Objectives. To examine the associations between paternal leave status and mental health symptoms in a large population-representative study of fathers after the birth of a child. Methods. We used data from the 2022-2023 Ohio Fatherhood Survey (OFS) to model the relationship between paid work leave factors and mental health (Patient Health Questionnaire-2 [PHQ-2] and Generalized Anxiety Disorder-2 [GAD-2]) by using weighted descriptive analyses and adjusted logistic regression modeling. Results. Fathers with unpaid leave were more likely to report anxiety symptoms (adjusted odds ratio [AOR] = 1.58; 95% confidence interval [CI] = 1.00, 2.48) compared with fathers with paid leave, while unmet needs were associated with increased depression (AOR = 3.21; 95% CI = 1.92, 5.37) and anxiety (AOR = 3.12; 95% CI = 2.02, 4.83) symptoms. Furthermore, barriers to work leave, including financial barriers (PHQ-2 = 74.6%; GAD-2 = 71.2%) were more prevalent among fathers who reported recent mental health symptoms. Conclusions. Paid paternal leave status and leave barriers are associated with mental health symptoms. Public Health Implications. Equitable paid paternal leave may strengthen mental health, highlighting a public health pathway toward improving father and family well-being. (Am J Public Health. Published online ahead of print June 18, 2026:e1-e10. https://doi.org/10.2105/AJPH.2026.308554).
Does a natural cycle result in higher clinical pregnancy rates (CPR) with foetal heartbeat compared to an artificial cycle for frozen-thawed embryo transfer (FET) preparation in ovulatory women? The CPR with foetal heartbeat did not differ between natural and artificial cycles in ovulatory women undergoing FET. Several protocols for endometrial preparation have been developed for the increasing number of FET cycles in reproductive medicine. In natural cycle FET (NC-FET), spontaneous ovulation is used to time the embryo thawing and transfer, while in artificial cycle FET (AC-FET), endometrial preparation involves sequential oestrogen and progesterone administration. Current evidence on pregnancy rates does not favour one regimen over the other in women with regular ovulatory cycles. We conducted a multicentre, open-label, randomised trial comparing NC-FET with AC-FET across five Belgian fertility centres. Between October 2018 and October 2024, 561 women were randomised (1:1) using a computer-generated allocation after written informed consent. The primary outcome was CPR with foetal heartbeat per cycle analysed on an intention-to-treat basis. Secondary outcomes included endometrial thickness, number of clinic visits for FET cycle monitoring and the rates of (biochemical) pregnancy, ongoing pregnancy, live birth, miscarriage, ectopic pregnancy, multiple pregnancy and cycle cancellation. Obstetric outcomes were recorded for all ongoing pregnancies. Women aged 18-45 with regular ovulatory cycles and normal uterine cavities undergoing FET after vitrification and warming of one or two day-3 embryos or blastocysts were included. In NC-FET, spontaneous ovulation was detected by serial ultrasounds and serum LH and oestradiol measurements. In AC-FET, oestradiol valerate (6 mg/day) was administered from cycle day 2 (increased to 8 mg/day after 1 week if endometrial thickness was <7 mm) and micronized progesterone (600 mg/day) was initiated once endometrial thickness reached ≥7 mm. Clinical pregnancy rates with foetal heartbeat were similar between NC-FET and AC-FET in both intention-to-treat (33.1% [94/284] vs 28.9% [80/277]; RR 1.15, 95% CI 0.89, 1.47) and as-treated analyses (34.3% [97/283] vs 31.8% [77/242]; RR 1.08, 95% CI 0.85, 1.38). Cycle cancellations were less frequent in NC-FET (3.9% vs 9.4%; RR 0.41, 95% CI 0.21, 0.82), but NC-FET required more monitoring visits (mean 3.0 vs 2.4; P = 0.0002). Caesarean section was more common after AC-FET (42.7% vs 20.2%; P = 0.003). Other reproductive, obstetric, and perinatal outcomes did not differ significantly between groups. The sample size was powered to detect a difference in CPR with foetal heartbeat, not for comparing live birth rates or obstetric outcomes. The study was performed in ovulatory women undergoing FET, and therefore, results may not be applicable to other populations. This RCT demonstrates no significant difference in CPR with foetal heartbeat in NC-FET and AC-FET in ovulatory women. Given recent data suggesting higher obstetric risks with AC-FET, NC-FET may be preferred in women with normal ovulatory cycles. The study