Iulian Bounegru Mădălina Nicoleta Matei

Background: The COVID-19 pandemic severely restricted access to routine dental care, resulting in delayed treatment and increased presentation of dental emergencies. When combined with SARS-CoV-2 infection, these conditions may significantly impair psycho-social well-being and quality of life (QoL). This study assessed the impact of dental emergencies on QoL in patients with COVID-19. Methods: A cross-sectional case–control study was conducted between January 2022 and April 2024, including 240 adult patients with confirmed COVID-19. The case group comprised 60 patients presenting with dental emergencies, while the control group included 180 COVID-19 patients without emergency dental needs. Quality of life was evaluated using the 32-item Quality-of-Life Inventory (QOLI), yielding a continuous global score (SBQ) and an ordinal quality-of-life category (CGV). Group comparisons were performed using Welch’s t-test and logistic regression, with effect sizes and 95% confidence intervals reported. Multivariable analyses were adjusted for age and sex. Results: Patients with dental emergencies reported markedly poorer global QoL compared to controls (mean SBQ difference = −2.04 points; Cohen’s d = −1.50; p < 0.001). The presence of a dental emergency was strongly associated with severe QoL impairment, with emergency patients showing substantially higher odds of unfavorable CGV categories (adjusted OR ≈ 20.4; 95% CI: 8.6–48.5; p < 0.001). These associations remained robust after adjustment for demographic covariates. Conclusions: Dental emergencies in patients with COVID-19 are associated with a profound deterioration in quality of life. Ensuring timely access to emergency dental services during public health crises may substantially reduce psycho-social burden and improve patient-centered outcomes.

Diseases doi: 10.3390/diseases14030086

Authors: Vladimir Djan Vladimir Galić Nemanja Galetić Rastislava Krasnik Stanislava Bodonji Ivana Fratrić Anna Uram Benka Izabela Fabri Galamboš Nikola Bošković Jelena Mačar Novaković

Introduction: Idiopathic adolescent scoliosis (IAS) is commonly managed non-surgically; however, patients with a Cobb angle >45° before skeletal maturity often require posterior spinal fusion. Because this procedure carries a risk of neurological complications, intraoperative neurophysiological monitoring (IONM) is essential for early detection of spinal cord compromise. Case report: We present a 13-year-old girl with rapidly progressing scoliosis (Cobb angle 78°) who developed intraoperative changes in motor evoked potentials (MEPs) during posterior fusion from L4 to Th2. Total intravenous anesthesia without muscle relaxants was used, and standard multimodal IONM with somatosensory evoked potentials (SSEPs), MEPs, and spontaneous/triggered electromyography was applied. After induction of general anesthesia and surgical exposure, pedicle preparation at Th8–Th9 was followed by increased bleeding from the vertebral bodies and an abrupt loss of MEPs in both lower limbs, most prominently in the tibialis anterior muscles, whilst SSEPs remained unchanged. Intraoperative radiography confirmed correct screw placement, and anesthetic variables were reassessed with no reversible cause identified. Because MEPs remained absent, a wake-up test was performed and demonstrated intact voluntary movement, allowing the surgery to continue. By the end of the procedure, MEPs recovered fully on the left side and partially on the right. The patient awoke without any postoperative motor deficit. Conclusion: It is well known that motor responses can show variability during surgery, including a gradual decrease due to prolonged anesthesia. After excluding anesthetic and mechanical factors, one of the hypothetical explanations for the transient MEP loss was temporary venous congestion and retrograde flow within the intravertebral and epidural/intraspinal venous networks, resulting in reversible spinal cord drainage impairment. Another hypothetical possibility was transient vasospasm from surgical manipulation without direct neural or vascular injury. This case highlights the critical role of continuous multimodal neuromonitoring in detecting reversible spinal cord dysfunction and guiding safe decision-making during complex scoliosis surgery.

Diseases doi: 10.3390/diseases14030085

Authors: Ahmed Fadiel Kenneth D. Eichenbaum Aya Hassouneh Kunle Odunsi

Using AI to analyze metabolite profiles provides critical insights into health, aging, and disease. Metabolomic signatures reveal how lifestyle and therapy impact organ function and cancer progression. This review highlights emerging toolkits for high-throughput data analysis, emphasizing their integration with other omics. Advanced AI approaches facilitate metabolic pathway mapping and accelerate biomarker discovery. By combining AI with multi-omics, researchers can optimize interventions and enhance precision medicine. This article serves as a resource demonstrating AI’s potential in diagnostics and drug discovery.

