Diseases

16 pages, 849 KB

Open AccessArticle

Beyond Linear Risk: A U-Shaped Association Between Platelet Reactivity and Mortality in Coronary Artery Disease

by Sholpan Zhangelova, Orazbek Sakhov, Lyazat Abisheva, Dmitriy Polyakov, Farida Rustamova, Aizhan Almukhanova, Galiya Umenova, Gulzada Nurgaliyeva, Aigyul Izhanova, Dana Akhmentayeva, Dina Kapsultanova and Friba Nurmukhammad

Diseases 2026, 14(6), 194; https://doi.org/10.3390/diseases14060194 - 29 May 2026

Abstract

Background: Optimal platelet inhibition is essential for minimizing both thrombotic and hemorrhagic complications in patients with coronary artery disease (CAD). Although high on-treatment platelet reactivity (HPR) has been consistently associated with adverse clinical outcomes, the relationship between platelet reactivity—measured as P2Y12 reaction units [...] Read more.

Background: Optimal platelet inhibition is essential for minimizing both thrombotic and hemorrhagic complications in patients with coronary artery disease (CAD). Although high on-treatment platelet reactivity (HPR) has been consistently associated with adverse clinical outcomes, the relationship between platelet reactivity—measured as P2Y12 reaction units (PRU)—and cardiovascular mortality remains incompletely characterized. In particular, potential non-linear associations have not been adequately explored. Objective: We aimed to investigate the association between PRU and cardiovascular mortality in patients with CAD, with a specific focus on identifying potential non-linear relationships. Methods: We conducted a retrospective observational cohort study including 1000 patients with angiographically confirmed CAD treated at a tertiary cardiology center in Almaty, Kazakhstan, between 2024 and 2025. Platelet reactivity was assessed using the VerifyNow P2Y12 assay. Multivariable logistic regression models were used to identify independent predictors of cardiovascular mortality. To assess potential non-linear associations between PRU and mortality, restricted cubic spline regression was applied with predefined knot placement. Model performance was evaluated in terms of discrimination (C-statistic) and calibration (Hosmer-Lemeshow goodness-of-fit test). Results: In conventional linear regression models, PRU was not independently associated with cardiovascular mortality (odds ratio [OR] ~1.00; p > 0.05). However, spline-based analyses demonstrated a statistically significant non-linear (U-shaped) relationship between PRU and mortality risk (p for non-linearity = X). Both low and high PRU values were associated with increased mortality, whereas intermediate PRU levels corresponded to the lowest observed risk. Additional independent predictors of mortality included advanced age, diabetes mellitus, and elevated inflammatory markers. Conclusions: Our findings reveal a significant non-linear association between platelet reactivity and cardiovascular mortality in patients with CAD. Both insufficient and excessive platelet inhibition appear to confer increased risk, suggesting that optimal PRU targets may lie within an intermediate therapeutic range. These results support a paradigm shift toward more individualized antiplatelet therapy strategies guided by platelet function testing. Full article

(This article belongs to the Special Issue Insights into the Management of Cardiovascular Disease Risk Factors)

14 pages, 620 KB

Open AccessArticle

Early Language Development in Infants and Toddlers with Hemato-Oncological Diseases: Preliminary Outcomes of a Shared Reading Intervention

by Giusy Melcarne, Roberta Maria Incardona, Giulia Marangon, Silvia Sorbara, Alessandra Biffi and Marta Tremolada

Diseases 2026, 14(6), 193; https://doi.org/10.3390/diseases14060193 - 29 May 2026

Abstract

Introduction: Children diagnosed with hemato-oncological cancers need intensive medical treatments and prolonged hospitalizations, which are associated with increased risk of impairment across multiple neurodevelopmental domains, particularly when exposure occurs within the first three years of life. Objective: This pilot study aimed to explore [...] Read more.

Introduction: Children diagnosed with hemato-oncological cancers need intensive medical treatments and prolonged hospitalizations, which are associated with increased risk of impairment across multiple neurodevelopmental domains, particularly when exposure occurs within the first three years of life. Objective: This pilot study aimed to explore early language performance in children under 36 months of age hospitalized in a pediatric hemato-oncology unit and to preliminarily investigate changes over time and potential associations with an early speech–language stimulation intervention based on shared reading. Specifically, the study investigated differences between language comprehension and production, as well as variations in linguistic outcomes according to gender and pathology type (liquid vs. solid). Methods: The study employed a sample of 29 children aged 2 to 36 months (M = 20.76, SD = 9.52). Baseline linguistic assessment was conducted using observational measures across multiple language domains, including lexical development (PinG), morphosyntactic abilities (PCGO, GALS), and articulatory skills (BAMF), together with an evaluation of general cognitive functioning (Griffiths). The intervention consisted of in-person shared reading sessions combined with concurrent parental counseling. Exploratory analyses were performed to examine changes over time and group-related differences. Results: Among the sample, lexical comprehension exceeded production (p < 0.001). Sex differences emerged only for lexical comprehension, with males performing worse than females (p = 0.048). Comparisons by diagnosis showed that children with solid tumors had significantly better articulation than those with hematologic malignancies (p = 0.018), with a trend toward higher morphosyntactic production. Longitudinal analyses on 13 children re-evaluated after six months of weekly shared reading intervention showed potential improvements in articulation, lexical production, and morphosyntactic production (all p < 0.01). Conclusions: These preliminary findings suggest that children in pediatric hemato-oncology settings may be vulnerable to expressive language difficulties. Shared reading interventions may represent a promising supportive approach for early language stimulation; however, further studies with larger samples and controlled designs are needed to better understand their potential contribution and effectiveness. Full article

(This article belongs to the Section Oncology)

26 pages, 3915 KB

Open AccessArticle

Combined Synbiotics and Omega-3 Polyunsaturated Fatty Acids Enhance Clinical and Histological Recovery in DSS-Induced Ulcerative Colitis: An Experimental Study in Rats

by Ioannis Varnalidis, Orestis Ioannidis, Athina Papadopoulou, Theophilos Poutahidis, Ioannis Taitzoglou, Aliki Brenta, Elissavet Anestiadou, Savvas Symeonidis, Stefanos Bitsianis, Ioannis Mantzoros, Manousos George Pramateftakis, Efstathios Kotidis and Stamatis Angelopoulos

Diseases 2026, 14(6), 192; https://doi.org/10.3390/diseases14060192 - 29 May 2026

Abstract

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which alterations in the gut microbiota and dietary lipid composition play a central role; this study aimed to evaluate the effects of synbiotics, omega-3 polyunsaturated fatty acids, and their combination on clinical, [...] Read more.