was an investigator-initiated study supported by internal KU Leuven funding (Project number C14/18/106 and C14/24/152) and funding from the Research Foundation Flanders (G.084515N and G.0B1819N to J.V.). K.P. has received grants from Ferring. C.B. has received speaker fees from Gedeon Richter, paid to her institution; travel support from Gedeon Richter, Ferring Pharmaceuticals, and Intuitive; and holds a leadership role as Senior Deputy of the ESHRE SIG Endometriosis and Endometrial Disorders. C.T. has received grants from Merck SA, paid to her institution; consulting fees and speaker fees from Gedeon Richter; travel support from Ferring and Gedeon Richter; and holds leadership roles as Deputy Editor of JNIG and as a board member. A.V. has received speaker fees from Gedeon Richter, paid to his institution, and holds a leadership role as Senior Deputy of the ESHRE SIG Endometriosis and Endometrial Disorders. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. This trial has been registered at ClinicalTrials.gov (NCT03642665). 17 July 2018. 27 October 2018.
The onset of depression and depressive symptoms spikes during adolescence, and the prevalence of depression in adolescents appears to be increasing over time (Daly, 2022). In previous research, we found that greater integration of an allostatic interoceptive system (AIS), a brain system involved in the predictive regulation of the body, prospectively predicted more depressive symptoms in adolescents two years later, mediated by a greater tendency to ruminate (Frye et al., 2025). This pattern of brain organization may reflect excessive internal focus. Here, we examine the potential moderating effect of emotional awareness on the relationship between AIS integration and prospective depression symptoms. Specifically, using data from a larger longitudinal study of adolescents beginning in 6th -8th grade, we test whether trait emotional clarity or emotional attention moderates the relationship between AIS global efficiency during a resting-state fMRI scan and prospective depressive symptoms assessed an average of two years later (N = 117, 55% female, M initial age= 12.99, M age at follow-up= 14.74). We found that for adolescents who paid little attention to their emotions, greater AIS integration was related to lower prospective depressive symptoms, whereas for adolescents who paid above-average attention to their emotions, greater AIS integration was related to greater prospective depressive symptoms. These findings contribute to an emerging understanding of the role of the allostatic-interoceptive system in depression in adolescents by showing that the relationship between system integration and prospective depressive symptoms differs depending on adolescents' emotional attention. The online version contains supplementary material available at 10.1007/s42761-025-00347-4.
When nurses decide upon accepting a position, it is often a multifaceted decision that involves evaluating several job attributes simultaneously. To examine the factors that motivate the job choices of registered nurses (RNs) at a large multispecialty academic medical center in the U.S. Midwest. All direct care RNs including those working in inpatient, ambulatory, and remote settings working at our healthcare organization received an emailed survey link with an invitation to participate in the study. This study used discrete choice experiment (DCE) methods to examine RN job preferences. The DCE used six attributes to describe hypothetical nursing jobs. The attributes included appropriate nurse-to-patient ratio, salary, consistency in work schedule, work-related incentives, paid time off scheduling, and nurse manager support. A mixed logit model was used to estimate mean preference weights for the different attribute levels. A latent class analysis (LCA) was used to examine the number of preference classes in the sample. The analysis included 1,667 respondents. The mixed logit model results showed the highest relative importance weight on the salary attribute (0.311) followed by appropriate nurse-to-patient ratio (0.202), paid time off scheduling (0.149), nurse manager support (0.140), consistency in work schedule (0.125), and work-related incentives attributes (0.073). The LCA showed that there were four preference classes. Monetary and nonmonetary attributes were found to motivate RNs' job choices. The results from this study can be used to inform local recruitment and retention initiatives based on the average or subgroup RN preferences.
