Tag: pubmed

JAMA Intern Med. 2025 Jun 16. doi: 10.1001/jamainternmed.2025.1853. Online ahead of print.

ABSTRACT

IMPORTANCE: Cystic fibrosis is one of the most commonly diagnosed autosomal recessive disorders in the US. It is estimated that more than 10 million individuals are heterozygous for a pathogenic CFTR gene variant in the US (heterozygotes). The phenotypic risk of these heterozygotes is not well defined, particularly among populations of predominantly non-European genetic ancestry. Understanding disease risk across each population can improve management strategies for all.

OBJECTIVE: To examine associations of diseases across the phenome with CFTR heterozygotes.

DESIGN, SETTING, AND PARTICIPANTS: The All of Us Research Program is a US-based ongoing longitudinal cohort study whose enrollment started nationally in 2018. In this genetic association study, whole-genome sequencing data were linked to electronic health records (EHRs) and surveys. Participants were 18 years and older. Similarity to genetic ancestral groups was genetically inferred using All of Us data and 2 large reference datasets, the 1000 Genomes Project and Human Genome Diversity Project. This analysis was conducted between February and April 2025.

EXPOSURES: A single pathogenic CFTR variant.

MAIN OUTCOMES AND MEASURES: The main variables included clinical diagnoses documented in EHRs. Multivariable-adjusted phenome-wide association studies were performed. The main measures were odds ratios (ORs), indicating risk for a particular disease or condition.

RESULTS: Overall, 363 pathogenic variants were identified in the cohort. Among 317 964 adult participants (55.7% female; mean [SD] last age in EHR, 56.1 [16.9] years), 7957 heterozygotes and 280 995 noncarriers were identified. Participants were followed up through EHRs with a mean (SD) follow-up of 12.4 (9.0) years. The genetically inferred ancestral distribution of the cohort was 18.0% African, 16.2% American or Admixed American, 2.1% East Asian, 53.4% European, 0.3% South Asian, and 0.4% West Asian. Frequencies of heterozygotes varied by groups of genetic similarity to reference populations: 3.62% in participants most genetically similar to a European reference population (n = 169 812), 1.35% in participants most genetically similar to an African reference population (n = 57 297), and 1.86% in participants most genetically similar to an Admixed American reference population (n = 51 483). A total of 2909 phenotypes were analyzed. No statistically significant associations were identified in heterozygotes of all populations combined or within each genetic ancestral group. Among 52 cystic fibrosis-associated diseases, although an elevated risk of respiratory diseases and infections was observed in some heterozygotes (allergic bronchopulmonary aspergillosis [OR, 2.50; 95% CI, 1.27-4.95]; bronchiectasis [OR, 1.21; 95% CI, 1.00-1.47]; pneumonia due to Streptococcus pneumoniae [OR, 1.54; 95% CI, 1.05-2.26]; chronic obstructive pulmonary disease [OR, 1.14; 95% CI, 1.05-1.24]; asthma [OR, 1.08; 95% CI, 1.01-1.15]; and Pseudomonas infection [OR, 1.34; 95% CI, 1.03-1.74]), effect sizes of these associations were several orders of magnitude lower than those found in homozygotes or predicted compound heterozygotes.

CONCLUSIONS AND RELEVANCE: In this genetic association study, most heterozygotes did not appear to have a substantially higher risk of cystic fibrosis-associated diseases during their adulthood compared to noncarriers. Additional studies are needed to investigate the underlying factors for the elevated risk of respiratory and infectious diseases in some heterozygotes.

PMID:40522671 | DOI:10.1001/jamainternmed.2025.1853

JAMA Netw Open. 2025 Jun 2;8(6):e2515980. doi: 10.1001/jamanetworkopen.2025.15980.

ABSTRACT

IMPORTANCE: The onset of the COVID-19 pandemic created urgency for advance care planning, including documenting goals-of-care conversations (GoCCs), while seismically disrupting usual health care delivery. Characterizing trends in GoCC rates during the pandemic can provide insight into the extent to which health care systems prioritized advance care planning in the face of competing clinical demands, shifts to telemedicine, and staffing shortages.

OBJECTIVE: To determine how the COVID-19 pandemic was associated with changes in outpatient first-ever GoCCs.

DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of patients eligible for their first-ever documented GoCC in outpatient clinics at 123 US Veterans Health Administration facilities nationwide from March 2019 to February 2023.

EXPOSURE: COVID-19 pandemic.

MAIN OUTCOMES AND MEASURES: National- and facility-level weekly GoCC rates, defined as number of first-ever documented GoCCs per 100 000 outpatient appointments. Secondary analyses examined associations between facility-level characteristics and facility GoCC rates.

RESULTS: Of 5 027 956 patients nationally, 124 216 (2.5%) had a first-ever outpatient GoCC during the study period (facility-level range: 0.01%-26.3%). The mean (SD) weekly national first-ever outpatient GoCC rate was 99.6 (12.1) in the year preceding the pandemic. At pandemic onset, mean weekly outpatient GoCC rates dropped to a nadir of 74.1 (week of March 21, 2020), then sharply increased, peaking at 177.4 (week of April 18, 2020), before steadily declining to pre-COVID-19 rates and ending with a COVID year 3 mean (SD) of 96.6 (11.5). At the facility level, 29 of 123 facilities (23.6%) significantly increased outpatient GoCC rates in the early pandemic and maintained or further improved through COVID year 3, with significant rate increases pre-COVID to COVID year 3.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of outpatient GoCC rates, the early COVID-19 pandemic was associated with initial disruption and then with increased first-ever outpatient GoCC rates nationally. Despite unprecedented challenges to health care delivery, several facilities increased GoCC rates during the first COVID-19 surge and maintained increased rates through 2023. These facilities could serve as models for best practices to improve advance care planning.

PMID:40522660 | DOI:10.1001/jamanetworkopen.2025.15980

JAMA Netw Open. 2025 Jun 2;8(6):e2515986. doi: 10.1001/jamanetworkopen.2025.15986.

ABSTRACT

IMPORTANCE: Sudden unexpected infant death (SUID) is the leading cause of postneonatal mortality, with disparities attributed to social determinants of health (SDOH). SUID in the Hispanic population has received limited attention, despite the fact that one-fourth of US children are Hispanic.

OBJECTIVE: To compare SUID rates and risk factors among Hispanic and non-Hispanic infants, and associated interactions among SUID, SDOH, and acculturation.

DESIGN, SETTING, AND PARTICIPANTS: This US nationwide retrospective cohort study used US National Center for Health Statistics (NCHS) linked birth and infant death data, and Pregnancy Risk Assessment Monitoring System (PRAMS) data from 1996 to 2017. All live births (NCHS) or participants (PRAMS) with documented maternal ethnicity were included. Data were analyzed from February to October 2024.

EXPOSURE: Maternal Hispanic ethnicity.

MAIN OUTCOMES AND MEASURES: The primary outcome was postneonatal SUID occurring at age 28 to 364 days, as designated by International Classification of Diseases, Ninth Revision codes 798, 799, and 913 (1996-1999), and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes R95, R99, and W75 (2000-2017). Odds ratios (ORs) were calculated by exposure, and adjusted ORs controlled for risk factors in a multivariable model. Maternal nativity variables associated with race, poverty, local SUID rates, and region of origin were investigated. Subgroup analysis explored the relative association of Hispanic ethnicity with SUID risk factors. Maternally reported risk factors were compared according to Hispanic ethnicity.

RESULTS: Among 88 067 608 live births (median [IQR] maternal age, 27 [22-32] years; median [IQR] gestational age, 39 [38-40] weeks) and 54 828 SUID deaths, there were 7173 SUID deaths among 19 887 156 Hispanic infants. The SUID rate was lower for Hispanic infants (0.36 deaths per 1000 live births) than for non-Hispanic infants (0.70 deaths per 1000 live births), across essentially all factors analyzed. Overall, Hispanic infants had 33% lower odds of SUID than non-Hispanic infants (adjusted OR, 0.67; 95% CI, 0.65-0.69). Infants of non-US-born Hispanic mothers had lower SUID rates, regardless of race, county-level poverty, local SUID rates, or Hispanic region of origin, except Puerto Rican infants. Altered associations with detrimental and protective factors were found, despite a mixed picture of risk.

