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PubMed2026

Obtaining a Diagnostic Yield via Scan findings prior to the introduction of SEquencing retrospectivelY (ODYSSEY): a cohort study.

OBJECTIVE: To determine the retrospective yield of prenatal exome sequencing (PES) by establishing the proportion of children with a postnatal monogenic diagnosis that could have been diagnosed prenatally if PES had been available. METHODS: The study cohort comprised a sample of children in Northern Ireland, born between January 2010 and January 2018 (predating routine availability of PES), who received a monogenic diagnosis postnatally via next generation sequencing as part of either of two UK-wide studies (the 100 000 Genomes Project (2015-2018) or the Deciphering Developmental Disorders study (2011-2015)). Clinical data were collected retrospectively and correlated with the current UK National Health Service PES protocol, including the phenotypic eligibility criteria for PES and the associated fetal anomalies gene panel. Cases were considered retrospective diagnoses if the fetal phenotype would have been eligible for PES and the diagnostic gene was included on the test panel, meaning prenatal diagnosis in this current era could have been feasible. RESULTS: Of 101 children, 17.8% (95% CI, 10.3-25.3%) had both an eligible fetal structural anomaly (FSA) (i.e. high-risk FSA) and a diagnostic gene on the associated test panel, meaning that they could have been diagnosed prenatally in the current clinical landscape. The median length of the diagnostic odyssey for this subgroup of children was 3.7 years (1354 (range, 822-2450) days). Moreover, 58.4% (n = 59) of cases had no anomalies detected prenatally and 19.8% (n = 20) had a FSA that would not meet the eligibility criteria for PES (low-risk FSA). Although these cases would have been ineligible for PES under the current clinical pathway, 89.9% (n = 71/79) were affected by severe or profound syndromes. Postnatally, the most common functional anomalies were neurodevelopmental delay/intellectual disability and/or behavioral abnormality, which were observed in 80.2% (n = 81) of the included children. However, 80.2% (n = 65/81) of these affected children did not present with fetal anomalies eligible for PES. CONCLUSIONS: Almost one-fifth of children with a monogenic condition included in this study could have received a diagnosis via modern PES, avoiding a diagnostic odyssey lasting almost 4 years. However, despite having a monogenic condition, over half of the children did not present with any structural anomalies in utero. This demonstrates the degree to which fetal imaging is limited in its ability to reassure parents of the absence of a fetal genetic syndrome. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Humans↗

PubMed2026

Outcomes of Suture Tape-Augmented ACL Reconstruction in Patients With High Internal Rotational Tibial Subluxation: A Minimum 3-Year Cohort Study.

BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) using hamstring tendon (HT) autografts faces persistent challenges of graft failure, especially in patients with high internal rotational tibial subluxation (IRTS). HYPOTHESIS: Patients with high IRTS who undergo HT autograft ACLR with suture tape augmentation (STA) will have lower graft failure rates and superior clinical outcomes as compared with those without STA. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective cohort study included patients with high IRTS-defined as lateral minus medial anterior tibial subluxation >5.8 mm based on prior studies-who underwent primary ACLR using HT autografts with STA and had a minimum follow-up of 3 years. Propensity score matching (1:1) was performed to identify a control group of patients with similarly high IRTS who underwent HT ACLR without STA. Postoperative outcomes were assessed by the International Knee Documentation Committee score, Lysholm score, and Tegner activity scale, as well as by return-to-sport status and graft failure. Clinically meaningful improvements were evaluated by the minimal clinically important difference, Patient Acceptable Symptom State, and substantial clinical benefit. RESULTS: This study included 62 patients with high IRTS: 31 with STA and 31 matched controls. The mean IRTS was 6.6 mm (range, 5.9-8.9) in the STA group and 6.8 mm (range, 5.8-8.7) in the control group. The mean patient age was 32.9 years (range, 20-50), and the mean follow-up was 3.8 years (range, 3.1-5.0). At final follow-up, the STA group showed significantly higher proportions of patients achieving the minimal clinically important difference (93.5% vs 74.2%; P = .038), Patient Acceptable Symptom State (96.8% vs 74.2%; P = .012), and substantial clinical benefit (54.8% vs 25.8%; P = .020). The return-to-sport rate was also higher in the STA group (74.2% vs 48.4%; P = .037). Additionally, the STA group demonstrated a lower graft failure rate (0% vs 12.9%; P = .039). CONCLUSION: For patients with high IRTS, STA in ACLR with HT autografts is associated with improved clinical outcomes, a higher return-to-sport rate, and a lower risk of graft failure at midterm follow-up.