Diseases doi: 10.3390/diseases14030084

Authors: Luis Alberto Gaitán-Cepeda Brenda Daniela Ortega-Hidalgo César Esquivel-Chirinos Iñigo Gaitán-Salvatella Stephany Paladines-Calle Daniela Carmona-Ruíz

Background/Objectives: Interest in Oral Kaposi’s sarcoma (OKS) has declined recently, potentially causing diagnostic errors due to physicians’ unfamiliarity with its presentation. This review describes clinical and demographic characteristics of OKS patients across epidemiological groups. Methods: A literature search of studies published from 1957 to December 2024 was conducted using PubMed, Web of Science, Cochrane Library, Scopus, and Google Scholar. Studies with confirmed oral Kaposi sarcoma were included, while those with incomplete data were excluded. Cases were grouped into classic, endemic, epidemic (AIDS-related), iatrogenic, and HIV-negative males who have sex with males. Sex distribution, mean age, clinical appearance, lesion topography, and cause-related information for iatrogenic forms were recorded. Results: A total of 1812 articles were identified through database search. During initial screening, 1162 articles were excluded as duplicates. Of the remaining 650 papers, 338 were dismissed based on title and abstract. Of the remaining 312 articles for full-text review, 93 could not be accessed, leaving 219 articles for analysis. After screening, 123 were excluded, resulting in 117 articles for review. These were categorized as: 16 classical KS, 7 endemic-African, 20 iatrogenic, 70 epidemic-HIV/AIDS-related, and four articles reporting cases among MSM not related to HIV infection. A total of 152 patients with OKS were analyzed. Mean age was 38.04 years (range, 2–86 years), and 75% were male. Of all cases, 64.4% were epidemic, 13.8% iatrogenic, 10.5% classical, and 4.6% endemic. The palate was most common (44.6% of lesions), followed by gingiva (25.3%). Nodular or papular presentations were most frequent. Conclusions. OKS occurs in all KS epidemiological forms, and since this tumor can mimic gingival and periodontal lesions, dentists and physicians must be alert to identify oral Kaposi’s sarcoma.

Diseases doi: 10.3390/diseases14020083

Authors: Silvia Afonso Joana Gonçalves Ana T. Brinca Luana M. Rosendo Tiago Rosado Ana Paula Duarte Eugenia Gallardo

Background/Objectives: Cannabinoids are increasingly recognised for their therapeutic potential beyond well-established indications such as chronic pain, multiple sclerosis, and specific epileptic syndromes. Recent advances have highlighted their possible role in less-common or orphan diseases, opening new avenues for pharmaceutical research and clinical application. Methods: This review provides a critical synthesis of the most recent evidence (2020–2025), available in PubMed and Scopus, regarding the use of cannabinoids in conditions including refractory epilepsies beyond Dravet and Lennox–Gastaut syndromes, movement disorders such as dystonia and Tourette syndrome, rare dermatological diseases like epidermolysis bullosa, and emerging data in Crohn’s disease. Results: Negative outcomes, such as those reported in Fragile X syndrome trials, are also discussed as instructive examples of methodological and pharmacological challenges. Particular attention is given to the optimisation of pharmaceutical formulations and advanced separation technologies, including oromucosal sprays, transdermal gels, and novel nanocarrier systems, which aim to overcome issues of bioavailability and variability in patient response. Finally, safety concerns, regulatory aspects, and the need for robust clinical trials are addressed. Conclusions: Overall, cannabinoids represent a promising yet underexplored therapeutic option in rare and complex disorders, warranting further investigation supported by innovative pharmaceutical approaches.