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which alterations in the gut microbiota and dietary lipid composition play a central role; this study aimed to evaluate the effects of synbiotics, omega-3 polyunsaturated fatty acids, and their combination on clinical, macroscopic, microbiological, and histopathological outcomes in dextran sodium sulfate (DSS)-induced colitis in Wistar rats. Methods: Seventy-two male Wistar rats were randomly allocated to four groups (n = 18/group) and received 5% DSS in drinking water for eight days to induce colitis. Following DSS withdrawal and histological confirmation of colitis in sentinel animals, groups were treated for 8 days as follows: DSS (control), DSS-S (synbiotics, Ecologic^® 825), DSS-Ω3 (omega-3 fatty acid-enriched diet, ProSure^®), or DSS-S&Ω3 (combined therapy). Eight rats per group were sacrificed on days 4 and 8 post-DSS. Body weight, Disease Activity Index (DAI), distal colon length, hematologic parameters, bacterial translocation to the liver and mesenteric lymph nodes, histological colitis score, and myeloperoxidase (MPO)-positive cell counts were assessed. Results: DSS induced severe colitis characterized by diarrhea, rectal bleeding, and extensive mucosal erosions. After 8 days of treatment, the DSS-S&Ω3 group showed the greatest body-weight recovery (206.1→222.9 g, p < 0.05 vs. other groups), significantly preserved distal colon length, and the largest reduction in DAI (p < 0.05). Both the DSS-S and DSS-S&Ω3 groups demonstrated reduced bacterial translocation compared with DSS. The DSS-Ω3 group demonstrated persistent MPO-positive neutrophil infiltration compared with the DSS-S and DSS-S&Ω3 groups, whereas combined therapy was associated with lower MPO-positive cell counts. Histological colitis scores were significantly improved only in the DSS-S&Ω3 group (p < 0.05). Conclusions: In this DSS colitis model, the DSS-S&Ω3 group demonstrated superior clinical and histological outcomes compared with DSS-S or DSS-Ω3 alone, supporting further evaluation of combined synbiotic and omega-3 therapy as an adjunctive approach in ulcerative colitis. Full article

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11 pages, 996 KB

Open AccessCase Report

From Suspected Congenital Cytomegalovirus Infection to Malan Syndrome: Delayed Genetic Diagnosis Due to Diagnostic Anchoring

by Gordana Kovacevic, Sanja Cirkovic, Gordana Petrovic, Maja Stanojevic, Tanja Lalic, Nikola Ilic, Slavica Ostojic, Marina Siljic, Biljana Alimpic, Milanka Tesic, Predrag Ilic, Jovana Krstic, Jana Cirkovic and Adrijan Sarajlija

Diseases 2026, 14(6), 191; https://doi.org/10.3390/diseases14060191 - 28 May 2026

Abstract

Background: Diagnostic anchoring to a presumed infectious etiology may delay recognition of underlying genetic disorders in children with neurodevelopmental impairment. Case presentation: A case of a child with sensorineural hearing loss, visual impairment, and developmental delay is reported; cytomegalovirus (CMV) infection was identified [...] Read more.

Background: Diagnostic anchoring to a presumed infectious etiology may delay recognition of underlying genetic disorders in children with neurodevelopmental impairment. Case presentation: A case of a child with sensorineural hearing loss, visual impairment, and developmental delay is reported; cytomegalovirus (CMV) infection was identified at 6 months of age based on positive serology and detection of viral DNA in serum and urine. Given the timing of testing, congenital CMV infection (cCMV) could not be definitively confirmed. Antiviral therapy with valganciclovir was administered. Despite antiviral treatment, severe neurodevelopmental impairment and hearing loss persisted, associated with facial dysmorphism, bilateral cryptorchidism, pectus excavatum, and optic nerve hypoplasia, findings not fully attributable to CMV infection. Brain magnetic resonance imaging (MRI) showed nonspecific findings. Chromosomal microarray analysis (CMA) performed at 4.5 years of age identified a heterozygous 908 kb de novo microdeletion at 19p13.2p13.13 containing NFIX (MIM *164005) and other morbid genes. The de novo variant was confirmed by parental testing, and the unifying genetic diagnosis of NFIX-related Malan syndrome (MIM#614753) was established. Conclusions: This case emphasizes the importance of reconsidering the initial diagnosis when the clinical phenotype is not fully consistent with an infectious etiology. Early genomic testing, including CMA, may facilitate timely recognition of underlying genetic syndromes in children with complex neurodevelopmental presentations. Full article

9 pages, 456 KB

Open AccessCommunication

Frequency of Non-Type I/II CALR Mutations in Patients Undergoing Molecular Diagnostics for Myeloproliferative Neoplasms

by Tatiana Makarik, Elena Nikulina, Svetlana Treglasova, Elena Stepanova, Natalia Chernova, Bella Biderman, Alina Kokhno and Andrey Sudarikov

Diseases 2026, 14(6), 190; https://doi.org/10.3390/diseases14060190 - 28 May 2026

Abstract

Background/Objectives: Somatic CALR gene insertions/deletions in exon 9, causing frameshift, are a diagnostic sign of myeloproliferative neoplasms (MPNs). Besides the most common somatic mutations of type I (52 bp deletion) and type II (5 bp insertion), there are rare ones whose significance is [...] Read more.