Humans↗

PubMed2026

Evaluating Wearable Devices for Remote Monitoring in Psychosis: Pilot Study Nested Within the CONNECT Cohort Study.

BACKGROUND: Digital remote monitoring technologies, including smartphones and wearables, offer promising avenues for early detection of psychosis relapse. However, selecting devices that are acceptable to participants and produce high-quality data remains challenging. OBJECTIVE: The aim of this nested pilot study was to assess the acceptability and data quality of 3 commercially available wearable devices in people with psychosis recruited to the CONNECT cohort study. METHODS: Participants recruited to the CONNECT study before July 31, 2024, were included in the pilot study and selected 1 of 3 wearable devices: a Fitbit Charge 5, Samsung Galaxy Watch 5, or Apple Watch SE. Baseline demographics were compared between device groups. Acceptability of devices to participants was assessed through a Wearable Device Satisfaction Questionnaire after 3 months of use, with the proportion of positive responses to each question calculated and compared. Data completeness was also assessed by calculating the number (and percentage) of valid days of step count, heart rate, and sleep data, and comparing between groups. Data quality was assessed through summarizing the amount of troubleshooting required, additional metrics available from the wearables, and continuity of data completeness by calculating the proportion of participants with at least 3 days of heart rate data per week for the first 20 weeks of follow-up. Predefined criteria were used to determine the next steps for the wider CONNECT study: if one device was superior, this would be selected; if none were found to be superior and the Fitbit was found to be noninferior, then Fitbit would be retained. RESULTS: Of the first 107 participants recruited to CONNECT, 105 were included in the pilot study evaluation. The Samsung Galaxy Watch was selected most frequently by participants (46/105, 43.8%), followed by the Apple Watch (27/105, 25.7%), and Fitbit Charge (23/105, 21.9%). Differences in participant demographics were observed across device groups. Self-reported acceptability after use did not differ substantially between devices. However, in terms of data completeness, the median proportion of valid heart rate data days was significantly lower for Samsung Galaxy (median 31.2%, IQR 8.5%-46.0%) compared to Fitbit (median 80.1%, IQR 26.7%-95.0%; P=.003) and Apple Watch (median 49.3%, IQR 21.5%-86.0%; P=.02). There was no significant difference between Fitbit and Apple Watch. Similar patterns were observed for step count and sleep data. The Samsung Galaxy Watch required more frequent troubleshooting for data flow issues and lacked additional physiological metrics, available from the other devices. CONCLUSIONS: Due to comparatively lower data quality and technical performance, the Samsung Galaxy Watch was discontinued for use in the subsequent phase of the CONNECT study. The study highlights the importance of incorporating nested evaluations of devices in long-term research.

Humans↗

PubMed2026

Higher Rates of PASS and SCB After Arthroscopic Subspine Decompression Are Associated With a Positive Diagnostic AIIS Injection: A Propensity Score-Matched Cohort Study.

BACKGROUND: Hip arthroscopy effectively treats femoroacetabular impingement syndrome (FAIS), but persistent pain may be related to concomitant extra-articular pathology such as subspine impingement syndrome (SSI). Standard diagnosis of SSI often relies on 3-dimensional computed tomography (3D-CT) morphology (Hetsroni type II/III), although this morphology is common in individuals who are asymptomatic and correlates poorly with symptoms. PURPOSE: To compare minimum 2-year clinical outcomes after arthroscopic subspine decompression in patients with concurrent FAIS and type II/III anterior inferior iliac spine (AIIS) morphology, stratified by diagnostic method: 3D-CT morphology alone versus 3D-CT morphology plus a positive ultrasound-guided diagnostic injection. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included patients aged 18 to 55 years with type II/III AIIS morphology who underwent primary hip arthroscopy for FAIS and SSI between January 2021 and November 2023 and had minimum 2-year follow-up. Patients diagnosed by CT morphology alone (CT classification group) were propensity score matched 1:1 to patients with a positive ultrasound-guided AIIS injection (injection group), with 57 patients per group. Matching variables were age, sex, body mass index, lateral center-edge angle, alpha angle, Tönnis grade, and Beighton score. All patients underwent arthroscopic subspine decompression. Patient-reported outcomes and rates of achieving the minimal clinically important difference, Patient Acceptable Symptom State (PASS), and substantial clinical benefit (SCB) were compared. RESULTS: Preoperative patient-reported outcome scores were similar between groups (all P > .05). At minimum 2-year follow-up, the injection group had significantly better scores on the modified Harris Hip Score (90.8 vs 84.2), Hip Outcome Score-Activities of Daily Living (88.4 vs 82.4), Hip Outcome Score-Sports Subscale (71.9 vs 64.1), 12-item International Hip Outcome Tool (83.9 vs 76.1), and visual analog scale for pain (1.2 vs 2.0) (all P < .001). Minimal clinically important difference rates were high in both groups, with higher rates in the injection group for modified Harris Hip Score (93% vs 77%; P = .033) and Hip Outcome Score-Activities of Daily Living (91% vs 75%; P = .042). PASS and SCB rates were significantly higher in the injection group across all patient-reported outcome measures (all P < .05). Revision and complication rates were low and did not differ significantly between groups. CONCLUSION: Both groups improved significantly after arthroscopic subspine decompression. However, patients with a positive ultrasound-guided diagnostic AIIS injection achieved higher PASS and SCB rates than those selected by CT morphology alone, suggesting that injection-confirmed SSI may improve patient selection for subspine decompression.