Ion-track-etched membranes (ITEMs) have emerged as a distinct class of nanostructured materials and represent a versatile platform that offers precise control over pore shape, size, and areal density. These membranes offer considerable mechanical and chemical stability, making them valuable for a variety of applications, including nanoionic rectifiers, sensors, nanoiontronics devices, and energy harvesting systems. The chemical etching process of ITEMs introduces carboxylic acid groups on the surface, which serve as the sites for functionalization. Functionalization is crucial for using the ITEMs in sensor applications. ITEM-based sensors provide considerable sensitivity and selectivity. Moreover, the sensors have a low limit of detection compared to other traditional sensors. ITEMs also exhibit memristive behavior (hysteresis loop) and can perform logic gate functions. These attributes are crucial for nanoionic fluidic-based neuromorphic computing. Moreover, ITEMs can serve as efficient platforms for osmotic energy harvesting (OEH) as well as membrane-assisted cooling and dehumidification applications. This review article articulates the fundamentals of ITEMs, fabrication strategies, the origins of surface-charge-dominated ion-transport mechanisms under nanoconfinement, and chemical functionalization approaches. In addition to that, concepts of ionic rectification, hysteresis, and nonlinear functionalities related to the memristor and neuromorphic computing are also discussed. Moreover, special attention was paid to OEH systems, and power densities obtained with different membranes were also discussed and compared. The review article also provides insights into next-generation nanoionic systems by combining the concepts of nanofluidics and electrochemistry. In addition, a comprehensive analysis of the current challenges and future opportunities in developing multifunctional, scalable, and sustainable ITEM technologies is also presented.
Traffic emissions comprise a complex mixture of pollutants, including tailpipe (exhaust), nontailpipe (e.g., brake and tire wear, resuspended road dust), and noise pollution. While regulations have drastically reduced tailpipe emissions, the growing vehicle fleet and miles traveled have contributed to rising levels of nontailpipe and noise emissions. These under-regulated exposures, often rich in toxic transition metals, may pose significant health risks, particularly when noise acts as a co-exposure that may influence traffic-related effects. We examined lung function effects associated with nontailpipe exposures in the Children's Health Study (CHS), a cohort of over 1,200 children from eight Southern California communities. Participants underwent lung function testing for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at three time points between 2008 and 2012. Participant-specific estimates of particulate matter (PM) mass and metal exposures were developed by applying spatiotemporal regression models to measurements of quasi-ultrafine (PM0.2, aerodynamic diameter ≤0.2 µm), fine (PM0.2-2.5), and coarse (PM2.5-10) particles collected at 220 locations across two seasons. We used supervised variable selection of over 150 variables, including meteorology, roadway and traffic characteristics, land use, and dispersion-modeled estimates of tailpipe emissions. Particular attention was paid to PM components with high oxidative potential or those serving as markers for nontailpipe sources. Traffic noise exposures were estimated at a 20-m resolution along roadways using two approaches: (1) mobile measurements of A-weighted equivalent noise levels (LAeq in decibels [dB]) collected in Long Beach and modeled using machine learning; and (2) CadnaA, an acoustic model applied to generate LAeq across all communities. We used mixed effects models to evaluate associations between exposures and lung function, adjusting for covariates and accounting for repeated measures. Spatiotemporal PM models showed strong performance (leave-one-community-out cross-validation coefficient of determination [R2] 0.59-0.82; 10-fold cross-validation R2 0.76-0.92). Incorporating intersection-based hotspots and meteorology substantially improved accuracy. Noise models using extreme gradient boosting (XGB) achieved high accuracy (leave-one-route-out cross-validation R2 = 0.71, root mean square error [RMSE] 4.54 dB; fivefold cross-validation R2 = 0.96, RMSE 1.8 dB), with traffic volume, road proximity, and meteorology as top predictors. LAeq estimates from XGB performed well on smaller roads, while CadnaA performed better on highways. Both approaches captured fine-scale spatial variation in traffic-related noise. Epidemiologically, coarse and fine nontailpipe metals, especially iron (Fe) and copper (Cu) as markers of road dust and brake wear, were consistently and significantly associated with reduced FEV1 and FVC. These associations persisted after adjusting for PM mass, and were stronger than those of tailpipe markers like fine elemental carbon (EC2.5, diesel) and quasi-ultrafine organic carbon (OC0.2, gasoline). Traffic noise was not independently