CONCLUSIONS AND RELEVANCE: In this cohort study of SUID in infants born from 1996 to 2017, Hispanic infants had lower SUID rates than non-Hispanic infants, despite adverse SDOH. Risk factors operated differently in Hispanic infants, challenging current conceptualizations of risk. Understanding how risk operates in Hispanic populations can help to better address the mortality burden of SUID.

PMID:40522659 | DOI:10.1001/jamanetworkopen.2025.15986

JAMA. 2025 Jun 16. doi: 10.1001/jama.2025.7420. Online ahead of print.

NO ABSTRACT

PMID:40522649 | DOI:10.1001/jama.2025.7420

JAMA Pediatr. 2025 Jun 16. doi: 10.1001/jamapediatrics.2025.1600. Online ahead of print.

ABSTRACT

IMPORTANCE: Programs that provide home visiting in early life have been proposed as a way to reduce early childhood adversity and improve child health outcomes. More evidence is needed to understand these programs’ impact when delivered at scale.

OBJECTIVE: To evaluate how receiving home visits through the Nurse-Family Partnership (NFP), a program designed to support young and low-income families, impacted children’s utilization and health outcomes in the 2 years after birth.

DESIGN, SETTING, AND PARTICIPANTS: The NFP is a home visiting program designed with the aim of reducing the incidence of adverse health outcomes in early childhood. In this study, we used data from a randomized clinical trial that enrolled 5670 Medicaid-eligible pregnant people in South Carolina who were randomly assigned at a 2:1 ratio to the NFP treatment (n = 3806) or usual care (n = 1864) between 2016 and 2020. The trial was conducted in 9 NFP-implementing authorities. Participants were eligible if they were fewer than 28 weeks pregnant with their first child, aged 15 years or older, and income eligible for Medicaid (income <200% of the federal poverty level). Data analysis was performed from June 2023 to July 2024.

INTERVENTION: The treatment group was offered NFP home visits during pregnancy and 2 years postpartum, while the control group received usual care.

MAIN OUTCOMES AND MEASURES: The primary outcome was a composite measure that included child mortality and claims related to major injury or concern for abuse or neglect within the first 2 years of life. Secondary outcomes included emergency department utilization and preventive health care measures, such as well-child visits and their components, including screenings for cognitive development, blood lead levels, fluoride varnish application, and dental health. We used an intent-to-treat approach with a linear regression model to estimate the treatment effect of NFP on early childhood outcomes by comparing participants assigned to the control and treatment group, regardless of whether they used NFP services.

RESULTS: Among enrolled participants, 4932 individuals were tracked to a live birth (3295 in the intervention group and 1637 in the control group) and were analyzed for child health and utilization outcomes once their child turned 2 years old. Mean (SD) participant age was 22.5 (4.7) years. The incidence of the composite adverse outcome was 27.3% and 26.8% in the intervention and control groups, respectively (adjusted between-group difference, 0.4 percentage points; 95% CI, -2.3 to 3.0), with no statistically significant differences between elements of the composite primary outcome. Among participants assigned to receive NFP, their children were less likely to use the emergency department by 2.9 percentage points (95% CI, -5.5 to -0.3), a 4% reduction relative to the rate of 72.8% in the control group. Once we adjusted for multiple hypothesis testing, this outcome was no longer statistically significant. Assignment to NFP did not significantly impact the likelihood of receiving the guideline number of well-child visits or preventive services.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, assignment to intensive nurse home visiting services did not reduce the likelihood of adverse outcomes in early childhood measured through administrative data. More evidence is needed to understand whether delivering intensive home visiting services at scale to a Medicaid population influences other child outcomes, including longer-term developmental outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03360539.

PMID:40522648 | DOI:10.1001/jamapediatrics.2025.1600

JAMA Pediatr. 2025 Jun 16. doi: 10.1001/jamapediatrics.2025.1612. Online ahead of print.

ABSTRACT

IMPORTANCE: Mothers and children in low-income households are more likely to experience worse mental and physical health than those from higher-income households.

OBJECTIVE: To determine the effect of 4 years of monthly unconditional cash transfers on the mental health of mothers with low-income and the physical health of mothers and children.