Humans↗

PubMed2026

Preoperative Proximal Migration of the Radial Head as an Independent Predictor of Suboptimal Outcomes After Osteochondral Autograft Transplantation for Capitellar Osteochondritis Dissecans: A Retrospective Cohort Study.

BACKGROUND: Osteochondral autograft transplantation (OAT) is widely performed for capitellar osteochondritis dissecans (OCD). However, preoperative predictors of suboptimal postoperative outcomes remain unclear. PURPOSE/HYPOTHESIS: The authors aimed to evaluate clinical outcomes after OAT for capitellar OCD and identify preoperative risk factors associated with suboptimal outcomes. They hypothesized that radiographic indicators of disease severity, including preoperative proximal migration of the radial head, lesion size, and lateral wall disruption, would be associated with suboptimal postoperative clinical outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The records of adolescent athletes who underwent OAT for capitellar OCD with a minimum 2-year follow-up were retrospectively reviewed. Clinical outcomes included elbow range of motion (ROM) and Timmerman-Andrews (T-A) score. A suboptimal outcome was defined as a postoperative T-A score <160. Preoperative radiographs were used to measure proximal migration of the radial head relative to the coronoid process, hypertrophy of the radial head, OCD lesion area, and a 5-grade lateral wall disruption classification; measurement reliability was assessed. Multivariate logistic regression analysis was performed to identify independent predictors of a suboptimal outcome, and receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for proximal migration. RESULTS: A total of 69 elbows (mean age, 13.6 years; mean follow-up, 48 months) were included. ROM and T-A scores improved significantly after OAT, and all athletes returned to any sports. Of these, 50 elbows (72%) achieved good outcomes, whereas 19 (28%) had suboptimal outcomes. Preoperative proximal migration was significantly greater in the suboptimal outcome group compared with the good outcome group (mean, 2.1 ± 2.3 vs 0.5 ± 1.7 mm; P = .002), as were lesion area (mean, 70 ± 16 vs 58 ± 20 mm2; P = .02) and lateral wall disruption grade (median, 5 vs 3; P = .01). On multivariate analysis, proximal migration of the radial head was the only independent predictor of a suboptimal outcome (adjusted OR, 1.47 per 1-mm increase; 95% CI, 1.03-2.09; P = .033). ROC analysis showed an area under the curve of 0.72 with an optimal cutoff of 2.2 mm (sensitivity, 56%; specificity, 84%). CONCLUSION: OAT resulted in significant clinical improvement in adolescents with capitellar OCD; however, 28% of patients were classified as having suboptimal outcomes. Preoperative proximal migration of the radial head is an independent predictor of a suboptimal postoperative outcome. A value >2.2 mm may indicate advanced radiocapitellar incongruity, a condition in which OAT may be less effective.

Humans↗

PubMed2024

Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options (PRECODE): study protocol of a prospective, non-randomized, cohort study.