associated with lung function but strongly confounded the OC0.2-FEV1 association (noise-adjusted FEV1 was 33% larger in magnitude), suggesting co-occurrence or shared spatial patterns between noise and tailpipe emissions. In contrast, green space was directly associated with better lung function and acted as a confounder, attenuating nontailpipe PM component associations while strengthening that of OC0.2. This study highlights the lung function impacts of PM components, the role of traffic noise, and the influence of green space. From an exposure modeling standpoint, a major takeaway is the importance of meteorology and intersection features for PM components, and meteorology, traffic volume, and land use for traffic noise. Nontailpipe metals had the strongest and most consistent associations with reduced lung function, likely via oxidative stress pathways. Noise influenced the associations of tailpipe markers, reflecting a separate stress mechanism. Green space emerged as a protective factor, highlighting its potential to influence adverse associations between traffic-related air pollution and children's respiratory health. As nontailpipe sources grow in importance with increased electric vehicle adoption, mitigation strategies should target brake, tire, and road wear. Regulatory actions, lighter electric vehicle designs, and regenerative braking could help. Simultaneously, expanding green space offers a feasible, co-beneficial intervention to buffer both air and noise pollution and to promote children's respiratory health.
Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy that may be influenced by infectious, demographic, and healthcare-related factors. Although increasing attention has been paid to neurological complications during the COVID-19 pandemic, the global burden, inequalities, and future trends of GBS remain insufficiently characterized. This population-based observational epidemiological study used data from the Global Burden of Disease Study 2021 to assess the burden of GBS across 204 countries and territories from 1990 to 2021. The main outcomes included prevalence, years lived with disability (YLDs), age-standardized prevalence rate (ASPR), age-standardized YLD rate (ASYR), and estimated annual percentage change (EAPC). Analyses were stratified by sex, age group, country, region, and socio-demographic index (SDI). Inequality analysis, decomposition analysis, Joinpoint regression, and Bayesian age-period-cohort modeling were further used to assess socioeconomic disparities, driving factors, temporal changes, and future trends. From 1990 to 2021, the global burden of GBS increased substantially. In 2021, the global number of prevalent cases reached 471,850, and the ASPR was 5.91 per 100,000 population. The corresponding number of YLDs was 139,639, with an ASYR of 1.75 per 100,000 population. The burden was lowest among children younger than 5 years and increased progressively with age. Males generally had a higher burden than females, particularly among older adults. Low-SDI regions experienced disproportionately higher ASPR and ASYR, indicating substantial global inequalities. The increases observed after 2019 temporally coincided with the COVID-19 pandemic; however, this association should be interpreted cautiously. Decomposition analysis suggested that epidemiological changes, population growth, and population aging collectively contributed to the increasing burden of GBS. The global burden of GBS increased markedly from 1990 to 2021, with substantial regional, sex-, age-, and SDI-related heterogeneity. The post-2019 increase temporally coincided with the COVID-19 pandemic, but causal inference should be avoided due to the observational nature of this study. Strengthening neurological surveillance, improving early diagnosis and treatment capacity, and reducing healthcare disparities in low-SDI regions may help mitigate the future burden of GBS.
The last several years have seen increased scholarly attention paid to the use of race in clinical algorithms and practice guidelines.1 Whether it be attempts at race correction, race norming or race adjustment the inappropriate use of race as independent proxy for biologic variables is being vigorously challenged.2 Several organized medicine bodies have issued policy and/or positions declaring opposition to race-based medicine and commitment to critically examining the role of race and racism as structural contributors to outcome disparities.3,4,5 In terms of the investigative underpinnings that support the development of clinical algorithms, in a 2024 study entitled Rethinking the Use of Race in Biomedical Research, the National Academies of Science Medicine and Engineering panel encouraged researchers to "refrain from making unsupported inferences from the analysis, such as relying on race and ethnicity as causal attributes that drive biomedical research outcomes".6 The scientific literature is replete with examples beyond the scope of risk determining algorithms and equations where race is embedded as a variable that can deleteriously influence clinical decision-making.