DESIGN, SETTING, AND PARTICIPANTS: This was a parallel-group, randomized clinical trial conducted from May 2018 to July 2023. Mother-infant dyads were recruited (May 2018-June 2019) from postpartum wards in 12 hospitals in 4 cities: Omaha, Nebraska; Minneapolis/St Paul, Minnesota; New Orleans, Louisiana; and New York, New York. Data were analyzed from September 2023 to February 2025.

INTERVENTIONS: Mothers were randomly assigned to receive either a high-cash gift ($333 per month) or a low-cash gift ($20 per month) on debit cards. The cash gifts continued for the first 6 years of their children’s lives. Data analyzed here were collected after 4 years of monthly transfers.

MAIN OUTCOMES AND MEASURES: Outcomes were preregistered and measured around the child’s fourth birthday. Maternal outcomes included depression, anxiety, and body mass index (BMI). Child outcomes included age- and sex-adjusted BMI percentile and maternal report of child health (overall health, times sick in the past year, and presence of chronic health conditions).

RESULTS: A total of 1000 mother-infant dyads (mean [SD] maternal age, 27.0 [5.8] years) were included in this study. Among those mothers, 400 were randomly assigned to receive the $333 high-cash gift and 600 received the $20 low-cash gift on debit cards. Data were available from 891 mother-child dyads. No statistically detectable group differences were found in maternal depressive symptoms (effect size [ES], 0.04; 95% CI, -0.08 to 0.17; P = .51), anxiety (ES, 0.12; 95% CI, -0.02 to 0.25; P = .09), or BMI (ES, -0.06; 95% CI, -0.21 to 0.09; P = .42). In addition, there were no statistically detectable group differences in child BMI percentile (ES, -0.03; 95% CI, -0.17 to 0.12; P = .73) or overall child health (ES, 0.08; 95% CI, -0.07 to 0.22; P = .30).

CONCLUSIONS AND RELEVANCE: Monthly unconditional cash transfers totaling approximately $15 000 over 4 years to mothers with low incomes did not improve maternal mental health, maternal or child BMI, or maternal report of children’s health. These results could reflect the absence of causal connections between cash transfers and health, the possibility that impacts of early childhood income may not appear until later in life, or that an 18% increase in income is insufficient to overcome the structural vulnerabilities associated with poverty that contribute to health.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03593356.

PMID:40522644 | DOI:10.1001/jamapediatrics.2025.1612

JAMA. 2025 Jun 16. doi: 10.1001/jama.2025.8126. Online ahead of print.

ABSTRACT

IMPORTANCE: Mortality of American Indian and Alaska Native (AI/AN) persons is known to be high but may be underreported in routine vital statistics.

OBJECTIVE: To estimate age-specific mortality rates and life expectancy for non-Hispanic AI/AN individuals and other racial and ethnic groups, using self-identified race and ethnicity data in a national cohort, circumventing errors due to racial misclassification on death certificates.

DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study used data from the Mortality Disparities in American Communities (MDAC) study, a nationally representative cohort created through the US Census Bureau’s linkage of the 2008 American Community Survey (ACS) with death records from the National Vital Statistics System through 2019. The cohort included 4 135 000 ACS respondents, including 30 500 who self-identified as AI/AN (alone) and 58 000 who self-identified as AI/AN alone or in combination with another race (AI/AN-AiC).

EXPOSURE: Self-identified race and ethnicity.

MAIN OUTCOMES AND MEASURES: Age-specific mortality rates and life expectancy, estimated using continuous time, nonparametric period survival curves by self-identified race and ethnicity; comparisons to estimates from the US Centers for Disease Control and Prevention (CDC) WONDER database based on race and ethnicity reported on death certificates; and classification ratios for self-reported vs death certificate-recorded AI/AN race among decedents in the MDAC. Analyses were stratified by time period, sociodemographic factors, and cause of death.

