Liu W et al. · Jul 1, 2026
Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as 'HPV-associated cervical poorly cohesive carcinomas' (HPV-associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV-associated CPCC cases were analyzed and classified into three histological subtypes: signet-ring cell carcinoma (n = 4), not otherwise specified (n = 6), and mixed types (n = 6). All patients were Chinese (median age: 46 years; range: 30-66). Vaginal bleeding was the primary presenting symptom (100.0%). High-risk human papillomavirus (HPV) was identified in all tumors, with HPV-18 as the predominant genotype (n = 13), HPV-16 in two cases, and a single case exhibiting concurrent infection with HPV-16, -18, and -58. Overall, 56.3% presented with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB-IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody-drug conjugate targets was observed, with HER2-low expression (33.3%), and positive staining for Trop-2 (85.7%), nectin-4 (42.9%), and tissue factor (92.3%). During follow-up, disease-specific mortality was 50.0%. The 3-year overall survival rate was 56.3%, which was significantly lower in advanced-stage disease (45.0%) than in early-stage disease (75.0%). Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.
Medicine
Tomberli L et al. · Jul 1, 2026
Background A strong sense of school belonging (SoSB) supports students' emotional well-being, engagement, and adjustment. For students hospitalized because of chronic or complex conditions, maintaining SoSB is challenging yet essential for successful school reintegration. Methods Using a Grounded Theory approach, this study combined interviews with 16 parents, 32 mainstream teachers, 31 hospital teachers, and one association, alongside drawings from 14 hospitalized students. Data were collected pre- and post-COVID-19. Drawings were analyzed through a meaning-making approach, and all materials underwent iterative coding and constant comparison. Results Students reported strong emotional bonds with hospital teachers but felt forgotten by their mainstream schools. Peer contact was limited, and teachers felt unprepared to manage absences and reintegration. Structural gaps and weak communication between schools hindered continuity. Both formal (e.g., remote lessons) and informal (e.g., messages, drawings) exchanges, along with psychologists and associations, emerged as protective factors. Implications for school health policy, practice, and equity Findings highlight the need for integrated school-health policies, teacher training, and structured collaboration to ensure equitable relational continuity. Conclusions Promoting SoSB during hospitalization is crucial for recovery, resilience, and educational equity.
Medicine
Han Y et al. · Jul 1, 2026
Background Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance. Purpose To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment. Methods TUM-SAM integrates nnU-Net-based lesion detection with a tumor-adapted Med-SAM segmentation model to enable prompt-free, fully automated segmentation. Training used 301 patients (2548 lesions), and external evaluation used an independent cohort of 105 patients (397 lesions). Segmentation accuracy was benchmarked against DeepMedic and nnU-Net using Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (HD95). Two physicians contoured all external cases, and a third physician contoured a 20-patient subset for a blinded, tumor-level, multi-rater preference study. Pairwise contour preferences were analyzed using a Bradley-Terry probabilistic model to obtain bias-adjusted estimates of relative contour quality while accounting for rater-specific tendencies and case difficulty. Results In the external cohort, TUM-SAM achieved a lesion-wise detection sensitivity of 0.94 and outperformed DeepMedic and nnU-Net across all tumor sizes, with a mean DSC of 0.84 and HD95 of 1.9 mm (nnU-Net/DeepMedic: DSC 3.3 mm). Across voxel-wise evaluation, TUM-SAM's geometric performance fell within the range of inter-observer variability among physicians and was sensitive to reference construction. In contrast, in the blinded rater study, experts preferred TUM-SAM-generated contours over individual physician contours in 81-87% of raw comparisons; Bradley-Terry analysis yielded conservative, bias-corrected win probabilities of 55-56%, indicating consistent preference after adjustment for rater and case difficulty. Conclusion Using a bias-controlled, blinded multi-rater evaluation framework, TUM-SAM demonstrates brain metastasis segmentation quality that is consistently preferred by expert physicians, highlighting the limitations of agreement-based voxel-wise metrics under inter-observer variability. These findings underscore the dependence of conventional evaluation on reference definition and support preference-based assessment as a complementary approach for evaluating AI segmentation quality in BM MRI.