Background/Objectives: Somatic CALR gene insertions/deletions in exon 9, causing frameshift, are a diagnostic sign of myeloproliferative neoplasms (MPNs). Besides the most common somatic mutations of type I (52 bp deletion) and type II (5 bp insertion), there are rare ones whose significance is not always clear. This study evaluates the frequency of rare mutations and demonstrates a germline rather than somatic nature for some of them. Methods: A retrospective analysis of 8417 blood samples subjected to molecular diagnosis of myeloproliferative neoplasm (MPN) was performed. Cases suspected as germline variants were sequenced, and paired samples (when available) of buccal epithelium were analyzed. Results: We have identified 632 CALR gene mutation-positive cases. Most of the cases were typical insertions/deletions (5 bp/52 bp). Non-type I/II frameshift or nonframeshift mutations were observed in 68 cases (11%). The buccal swab samples obtained from 4 patients confirmed the germline nature of these variants. It is worth noting that the MPN diagnosis for three of these patients was made considering the presence of the JAK2 V617F mutation (two cases) or BCR::ABL1 translocation (one case). In one case, the diagnosis of MPN was reclassified to CML. Conclusions: Non-type I/II CALR mutations, according to our data, could be found in 0.8% of MPN-suspected cases, and may not be associated with the diagnosis. The detection of a non-standard CALR mutation with an allelic frequency close to 50% should raise suspicion of the possibility of a germline CALR variant, and such cases should be investigated further. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis, Precision Medicine, and Artificial Intelligence in Hematologic Malignancies)

12 pages, 642 KB

Open AccessArticle

Associations Between Problematic Internet Use, Attentional Control, and Mental Health Symptoms in Romanian Adults: A Cross-Sectional Study

by Rebeca-Isabela Molnar, Camelia Sandu, Otilia-Rodica Buțiu, Horia Marchean, Dan Valeriu Nicolae Molnar and Adriana Mihai

Diseases 2026, 14(6), 189; https://doi.org/10.3390/diseases14060189 - 26 May 2026

Abstract

Introduction: Problematic internet use has been increasingly associated with depression, anxiety and other psychiatric symptoms; however, its impact on attentional functioning has not been thoroughly researched. This cross-sectional study was conducted in Târgu Mureș, Romania, and aimed to examine the associations between problematic [...] Read more.

Introduction: Problematic internet use has been increasingly associated with depression, anxiety and other psychiatric symptoms; however, its impact on attentional functioning has not been thoroughly researched. This cross-sectional study was conducted in Târgu Mureș, Romania, and aimed to examine the associations between problematic internet use, attentional control, and symptoms of depression and anxiety in adults, and to determine whether problematic internet use independently predicts attentional control after accounting for emotional symptoms. Methods: A cross-sectional study was conducted on 224 adults who completed an anonymous online survey between 1 January 2026 and 1 April 2026. Problematic internet use was assessed using the Compulsive Internet Use Scale-14 (CIUS-14), attentional control using the Attentional Control Scale (ACS), depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9), anxiety symptoms using the Generalized Anxiety Disorder-7 scale (GAD-7), and eating disorder risk using the SCOFF questionnaire. Descriptive statistics, internal consistency analyses, Pearson correlations, group comparisons according to the CIUS-14 screening threshold, and multiple linear regression analyses were performed. Results: Problematic internet use was significantly associated with lower attentional control (r = −0.493, p < 0.001), higher depressive symptoms (r = 0.408, p < 0.001), and higher anxiety symptoms (r = 0.467, p < 0.001). In the regression model, problematic internet use remained the only significant independent predictor of attentional control (B = −0.597, p < 0.001), whereas depressive and anxiety symptoms were not significant after adjustment. Participants above the CIUS-14 screening threshold reported significantly lower attentional control and higher depression and anxiety scores than those below the threshold. Conclusions: Problematic internet use was associated with poorer attentional control and greater emotional symptom severity in Romanian adults. These findings suggest that problematic internet use may be linked to a broader cognitive–emotional vulnerability profile. However, because of the cross-sectional design, self-report measures, convenience sampling, and lack of detailed information on specific online activities, the findings should be interpreted cautiously. Longitudinal studies using objective cognitive measures and more detailed assessment of digital behaviors are needed. Full article

(This article belongs to the Special Issue The Future of Mental Health: Bridging the Translational Gap Between Mechanism, Practice, and Ethics)

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14 pages, 1173 KB

Open AccessSystematic Review

Subclinical Myocardial Dysfunction Post Kawasaki Disease: A Systematic Review and Meta-Analysis

by Dafni Charisopoulou, Sotiria Iliopoulou, Stelina Al Kagiet, Nikolaos Antoniou, Parthena Theodoridou, Kyriakos Tsantekidis, Eftsathios Oflidis, Christos Karakatsanis, Panagiotis Theodorou and George Koulaouzidis

Diseases 2026, 14(6), 188; https://doi.org/10.3390/diseases14060188 - 26 May 2026

Abstract

Background: Kawasaki disease (KD) is an acute childhood vasculitis with well-recognized coronary involvement, but subtle long-term myocardial dysfunction may persist despite preserved conventional systolic indices. Two-dimensional speckle-tracking echocardiography enables sensitive assessment of left ventricular global longitudinal strain (GLS). Methods: A systematic review and [...] Read more.

Background: Kawasaki disease (KD) is an acute childhood vasculitis with well-recognized coronary involvement, but subtle long-term myocardial dysfunction may persist despite preserved conventional systolic indices. Two-dimensional speckle-tracking echocardiography enables sensitive assessment of left ventricular global longitudinal strain (GLS). Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020. PubMed, Scopus, Web of Science, and Google Scholar were searched for studies evaluating post-acute GLS in children or adolescents with prior KD compared with healthy controls. The outcome measure was the mean difference (MD) in GLS (KD minus control). Random-effects models were used for the primary analysis. Results: Four case–control studies involving 192 patients with prior KD and 138 healthy controls were included in the quantitative synthesis. Compared with controls, patients with prior KD had significantly less negative GLS values, indicating worse longitudinal deformation (pooled MD, 0.77%; 95% CI, 0.18 to 1.36; Z = 2.34; p = 0.019). Between-study heterogeneity was low (Q = 3.17, I² = 5.3%, tau² = 0.030). Leave-one-out analysis showed that the overall direction of effect remained positive, although confidence intervals widened when individual studies were omitted. Interpretation of the funnel plot was limited by the small number of studies. Conclusions: Children and adolescents with a history of KD demonstrate a modest but significant reduction in LV GLS during follow-up, consistent with persistent subclinical myocardial dysfunction. Speckle-tracking echocardiography may provide incremental value in the long-term cardiac assessment of selected patients with prior KD. Full article

(This article belongs to the Section Cardiology)

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13 pages, 1364 KB

Open AccessArticle

Gastric Juice miR-106a-5p as a Non-Invasive Biomarker of Neuroinflammation and Neurodegeneration: A Prospective Observational Study

by Sabrina Birsan, Iulian Roman-Filip, Mihai Rusu, Fratila Anca, Adrian Boicean, Pogony Sebastian, Grama Blanca and Corina Roman-Filip

Diseases 2026, 14(6), 187; https://doi.org/10.3390/diseases14060187 - 25 May 2026

Abstract

Background: Neuroinflammation is a key contributor to the progression of several neurodegenerative disorders, including Alzheimer’s disease, stroke, and small vessel disease. Emerging evidence highlights the role of circulating microRNAs (miRNAs) as non-invasive biomarkers of neuroinflammation and neuronal injury. miR-106a-5p, a member of the [...] Read more.