RESULTS: Life expectancy of self-identified AI/AN individuals was 72.7 years (73.9 for AI/AN-AiC individuals), 6.5 years less than the US-wide average of 79.2 years. The AI/AN vs US average life expectancy gap widened from 4.1 years in 2008 to 2010 to 8.0 years in 2017 to 2019. Among self-identified AI/AN and AI/AN-AiC decedents, only 59.0% and 39.8% had AI/AN race reported on their death certificates, yielding classification ratios of 1.26 and 1.81, respectively. AI/AN race was most frequently underreported for heart disease and cancer deaths and less frequently for deaths from violence, drugs, and alcohol. In CDC WONDER data (based on race and ethnicity from death certificates), age-standardized mortality was 5% higher for AI/AN individuals than the US average (1067 vs 1016 deaths per 100 000). In MDAC data, mortality for self-identified AI/AN individuals was 42% higher (1420 vs 999 deaths per 100 000). The AI/AN life expectancy gap was 2.9 times larger in the MDAC than in unadjusted official statistics.

CONCLUSIONS AND RELEVANCE: This longitudinal cohort study found that large life expectancy differences between AI/AN individuals and other US residents have been underestimated due to racial misclassification on death certificates, resulting in the statistical erasure of Indigenous people in routine vital statistics.

PMID:40522635 | DOI:10.1001/jama.2025.8126

Ophthalmol Ther. 2025 Jun 16. doi: 10.1007/s40123-025-01182-3. Online ahead of print.

ABSTRACT

INTRODUCTION: The use of optical coherence tomography (OCT) as a potential tool for the measurement of vitreous inflammation has been previously described as a more objective and reproducible method when compared to historically known subjective scales. In this study, our objective is to evaluate OCT’s ability to characterize vitreous hyperreflective dots (VHDs) across eyes with varying conditions, including healthy controls, vitreous degenerations, intraocular inflammation, and others.

METHODS: We utilized a purpose built semiautomated software comprising an image binarization tool to segment OCT scans of 61 eyes, comprising 15 eyes with vitreous degenerations, 20 uveitic eyes, 17 healthy controls, and 9 with other eye conditions. The vitreous dot index (VDI) was computed by determining the number of dots (VDI-N) and the dot area (VDI-A). VHDs were identified as the hyperreflective shadows observed in OCT images within segmented areas of the vitreous, stratified as zones I, II, and III. We compared the difference between groups using analysis of variance (ANOVA). Intergrader reliability was evaluated by comparing results obtained by two trained independent graders, employing intraclass correlation coefficient (ICC) analysis.

RESULTS: When the medians of VDI-N and VDI-A were compared in healthy controls, patients with uveitis, patients with vitreous degeneration, and others, patients with vitreous degeneration had the highest VDI-N median (2.61 ± 2.76 mm³ p < 0.001) followed by healthy controls (0.48 ± 0.87 mm³ p < 0.001) in zone l. As for VDI-A in the same zone, healthy controls had the greatest median (0.71 ± 0.96, p < 0.001) among the different groups. In zone II, uveitis and the healthy control group had similar medians for VDI-N (0.03 ± 0.36 and 0.03 ± 0.29, p < 0.001 respectably) and VDI-A was greater in the vitreous degeneration group (0.40 ± 0.50 p < 0.001). Zone III had lower VDI-N and VDI-A; patients with uveitis and patients with vitreous degeneration had equal VDI-N (0.00 ± 0.03 p < 0.001) and patients with uveitis had the higher VDI-A among the rest of the groups (0.00 ± 0.65 p < 0.001). For the total vitreous (TV), the highest VDI-N was found in patients with vitreous degeneration (2.92 ± 2.85 p < 0.001) while the highest VDI-A was in the uveitis group patients (0.66 ± 1.31) p < 0.001. The average vitreous dot density index and the average vitreous dot reflectivity index (VDRI) in the TV were greater in patients with vitreous degeneration (2.15 × 10^-5 ± 1.52 × 10^-5) and patients with uveitis (0.13 ± 0.08), respectively. When comparing VDI markers using a Kruskal-Wallis nonparametric one-way ANOVA test, we found that only the average vitreous dot reflectivity index in zone I and VDI-A in TV were statistically significant. However, only the reflectivity index was significant when comparing patients with vitreous degeneration and healthy controls in a pairwise analysis.

CONCLUSION: While vitreous inflammation scales must evolve toward more objective metrics, our findings suggest that VHDs on OCT can act as confounders, as they may represent normal vitreous cells or even the presence of vitreous degeneration. The reflectivity index appears to have better reproducibility than simple count; however, when searching for a more objective parameter for measuring vitreous inflammation, vitreous degeneration must be considered.

