EClinicalMedicine最新文献

Background: Diagnostic advancements and classification updates appear to have reshaped the natural history of smoldering multiple myeloma (SMM), though this evolution has not been empirically quantified. We conducted a systematic review to evaluate temporal changes in SMM prognosis.

Methods: PubMed, EMBASE and the Cochrane library databases were searched from January 1990 to November 2025, yielding 1415 reports, of which 14 studies met inclusion criteria. To reconstruct individual-level data, published time to progression (TTP) curves were digitized using a Shiny web application. Kaplan-Meier (KM) survival curves and meta-analyses were generated in RStudio. PROSPERO ID 1068697.

Findings: Progression risk at two and ten years for all-risk patients was 22.8% and 60.1%, respectively; these increased to 44.7% and 85.6% in high-risk patients. Landmark analysis from year five revealed attenuated progression rates: 14.2% and 30.8% for all-risk, and 22.5% and 50.6% for high-risk patients at two and five years post-landmark, respectively. Studies enrolling most patients before 2014 showed higher progression rates than in more recent cohorts (Spearman's rho = 0.645, p = 0.034), but this trend did not reach statistical significance in high-risk groups (rho = 0.360, p = 0.272). Meta-analytic data further supported elevated progression in older cohorts.

Interpretation: SMM appears to follow a more indolent trajectory in recent years, likely due to improved diagnostic precision and exclusion of biomarker-defined or subclinical MM. Enhanced predictive models may better guide therapeutic decision-making, targeting treatment to those most likely to benefit and avoiding the burden of unnecessary intervention in low-risk individuals.

Funding: Supported by the Austrian Forum Against Cancer.

Background: Globally, around 2 million pregnancies each year end in stillbirth, with the majority occurring in low and middle-income countries. The association between gestational diabetes mellitus (GDM) and stillbirth has been widely researched but the evidence is increasingly controversial. The aim of this study is to evaluate the risk of stillbirth associated with GDM, and examine whether this risk differs according to country income status and GDM screening method.

Methods: We searched Scopus, Cinahl, Cochrane Central, ISRCTN, Medline, Embase and Epistemonikos on the 9th May 2025 from inception to May 2025 with no restrictions based on language, study location or time. We included cohort studies that estimated the association of interest. We conducted a random effects meta-analysis by study design and sub-group analyses by country income level and GDM screening method. (PROSPERO CRD4201800057).

Findings: 101 included studies (92,915,856 women) presented unadjusted results, 19 reported adjusted results (63,629,536 women). Meta-analysis of adjusted cohort data did not show evidence of an association between a diagnosis of GDM and the risk of stillbirth worldwide (OR 0.81, 95% CI: 0.68-0.97; I² = 87.7%; n = 19 studies). However, when stratified by country income level a diagnosis of GDM was associated with a reduction in the odds of stillbirth in high income countries (OR 0.73, 95% CI: 0.65-0.82; I² = 31.9%; n = 13 studies), but this was not observed in upper and lower middle income countries, (OR 1.17, 95% CI: 0.71-1.93; I² = 59.7%; n = 6 studies). There were no adjusted estimates from low-income countries. There was no evidence of a difference by GDM screening method.

Interpretation: Increased screening, timely diagnosis and effective management strategies for GDM in high-income countries, such as induction of labour and increased antenatal care, may be responsible for the reduced risk of stillbirth in women with GDM. Further research is needed to identify the optimum strategy for screening and management in low and middle-income settings to reduce preventable stillbirths worldwide.

Funding: None.

Background: Suicide rates have risen among young people, making it a leading cause of adolescent death worldwide. Although several pharmacological treatments have been approved in the context of definite underlying conditions, their broader efficacy in reducing suicidality remains unclear.

Methods: A structured review was conducted on pharmacological treatments for suicidality in under 18s. PubMed, Embase, PsycINFO, and Cochrane Library were searched from inception to 31 July 2025. Eligible studies included patients <18 years with suicidality treated with antidepressants, mood stabilisers, or antipsychotics. Exclusion criteria were non-pharmacological interventions, non-suicidal self-injury-only studies, reviews, and grey literature. Both interventional and observational designs were considered. Four authors independently screened, extracted, and appraised data using Joanna Briggs Institute tools. The primary outcome was suicidality reduction, synthesised narratively. This study is registered with PROSPERO, CRD42024548628.