Diseases doi: 10.3390/diseases14020082

Authors: Karime Montes-Escobar Christian Eduardo Ramirez-Veloz Maribel Cecilia Pérez-Pirela Roy Lincoln Solórzano Giler Felix Vicente Zambrano Pico Fanny Soraya Reyes-Mena Julio Torres Yulixis Cano Aline Siteneski

Background/Objectives: Encephalitis and related acute encephalopathic syndromes represent severe neurological conditions with diverse etiologies and variable clinical outcomes. This study aimed to analyze nationwide hospitalization patterns for encephalitis-related diagnoses in Ecuador between 2018 and 2024. Methods: We used data from the Ecuadorian National Institute of Statistics and Census to estimate age-adjusted hospitalization and mortality rates according to ICD-10 codes. Binary and multinomial logistic regression models were employed to identify sociodemographic factors and diagnostic categories of encephalitis associated with hospitalization and in-hospital mortality. Results: A total of 1560 hospitalizations related to encephalitis-spectrum diagnoses were recorded, with an overall age-adjusted rate of 0.127 per 100,000 inhabitants and 6.0% in-hospital mortality. Unspecified encephalitis and encephalomyelitis were the most common diagnostic categories. Adolescents (10–19 years) were more frequently diagnosed with acute disseminated and bacterial meningoencephalitis, while patients aged ≥70 had higher odds of “other” encephalitis subtypes and the highest mortality risk (aOR = 0.265; 95% CI: 0.116–0.608). Indigenous individuals were more likely to be diagnosed with acute disseminated encephalitis, and Black individuals showed a higher risk for myelopathy associated with human T-cell lymphotropic virus type 1-associated myelopathy. Conclusions: Age and ethnicity significantly influence hospitalization due to encephalitis-related diagnoses in Ecuador. These findings provide epidemiological rates for a lower-middle–income country where the lack of precise diagnosis, age, and ethnicity contribute to the vulnerability of encephalitis.

Diseases doi: 10.3390/diseases14020081

Authors: Vittorio Del Fabro Lara Gullo Giuliana Giunta Giuseppina Uccello Claudia Bellofiore Cristina Lo Faro Dario Leotta Federica Elia Veronica Vecchio Chiara Sorbello Ugo Consoli Alessandra Romano Francesco Di Raimondo Manlio Fazio Fabio Stagno Concetta Conticello

Background: Multiple myeloma (MM) is a clonal plasma cell neoplasm representing the second most common hematological malignancy. The combination of daratumumab, lenalidomide and dexamethasone (D-Rd) was first approved by the EMA (European Medicines Agency) for the treatment of relapsed/refractory multiple myeloma (RRMM) patients, and was subsequently approved for first-line therapy, based on the results of POLLUX and MAIA trials, respectively. Methods: In this survey, we retrospectively collected data from 96 consecutive transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients treated with the D-Rd combination. Results: The median age was 73 years; the median progression free survival (mPFS) and median overall survival (mOS) were not reached (NR); the overall response rate (ORR), defined as patients who obtained at least a partial response (PR), was 90%; 59% of patients achieved a very good partial response (VGPR) or better. A strong negative correlation was observed between treatment response and elevated beta-2-microglobulin levels. Conclusions: This study confirms the efficacy of the D-Rd combination as first-line therapy for TIE-NDMM patients, suggesting that achieving at least a PR—and particularly a VGPR—may represent a strong predictor of long-term remission and survival, even in the era of new combinations based on the use of quadruplets.

Diseases doi: 10.3390/diseases14020080

Authors: Stella Baliou Manolis N. Tzatzarakis Andreas G. Tsantes Elena Vakonaki Petros Ioannou Michalis Kyriakakis Eleftheria Hatzidaki Iordanis Pelagiadis Eftichia Stiakaki Aristides Tsatsakis

With each replication cycle, telomeres shorten. Telomerase can slow or reverse the rate of telomere shortening. In the era of cancer immunotherapy, telomerase is a promising tumor-associated antigen due to its widespread and specific expression in cancer cells and its strong immunogenicity. Interestingly, telomerase-based vaccines eradicate telomerase-expressing cancer cells by increasing antigen-specific T-cell responses rather than by directly inhibiting telomerase enzymatic activity as telomerase inhibitors function. To support this, telomerase-based vaccines, including DNA, mRNA, peptide-, and cell-based vaccines, have been evaluated in clinical settings to elucidate their molecular mechanisms of action. The aim of this review is to present the clinical effectiveness of telomerase vaccines alone or in combination with immunotherapy. In particular, the therapeutic effectiveness of telomerase vaccines is influenced by the tumor microenvironment and can be substantially increased by combining them with immune checkpoint inhibitors. To further optimize telomerase-based vaccines, we discuss translational challenges and highlight the need for further optimization.