BACKGROUND: Genomic profiling of advanced solid cancer in patients with no further evidence based standard treatment options is a novel approach to identify potential experimental treatment options based on specific genomic alterations. Due to the expected short survival of these patients timely assessment of potential druggable targets is critical to minimize the risk of deterioration during the analysis. The primary objective of this prospective study is to evaluate the turnaround time for genomic profiling and the clinical investigational procedures. The secondary objectives are to investigate how often genomic alterations in tumor tissue gives rise to a matched treatment offer and evaluate the clinical outcome. METHODS: The PRECODE study is a prospective, non-randomized, single-center cohort study conducted at Departments of Oncology and Pathology, Odense University Hospital, Denmark. Enrollment between March 1, 2019 and December 31, 2024. Eligibility criteria are age ≥ 18 years, written informed consent, advanced solid tumors, exhausted treatment options, ECOG performance status 0-2, adequate organ function and life expectancy ≥ 3 months. A core needle biopsy is analyzed by next generation sequencing using a pan-cancer comprehensive panel. Results are discussed weekly at institutional/local and national multidisciplinary tumor boards. DISCUSSION: Strategies and methods for genomic profiling of advanced solid cancers differ. Rapid analysis and interpretation of sequencing data are key to avoiding delays in initiation potential experimental treatments, as these late-stage patients may quickly deteriorate. Although a highly optimized setup with fast-track clinical evaluation and genomic profiling has been established a subset will not be offered a targeted treatment due to deterioration. Local and national multidisciplinary teams have been established to optimize individualized treatment decisions. After genomic profiling a subset of patients will take part in clinical trials, which will constrain the reporting of overall survival or progression free survival. TRIAL REGISTRATION: Danish Ethics Committee, Projekt-ID: S-2018014, date of approval: 27- FEB- 2019) Danish Data Protection Agency (Journal no: 18/58329, date of approval: 23-NOV-2018). CLINICALTRIALS: gov Identifier: NCT05385081 (retrospectively registered).

Humans↗

PubMed2026

Proteomics-driven discovery of intervention windows and risk subtypes in osteoporosis: A prospective cohort study.

Given the limited feasibility of population-wide bone mineral density screening and the infrequency of long-term monitoring in healthy individuals, identifying the window for early intervention and the populations to be prioritized for screening is critical. This study aimed to identify intervention windows for osteoporosis and to determine potential high-risk subtypes within the healthy population. Based on proteomic data from 41,408 healthy adults, we conducted the DE-SWAN method to identify change peaks in plasma protein during the pre-diagnostic osteoporosis phase, and employed finite Gaussian mixture model-based clustering to delineate high-risk subtypes of osteoporosis. We identified 122 protein biomarkers significantly associated with osteoporosis risk throughout the follow-up period. Importantly, we identified two critical peaks occurring approximately 10 and 6 years before diagnosis, with the former enriched in immune-related pathways and the latter prominently involving responses to retinoic acid and glucocorticoids. Furthermore, one high-risk subtype for osteoporosis was identified in both males and females, termed the Frailty and Obesity Subtype. This subtype is characterized by a high degree of frailty and obesity, accompanied by a significantly elevated risk of both osteoporosis and fractures. Finally, we developed a predictive model comprising 10 proteins for identifying high-risk subtypes of osteoporosis, which demonstrated better performance than the traditional risk factor model (AUC: 0.743 vs. 0.680). Our findings demonstrate that proteomic profiling can reveal early molecular changes and identify high-risk subtypes years before clinical onset, providing a foundation for screening and precision prevention of osteoporosis.

Proteomics↗

PubMed2024

Association of urinary levels of trace metals with type 2 diabetes and obesity in postmenopausal women in Korea: A community-based cohort study.

Several toxic metals have been associated with metabolic diseases like obesity and diabetes mellitus (DM) in humans. However, knowledge regarding the influence of many trace elements, especially in combination with essential elements is limited. This study aims to address this research gap by investigating the associations of both non-essential and essential inorganic trace elements in urine with DM and obesity, employing a group of postmenopausal women (n = 851) from the Korean Genome and Epidemiology Study (KoGES) cohort. Urine samples were collected during 2017-2018, and were analyzed for 19 trace elements using inductively coupled plasma-mass spectrometry and an automatic mercury analyzer. Outcomes of interest were metabolic diseases (DM and obesity) and DM-related traits (insulin resistance and β-cell function). After adjustment of covariates, such as age, alcohol consumption, smoking status, educational level, and daily energy intake, urinary Zn, Ni, Tl, and U levels were associated with the prevalence of DM and homeostatic model assessment (HOMA) for insulin resistance (IR) in the postmenopausal women. In the whole mixture model, however, no significant association was observed for the prevalence of DM. Urinary levels of Zn were negatively associated with HOMA of β-cell function (HOMA-β), positively correlated with HbA1c levels, HOMA-IR, and prevalent DM. In addition, urinary Zn, Co, Tl, and Cs were positively associated with obesity (body mass index ≥25 kg/m2). The present observation shows that several individual elements and their mixtures may be associated with the prevalence of DM, IR, or obesity.

Humans↗

PubMed2026

Population-level impact of HPV vaccination: a global systematic review of ecological, cross-sectional, and cohort studies.

