EClinicalMedicine最新文献

Background: High body mass index (BMI) is a modifiable cancer risk factor, projected to surpass smoking as the leading preventable risk factor. The impact of weight change from late adolescence to adulthood on cancer risk remains unclear. We aimed to assess the association between adolescence-to-adulthood BMI trajectories and obesity-related cancer risk.

Methods: A population-based cohort study of 800,024 people (45.1% women) insured by a large state-mandated health provider. BMI was measured during military pre-recruitment evaluations during 1967-2018 in adolescence and in subsequent clinic visits in adulthood during 1998-2020. Follow-up began one year after an adult BMI measurement until cancer diagnosis, death, transfer to another health provider, or December 16, 2021. BMI trajectories from adolescence to adulthood were classified as lean-to-lean, lean-to-high, high-to-lean, and high-to-high (cutoff: sex-specific and age-specific 85th percentile in adolescence, defined according to the United States Centers for Disease Control and Prevention growth charts, and 25 kg/m² in adulthood). Weight change was also assessed per 5% increments. The primary outcome was obesity-related cancers including esophagus, postmenopausal breast, liver and gallbladder, stomach, pancreas, colon and rectum, kidney, multiple myeloma, thyroid, uterus and ovary. The secondary outcome was obesity-related cancers diagnosed before age 50 years (early-onset cancers). Cox proportional hazards models were applied.

Findings: During 7,610,263 person-years, 6,376 people were diagnosed with obesity-related cancers, at a mean age of 53.3 ± 9.8 years. Adjusted hazard ratios (HRs) were 1.31 (95% confidence interval [CI], 1.24-1.39) for lean-to-high, 1.01 (95% CI, 0.78-1.31) for high-to-lean, and 1.47 (95% CI, 1.34-1.61) for high-to-high groups, compared to the lean-to-lean group. Respective HRs for early-onset obesity-related cancers were 1.33 (95% CI, 1.20-1.47), 0.88 (95% CI, 0.60-1.31), and 1.39 (95% CI, 1.20-1.61). Each 5% weight gain conferred a 3% increased hazard (95% CI, 1.02-1.03), with a similar 3% increase for early-onset cancers (95% CI, 1.02-1.04). Cancer-specific risks included 3% (95% CI, 1.02-1.04) for postmenopausal breast cancer, 3% (95% CI, 1.01-1.04) for colorectal cancer, 4% (95% CI, 1.02-1.05) for thyroid cancer, 5% (95% CI, 1.04-1.07) for kidney cancer, and 8% (95% CI, 1.06-1.09) for uterine cancer. Some cancers, including leukemia and non-Hodgkin's lymphoma, were not associated with weight gain but were positively associated with high adolescent BMI.

Interpretation: Maintaining a healthy BMI from adolescence to adulthood may reduce obesity-related cancer risk, including early-onset, highlighting the importance of early weight management strategies.

Funding: Novo Nordisk, Israel.

Background: Sleep disturbances are common in individuals with substance use disorders (SUDs), often persisting beyond initial abstinence and hindering recovery. However, the underlying sleep abnormalities warrant further investigation, particularly given mixed findings regarding specific substances.

Methods: This systematic review and meta-analysis aimed to identify sleep-related abnormalities associated with alcohol (AUD), benzodiazepine (BUD), cannabis (CaUD), cocaine (CoUD), methamphetamine (MUD), nicotine (NUD), and opioid (OUD) use disorders. We systematically searched Embase, PsycINFO, PubMed, Scopus, and Web of Science until November 2025, following a pre-registered protocol (PROSPERO: CRD42024531160).

Findings: We conducted a systematic review of 43 eligible publications involving approximately 7500 participants, using both objective (eg, polysomnography) and subjective (eg, Pittsburg Sleep Quality Index [PSQI]) measures. Results showed that total sleep time (TST) was reduced in AUD (-14.32, 95% CI = -16.69 to -11.96; I² = 0%), NUD (-0.33, 95% CI = -0.59 to -0.06; I² = 37%), and OUD (-38.16, 95% CI = -63.04 to -13.28; I² = 0%). Slow-wave sleep (SWS) was reduced in AUD (-3.68, 95% CI -4.99 to 2.38; I² = 73%) and CoUD (-30.69, 95% CI = -47.27 to -14.10; I² = 90%). Sleep quality, measured by the PSQI, was poorer in AUD (4.89, 95% CI = 3.01 to 6.77; I² = 98%), CoUD (0.98, 95% CI = 0.04-1.93; I² = 0%) and NUD (2.64, 95% CI = 0.41-4.88; I² = 96%). Results for CaUD could not be meta-analyzed due to scarcity of data. No study met criteria to be included for BUD or MUD.