Findings: Twenty-three articles out of 1747 met inclusion criteria, totalling 2235 participants. Risk of bias across studies was low-to-moderate for nearly all studies (22/23). However, the majority employed weaker study designs and targeted underlying diagnoses, with suicidality rarely assessed as a primary outcome. Esketamine (four studies, n = 211) and ketamine (four, n = 6) use in major depressive disorder induced rapid reduction of acute suicidality within 24 h. In the longer term, lithium (three, n = 923) was beneficial in reducing suicidality in youths with bipolar disorder. Sertraline, citalopram, escitalopram, fluoxetine and duloxetine (six, n = 906) yielded inconsistent results. Other agents, including valproate, lamotrigine and antipsychotics such as clozapine and quetiapine exhibited some benefit in reducing suicidality, but findings were limited to small-scale studies.

Interpretation: Evidence remains scarce and heterogeneous. Esketamine and lithium appear promising for acute and chronic suicidality, respectively. Further high-quality studies investigating suicidal thoughts and behaviours as independent treatment targets are needed to guide clinical decision-making.

Funding: None.

Background: Major adverse cardiovascular events (MACE) are common early after liver transplantation (LT) as reported in the United States, but incidence is not well described in a European cohort. With lower MACE rates reported after kidney transplantation in the United Kingdom versus the United States, it is important to determine if a similar incongruity exists after LT.

Methods: In this large retrospective, population cohort study, we studied all LT procedures performed in England between 1st April 2002 and 31st March 2023 (n = 10,213). MACE data was obtained from Hospital Episode Statistics, an administration data warehouse for any hospitalization to English NHS hospital, and defined as any of the following: myocardial infarction, stroke, unstable angina, heart failure, any coronary revascularization procedure and any cardiovascular-defined death.

Findings: MACE-related 1-year mortality was low at 0.1% (n = 11). Overall, MACE occurred in 268 (2.6%) LT recipients within the first year after LT, of which 125 (1.2%) occurred within the first month. The commonest observed MACE was stroke (n = 129, 1.3%), followed by myocardial infarction (n = 89, 0.9%). After adjustment, MACE within the first year was associated with increased risk for long-term all-cause mortality (Hazard Ratio 1.37, 95% CI 1.05-1.79, p = 0.021). In a competing risk regression model, with non-cardiac death a competing risk, the following were independently associated with increased risk of MACE after LT: increasing age, male sex, diabetes, and higher Charlson co-morbidity score.

Interpretation: MACE and cardiovascular death are uncommon within the first-year post LT in England. However, liver transplant recipients with non-fatal MACE have inferior long-term survival. Further work is warranted to determine the best strategy to mitigate cardiac risk stratification for LT candidates and evidence-based strategies to mitigate cardiovascular risk after LT must be encouraged.

Funding: Nothing to disclose.

Background: Chronic pelvic pain affects one in four women. Botulinum toxin, approved for chronic migraine and cervical dystonia pain, is an emerging treatment for other pain conditions. We evaluated intramuscular pelvic floor botulinum toxin injection in women with endometriosis-associated chronic pelvic pain and pelvic floor muscle spasm, hypothesising that botulinum toxin might reduce both spasm and pain.

Methods: In this a randomised, double-masked, parallel, phase 2 trial, women with pelvic floor spasm and pain despite standard endometriosis-specific and pain treatment were randomily assigned 1:1 to injection of 100 Units onabotulinumtoxinA (15 participants) or saline placebo (14 participants) into pelvic floor muscles. The primary outcome was patient report of benefit or no benefit assessed 1 month after masked injection. Patients could choose an open injection from 1 to 12 months after masked injection. Secondary outcomes (pain rating, pain medication usage, effect duration, and other participant-reported measures) were compared to baseline ratings. This study is registered with ClinicalTrials.gov, NCT01553201.

Findings: 29 participants were recruited between July 24, 2014 and May 8, 2018. All enrolled women completed the study. At 1 month, significantly more women in the toxin group reported benefit (11 (73%) of 15 vs 4 (29%) of 14; p = 0.027). Women receiving toxin attained a greater percent benefit (p = 0.034) and longer duration (p = 0.023) of pain relief. Those with at least moderate baseline pain had lower pain scores after toxin (p = 0.028). Benefit was present at 1 year in 16 of those requesting open injection (7 of 14 receiving placebo; 9 of 13 receiving toxin). 20 (77%) of 26 patients used less pain medication at 1-year (p < 0.0001), with 12 (92%) of 13 in the BoNT group and eight (62%) of 13 in the placebo group using less medication (p = 0.061). Adverse events were non-serious with no grade 3 or 4 adverse events or deaths, and were similar in both cohorts following masked and open injections.

Interpretation: This study demonstrates the efficacy and safety of pelvic floor botulinum toxin injection for women with endometriosis-associated chronic pelvic pain and pelvic floor spasm.

Funding: The study was supported by the Intramural Research Program of the U.S. National Institutes of Health (NIH). Allergan, Inc. provided study drug and independent monitoring funds under a Clinical Trial Agreement with NIH and had no other role in the study.

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.