Diseases doi: 10.3390/diseases14020079

Authors: Lenci K. Vázquez-Jiménez Alonzo González-González Timoteo Delgado-Maldonado Rogelio Gómez-Escobedo Benjamín Nogueda-Torres Ana Verónica Martínez-Vázquez Eyrá Ortiz-Pérez Charmina Aguirre-Alvarado Verónica Alcántara-Farfán Joaquín Cordero-Martínez Lorena Rodríguez-Páez Adriana Moreno-Rodriguez Gildardo Rivera

Background: Chagas disease is a major public health problem, especially in Latin American countries, and benznidazole and nifurtimox are currently the only drugs available for its treatment. However, they present several disadvantages, such as low availability, high toxicity, and limited efficacy, which often result in treatment discontinuation. In recent decades, bioinformatics studies have accelerated the field of drug repurposing, reducing time and costs. In this study, the aim was to identify novel cruzain inhibitors from the analogs of FDA-approved drugs with trypanocidal activity. Methods: A ligand-based virtual screen, along with molecular docking analysis, was carried out, and the selected compounds were evaluated for their trypanocidal activity against trypomastigotes of two endemic Mexican strains and their inhibitory activity on cysteine proteases. Results: A cefsulodin analog (LC50 = 126.18 and 77.50 µM), two flucloxacillin analogs (LC50 = 94.05 and 101.73 µM; 48.74 and 64.49 µM), and one piperacillin analog (LC50 = 48.46 and 83.68 µM) had better trypanocidal activity and selectivity index against the NINOA and INC-5 strains than the reference drugs. Enzymatic evaluation showed that all four compounds inhibited cysteine proteases (IC50 < 840.03 µM). Furthermore, molecular dynamics simulations predicted the stability of the compound–protein complex, while the docking test on human cathepsin L predicted their potential selectivity. Finally, our in silico analysis of ADMET properties showed that all compounds exhibited favorable profiles. Conclusions: These results encourage the development of new and more potent anti-Trypanosoma cruzi agents using FDA-approved drugs as scaffolds.

Diseases doi: 10.3390/diseases14020078

Authors: Katarzyna Charkiewicz-Szeremeta Emilia Sawicka-Śmiarowska Marlena Dubatówka Małgorzata Knapp Klaudia Mickiewicz Jacek Jamiołkowski Andrzej Raczkowski Marcin Kondraciuk Anna Szpakowicz Katarzyna Ptaszyńska Karol A. Kamiński

Background: The number of patients with chronic coronary syndromes (CCS) is growing, influenced by factors such as increasing life expectancy and prevalence of risk factors. Thus, cardiovascular (CV) disease remains the leading cause of mortality and morbidity worldwide. The main objective of the study was to identify factors associated with long-term survival in patients with chronic coronary syndrome, with a focus on kidney function described by eGFR and albuminuria (assessed by uACR). Methods: The study comprised a total of 257 patients from Bialystok (Poland), aged ≤ 80 years, who 6–18 months earlier were hospitalized for acute coronary syndrome or elective myocardial revascularization. During the 80-month follow-up, 40 (15.6%) patients died, while there was no information about three (1.2%) patients. Patients with preserved eGFR and without albuminuria were characterized by the longest survival, with deterioration of prognosis in groups of progressive kidney dysfunction as defined by KDIGO based on eGFR and uACR. The primary endpoint was death from any cause. Results: Those who survived the 80-month follow-up period were younger (p < 0.001), had a lower waist circumference (p = 0.028), higher diastolic blood pressure (p = 0.026), lower NTproBNP (p < 0.001) and hsCRP (p = 0.001) concentrations, reduced eGFR (p = 0.004) and increased ACR (p = 0.023) were strongly associated with mortality. In logistic regression analysis with stepwise elimination of variables, the strongest factors affecting survival were hemoglobin concentration, left ventricle ejection fraction (LVEF) and hsCRP. Conclusions: Measurement of albuminuria, in addition to eGFR, allows patients to be correctly classified into CV risk categories and facilitates appropriate treatment of patients with CCS. Higher diastolic blood pressure (but still within normal range) was found in patients who later survived 6 years. Measurements of hsCRP, hemoglobin concentration and LVEF help to identify CCS patients at the highest risk of mortality in long-term follow-up.