Fever was the main symptom of nontraumatic diseases in antiquity. Increased body temperature was detected by the physician through palpation of the skin and the pulse. Hippocrates of Cos described fever in several books and numerous case studies. The great physician paid more attention to the duration and temporal distribution of the fever than to its intensity. Among the accompanying symptoms, somnolence, coma and delirium were particularly feared. More than half a millennium later, Galen of Pergamum extensively documented the fever theory of antiquity once again. The choice of conservative treatment was influenced by the patient's general condition and the frequency of fever recurrence. If it failed, phlebotomy was available as a last resort. Retrospective diagnostics have identified malaria as the principal cause of fever epidemics in antiquity. The ancient physicians often described the threat to humans from wind and water but did not recognize or at least consider the causal connection between the swarms of mosquitoes rising from the swamps and the widespread fever. Fieber war das Leitsymptom der nichttraumatischen Erkrankungen in der Antike. Die Erhöhung der Körpertemperatur wurde von den Ärzten durch Palpation der Haut und des Pulses nachgewiesen. Hippokrates von Kos hat das Fieber in mehreren Büchern und zahlreichen Kasuistiken beschrieben. Der große Arzt des Altertums hat der Dauer und zeitlichen Verteilung des Fiebers mehr Beachtung geschenkt als der Intensität. Unter den Begleitsymptomen waren Somnolenz, Koma und Delir am meisten gefürchtet. Mehr als ein halbes Jahrtausend später hat Galen von Pergamon die Fiebertheorie der Antike erneut umfangreich dokumentiert. Die Art der konservativen Behandlung war vom Allgemeinzustand der Patienten und der Rezidivhäufigkeit des Fiebers geprägt. Wenn sie versagte, stand als letztes Mittel die Phlebotomie zur Verfügung. Die retrospektive Diagnostik hat Malaria als Hauptursache der Fieberepidemien des Altertums identifiziert. Die antiken Ärzte haben die Bedrohung der Menschen durch Wind und Wasser vielfach beschrieben, den kausalen Zusammenhang zwischen den aus den Sümpfen aufsteigenden Mückenschwärmen und dem seuchenhaften Fieber aber nicht erkannt oder auch nur erwogen.
Ecosystem conservation entails maintaining human-nature harmonious coexistence. Its primary challenge lies in addressing human awareness and individuals' empathy fatigue within the process. Although existing research has demonstrated the significance of ecosystem, concerns over its destruction, and awareness of conservation, only insufficient attentions paid on its sustainability. Therefore, this study proposes that awareness decline leads to empathy fatigue in human-nature harmonious coexistence. Integrating empathy theory and the concept of fatigue, a model has been introduced to understand the empathy fatigue. Guided by this framework, this study employs a mixed-methods approach combining natural language processing and qualitative analysis. Taking Japan's nuclear wastewater discharge-a case exemplifying the awareness decline-as its subject, it explores core questions: user segmentation, the evolution of discourse patterns, and underlying mechanisms. This study continuously monitored and collected 2227 valid comments from YouTube between January 2021 and November 2025. It constructed a three-tier mechanism model- "attention bubble-cascading exit-discourse coreization" -based on four dimensions: structural fragility, exit timing, discourse evolution, and mechanism integration, validating the empathy fatigue framework. This study reveals the evolutionary path of public environmental engagement shifting from "emotion-driven mass participation" to "cognition-driven elite participation". It identifies key factors and their roles within attribution mechanisms, including responsibility allocation, user commitment levels, discourse rationalization, and empathy transformations. By proposing the theory of empathy fatigue, this study interprets the dual-dimensional structure of decreased affective empathy fatigue and increased cognitive empathy in ecosystem conservation, providing significant insights for interpreting and practicing long-term communication and participation mechanisms in ecosystem conservation.