BACKGROUND: Human papillomavirus (HPV) causes approximately 4.5% of cancers globally, with the highest burden in low- and middle-income countries (LMICs). Since their introduction in 2006, HPV vaccination programs have led to substantial declines in HPV-related outcomes, although impact varies across settings. RESEARCH DESIGN AND METHODS: We conducted a systematic review to evaluate the population-level impact of HPV vaccination on HPV infection, cervical intraepithelial neoplasia grade 2 or higher (CIN2+), genital warts, invasive cervical cancer (ICC), and oropharyngeal cancer (OPC), and examined the influence of coverage, age at initiation, and vaccine type. The review followed PRISMA 2020. RESULTS: Of 13,549 records screened, 63 were included: 9 assessed HPV infection, 24 on CIN2+, 25 on genital warts, and 7 on ICC. Greatest reductions were observed in settings with at least 70% coverage and early vaccination prior to sexual debut, typically achieved through school-based programs. Reported declines ranged from 58-100% for HPV infection, 30-88% for CIN2+, 60-90% for genital warts, and 70-88% for ICC. CONCLUSIONS: HPV vaccination offers strong protection, especially when delivered early and at high coverage within schools. Expanding access and prioritizing underserved populations are essential to achieving global cancer prevention goals. Limitations include heterogeneity across designs, outcome definitions, and follow-up.

Humans↗

PubMed2025

Discovery of Respiratory Pathogens in People Living With HIV in the African Cohort Study.

INTRODUCTION: Respiratory infection outbreaks pose a threat to the readiness of the United States and allied armed forces. Predicting and preventing such outbreaks requires understanding of the epidemiology of potential respiratory pathogens in communities where service members live and work. We conducted pan-viral surveillance of respiratory specimens from people living with HIV or without HIV but under the risk enrolled in the U.S. Military HIV Research Program's African Cohort Study to determine the prevalence and possible clinical presentation of viruses in this population. METHODS: The African Cohort Study is an open-ended prospective cohort study that enrolls people with and without HIV aged ≥15 years at 12 clinical sites in Kenya, Tanzania, Uganda, and Nigeria. The study follows participants every 6 months and collects social, demographic, clinical, and laboratory data. A total of 131 respiratory samples, collected from March 2022 to February 2023 from participants in South Rift Valley Province, Kenya, who had symptoms of respiratory illness or a positive COVID-19 test, were analyzed using a pan-viral hybridization metagenomic next-generation sequencing approach. Libraries were sequenced on the Illumina Next-generation Sequencing System NovaSeq 6000. Sample data were run through several pathogen discovery pipelines. RESULTS: Full genome and partial genome sequences were assembled for several respiratory viruses including SARS-CoV-2, human coronavirus HKU1, human adenovirus 62, human metapneumovirus, human mastadenovirus B (coinfection with SARS-CoV-2), human mastadenovirus C (coinfection with SARS-CoV-2), and human parechovirus 3 (coinfection with adenovirus 62). The results showed that SARS-CoV-2 lineages correspond with lineages circulating during March 2022 to February 2023 and revealed additional viral respiratory pathogens and viruses known to be associated with HIV. CONCLUSIONS: These preliminary results suggest that continued genomic surveillance efforts are needed for data-driven decisions on force health protection, prevention of emerging respiratory infections, and mitigation of impacts on military readiness caused by infectious diseases.

Humans↗

PubMed2026

Positive association between apolipoprotein B and colorectal cancer risk: Findings from a 14-year follow-up cohort study and Mendelian randomization analyses.

BACKGROUND: The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. OBJECTIVE: To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. METHODS: In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. RESULTS: Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. CONCLUSION: Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings.

Humans↗

PubMed2026

Maternal Intake of Vitamins A, C, D, and E During Pregnancy and Risk of Type 1 Diabetes in the Child: The Norwegian Mother, Father, and Child Cohort Study.