Diseases doi: 10.3390/diseases14020077

Authors: Dorin Novacescu Talida Georgiana Cut Adelina Baloi Alexandra Herlo Ioana-Melinda Luput-Andrica Andra Elena Saizu Amelia Uzum Maria Daniela Mot Flavia Zara Dorel Sandesc Voichita Elena Lazureanu Adelina Marinescu

Background/Objectives: Clostridioides difficile infection (CDI) is a major healthcare-associated infection associated with profound antibiotic-induced gut microbiome disruption that frequently persists after clinical resolution. This pilot study aimed to characterize early post-infectious gut microbiome recovery following an inaugural CDI episode and to descriptively assess microbiome remodeling during adjunctive multi-strain probiotic supplementation. Methods: Adult patients with mild-to-moderate CDI were prospectively enrolled after completing standard antimicrobial therapy and received a 30-day course of a high-potency, 10-strain probiotic formulation. Stool samples were collected before and after supplementation and analyzed using 16S rRNA gene sequencing with microbiome-inferred functional profiling, alongside targeted screening for enteric protozoa and yeasts. Results: Five patients completed paired analyses. At baseline, all patients exhibited severe dysbiosis characterized by markedly reduced microbial diversity, depletion of Actinobacteria and short-chain fatty acid-producing taxa, expansion of Proteobacteria, and unfavorable inferred metabolic signatures. After supplementation, four of five patients were observed to exhibit increased microbial diversity and partial improvement in global dysbiosis indices. Microbiome recovery was heterogeneous and non-linear, involving variable reductions in Proteobacteria, recovery of Actinobacteria, or both, with incomplete normalization of taxonomic balances and inferred functions. Enterotype shifts were observed in three patients, consistent with ecological reorganization rather than full restoration. Baseline protozoal colonization resolved in affected patients, while fungal dynamics showed clearance or species-level replacement. No early CDI recurrences were observed during follow-up. Conclusions: Interpretation is limited by the single-arm design without a control group, which precludes distinguishing supplementation-associated changes from natural post-antibiotic recovery. Even so, our findings highlight the complexity and inter-individual variability of early post-CDI microbiome recovery and support further investigation of integrative microbiome profiling to describe post-infectious dysbiosis dynamics.

Diseases doi: 10.3390/diseases14020076

Authors: Rebecca Godfrey Otto Fenske Raj Selvaraju Ana Frappell Emine Cicek Imad Mohamed Imran Achuth Hosur Eleonora Manca Nitasha Singh Susan Ellery Victoria Parish David Hildick-Smith Jack McCready Sabina Dizdarevic Rachel Buxton-Thomas John Silberbauer Alexander Liu

Background: Cardiac sarcoidosis (CS) is associated with potentially serious complications, including heart failure and life-threatening arrhythmias. The diagnosis and management of CS is multifaceted, requiring a multi-disciplinary team (MDT)-based approach. A new regional CS clinical service was established in Sussex County (UK) in January 2025. This service is based on a core of cardiologists working with a wider MDT, including specialists in pulmonary sarcoidosis, nuclear medicine and cardiac electrophysiology. This study assessed the clinical performance of this new service. Methods: Patients with suspected CS referred to the Sussex CS Service between January and December 2025 were included, as compared to a control cohort of patients referred for CS assessment before the service was conceived. Results: Of the 51 CS service referrals, 13 patients fulfilled the Heart Rhythm Society (HRS) criteria, all of whom were correctly diagnosed with CS, whilst only two out of seven HRS-positive control patients were correctly diagnosed. In the 38 HRS-negative CS service referrals, 8 patients (21%) were still given a clinical CS diagnosis compared to none in the HRS-negative controls. Of the 21 patients diagnosed with CS, 7 (33%) had active myocardial inflammation and 8 (38%) had LV systolic dysfunction. Where indicated, immunosuppressive and heart failure therapies were initiated in all patients. Eight CS patients (38%) underwent implantable cardioverter defibrillator implantation. No deaths or heart failure hospitalisations occurred within the first 11 months. Conclusions: An MDT-based CS service model can provide multi-faceted care to patients, without major short-term adverse outcomes. The service model replicability and long-term outcomes require further assessment.