Background: Neuroinflammation is a key contributor to the progression of several neurodegenerative disorders, including Alzheimer’s disease, stroke, and small vessel disease. Emerging evidence highlights the role of circulating microRNAs (miRNAs) as non-invasive biomarkers of neuroinflammation and neuronal injury. miR-106a-5p, a member of the miR-17~92 cluster, is known to regulate inflammation, apoptosis, and vascular function. While typically studied in plasma or cerebrospinal fluid, gastric juice miRNAs represent a novel and underexplored source for biomarker discovery within the gut–brain axis. This exploratory study aimed to investigate the association between gastric juice miR-106a-5p expression and markers of neuroinflammation, including C-reactive protein (CRP), lactate dehydrogenase (LDH), and imaging-based evidence of neurodegeneration. Methods: A prospective, observational study was conducted on 38 participants (22 with neurodegenerative pathology and 16 healthy controls). Gastric juice samples were analyzed for miR-106a-5p using RT-qPCR, normalized to U6 snRNA. ΔCt values were used to determine relative expression. Statistical analyses included t-tests/Wilcoxon tests, ROC curve analysis, and correlation testing, with significance set at p < 0.05. Results: Patients with neurodegenerative changes exhibited significantly lower gastric miR-106a-5p expression compared to controls (p = 0.044). Elevated CRP and LDH levels were associated with higher ΔCt values (indicating lower expression), with p-values of 0.019 and 0.023, respectively. ROC analysis showed moderate diagnostic accuracy (AUC = 0.701) for miR-106a in identifying neurodegenerative status. miR-106a levels also correlated inversely with carotid intima-media thickness and brain MRI abnormalities, also reduced gastric miR-106a-5p expression is associated with systemic inflammation and neuroimaging evidence of neurodegeneration. Conclusions: While causality cannot be inferred, these findings suggest that gastric miR-106a may serve as a promising non-invasive biomarker within the gut–brain axis framework. Further longitudinal and mechanistic studies are warranted to validate its clinical utility and explore its potential role in monitoring neuroinflammatory conditions. Full article

(This article belongs to the Special Issue The Future of Mental Health: Bridging the Translational Gap Between Mechanism, Practice, and Ethics)

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12 pages, 701 KB

Open AccessReview

Growth Outcomes in Children with Familial Mediterranean Fever: A Question Beyond Chronic or Relapsing Inflammation

by Ignazio Cammisa, Clelia Cipolla and Donato Rigante

Diseases 2026, 14(6), 186; https://doi.org/10.3390/diseases14060186 - 23 May 2026

Abstract

Background/Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by missense MEFV mutations, leading to recurrent episodes of interleukin (IL)-1β-mediated inflammation, and represents a model of cytokine-induced growth hormone (GH) resistance. Chronic or relapsing inflammatory bouts may impair growth in FMF children [...] Read more.

Background/Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by missense MEFV mutations, leading to recurrent episodes of interleukin (IL)-1β-mediated inflammation, and represents a model of cytokine-induced growth hormone (GH) resistance. Chronic or relapsing inflammatory bouts may impair growth in FMF children through functional alterations of the GH-insulin-like growth factor 1 (IGF-1) axis; however, the impact and reversibility of growth deficit remain unclear. The aim of this review is to assess data related to linear growth in young patients with FMF. Methods: This scoping review was conducted following PRISMA guidelines, searching for studies evaluating growth outcomes in FMF via the PubMed database. Fourteen studies, including 1144 children, were analyzed, evaluating height, growth velocity, IGF-1 levels, and treatment effects of colchicine or IL-1–targeted biologics. Results: Growth was generally preserved in a considerable number of children with FMF. Longitudinal analyses showed improvement in height standard deviation scores (HSDS) along with earlier and higher cumulative doses of colchicine. FMF attack frequency and overall disease severity modestly seemed to influence growth, whereas inflammatory markers were inconsistently correlated with growth parameters. Biologic therapies targeting IL-1 (canakinumab and anakinra) also showed positive effects on HSDS. Children with specific MEFV variants (such as M694V) or higher disease activity scores were at risk of developing a subtle growth impairment. Conclusions: Data on final height, though limited, suggest the preservation of growth in most pediatric patients with FMF. The maintenance of a normal linear growth is related to regular treatment with colchicine, though IL-1 blockers also appear to be beneficial in refractory FMF cases. These data highlight the importance of periodic, proactive check-ups and regular growth monitoring in children with FMF. Full article

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16 pages, 4508 KB

Open AccessArticle

Presence and Dominance of Lactobacillus in the Endometrial Microbiome and Age-Related Associations in Patients with Recurrent Reproductive Failure

by Tatyana Bodurska, Tihomir Totev and Emiliana Konova

Diseases 2026, 14(6), 185; https://doi.org/10.3390/diseases14060185 - 22 May 2026

Abstract

Objectives: To evaluate the presence and dominance of Lactobacillus in the endometrial microbiome and their age-related associations in a large group of Bulgarian patients with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) who attend our clinic. Methods: This retrospective study included [...] Read more.