Medicine
Kuchar L et al. · Jul 1, 2026
Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disorder caused by deficient activity of lysosomal alpha-galactosidase A (AGAL, E.C. 3.2.1.22) due to pathogenic variants in the GLA gene (HGNC:4296, Xq22.1). Plasmatic deacylated globotriaosylceramide (lysoGb3) is elevated in FD patients as a reflection of lysosomal accumulation of Gb3. Specific (AGALopathic) GLA variants have been recently shown to accumulate within the secretory pathway and trigger endoplasmic reticulum stress and unfolded protein response rather than result in profound enzymatic deficiency. In part due to lack of integrative measures of clinical severity and biochemical/molecular parameters, specific impacts and consequences of X-chromosomal inactivation (XCI) on clinical manifestation in FD female heterozygotes still remain to be fully understood. Our study aimed at evaluation of XCI (% of inactive wt GLA allele) in untreated female FD heterozygotes with classic FD (n = 17), late-onset FD (n = 19) and individuals carrying GLA variants (p.(L394P) (n = 7), p.(A143T) (n = 4), and p.(D313Y) (n = 4)) with predominant AGALopathic effects. XCI was correlated with age of the patients, clinical phenotype, (residual) AGAL activity, and lysoGb3. AGAL activity corresponded to XCI independently of the type of the GLA mutation. The best separation of the clinical phenotypes (classic FD, late-onset FD and AGALopathy) was achieved by correlating XCI to the ratio of AGAL activity to lysoGb3. This three parametric calculated marker was then confronted with the Mainz Severity Score Index (MSSI) to generate an Integrative Clinical-Laboratory quotient (ICLq). ICLq discriminated the three female patient groups and demonstrated group-dependent differences in its average age-related increase.
Medicine
Khodarahmi M et al. · Jul 1, 2026
Introduction Diminished ovarian reserve (DOR) represents a significant contributor to female infertility and adverse reproductive outcomes. Although diet may play a role, the specific impact of phytochemical-rich dietary patterns remains underexplored. So, we aimed to investigate the association between adherence to a dietary phytochemical index (DPI) and the likelihood of DOR among women attending fertility clinics. Methods This case-control study enrolled 370 women, comprising 120 individuals diagnosed with DOR and 250 age- and body mass index (BMI)-matched controls with normal ovarian reserve. A validated semi-quantitative food frequency questionnaire (FFQ) was applied to assess dietary intakes and, accordingly, DPI was calculated as the proportion of total energy intake obtained from phytochemical-abundant foods. Antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) measurements were utilized as indicators of ovarian reserve. The association between DPI and the odds of DOR was investigated using multivariable logistic regression models. Results Our findings showed that higher DPI was associated with a reduced odds of DOR (Q4 vs. Q1 OR: 0.79; 95% CI: 0.55-0.93; p-trend = 0.010). After adjustment for physical activity and energy intake, the association remained significant (OR: 0.80; 95% CI: 0.54-0.95; p-trend = 0.033). In the fully adjusted model, which included additional adjustments for fat mass and body mass index, women in the highest DPI quartile had 27% lower odds of DOR compared to those in the lowest quartile (OR: 0.73; 95% CI: 0.42-0.97; p-trend = 0.02). Besides, in the control group, AFC differed significantly across DPI quartiles (p Conclusion Our findings suggest that a phytochemical-rich diet may help reduce the odds of DOR, highlighting the role of diet in reproductive health. However, further prospective studies and mechanistic research are warranted to confirm these results and clarify underlying pathways.
Medicine
van der Gaag M et al. · Jul 1, 2026
Aims The staging model in psychiatry is heuristic and evolving, provoking debate and stimulating alternative views. This paper reviews major controversies in the field of staging and prevention of psychosis. Methods We review the literature on the classification model, the continuum model and the dynamic systems model applied to psychiatry. Other controversies are stigmatisation of early detection, the prevention paradox and the interpretation of data on prevention of transition to psychosis. Results DSM classifications still lack validity. The continuum model supports preclinical stages but has no discrete conversions to different stages of illness. The emerging dynamic systems model builds on the interaction of symptoms eliciting networks of symptoms, while at the same time it explains sudden catastrophic shifts (transitions) between different states of equilibrium. Stigmatisation of early psychosis can be balanced against the benefits of early interventions. The prevention paradox states that only a minority of first episode cases arises from the high-risk group. However, there are many reasons to combine indicated prevention with population-based preventive interventions. A long-lasting controversy is on the interpretation of the research data. Several meta-analyses are reviewed on methodological issues. Conclusion The staging model is adequate to conceptualise psychiatric disorders and the progress over time in more chronic stages. No one is suggesting that help-seeking patients with an ARMS should be denied access to psychosocial treatment and it is recommended and necessary to continue building age and stage specific services to treat them and continue with research into risk factors and helpful interventions.