Diseases doi: 10.3390/diseases14020075

Authors: Georgios Vournas Leonidas Mourgos Michael Doumas Evangelos N. Liberopoulos Kalliopi Kotsa Theocharis Koufakis

Background: Atherosclerotic cardiovascular disease (ASCVD) frequently coexists with type 2 diabetes (T2D), amplifying morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RA) confer significant cardiovascular benefits and are recommended for patients with T2D and established ASCVD. However, real-world use may not reflect a complication-driven therapeutic approach. Methods: This retrospective study included adults with T2D and established ASCVD (prior myocardial infarction, ischemic stroke, transient ischemic attack, or symptomatic peripheral arterial disease) consecutively admitted to the internal medicine and cardiology departments of a tertiary hospital over a 60-day period. Pre-admission medication use, comorbidities, and laboratory parameters were recorded. Factors associated with GLP-1 RA use were assessed using logistic regression before and after 1:1 propensity score (PS) matching. Results: Among 202 eligible patients, 49 (24.3%) were treated with a GLP-1RA. GLP-1RA users were younger (71.9 vs. 77.8 years, p < 0.001), had lower hypertension prevalence (61.2% vs. 78.4%, p = 0.02), and were more frequently on insulin (69.4% vs. 25.5%, p < 0.001) and sodium-glucose cotransporter 2 inhibitors (55.1% vs. 28.1%, p = 0.001). After PS matching (48 pairs), demographic and comorbidity differences were attenuated, although insulin remained strongly associated with GLP-1RA therapy (Odds Ratio 11.85, p < 0.001). Neither cardiovascular disease burden—captured through the presence of multiple cardiovascular comorbidities—nor renal function were independently associated with GLP-1RA use after adjustment. Conclusions: In patients with T2D and established ASCVD, GLP-1RA use was more strongly associated with the intensity of glucose-lowering therapy—particularly insulin use—than with cardiovascular or renal risk profiles. These findings should be interpreted with caution given the retrospective observational design and the limited availability of glycated hemoglobin, anthropometry and diabetes duration data. However, they suggest that, in real-world clinical practice, GLP-1RA prescribing may remain predominantly glucose-centric rather than complication-driven, underscoring the need for improved implementation of contemporary diabetes guidelines.

Diseases doi: 10.3390/diseases14020074

Authors: Safya E. Esmaeel Altaf Saleh Mahdi Alanazi Alnzi Nouf Mofareh Mulahed Alanazi Rose Dahi Khamis Alanazi Amal Mohammed Shahi Alruwaili Areeb Rawaf Mohammed Alanzi Ahad Wadi Alnagzi Alanazi Yousef Wasmi Alenezi Ahmed Saleh Alanazi Rimas Khalid A. Alanazi Baraah Abu Alsel Eslam K. Fahmy Manal S. Fawzy

Background/Objectives: Chronic kidney disease (CKD) poses a significant health burden for individuals with diabetes mellitus, increasing morbidity and mortality. Understanding CKD and its risk factors is essential for early detection, effective management, and prevention of complications. This study aimed to assess CKD awareness as the primary outcome and to explore self-reported CKD prevalence and associated factors as secondary outcomes among patients with diabetes in the Northern Border Region, Saudi Arabia. Methods: A cross-sectional survey was conducted among 389 adults with a self-reported physician diagnosis of diabetes in the specified region, using a validated, self-administered online questionnaire. Data were analyzed to evaluate CKD awareness and identify perceived risk factors and factors associated with self-reported CKD. Results: Of the participants, 182 (46.8%) demonstrated good awareness of CKD, while the self-reported prevalence of CKD was 83 (21.3%). Males and unmarried participants were more likely to have good CKD awareness (p = 0.008 and 0.009, respectively). Significant associations were observed between self-reported CKD prevalence and age, sex, type of diabetes, family history of kidney disease, and comorbidities (all p < 0.05). Multivariate logistic regression showed that hypertension was strongly associated with self-reported CKD [aOR = 5.77; 95% CI: 3.12–10.67; p < 0.001], as was heart disease [aOR = 4.21; 95% CI: 1.35–13.13; p = 0.013]. Conclusions: Patients with diabetes in this region exhibited moderate awareness of CKD, with higher awareness among males and unmarried individuals. Hypertension and cardiac disease were significantly associated with self-reported CKD. These findings underscore the importance of targeted education, routine evidence-based screening, and structured management strategies for CKD within diabetes care and provide a basis for a regional strategic plan to strengthen CKD monitoring among patients with diabetes.