Objectives: To evaluate the presence and dominance of Lactobacillus in the endometrial microbiome and their age-related associations in a large group of Bulgarian patients with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) who attend our clinic. Methods: This retrospective study included 199 patients (mean age: 35.69 ± 5.16) with RIF (n = 103) and RPL (n = 96) who visited our fertility clinic between October 2019 and November 2022. Endometrial samples were analyzed using real-time PCR for target DNA sequences. Results: Overall, 62.8% (n = 125) exhibited an absence of Lactobacilli in their endometrial samples, with 63.1% (n = 65) of the RIF group and 62.5% (n = 60) of the RPL group showing a lack of Lactobacilli, with no statistically significant difference between the groups (p = 0.926). A Lactobacillus-dominant microbiome was found in 23.6% of the entire cohort (n = 47), 25.2% of the RIF group (n = 26) and 21.9% of the RPL group (n = 21). A reduced abundance of Lactobacilli was identified in 13.5% of the cohort (n = 27), though to differing degrees. There was no significant relationship between the abundance of Lactobacilli and belonging to the RIF or RPL group. A statistically significant difference was found in the mean age of two groups in cases with a Lactobacillus-dominant microbiome (mean age of 36.4 ± 4.8 years in the RIF group and 32.5 ± 3.5 years in the RPL group) (p = 0.004). Conclusions: Our findings demonstrate a high prevalence of non-Lactobacillus-dominant microbiomes in a large group of Bulgarian patients with RIF and RPL and significant age-related Lactobacillus changes in the microbiome of patients with RPL. These results point to the potential role of the uterine microbiome and support the need for further prospective studies, especially in cases of advanced maternal age. Full article

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15 pages, 1223 KB

Open AccessArticle

The Impact of Antithrombotic Therapy on Bleeding Complications in Percutaneous Liver Biopsy: Are the Withdrawal Criteria of Antithrombotic Agents in Japan Gastroenterological Endoscopy Society Guidelines for Gastroenterological Endoscopy Useful?

by Kensuke Kitsugi, Yoshisuke Hosoda, Go Murohisa, Yashiro Yoshizawa, Masaharu Kimata, Yosuke Kobayashi, Shuhei Unno, Toshihiro Takayanagi and Kazuhito Kawata

Diseases 2026, 14(6), 184; https://doi.org/10.3390/diseases14060184 - 22 May 2026

Abstract

Background: Bleeding is the most important complication of percutaneous liver biopsy. However, there are many unknowns regarding the management of antithrombotic agents in percutaneous liver biopsy. We investigated whether percutaneous liver biopsy could be performed safely by withdrawal of antithrombotic agents in accordance [...] Read more.

Background: Bleeding is the most important complication of percutaneous liver biopsy. However, there are many unknowns regarding the management of antithrombotic agents in percutaneous liver biopsy. We investigated whether percutaneous liver biopsy could be performed safely by withdrawal of antithrombotic agents in accordance with the criteria of gastroenterological endoscopy guidelines. Methods: A retrospective study was conducted on patients who underwent percutaneous liver biopsy. Antithrombotic agents were discontinued in accordance with the withdrawal criteria in the Japan Gastroenterological Endoscopy Society guidelines for gastroenterological endoscopy. Results: A total of 630 cases were enrolled, including 64 cases receiving antithrombotic therapy. Bleeding complications occurred in 6.7% of cases with antithrombotic therapy and 2.1% of patients without antithrombotic therapy, with no significant difference between the two groups (p = 0.069). Major bleeding requiring surgical intervention or transarterial embolization was not observed in cases with antithrombotic therapy. Only one case (1.6%) developed thromboembolism after withdrawal of antithrombotic agents. Even after propensity score matching, there was no significant difference in the bleeding complication rates between the cases with and without antithrombotic therapy in either tumor biopsy (p = 0.599) and non-tumor biopsy (p = 0.440). Univariate and multivariate analysis revealed that low platelet count (≤10 × 10⁴/μL) was a significant risk factor for bleeding complications (OR = 1.07, 95%CI 1.01–1.15, p = 0.034), whereas antithrombotic therapy was not a significant factor (OR = 2.7, 95%CI 0.79–9.22, p = 0.114). Conclusions: This study suggests that percutaneous liver biopsy may be performed safely in cases receiving antithrombotic therapy by discontinuation of antithrombotic agents in accordance with the withdrawal criteria of Japan Gastroenterological Endoscopy Society guidelines for gastroenterological endoscopy. Full article

(This article belongs to the Section Gastroenterology)

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11 pages, 252 KB

Open AccessArticle

Association Between Picky Eating and Stunting Among Ethnic Minority Children Aged 12–35 Months in a Mountainous Area of Northern Vietnam: A Cross-Sectional Study

by Thi Thu Ha Le, Thanh Hang Ngo, Thi Hoa Ho, Thi Thu Nguyen, Huu Chinh Nguyen, Thi Tu Quyen Bui, Thi Kieu Chinh Pham, Thi Thu Lieu Nguyen and Thi Huong Le

Diseases 2026, 14(6), 183; https://doi.org/10.3390/diseases14060183 - 22 May 2026

Abstract

Background: Stunting remains a major public health problem among ethnic minority children in mountainous areas of Vietnam. Picky eating has been suggested as a potential behavioral risk factor for poor child growth, but evidence from vulnerable rural populations remains limited. This study examined [...] Read more.

Background: Stunting remains a major public health problem among ethnic minority children in mountainous areas of Vietnam. Picky eating has been suggested as a potential behavioral risk factor for poor child growth, but evidence from vulnerable rural populations remains limited. This study examined the association between picky eating and stunting among ethnic minority children aged 12–35 months in Vietnam. Methods: This cross-sectional study was conducted from October to November 2025 in two communes of Phu Tho province, formerly part of Lac Son District, Hoa Binh Province, Vietnam. A total of 341 children aged 12–35 months and their caregivers were included. Data were collected using structured interviewer-administered questionnaires on feeding practices and child characteristics. Picky eating was assessed based on caregiver-reported behaviors. Anthropometric measurements were performed according to standard procedures, and height-for-age Z-scores were calculated using the WHO Child Growth Standards. Zinc status was assessed in a subsample of children. Bivariate and multivariable logistic regression analyses were conducted to identify factors associated with stunting. Adjusted odds ratios (AORs) with 95% confidence intervals (95% CIs) were reported. Results: The prevalence of picky eating was 39.6%, while 24.9% of children were stunted. Zinc deficiency was identified in 41.9% of children with available blood samples. In multivariable analysis, picky eating was significantly associated with increased odds of stunting (AOR = 3.63; 95% CI: 1.71–7.70). Snacking before main meals was also independently associated with stunting (AOR = 1.81; 95% CI: 1.01–3.24). In contrast, zinc deficiency was associated with stunting in crude analysis but was not statistically significant after adjustment. Other factors, including child age, sex, caregiver identity, and timing of complementary feeding, were not independently associated with stunting. Conclusions: Picky eating was common and was independently associated with stunting among ethnic minority children in this mountainous setting. These findings suggest that behavioral feeding practices, particularly picky eating and pre-meal snacking, warrant attention in nutritional programs targeting this population; however, longitudinal studies are needed to confirm the direction of this relationship. Full article