The purpose of this review is to describe the activity and function megakaryocytes and platelets in the myeloproliferative neoplasms (MPNs.) Specific attention is paid to how megakaryocytes relate to disease progression and altered hemostasis and how current therapies are beginning to target them. MPN megakaryocytes are hyperproliferative and induce further dysregulation within the niche via inflammatory cytokine secretion, while MPN platelets display a contradictory phenotype of baseline preactivation and functional exhaustion upon stimulation, due in part to mitochondrial dysregulation. Platelet transcriptomic profiling has further revealed disease subtype-specific gene expression and a shared thrombo-inflammatory profile. CALR-mutated MPNs have significantly advanced with the development of mutation-specific interventions in early clinical trials. Thrombotic and hemorrhagic complications represent the most common cause of morbidity in MPNs, however the mechanisms underlying this pathology remain opaque. Cytoreduction and antithrombotic therapies, the mainstay for treatment of MPNs, inadequately address platelet dysfunction, though emerging therapies targeting the MPN clone are promising. Thus, a deeper understanding of megakaryocyte and platelet biology in MPNs is essential for the development of precise therapeutic strategies to reduce thrombotic complications and improve patient outcomes.
Companion-based social interaction has become an emerging form of lightweight digital sociality among young Chinese users. Existing studies have mainly discussed its social background and cultural meanings, but less attention has been paid to the psychological mechanisms underlying users' participation intention. Drawing on the Stimulus-Organism-Response framework, this study examines how platform-level conditions and individual predispositions are associated with companion-seeking intention through perceived value. Platform information quality and social affordance are treated as environmental antecedents related to perceived functional value, while extraversion and social motivation are treated as individual antecedents related to perceived emotional value. Online interpersonal trust is further introduced as a moderating factor. The findings show that perceived functional value and perceived emotional value link antecedent factors to behavioral intention. Online interpersonal trust weakens several antecedent-to-value relationships, suggesting that trust may reduce users' reliance on other evaluative cues. This study clarifies the value-based mechanism of companion-based social interaction and extends the application of the SOR framework to lightweight digital social contexts.
Receiving health systems cannot improve refugee clinician integration pathways if no actor is responsible for the denominator, milestones, or stage-specific delays. England is a useful worked example. Published UK initiatives show that already-resident refugee and asylum-seeking doctors can reach NHS employment, supervised placements and professional registration, but they use different denominators, endpoints and follow-up conventions. They demonstrate feasibility without yielding a pathway metric that system-level purchasers, funders or regulators can compare, fund or improve. A minimum time-to-practice (TTP) specification would separate two clocks. A population or pre-pathway clock would record earlier dates, such as arrival, asylum-claim lodgement, first contact or first documentation of professional background, to show upstream delay and attrition. The pathway TTP clock would begin at pathway registration, when a minimum dataset is complete, a named pathway owner can act, and the case enters the reporting denominator. Two auditable milestones would then be measured from registration: TTP-1, the verified start of the first qualifying paid supervised placement; and TTP-2, practice-enabling, profession-equivalent registration. Work-eligibility status, documentation completeness, years out of practice and route complexity should be recorded to interpret variation rather than to exclude people from the denominator. TTP is not a measure of competence, programme effectiveness or speed alone. Its purpose is workforce governance: to define the denominator, milestones, safeguards and funding conditions needed to compare and improve a poorly observed route back into practice, while remaining distinct from active overseas recruitment.
Despite extensive studies of single hair-bundle dynamics, comparatively little attention has been paid to the collective dynamics arising in coupled hair-bundle systems. In this work, we investigate the collective dynamics of coupled hair bundles using a simplified dimensionless mechanical model that captures the essential nonlinear features of hair-bundle activity. We focus on two physically motivated interaction mechanisms: elastic and viscous coupling between neighboring bundles. The stability of synchronized motion is first analyzed using the master stability function framework and complemented by extensive numerical simulations. Our results demonstrate that within the present model, viscous coupling is significantly more effective than elastic coupling in promoting stable synchronization across a wide range of system parameters. Beyond complete synchronization, the network exhibits a variety of complex collective states, including non-stationary chimera patterns and clustered dynamics with distinct dynamical behaviors. Finally, we establish the occurrence of coherence resonance in the network, showing that an intermediate level of noise can enhance temporal regularity in the absence of external periodic forcing. These findings provide new insights into the mechanisms governing collective phenomena in interacting hair-bundle systems.