Diseases doi: 10.3390/diseases14020073

Authors: Hassaan Imtiaz Adil Sarvar Mohammed Avilash Mondal Lakshmi Sai Meghana Kodali Sai Gautham Kanagala Rupak Desai Umera Yasmeen Haritha Darapaneni Muhammad Usman Ghani Shweta Kambali Shrinivas Kambali Mohd S. Kanjwal

Background: Secondary pulmonary hypertension (SPH) predicts poor outcomes in obstructive sleep apnea (OSA) patients. This study examines sex/racial disparities, predictors, and inpatient mortality in SPH-related OSA hospitalizations. Methods: We used the National Inpatient Sample (2019) and ICD-10 codes to identify OSA-related hospitalizations with SPH. The burden of SPH and disparities by sex/race were assessed. We also compared the odds and predictors of in-hospital mortality in OSA patients with vs. without SPH. Results: Of total adult OSA hospitalizations (n = 2,317,136, median age of 66 [56–74] years, and males: 57.2%), 9.4% (218,795/2,317,136) had SPH. Females vs. males (11.3% vs. 8.1%) and Blacks vs. other race groups (13.5%) with OSA had a higher prevalence of SPH. The SPH cohort often consisted of females (51 vs. 41.9%), Blacks (20.9 vs. 14.0%), Medicare-insured (73.4 vs. 60.6%), and non-elective admissions (89.2 vs. 74.4%) vs. the non-SPH cohort. The SPH cohort also had a higher burden of complicated HTN (52.9 vs. 36.3%), DM with complications (42.7 vs. 32.4%), COPD (52.5 vs. 36.9%), history of prior MI (11.4 vs. 9.6%), and venous thromboembolism (10.4 vs. 8.4%). However, in-hospital mortality was more likely to be in males (OR 1.12; 95%CI 1.00–1.25, p = 0.048) vs. females, and OSA patients with metastatic cancer (OR 2.73; 95%CI 2.04–3.65) and solid non-metastatic tumors (OR 1.65; 95%CI 1.26–2.15) (p < 0.001). Conclusions: The prevalence of SPH with OSA was greater in females and Blacks, whereas males and Whites had higher subsequent inpatient mortality. More prospective studies are needed to understand the role of comorbidities on survival outcomes.

Diseases doi: 10.3390/diseases14020072

Authors: Juan Antonio Suárez-Cuenca Pablo Zermeño-Ugalde Diana Elisa Díaz-Jiménez Juan Antonio Pineda-Juárez Deyanhira Palacios-Colunga Alejandro Hernández-Patricio Eduardo Vera-Gómez Areli Romero-López María Fernanda Kuri-Pineda Andrea Ramírez-Coyotecatl Dulce Cecilia Vázquez-Ramos José Gutiérrez-Salinas Silvia García Christian Alejandro Delaflor-Wagner Christian Gabriel Toledo-Lozano Luis Montiel-López María Angélica Díaz-Aranda Alberto Melchor-López

Background: Sarcopenia is a progressive muscle disorder associated with metabolic syndrome (MS), in which early impairments in muscle strength and quality precede muscle mass loss. Simple, non-invasive measures such as handgrip strength, estimated appendicular skeletal muscle mass (eASM), and phase angle (PA) may aid early detection, while adipokines link muscle dysfunction to metabolic regulation. Objective: In the present study, we aimed to evaluate the association between sarcopenia markers and PA in patients with MS. Methods: A cross-sectional study was conducted in patients with MS, at a third-level hospital in Mexico City. Sarcopenia was assessed by handgrip strength and eASM; body composition and PA were measured using bioelectrical impedance; and plasma adipokines were quantified by ELISA. Results: Seventy-four (mean age, 57.7 years; 75% female; BMI, 32.5 kg/m2) participants with MS were included. Handgrip strength correlated with eASM (r = 0.64; p < 0.01) and PA (rho = 0.43; p < 0.01), and eASM also correlated with PA (rho = 0.40; p < 0.01) and predicted higher PA values (OR = 2.74; p = 0.042). The sarcopenic subgroup had lower brachial circumference and plasma adiponectin. Conclusions: Sarcopenia is frequent in MS and associated with lower adiponectin, suggesting a vulnerable condition. Functional/structural markers of sarcopenia showed significant correlation with PA, whereas combined methods may enhance the early detection and management of muscle deterioration in metabolic disease.