30 pages, 2103 KB

Open AccessSystematic Review

Total Neoadjuvant Therapy, Organ Preservation and Beyond: A State-of-the-Art Systematic Review and Critical Appraisal of Locally Advanced Rectal Cancer Management

by Nabil Ismaili

Diseases 2026, 14(5), 182; https://doi.org/10.3390/diseases14050182 - 21 May 2026

Abstract

Background: Locally advanced rectal cancer (LARC) management has evolved, but surgery (total mesorectal excision, TME) remains the curative cornerstone. Total neoadjuvant therapy (TNT) and organ preservation (OP) have emerged as response-adaptive strategies. We conducted a state-of-the-art systematic review to critically appraise TNT efficacy, [...] Read more.

Background: Locally advanced rectal cancer (LARC) management has evolved, but surgery (total mesorectal excision, TME) remains the curative cornerstone. Total neoadjuvant therapy (TNT) and organ preservation (OP) have emerged as response-adaptive strategies. We conducted a state-of-the-art systematic review to critically appraise TNT efficacy, trade-offs, OP feasibility, and emerging biomarkers. Methods: Following PRISMA 2020 guidelines, we searched PubMed, MEDLINE, Scopus, and EMBASE (1990–March 2026) plus ASCO/ESMO abstracts (2020–2026). We included phase II/III randomised controlled trials and major prospective studies evaluating neoadjuvant strategies in non-metastatic LARC. Risk of bias was assessed using RoB 2. Given heterogeneity, a narrative synthesis was performed (PROSPERO: CRD420251252675). Results: From 2847 records, 45 publications (30 trials) were included. For high-risk LARC (cT4, cN2, EMVI+, MRF+, tumour deposits), TNT improves disease-free survival and reduces distant metastases versus standard chemoradiotherapy (RAPIDO, PRODIGE 23, STELLAR, TNTCRT). However, TNT increases locoregional recurrence risk with short-course radiotherapy (RAPIDO: 10% vs. 6%; Polish II: no sustained overall survival benefit). Organ preservation is achievable in expert centres (OPRA: 54% 5-year TME-free survival; OPERA; CAO/ARO/AIO-16), but surgery remains the durable standard for most patients. De-escalation (PROSPECT, CONVERT, FOWARC, OCUM) avoids radiotherapy in low-risk (mrMRF−) patients without compromising local control. Lateral pelvic lymph node involvement (LPLN+) remains a negative prognostic factor even after TNT. Immunotherapy added to TNT (UNION, STELLAR II, SPRING-01, PRECAM) increases pCR rates (40–60%) but remains investigational. ctDNA-guided adaptation (CINTS-R) is feasible but requires mature data. Conclusions: Surgery (TME) is the definitive curative treatment for LARC. TNT is a preferred intensification strategy for high-risk patients, but trade-offs between systemic and local control must be individualised. Organ preservation is safe only for selected patients in expert centres. Immunotherapy-TNT combinations and ctDNA guidance are promising but not yet standard. This review provides an evidence-based roadmap for integrating these advances without losing sight of surgery’s central role. Full article

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25 pages, 5115 KB

Open AccessSystematic Review

Preoperative Melatonin for Women Undergoing Cesarean Section: A Systematic Review and Updated Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

by Zlatko Kirovakov, Andriana Jovanovska-Kirovakova, Angel Yordanov, Eva Tsoneva, Monika Obreykova and Plamen Penchev

Diseases 2026, 14(5), 181; https://doi.org/10.3390/diseases14050181 - 20 May 2026

Abstract

Introduction: Effective perioperative management in cesarean section remains essential to optimize maternal outcomes. Melatonin (M) has been proposed as a potential adjunct due to its analgesic, anxiolytic, and antiemetic properties; however, evidence from randomized controlled trials (RCTs) remains inconsistent. This meta-analysis aimed to [...] Read more.

Introduction: Effective perioperative management in cesarean section remains essential to optimize maternal outcomes. Melatonin (M) has been proposed as a potential adjunct due to its analgesic, anxiolytic, and antiemetic properties; however, evidence from randomized controlled trials (RCTs) remains inconsistent. This meta-analysis aimed to evaluate the efficacy and safety of preoperative melatonin compared with placebo in women undergoing cesarean section. Methods: A systematic search was conducted in PubMed, Scopus, and Cochrane from inception to 15 March 2026 for studies evaluating pregnant women undergoing elective cesarean section receiving preoperative melatonin versus placebo (P) (PROSPERO “CRD420261355468”). Heterogeneity was assessed using the I² statistic and Cochrane Q test. Risk ratios (RRs) and standardized mean differences (SMDs) were computed using a restricted maximum-likelihood estimator random-effects method. Trial Sequential Analysis (TSA) was performed to assess the robustness and sufficiency of the evidence. Results: Seven RCTs were included with 552 patients (melatonin: 278; placebo: 274). Preoperative melatonin significantly reduced opioid consumption in the overall pooled analysis (RR 0.31, 95% CI 0.12 to 0.80; p = 0.030; I² = 50%), and TSA supported the robustness of this opioid-sparing finding under the selected assumptions. Postoperative pain scores were also significantly lower in the melatonin group (SMD −2.10, 95% CI −2.43 to −1.78; p < 0.01; I² = 22%). The incidence of postoperative nausea showed a trend toward reduction in the conventional meta-analysis (RR 0.49, 95% CI 0.23–1.04; p = 0.057; I² = 34%); although TSA suggested a possible benefit, this finding should be considered exploratory. No significant difference was observed in intraoperative blood loss (SMD −0.33, 95% CI −1.53 to 0.88; p = 0.60; I² = 94%). Conclusions: Preoperative melatonin may be a promising adjunct in cesarean section, particularly for reducing postoperative pain and overall opioid consumption. TSA findings support the opioid-sparing result under selected assumptions, while the possible effect on postoperative nausea remains exploratory. Further high-quality trials are warranted before routine clinical implementation can be recommended. Full article