BACKGROUND: Dietary vitamins play a role in antioxidant defense and immunoregulation. However, prospective studies exploring the association between vitamin intakes during pregnancy and the child's risk of type 1 diabetes are limited. OBJECTIVES: This population-based prospective cohort study aimed to investigate the association between maternal intake of vitamins A, C, D, and E during pregnancy and risk of type 1 diabetes in children. METHODS: We included 85,244 children born between 2002 and 2009 in the Norwegian Mother and Child Cohort Study, with follow-up until 31 December, 2021. Maternal intake of vitamins from food and dietary supplements from conception to the 22nd week of pregnancy was assessed with a validated food frequency questionnaire. Cox proportional hazards regression was used to estimate hazard ratios (HRs), adjusting for background factors. RESULTS: During follow-up, 529 (0.6%) children were diagnosed with type 1 diabetes at a mean age of 9.4 y (standard deviation: 4.1 y) No associations were observed between maternal pregnancy intake of vitamin A [HR: 0.993; 95% confidence interval (CI): 0.983, 1.003/100 μg], vitamin C (HR: 1.000; 95% CI: 0.993, 1.007/10 mg), vitamin D (HR: 0.991; 95% CI: 0.978, 1.003/1 μg), or vitamin E (HR: 0.999; 95% CI: 0.996, 1.004/10 mg) and risk of type 1 diabetes in the child when adjusted for potential confounders. The results were similar when intakes were assessed separately from food and dietary supplements and after restriction to children with human leukocyte antigen DQ2 and/or DQ8 risk haplotypes. CONCLUSIONS: This prospective cohort study does not support the hypothesis that higher maternal intake of vitamins A, C, D, and E during pregnancy would decrease risk of type 1 diabetes in the child. Corroborated with previous evidence, our findings support a general pattern of null associations.

Humans↗

PubMed2026

Atopic dermatitis and the risk of osteoporosis and fractures: a meta-analysis of cohort studies.

BACKGROUND: This meta-analysis aims to evaluate the risk of osteoporosis and fractures in patients with atopic dermatitis (AD) by synthesizing data from cohort studies. We also provide a comprehensive analysis of fracture risks across different severities of AD and anatomical sites. METHODS: Following the PRISMA 2020 guidelines, a systematic search was conducted in PubMed, Embase, and the Cochrane Library up to May 30, 2025. Studies that investigated the relationship between AD and osteoporosis or fractures were included in the analysis. Data extraction and screening were performed independently by two reviewers. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). A random-effects meta-analysis was applied, alongside sensitivity and subgroup analyses. Publication bias was evaluated using funnel plots and Egger's test. RESULTS: Ten cohort studies, involving 368 to over 2 million AD patients, were included. NOS scores ranged from 7 to 8, indicating generally high study quality. The pooled analysis revealed a 56% increased risk of osteoporosis (OR = 1.56, 95% CI: 1.14-2.13; I2 = 99.9%, p < 0.0001) and an 8% increased risk of all-cause fractures (OR = 1.08, 95% CI: 1.05-1.10; I2 = 82.1%, p < 0.0001) in AD patients. Subgroup analyses demonstrated a progressive increase in fracture risk with the severity of AD. Specific risks were significantly higher for vertebral fractures (OR = 1.14, 95% CI: 1.08-1.20; I2 = 67.3%, p = 0.009) and lower limb fractures (OR = 1.11, 95% CI: 1.08-1.13; I2 = 65.0%, p = 0.014). Sensitivity analyses confirmed the robustness of these findings, and no significant publication bias was detected (p = 0.316). CONCLUSION: AD is associated with an increased risk of osteoporosis and fractures, particularly among patients with severe AD and those experiencing vertebral or lower limb fractures. These findings highlight the importance of targeted bone health monitoring in the clinical management of AD patients.Registration: (PROSPERO: CRD420251066550).

Humans↗

PubMed2025

Methylome profiling of cell-free DNA during the early life course in (un)complicated pregnancies using MeD-seq: Protocol for a cohort study embedded in the prospective Rotterdam periconception cohort.

INTRODUCTION: Placental DNA methylation differences have been associated with timing in gestation and pregnancy complications. Maternal cell-free DNA (cfDNA) partly originates from the placenta and could enable the minimally invasive study of placental DNA methylation dynamics. We will for the first time longitudinally investigate cfDNA methylation during pregnancy by using Methylated DNA Sequencing (MeD-seq), which is compatible with low cfDNA levels and has an extensive genome-wide coverage. We aim to investigate DNA methylation in placental tissues and cfDNA during different trimesters in uncomplicated pregnancies, and in pregnancies with placental-related complications, including preeclampsia and fetal growth restriction. Identified gestational-age and disease-specific differentially methylated regions (DMRs) could lead to numerous applications including biomarker development. METHODS AND ANALYSIS: Our study design involves three sub-studies. Sub-study 1 is a single-centre prospective, observational subcohort embedded within the Rotterdam Periconception cohort (Predict study). We will longitudinally collect maternal plasma in each trimester and during delivery, and sample postpartum placentas (n = 300). In sub-study 2, we will prospectively collect first and second trimester placental tissues (n = 10 per trimester). In sub-study 3 we will retrospectively collect plasma after non-invasive prenatal testing (NIPT) in an independent validation case-control cohort (n = 30-60). A methylation-dependent restriction enzyme (LpnPI) will be used to generate DNA fragments followed by sequencing on the Illumina NextSeq2000 platform. DMRs will be identified in placental tissues and cell types, and in cfDNA related to gestational-age or placental-related complications. (Paired) placental methylation profiles will be correlated to DMRs in cfDNA to aid tissue-of-origin analysis. We will establish a methylation score to predict associated diseases. DISCUSSION: This study will provide insights in placental DNA methylation dynamics in health and disease, and could lead to clinical relevant biomarkers.