Interpretation: These findings suggest specific relationships between specific addictive substances and sleep, highlight areas of convergence in these relationships, and indicate instances in which the same drug is related with both objective and subjective alterations. Further research is needed to explore further, at a meta-analytical level, relationships between sleep and specific substances.

Funding: National Institute on Drug Abuse.

Background: Cortisol has a circadian rhythm with an early morning rise, loss of this rhythm is associated with poor health. Our objective was to test the hypothesis that restoring the early morning cortisol rise will improve fatigue and quality of life (QoL) by comparing twice daily Chronocort with once daily Plenadren in patients with adrenal insufficiency.

Methods: A randomised, double-blind, double-dummy, cross-over study with no washout in 58 patients (29 in each arm) with primary adrenal insufficiency comparing four weeks' Chronocort, 15 mg at night and 10 mg in the morning, a formulation that restores early morning cortisol levels, with four weeks' once daily Plenadren 25 mg, which only restores daytime cortisol levels. The primary endpoint was the 07:00 h serum cortisol level and secondary endpoints measures of fatigue and QoL. The trial was registered on ClinicalTrials.gov and EU Clinical Trials Register (NCT NCT05222152; Eudract 2021-000144-21), initiated on 11th January 2022 and completed on 18th October 2023.

Findings: Patients met the primary endpoint and achieved a physiological early morning serum cortisol, median 417 nmol/L on Chronocort versus 6 nmol/L on Plenadren (P < 0.0001). For secondary outcomes the majority of QoL and fatigue measures showed significant benefits for Chronocort including the disease-specific questionnaire AddiQol (P = 0.02), the fatigue questionnaire PROMIS 7b (P = 0.02), SF-36 physical component score (P = 0.01), and EQ-5D-5L (P = 0.02). The Multidimensional Assessment of Fatigue (MAF) was not significantly different between treatments; however, a pre-specified sensitivity analysis showed that in the first treatment period, Chronocort reduced the MAF Score (P = 0.008), suggesting a carry-over effect from period 1 to 2. A post hoc analysis of immune profile in a subset of 19 patients showed that those on Chronocort had an increase in circulating number or frequency of neutrophils, natural killer and natural killer T cells compared to both baseline glucocorticoid treatment and Plenadren treatment.

Interpretation: Restoring the early morning cortisol levels with twice daily Chronocort 15 mg at night 10 mg in the morning improved health-related quality of life, fatigue and the immune profile compared with 25 mg daily Plenadren.

Funding: Neurocrine UK Ltd.

Background: Social transition can be an important and accessible aspect of gender affirmation, allowing trans and gender diverse young people to authentically express their identities, including through adoption of chosen name, pronouns, and changes to appearance. These changes may take place in a single context, such as at home, or across multiple settings, including school, with friends, and online. Currently, it is unclear how this process is being captured in the literature, including whether it has been measured comprehensively and consistently.

Methods: This scoping review (PROSPERO: CRD42022333058) explored how social transition has been defined and operationalised in studies involving trans young people (under 18), detailing practices (i.e. specific changes) of social transition and contexts where these changes occurred. Systematic searches were conducted in Embase, MEDLINE, and PsycInfo databases to August 2025. Studies were eligible if they included a definition and/or measure of social transition.

Findings: Among 40 included studies, definitions (n = 37 studies) and measures (n = 29 studies) varied widely. Some studies did not distinguish between specific practices of social transition, such as changes to name, pronouns, or appearance, when defining (4/37) and measuring (6/29) the construct. However, many studies omitted reference to the contexts in which these practices occurred (19/37 definitions; 14/29 measures), assuming practices took place uniformly across all contexts. Many also relied on a binary measure of social transition (15/29 measures), failing to capture the diverse ways in which individuals enact their social transition. No measurement tools were used consistently.