PMID:40522626 | DOI:10.1007/s40123-025-01182-3

Drugs Real World Outcomes. 2025 Jun 16. doi: 10.1007/s40801-025-00500-2. Online ahead of print.

ABSTRACT

BACKGROUND: Herpes zoster commonly occurs in older adults, whose renal function often declines, necessitating careful dosing of antivirals such as acyclovir, valacyclovir, and famciclovir. Insufficient dose adjustment can increase central nervous system (CNS) disturbance risk. Although previous reports show varying neurotoxic risk among these drugs, the safety profiles of these drugs remain underexplored. CNS disturbance significantly impacts quality of life, but it is rare and primarily documented through case reports, with little thorough investigation or comparison across drugs.

OBJECTIVE: This study aims to evaluate the potential risks of CNS disturbance associated with acyclovir and valacyclovir compared with famciclovir in patients with herpes zoster, highlighting the potential influence of renal function and dose adjustments.

METHODS: We conducted a population-based cohort study using data from the National Health Insurance and the Late-Stage Medical Care System for the Elderly in Japan, including patients diagnosed with herpes zoster and newly prescribed oral or intravenous antiviral drugs between April 2012 and September 2021. The outcome was defined as the occurrence of CNS disturbance within 1 month from the index date. Patients with neurological, infectious or psychiatric disorders during the 1-year baseline period were excluded. The incidence of CNS disturbance with 95% confidence intervals (CIs) was compared between dialysis and nondialysis patients, owing to incomplete renal function data. In addition, we compared the incidence of CNS disturbance among groups using propensity score matching to adjust for confounders, with famciclovir users as the control group. Postmatching, risk differences with 95% CIs, and number needed to harm (NNH) were calculated.

RESULTS: The final cohort consisted of 82,646 patients (8646 acyclovir, 46,643 valacyclovir, and 27,357 famciclovir users). Severe renal dysfunction was associated with CNS disturbance. The CNS disturbance incidence was 0.33% in nondialysis and 2.29% (risk difference 1.96%, 95% CI [0.39-3.53]) in dialysis patients using acyclovir/valacyclovir versus 0.18% and 0.60% (risk difference 0.42%, 95% CI [- 0.76 to 1.6]) for famciclovir, respectively. After propensity score matching, CNS disturbances were observed in 0.50% of patients in the acyclovir group versus 0.17% in the famciclovir group and in 0.29% of patients in the valacyclovir group versus 0.17% in the famciclovir group. The risk of CNS disturbance remained higher in both the acyclovir group (risk difference 0.33%, 95% CI [0.16-0.51], NNH 278) and the valacyclovir group (0.12%, [0.04-0.19], 833) compared with the famciclovir group.

CONCLUSIONS: Acyclovir and valacyclovir, when compared with famciclovir, are associated with an increased risk of CNS disturbance in patients with herpes zoster, particularly among those with severe renal dysfunction. These findings highlight the importance of careful consideration of renal function when determining antiviral dosing and support the development of clinical guidelines to enhance the safety of antiviral treatments, though further investigation into additional kidney function stages is needed.

PMID:40522612 | DOI:10.1007/s40801-025-00500-2

Sports Med. 2025 Jun 16. doi: 10.1007/s40279-025-02200-x. Online ahead of print.

ABSTRACT

This review reflects on the lessons and limitations of the first large, collaborative replication project in sports and exercise science. We discuss the challenges and barriers faced, while also exploring the broader contribution of replication to the field. This project faced many practical challenges when preparing studies for replication, specifically the poor reporting of statistical information, the availability of original raw data and the prioritisation of feasibility at the risk of some bias. However, we believe these issues reflect the larger sports and exercise science field. Therefore, our research culture needs to change to minimise the active engagement in behaviours that reduce reproducibility and replicability, and enable collective evaluation of research in line with the foundations of scientific rigour. In addition, discourse with the original study authors was a challenging process as many were unwilling to engage and this indicates a problematic perception of replication. We also reflect on the contribution of replication to theory development in sports and exercise science so that this review can serve as a valuable resource for understanding replication and can aid future replication efforts.

PMID:40522611 | DOI:10.1007/s40279-025-02200-x