Humans↗

PubMed2025

A viral clonality evenness score to predict progression to adult T-cell leukaemia in asymptomatic carriers of human T-lymphotropic virus type 1 in Japan: a retrospective longitudinal cohort study.

BACKGROUND: Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that occurs in approximately 2-7% of individuals with human T-lymphotropic virus type 1 (HTLV-1), after decades of asymptomatic infection. To address the urgent need for predictive biomarkers to identify asymptomatic carriers of HTLV-1 at high risk of progression to ATL, we aimed to evaluate viral clonality sequencing as a potential tool for risk stratification. METHODS: This retrospective longitudinal cohort study involved HTLV-1 carriers enrolled in the Joint Study on Predisposing Factors of ATL Development, a nationwide cohort study initiated in Japan in 2002. Participants were selected from this cohort on the basis of their baseline proviral load at the time of enrolment as an asymptomatic carrier, length of follow-up, and clinical outcome. The cohort was subdivided into three subgroups: the first comprising HTLV-1 carriers who developed ATL, the second comprising carriers with high proviral load (≥4%) who did not progress to ATL, and the third comprising carriers with low proviral load (<4%) who did not progress to ATL. DNA extracted from peripheral blood mononuclear cells collected at enrolment and at least one follow-up visit was analysed by HTLV-1 clonality sequencing and the proviral load was quantified. We calculated a viral clonality evenness (VCE) score, based on the Shannon Evenness Index, to quantify the uniformity of the clonal distribution of samples, for which 0 represents a perfectly monoclonal architecture and 1 indicates a completely polyclonal landscape. We then estimated the performance of proviral load thresholds and VCE scoring to classify the risk of progression to ATL using the area under the receiver operating characteristic curve (AUC), the accuracy, and Matthews correlation coefficient. VCEs were compared between participant subgroups with the Wilcoxon rank sum test. FINDINGS: 56 participants followed up by JSPFAD between Feb 6, 2003, and July 19, 2022, were included in this study: 17 who progressed to ATL (mean follow-up 8·3 years [SD 4·0]), 18 who had a high proviral load and did not progress to ATL (9·7 years [3·4]), and 21 who had a low proviral load and did not progress to ATL (7·5 years [3·0]). Clonality sequencing of samples from 39 participants who did not progress to ATL revealed hundreds to thousands of HTLV-1 integration sites at both timepoints, corresponding to multiple clones of low and uniform abundance, and these participants had high VCE scores (≥0·694) at baseline. By contrast, most participants (14 of 17) who progressed to ATL had a single predominant clone or two to four predominant clones at both timepoints, and lower VCE scores (<0·694) at baseline than those who did not progress (p<0·0001). AUCs were very similar for proviral load thresholds (91 [95% CI 80-98]) and VCE scoring (91 [78-100]), although when using methods that give equal weight to every individual, VCE scoring outperformed proviral load thresholds in predicting progression to ATL (accuracy: proviral load 0·76 [95% CI 0·76-0·77], VCE scoring 1·00 [0·99-1·00]; Matthews correlation coefficient: proviral load 0·23 [95% CI 0·19-0·24], VCE scoring 0·91 [0·80-1·00]). Prediction based on VCE scoring indicated no false positives, compared with 20% when using proviral load, although VCE scoring yields a greater number of false negatives (0·3% vs 0·1%). INTERPRETATION: The implementation of VCE scoring in clinical practice could inform early pre-emptive therapeutic interventions, exclusively targeting individuals with HTLV-1 at high risk and aiming to prevent progression to aggressive, treatment-refractory disease. Further validation, including independent confirmation of the performance of VCE scoring in multiple populations and the characterisation of its temporal dynamics, will be crucial to determine its clinical utility and potential integration into care pathways. FUNDING: Association Jules Bordet, FNRS-Télévie, FCC, WALInnov, FLF, JSPS-KAKENHI, and CoBiA.

Humans↗

PubMed2025

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

Humans↗

PubMed2026

Noncombustible Nicotine or Tobacco Product Use After Smoking Cessation and Major Vision-Impairing Diseases: A Nationwide Cohort Study.