Medicine
Allen J et al. · Jul 1, 2026
Issues Alcohol use disorder (AUD) shows sex-related differences in prevalence, harm and treatment response. Despite growing interest in sex differences, evidence synthesis evaluating pharmacotherapy effectiveness by sex remains limited. Approach Web of Science, PubMed, Scopus, PsycINFO and Cochrane were searched twice. Eligible records included RCTs or non-randomised studies of adults with AUD receiving pharmacological interventions (licensed or off-label), and reporting or providing outcomes (binary relapse or continuous alcohol consumption change) by sex. Multi-level random-effects models calculated risk ratios (RR) and standardised mean differences (SMD), with sex as a moderator. Key findings Twenty-eight studies (25,041 participants, 25% female) were included. No outcomes were rated low risk of bias; non-RCTs were moderate-to-high quality. Overall treatment effects vs. control were small for abstinence (RR = 0.96, 95% CI [0.52, 1.74]; 4 studies; I 2 = 95%) and modest for consumption reduction (SMD = 0.23, 95% CI [0.01, 0.45]; 13 studies; I 2 = 89%); sex did not meaningfully moderate these outcomes (ratio of RR = 1.04, 95% CI [0.87, 1.25]; ΔSMD = 0.05, 95% CI [-0.09, 0.18]). Power was low (median 13.7%), requiring ~6358 participants per group to detect the observed sex difference. Narrative synthesis suggested possible sex differences for naltrexone and baclofen, while highlighting the influence of drug (e.g., tolerability), participant (e.g., drinking motives) and design factors (e.g., recruitment setting) on treatment response. Implications AUD pharmacotherapies provide modest benefits, with sex differences remaining unclear. Future trials should be adequately powered, report sex-specific outcomes and consider adherence, tolerability and psychosocial moderators. Conclusion Evidence for sex-specific efficacy remains inconclusive. Patterns for naltrexone and baclofen warrant exploration in large, rigorously designed, sex-stratified trials.
Medicine
Nabhani R et al. · Jul 1, 2026
Background Antioxidants have gained significant attention for improving sperm parameters. Green tea and catechin, known for their potent antioxidant properties, are particularly interesting in this context. Objective This study investigated the in vitro effects of green tea extract (GTE) and (+)-catechin on semen quality parameters of Arabi rams during chilled storage. Methods The pooled and diluted semen was divided and supplemented with GTE and (+)-catechin (50, 100, 150 and 200 µg/mL levels). The control group did not receive any supplements. Sperm quality and semen pH were evaluated at 1, 24, 48 and 72 h after storage. Seminal plasma MDA level was measured at 72 h of semen storage. Results Supplementation with GTE and (+)-catechin improved sperm motility more than control (p Conclusions GTE and catechin enhance semen parameters during chilled storage, with optimal effects at specific concentrations. High levels of GTE may negatively impact sperm quality, underscoring the importance of precise dosing in semen preservation.
Medicine
Ma Y et al. · Jul 1, 2026
Background Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque-resident mechanisms through which the diabetic milieu promotes macrophage lipid-oxidative injury are not fully understood. Methods We used apolipoprotein E-deficient (ApoE -/- ) mice with Mex-3 RNA-binding family member A (MEX3A) deficiency and primary bone marrow-derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid-peroxidation injury. Results MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4-hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9-mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation-qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid-peroxidation injury in Mex3a-knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re-expression. Ferrostatin-1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4-linked ferroptosis-associated mechanism in plaque macrophages. Key points MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid-peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin-1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.
Medicine
Jeandel M et al. · Jul 1, 2026
Transmethylation reactions, which are crucial for regulating gene expression, require S-adenosyl-L-methionine (SAM) as methyl donor. The substrate for SAM synthesis is methionine, which can be produced by methionine synthase (MS) whose dysfunctions are associated with SAM synthesis alterations despite the presence of methionine in the milieu, suggesting a preferential use of the methionine produced de novo. This highlights the crucial role of MS activity and would imply nuclear import of SAM or MS nuclear localization, allowing protein-protein interactions with the methionine adenosyl-transferases (MAT) responsible for SAM production. Using subcellular fractions of human cells, biochemical and cellular approaches, including incorporation of 14 C-methyltetrahydrofolate, here we provide the experimental evidence of MS localization and activity in the nucleus where it interacts with MATα2, the catalytic subunit of MATII, and the methyltransferase DNMT3b. These results support the idea that spatial compartmentalization of one-carbon metabolism could play a major role in regulating the epigenome.
Medicine