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13 pages, 992 KB

Open AccessArticle

Tailored Surgical Treatment and Outcomes in Solid Pseudopapillary Neoplasms of the Pancreas: A Case Series of Five Consecutive Paradigmatic Cases

by Arianna Pontrelli, Giovanna Di Meo, Francesco Paolo Prete, Piercarmine Panzera, Giuseppe Massimiliano De Luca, Natale Calomino, Maria Teresa Mita, Belinda De Simone, Michele Bisceglie, Monica Maria Miccoli, Alfio Gianalberto Testini, Michele Covelli, Massimo G. Viola, Luigi Marano and Mario Testini

Diseases 2026, 14(5), 180; https://doi.org/10.3390/diseases14050180 - 20 May 2026

Abstract

Background: Solid pseudopapillary neoplasms of the pancreas (SPN-P) are rare, low-grade malignancies primarily affecting young women. While surgical resection is definitive, the optimal balance between oncological radicality and functional preservation remains a clinical challenge. This study evaluates tailored surgical strategies utilizing minimally invasive [...] Read more.

Background: Solid pseudopapillary neoplasms of the pancreas (SPN-P) are rare, low-grade malignancies primarily affecting young women. While surgical resection is definitive, the optimal balance between oncological radicality and functional preservation remains a clinical challenge. This study evaluates tailored surgical strategies utilizing minimally invasive and parenchyma-preserving techniques. Patients and Methods: We conducted a multi-institutional retrospective analysis of SPN-P cases treated between March 2020 and May 2023. Out of 167 pancreatic resections, five paradigmatic cases were identified. We analyzed the decision-making process for preoperative staging (CT/MRI/EUS-FNB), surgical approach (open, laparoscopic, or robotic), and the implementation of parenchyma-preserving versus formal resections. Results: The cohort included four females and one male (mean age 40.6 years; range 13–73). Surgical approaches were tailored to tumor location and patient characteristics: two patients underwent pancreatoduodenectomy (one laparotomic, one laparoscopic), two underwent distal pancreatectomy (one robotic, one laparoscopic), and one pediatric patient underwent laparoscopic parenchyma-preserving central pancreatectomy. R0 resection was achieved in all cases. No Grade B/C postoperative pancreatic fistulas (POPF) or complications Clavien-Dindo ≥III occurred. At a mean follow-up (FU) of 38.4 months (range 20–58), the disease-free survival rate was 100%. One patient developed new-onset diabetes mellitus following distal pancreatectomy. Conclusions: A tailored surgical approach—integrating robotic, laparoscopic, and parenchyma-preserving techniques—may enable excellent oncological outcomes while minimizing morbidity. For SPN-P, the choice of procedure should prioritize the preservation of pancreatic function, particularly in young patients, without compromising surgical margins. Full article

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18 pages, 769 KB

Open AccessSystematic Review

Alternative Therapeutic Approaches in the Management of Gastroparesis: A Systematic Review

by Desaree Tan, Serena Singh, Usha Krishnan and Vincent Ho

Diseases 2026, 14(5), 179; https://doi.org/10.3390/diseases14050179 - 20 May 2026

Abstract

Background: Gastroparesis is characterised by prolonged gastric emptying in the absence of mechanical gastric obstruction. When symptomatic, gastroparesis significantly impacts quality of life. While current consensus emphasises medical, surgical, or nutritional therapies, data evaluating the efficacy of alternative therapies remains scarce. Here, we [...] Read more.

Background: Gastroparesis is characterised by prolonged gastric emptying in the absence of mechanical gastric obstruction. When symptomatic, gastroparesis significantly impacts quality of life. While current consensus emphasises medical, surgical, or nutritional therapies, data evaluating the efficacy of alternative therapies remains scarce. Here, we review the efficacy of alternative therapies; acupuncture, electroacupuncture, moxibustion, and herbal medicine as management strategies. Methods: A systematic literature review of the literature was performed until February 2025. All papers were published from 2001 to 2024. This search focusses on the efficacy of acupuncture, electroacupuncture, moxibustion, and herbal medicines for management of gastroparesis. A comprehensive search was performed in PubMed, Embase, Medline, Google Scholar, Science Direct, and Web of Science. There were no language restrictions. Study outcomes were compared in a narrative synthesis and quality was assessed using Critical Appraisal Skills Programme (CASP) checklists. Results: We identified 68 studies of acupuncture, electroacupuncture, moxibustion, and herbal medicine as alternate therapies for gastroparesis. The total patient sample size of included studies was 4566, with a mean sample of 70.25 per study. The focus of studies comprising our review was electroacupuncture (11%), moxibustion (11%), acupuncture (29%), and herbal medicine (49%). Control comparisons were made with Mosapride, Metoclopramide, Domperidone, and Itopride. Conclusions: We found that alternative therapies are effective for the management of gastroparesis. However, the review was limited by heterogeneous study designs, incomplete methodological reporting, and publication bias. Future investigations must focus on long-term randomised control trials encompassing large sample sizes. Full article

(This article belongs to the Special Issue Recent Advances in Gastroenterology and Nutrition (2nd Edition))

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11 pages, 367 KB

Open AccessArticle

Clinical Course and Perinatal Outcomes of Pregnant Women with COVID-19 in Central Greece: A Prospective Cohort Study

by Christos Donoudis, Antonios Garas, Sotirios Sotiriou, Ioannis Pantazopoulos, Athanasios Pagonis, Eleni Zachari, Nikoletta Daponte, George Syrogiannopoulos, Ioanna Grivea and Alexandros Daponte

Diseases 2026, 14(5), 178; https://doi.org/10.3390/diseases14050178 - 19 May 2026

Abstract

Background: During the COVID pandemic increased rates of intensive care unit (ICU) admission, mechanical ventilation, caesarean delivery, and preterm birth among women with SARS-CoV-2 infection in pregnancy were recorded. Purpose: This study describes the clinical course and perinatal outcomes of pregnant women with [...] Read more.