OBJECTIVE: We assessed the risk of major vision-impairing eye diseases among smokers who quit combustible cigarettes (CC) and switch to noncombustible nicotine or tobacco products (NNTPs) compared with those who completely quit using tobacco. DESIGN: Retrospective cohort study. PARTICIPANTS: About 179 273 adults from the Korean National Health Insurance Service who smoked CC in 2011 to 2012 and reported cessation in 2018 to 2019, classified into complete quitters and NNTP switchers. METHODS: This nationwide longitudinal cohort study followed participants for up to 6 years and identified incident major vision-impairing eye diseases (cataract, glaucoma, age-related macular degeneration, diabetic retinopathy, and refractive and accommodation disorders) using standardized diagnostic codes. Propensity score matching was applied to emulate a pseudo-randomized comparison, balanced on key demographic, clinical, comorbidity, and lifestyle characteristics. Subdistribution hazard ratios (SHRs) were evaluated using the Fine-Gray subdistribution hazards model accounting for all-cause mortality as a competing risk. MAIN OUTCOME MEASURES: Adjusted SHRs for incident major vision-impairing eye diseases. RESULTS: Among 32 316 matched participants followed for a mean of 4.6 years, 6328 incident major vision-impairing eye disease events occurred. The incidence was 41.1 and 44.0 per 1000 person-years for complete quitters and NNTP switchers, respectively. Switching to NNTPs was associated with an increased risk of major vision-impairing eye disease (SHR, 1.07; 95% CI, 1.02-1.13). The risk elevation was most pronounced for diabetic retinopathy (SHR, 1.24; 95% CI, 1.00-1.53) and refractive and accommodation disorders (SHR, 1.07; 95% CI, 1.01-1.12). These findings were robust across inverse probability-weighted and Cox proportional hazards models. The association remained consistent in sensitivity analyses and across clinical subgroups. CONCLUSIONS: Transitioning from CC to NNTPs is associated with a modest but consistent increase in the risk of major vision-impairing eye diseases compared with complete nicotine abstinence. These findings challenge the assumption that substituting NNTPs for CCs is visually harmless and indicate that, from an ophthalmic perspective, complete cessation of all nicotine products should remain the preferred cessation goal.

Humans↗

PubMed2026

Gout and allopurinol adherence in newly diagnosed patients and the risk of fractures: a nationwide cohort study.

INTRODUCTION / OBJECTIVES: The association between gout and fractures remains controversial due to the competing effects of uric acid's antioxidant properties and gout-induced chronic inflammation. Our study aimed to evaluate the risk of fractures in newly diagnosed gout patients and to analyze the impact of Allopurinol medication adherence on this risk. METHODS: This nationwide cohort study utilized the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database (2002-2019). We identified 4,107 patients newly diagnosed with gout who remained on continuous allopurinol therapy during the 24-month medication assessment period and matched them 1:3 with 12,321 non-gout controls using propensity score matching. Allopurinol adherence was assessed via the Medication Possession Ratio (MPR) over a 24-month period and categorized into three groups: MPR < 0.3, 0.3 ≤ MPR < 0.8, and MPR ≥ 0.8. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for fractures (vertebral, hip, and distal radius). RESULTS: Gout patients demonstrated a significantly higher risk of overall fractures compared to the non-gout group (aHR 5.52; 95% CI 4.19-7.26). A significant inverse linear relationship was observed between allopurinol adherence and fracture risk (P for trend < .001). The risk was highest in the low-adherence group (MPR < 0.3; aHR 5.91; 95% CI 4.40-7.93) and relatively lower in the high-adherence group (MPR ≥ 0.8; aHR 4.77; 95% CI 2.94-7.72). Consistent trends were observed for vertebral (aHR 5.68) and hip (aHR 4.22) fractures. These associations remained consistent across all subgroups, including age, sex, and comorbidities. CONCLUSION: Newly diagnosed gout is associated with a substantially increased risk of fractures. Higher adherence to Allopurinol therapy is correlated with a significant reduction in this risk, suggesting that consistent urate-lowering therapy may mitigate gout-related bone fragility. Key Points • Newly diagnosed gout patients have a significantly higher risk of major osteoporotic fractures compared to the non-gout population. • A significant inverse linear relationship exists between Allopurinol adherence and fracture risk, with the highest adherence group (MPR ≥ 0.8) showing a relatively lower risk. • Consistent urate-lowering therapy (ULT) may mitigate bone fragility in gout patients by reducing systemic inflammatory burden caused by urate crystal deposition.

Humans↗