Although progress towards implementation of international agreements since publication of the UCL-Lancet Commission on Migration and Health in December, 2018, has been slow, global trends in migration and forced displacement have continued to rise. However, the COVID-19 pandemic showed that reaching refugees and migrants with health interventions is feasible with political will. The benefits of refugee-inclusive and migrant-inclusive health-care systems during emergencies (eg, COVID-19 and the war in Ukraine) are apparent, with numerous examples of inclusive policy making being rapidly introduced and innovative models developed to support health-care access, including preventive measures such as vaccination. Lessons from these successes should be learned and incorporated into future policy and practice. However, global political and financial uncertainty and disruption-combined with multiple conflicts and natural disasters-have increased individuals' need to move, which will continue to be exacerbated by the climate crisis. Although new conflicts and exacerbations of existing ones have led to a rise in forced displacement within and across national borders, labour migration has also risen dramatically, with the pandemic highlighting the health and social needs of these groups globally. The need for strong leadership and accountability, engagement of policy makers in the highest-level fora, and improved access to quality health services for refugees and migrants has never been greater. In this Review, nearly 8 years after the UCL-Lancet Commission on Migration and Health was published, we renew our call for action to: (1) improve health-care access and optimise outcomes for refugees and migrants by emphasising health in all migration and forced displacement policies; (2) establish data systems to monitor progress, together with appropriate use of new technologies to improve access, prevent harm, and safeguard privacy; (3) support research on adaptation to and mitigation of the health consequences of climate change on refugees and migrants; and (4) renew focus on the political determinants of health outcomes for people on the move. At this pivotal moment, with geopolitical, sociodemographic, and environmental turmoil, political leaders and societies can shape a better future by leveraging the human capital of migrants and upholding the human rights and dignity of all.
To assess the effects of stereotactic radiotherapy (SRT) for neovascular age related macular degeneration (AMD) beyond the two year primary outcome of the StereoTactic radiotherapy for wet Age-Related macular degeneration (STAR) trial. Randomised, double masked, sham controlled, device trial involving preplanned recall from standard care. 30 NHS hospitals in the UK. 411 participants aged at least 50 years with chronic, pretreated, active AMD. Participants received one-off 16 Gray SRT or sham SRT delivered using a robotically controlled device. After two years of monthly study visits, participants reverted to routine care, with anti-VEGF drug selection and dosing intervals based on local practice, but with masking maintained, and repeat data collection at years 3 and 4 study visits. The main efficacy outcome at year 4 was the number of anti-VEGF injections, tested for superiority (fewer injections). The other main outcome was visual acuity, tested for non-inferiority (five letter margin). Safety outcomes included adverse events, serious adverse events, and microvascular abnormalities. The same analyses were undertaken at years 2, 3, and 4. A within trial costing analysis was undertaken for participants with four years' follow-up. Of 411 participants (204 (58%) women), 274 were allocated to SRT and 137 to sham SRT. The year 4 intention-to-treat efficacy analysis included 222 (81%) participants in the SRT group and 106 (77%) in the sham SRT group. The SRT group received a mean of 19.1 (standard deviation 10.9) injections over four years versus 21.6 (11.3) with sham SRT, an adjusted decrease of 3.2 injections (95% confidence interval (CI) of difference -5.7 to -0.7). During years 3 and 4, the SRT group received a mean cumulative 8.4 injections versus 8.3 injections in the sham SRT group. The final change in visual acuity in the SRT group was 8.3 letters worse than in the sham group (95% CI of difference -12.7 to -4.0). Adverse event rates were similar between groups, but reading centre-detected microvascular abnormalities occurred in 126/218 SRT treated eyes (58%) and 16/102 (16%) sham SRT treated eyes. Although the overall reduction in intravitreal therapy was maintained to year 4, the inferior vision in SRT treated eyes effectively reversed the conclusions of the year 2 primary outcome analysis and no longer supports the use of SRT to treat neovascular AMD. Including standard care, masked, extended follow-up within a clinical trial may provide useful clinical insight. ClinicalTrials.gov NCT02243878.