Background: During the COVID pandemic increased rates of intensive care unit (ICU) admission, mechanical ventilation, caesarean delivery, and preterm birth among women with SARS-CoV-2 infection in pregnancy were recorded. Purpose: This study describes the clinical course and perinatal outcomes of pregnant women with COVID-19 across pre- and post-vaccination periods. Methods: This study included all pregnant women with confirmed SARS-CoV-2 infection who subsequently delivered at the University General Hospital of Larissa between March 2020 and May 2023. Demographics, comorbidities, gestational age at infection and at delivery, COVID-19 symptoms, need for hospitalization, obstetric complications, mode of delivery, and neonatal outcomes were documented. An assessment of ischemia-modified albumin (IMA) was performed in a subset of women. Results: A total of 327 women (including 14 twin gestations) were recorded. Most women experienced mild disease while a minority required hospital admission, or intensive care (1.8 and 0.3% for the studied population, respectively). Fever and upper respiratory symptoms predominated, while radiologic evidence of pneumonia was rare. Overall preterm birth (<37 weeks) occurred in 13% of pregnancies and caesarean section in about two thirds of deliveries. Neonatal outcomes were favorable, with low rates of neonatal intensive care unit (NICU) admission and no early neonatal deaths. IMA values were higher during acute infection and declined towards recovery. Conclusion: Pregnant women with COVID-19 in Central Greece had predominantly mild clinical courses and excellent perinatal outcomes. IMA may represent a biologically plausible marker of disease activity, but further studies are needed. Full article

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20 pages, 2412 KB

Open AccessArticle

EVG-Based Periarterial/Perivenous Invasion (periA/V) as a High-Sensitivity Surrogate Marker for Lymph Node Metastasis in pT1 Invasive Breast Carcinoma of No Special Type

by Chikara Mashiba, Akihiro Shioya, Takanobu Takata, Motona Kumagai, Miyako Shimasaki, Takeru Oyama, Yusuke Haba, Emi Morioka, Masafumi Inokuchi and Sohsuke Yamada

Diseases 2026, 14(5), 177; https://doi.org/10.3390/diseases14050177 - 19 May 2026

Abstract

Background/Objectives: Conventional assessments of lymphatic invasion in the primary tumor may fail to identify lymph node metastasis (LNM) in breast cancer. We evaluated periarterial or perivenous invasion (periA/V), using Elastica–van Gieson (EVG)-stained sections, as a histological marker associated with LNM in invasive breast [...] Read more.

Background/Objectives: Conventional assessments of lymphatic invasion in the primary tumor may fail to identify lymph node metastasis (LNM) in breast cancer. We evaluated periarterial or perivenous invasion (periA/V), using Elastica–van Gieson (EVG)-stained sections, as a histological marker associated with LNM in invasive breast carcinoma of no special type (IBC-NST), focusing on the impact of invasive tumor size. Methods: We retrospectively analyzed 213 IBC-NST cases. PeriA/V was defined as tumor nests in direct contact with perivascular elastic fibers on EVG-stained sections. Diagnostic performance was compared with that of conventional LI markers (hematoxylin and eosin and D2-40), with stratified analyses by pathological T category (pT1 vs. pT2–4) and pT1 subcategories (pT1a, pT1b, and pT1c). Results: LNM was observed in 87 cases (40.8%). Overall, periA/V demonstrated high sensitivity (97.7%) and negative predictive value (NPV; 93.5%). In pT1 tumors (n = 130), periA/V achieved 100% sensitivity and 100% NPV (27/27), and was consistently present in all node-positive pT1b–c tumors. In multivariate analyses, periA/V remained independently associated with LNM in the pT1 group (odds ratio [OR]: 16.08, p = 0.003) and pT1c subgroup (OR: 14.7, p = 0.010). In pT2–4 tumors, periA/V became frequent regardless of nodal status, indicating reduced discriminatory value. Conclusions: In this exploratory single-center cohort, EVG-based periA/V demonstrated high sensitivity for LNM in pT1 IBC-NSTs, with periA/V negativity consistently observed among node-negative cases. These preliminary findings suggest that periA/V may potentially contribute to LNM risk assessment in early-stage breast cancer. Full article

(This article belongs to the Section Oncology)

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61 pages, 2300 KB

Open AccessSystematic Review

Effects of Heat Waves on Hospitalizations, Emergency Department Visits, and Outpatient Care in Frail Older Adults: A Systematic Review and Meta-Analysis

by Antonio Pinto, Flavia Pennisi, Stefania Borlini, Emanuele De Ponti, Carlo Signorelli, Andrea Cozza, Vincenzo Baldo and Vincenza Gianfredi

Diseases 2026, 14(5), 176; https://doi.org/10.3390/diseases14050176 - 18 May 2026

Abstract

Background/Objectives: Heat waves are increasingly frequent and intense climate events with significant implications for public health, particularly among frail older adults. While most evidence has focused on mortality and morbidity, healthcare service utilization represents an additional and potentially more sensitive indicator of heat-related [...] Read more.

Background/Objectives: Heat waves are increasingly frequent and intense climate events with significant implications for public health, particularly among frail older adults. While most evidence has focused on mortality and morbidity, healthcare service utilization represents an additional and potentially more sensitive indicator of heat-related health burden. Methods: A systematic review and meta-analysis was conducted following the PRISMA guidelines and prospectively registered in PROSPERO (CRD420251107598). PubMed/MEDLINE, Scopus, and Web of Science were searched up to August 2025. This study aimed to systematically review and quantitatively synthesize the evidence on the association between heat wave exposure and healthcare utilization—including hospitalizations, emergency department (ED) visits, and outpatient care—among frail older adults. Pooled effect estimates (RRs, IRRs, and ORs) were calculated using random-effects models. Heterogeneity was assessed using the I² statistic, and sensitivity analyses were performed by outcome type, effect measure, and risk of bias. Results: Fifty-five studies met the inclusion criteria. Heat wave exposure was consistently associated with increased healthcare utilization. Both hospitalizations and ED visits showed significant increases during heat wave periods, with results remaining robust across sensitivity analyses. Evidence on outpatient care was limited but suggested a similar pattern. Substantial heterogeneity was observed across studies, reflecting variability in exposure definitions, populations, and study designs. Overall, the methodological quality of the included studies was acceptable, with most presenting a low-to-moderate risk of bias. Conclusions: Heat waves are associated with increased healthcare utilization among frail older adults, indicating a relevant burden on healthcare systems. Healthcare utilization may represent a sensitive indicator of heat wave impact, complementing traditional clinical outcomes. Full article

(This article belongs to the Special Issue Frailty and Frequent Hospitalizations in Older Adults: Risk, Management, and Interventions)

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