Interpretation: Current definitions and measures of social transition in research with trans and gender diverse young people are inconsistent and incomplete. As a result, they fail to capture the complex nature of social transition, limiting comparability between studies and hindering understanding of its complexities and impacts. Comprehensive, standardised measures to capture this concept are urgently required.

Funding: There was no funding source for this study.

Three different PARP (Poly (ADP-ribose) Polymerase)-inhibitors have been approved in combination with androgen receptor pathway inhibitors (ARPIs) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Regulatory authorities, however, have divergent opinions. Although the US Food and Drug Administration (FDA) has limited approval of two PARP-inhibitors to patients with BRCA mutations or other alterations in homologous recombination repair (HRR) genes, the European Medicines Agency (EMA) has approved the indication for the overall mCRPC population, irrespective of HRR status. Of all trials, only MAGNITUDE, evaluating niraparib and abiraterone, led to aligned conclusions from both the EMA and FDA, as its design effectively identified the subgroup most likely to benefit. The discrepancies observed in the assessment of the other two trials stem from limitations in their designs. A key issue with PROpel is the lack of patient stratification based on known biomarkers, and the subgroup analysis is underpowered. In TALAPRO-2, although an enriched cohort is included, combining these data with the all-comers cohort results in a potentially misleading conclusion. Currently, there is a need for harmonisation in biomarker-driven trial designs and the definition of homologous recombination repair deficiency (HRD). Access to biomarker and clinical data from all PARP-inhibitor trials would allow researchers to clarify the impact of different HRR mutations on outcomes.

Background: With major increases in facility births in low- and middle-income countries (LMICs) since 1995, a key question is what types of facilities met the increased demand. Understanding the evolving delivery landscape is crucial to informing debates about optimal models for balancing access, quality, and equity. We studied the distribution of delivery location by health facility level and sector (private versus public) in 130 LMICs from 1995 to 2023.

Methods: We used 745 data sources with delivery location information in our analysis. We first categorised births as in-facility or not, then further classified facility births by level (hospital or lower-level) and sector (public or private). We used spatiotemporal Gaussian process regression to model the share of births by facility type from 1995 to 2023 and compared delivery patterns to development and health indicators.

Findings: In 2023, 47.5% (95% uncertainty interval [UI] 46.4-48.6) of deliveries in LMICs were in public hospitals, 19.2% (18.3-20.2) were in private hospitals, 13.0% (12.3-13.8) were in lower-level public facilities, 2.0% (1.9-2.2) were in private lower-level facilities, and the remaining 18.2% (17.3-19.2) were outside health facilities. In 106 countries, more than half of deliveries were in public hospitals, while in 12 countries, public lower-level facilities provided care for more than half of births. In only two countries were private hospitals used for more than half of births, while in the remaining ten countries no facility type provided the majority of care. Between 1995 and 2023, nearly two-thirds (62.1%) of the 41.0 percentage-point increase in facility births was borne by public hospitals. Delivery in lower-level facilities was more common in countries with lower levels of development and higher neonatal mortality rates.

Interpretation: The mix of delivery locations represents the diversity of health systems worldwide. Our analysis highlights the pivotal and growing role of public hospitals in delivery care, though public lower-level delivery care is common in high-mortality contexts. Policy makers should account for the facility mix and the complex roles of public and private sectors when designing strategies to improve maternal and perinatal outcomes.

Funding: The Gates Foundation.

Background: Despite progress in reducing global tuberculosis (TB) incidence, ongoing funding disruptions threaten to reverse gains. Timely, accurate diagnosis integrated with rapid treatment is critical to reducing morbidity, mortality, and transmission-but remains costly, particularly for decentralized approaches. As global health budgets tighten, identifying the optimal cost for molecular TB diagnostics instruments is critical to inform scale-up decisions.