Patients with acute myeloid leukemia (AML) treated with hypomethylating agents and venetoclax (HMA-VEN) may be at risk for cardiovascular complications. The incidence, associations, and prognostic implications of these events remain poorly defined. The purpose of this study was to evaluate the incidence, risk factors, and prognostic significance of major adverse cardiovascular events (MACE) in AML patients treated with HMA-VEN and to identify clinical and genetic predictors. We conducted a multicenter retrospective cohort study across 6 U.S. health care systems between January 2017 and July 2024. The study included 1,012 adults (mean age 69 ± 12.5 years; 57% male) with newly diagnosed or relapsed/refractory AML treated with HMA-VEN. The primary outcome was MACE, defined as atrial fibrillation, heart failure, left ventricular ejection fraction reduction, stroke/transient ischemic attack, acute coronary syndrome, angina, ventricular tachycardia/fibrillation, myocarditis, or cardiovascular death. The secondary outcome was noncardiac mortality. Variables associated with MACE and mortality were analyzed using Fine-Gray competing risk and Cox proportional hazards models. MACE occurred in 20% of patients (n = 200), with a median time to first MACE of 120 days and a 12-month cumulative incidence of 17%. Atrial fibrillation (6%), stroke/transient ischemic attack (5%), left ventricular ejection fraction reduction (5%), and heart failure (4%) were most frequent. Diabetes independently predicted MACE (subdistribution HR: 1.4; 95% CI: 1.03-1.89; P = 0.031). In the matched cohort, MACE was associated with increased mortality (73% vs 56%; HR: 1.96; 95% CI: 1.59-2.42; P < 0.001). MACE are frequent and occur early in patients with AML treated with HMA-VEN, particularly in patients with diabetes, and are associated with lower survival.
Antibody-drug conjugates (ADCs) have transformed the cancer therapeutic landscape over the past two decades, profoundly shaping treatment outcomes across a wide array of indications. Three ADCs are currently approved for previously treated gynaecological cancers: mirvetuximab soravtansine for folate receptor-α-positive ovarian cancer, trastuzumab deruxtecan for solid tumours expressing HER2 (defined as a staining intensity on immunohistochemistry of 3+) and tisotumab vedotin for cervical cancer (independent of tissue factor expression). Current research priorities include identifying novel targets, better understanding mechanisms of resistance and sequencing strategies, and optimal management of the toxicities of ADCs. Moreover, rational combinations could reinforce and extend the clinical potential of these agents, as has already been demonstrated with the addition of ADCs to immune checkpoint inhibitors in an effort to amplify antitumour immunity and prolong the durability of clinical responses. In this Review, we provide an overview of the current landscape of ADCs in gynaecological malignancies, highlighting key advances and future opportunities.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
The growth in evidence-based medicine clearly benefits patient care but it is important that evidence is accessible and usable. Translating research results into usable, meaningful information can be challenging and impede the implementation of robust evidence. There are many aspects to making the statistical parts of a research study actionable for practicing clinicians and policy makers. These include ensuring that the right questions are asked, the study is designed appropriately, and results are transparent and applicable to the clinical setting. In this perspectives-style article we offer guidance on these considerations by highlighting several approaches that we have found effective for improving the interpretability and practical application of statistical findings. Our over-arching aim is to stimulate interdisciplinary dialogue throughout the research process. Specifically, we discuss the interpretation of p-values, effect estimates, differences between means, scaling regression coefficients, unadjusted/adjusted estimates, Minimal Clinically Important Difference, absolute and relative risk, and suggest how clinical meaning can be enhanced by presenting the same information in different but complementary ways. We conclude with a recommendation that study teams prioritize interdisciplinary discussions around clinical meaningfulness throughout our research studies to maximize their clinical impact.