Methods: We developed a probabilistic patient pathway model to assess the cost-effectiveness of decentralizing TB testing across primary healthcare facilities in high-burden settings. Scenarios varied by facility testing density (low, medium, high) and anticipated testing volume increases (none, partial, full). We included the effects of instrument downtime and calculated the maximum instrument + warranty prices at which fully decentralized testing would be considered cost-effective at a $500/disability-adjusted life year (DALY) averted threshold.

Findings: Decentralization with increased testing averted up to 23% more DALYs than centralized testing but was not cost-effective at current instrument + warranty prices. Partial decentralization to the largest 20% of facilities approached cost-effectiveness (<$1000/DALY) with full testing increase. For full decentralization to meet the $500/DALY threshold, maximum viable instrument + warranty prices for low-throughput instruments ranged from $0 (no uptake increase) to $410-$6048 (increased testing uptake, low- to high-testing density settings).

Interpretation: At current prices, decentralized molecular TB testing is unlikely to be cost-effective, even with improved uptake, systemwide. However, meaningful reductions in instrument + warranty costs could make both full and partial decentralization viable. As countries face tighter budgets, clear price targets for cost-effectiveness can help guide procurement and investment decisions in TB diagnostics.

Funding: BMGF, Willem Bakhuys Roozenboomstichting.

Background: The number of transgender and gender-diverse (TGD) minors seeking medical care continues to increase, however data on long-term effects of gender-affirming hormone therapy (GAHT) started in adolescence remain limited.

Methods: This single center study (Ghent University Hospital, Belgium) included a cohort of TGD individuals registered female at birth (RFAB, n = 91) and registered male at birth (RMAB, n = 26) who commenced GAHT during adolescence and were followed into adulthood for up to 10 years. Participants were enrolled retrospectively between September 2023 and December 2024. Outcomes assessed cross-sectionally included areal bone mineral density (aBMD), body composition, handgrip strength, and overall life satisfaction. Lifestyle factors such as alcohol and tobacco use, illicit drug use, and physical inactivity were also examined. Retrospective longitudinal data on aBMD and body composition from the start of medical gender-affirming treatment to the moment of study participation were also analyzed.

Findings: Median age at start of GAHT 17.2 (1.7) years for RFAB, 17.0 (2.2) years for RMAB; median GAHT duration at the enrollment 6.0 (2.4) years and 6.6 (3.4) years, respectively. aBMD z-scores remained within the normal range for both RFAB and RMAB participants, with scores aligning more closely to sex registered at birth (SRAB) in RFAB, and to affirmed gender (AG) in RMAB participants. Bone density was influenced by BMI, vitamin D levels, and smoking status, with those who had received GnRH agonists showing lower aBMD at specific sites. No pathological fractures were reported. Body composition shifted toward AG-typical fat and lean mass distribution, with some RFAB individuals exhibiting elevated visceral fat area. Handgrip strength in RFAB participants approached cisgender male reference values, while RMAB individuals showed intermediate values. Psychosocial outcomes indicated generally good self-rated health and life satisfaction, although a subset of participants, particularly among RMAB, reported lower life satisfaction.

Interpretation: Long-term GAHT initiated during adolescence promotes alignment of bone density, body composition, and muscle strength consistent with gender identity, without evidence of clinically significant adverse effects. Modifiable lifestyle factors remain important determinants of skeletal health. Overall, participants reported good general health and life satisfaction.

Funding: This work was supported by a project grant from the Research Foundation Flanders (FWO; GE065819N).

Sharing clinical research data is key for increasing the pace of medical discoveries that improve human health. However, concern about study participants' privacy, confidentiality, and safety is a major factor that deters researchers from openly sharing clinical data even after deidentification. This concern is further enhanced by the evolution of artificial intelligence (AI) approaches that pose an ever-increasing threat to the reidentification of study participants. Here, we discuss the challenges AI approaches create that are blurring the lines between identifiable, and non-identifiable data. We present a concept of pseudo-reidentification, and discuss how these challenges provide opportunities for rethinking open data sharing practices in clinical research. We highlight the novel open data sharing approach we have established as part of the AI-READI (Artificial Intelligence Ready, and Exploratory Atlas for Diabetes Insights) project, one of the four Data Generation Projects funded by the National Institutes of Health Common Fund's Bridge2AI Program.