Exposure to fine particulate matter (PM2.5), a major component of ambient air pollution, is associated with worse short-term respiratory outcomes in cystic fibrosis (CF). The relationship between air pollution exposure over time and lung disease progression in CF is unknown. To elucidate how PM2.5 affects the rate of age-related decline in forced expiratory volume in one second (FEV1) among adults with CF. Retrospective open cohort study of pwCF ≥ 26 years in the U.S. CF Foundation Patient Registry between 2003-2019. Annual average PM2.5 was estimated at the population-weighted center of each participant's zip code using a spatiotemporal model. We examined the effect of PM2.5 on the age-related change in FEV1 z-score by mixed effects linear regression, adjusting for relevant demographic and clinical covariates, and stratifying by 5-year cohorts of birth year to account for secular improvements in FEV1 and PM2.5 over time. 11,392 adults with CF age ≥ 26 contributed 81,944 person-years of follow-up. Mean ambient PM2.5 levels over the study period were 9.1 µg/m3 (7.5-10.4). The average annual age-related change in FEV1 z-score was -0.057 (95% CI -0.081, -0.033). After covariate adjustment, we did not find evidence of an adverse association between PM2.5 and annual change in FEV1 z-score in the overall cohort [+0.002 per 3 µg/m3 change in PM2.5 (95% CI -0.001, 0.005)] or across birth cohorts. In this large U.S. study, we did not detect an effect of ambient PM2.5 exposure at the zip code level on long-term lung function trajectory in adults with CF. Consideration of other windows of potential vulnerability to exposure, such as during childhood, may help further explain the relationship between air pollution and long-term outcomes in CF. Cystic Fibrosis Foundation, CIR Northwest, Seattle Children's Research Institute.
Few non-invasive approaches are available for improving coronary function in intermediate-risk chronic coronary syndrome (CCS) patients. Over the past 30 years, enhanced external counterpulsation (EECP) has been widely accepted and recommended for treating CCS in clinical guidelines. However, the effect of EECP on coronary function remains to be quantitatively validated in intermediate-risk CCS patients. Fractional flow reserve (FFR) is a gold standard (quantitative index) of coronary artery function, and FFR < 0.80 is regarded as an indicator for percutaneous coronary intervention (PCI) in clinical decision-making. However, FFR is invasive and cannot be performed repeatedly within a short time interval; therefore, FFR is not suitable for large-scale verification of the effect before and after EECP treatment. Conversely, with advancements in numerical theory and computation hardware, FFR derived from coronary computed tomography angiography (FFRCT) performs similarly to FFR used in coronary artery function measurement. Additionally, FFRCT is non-invasive and highly acceptable to patients. Therefore, in this study, we aim to explore whether EECP therapy can improve FFRCT in patients with intermediate-risk CCS and further enhance the long-term prognosis of CCS. This prospective, multicentre, randomised controlled trial is blinded to the examination executors and analysts. One hundred four participants will be recruited, and they will be divided into the EECP and control groups. The primary outcome of this study is the between-group difference in FFRCT changes from baseline to follow-up. The secondary outcomes refer to between-group differences in ΔFFRCT, wall shear stress, axial plaque stress, total exercise time, time to 1 mm ST-segment depression, Seattle Angina Questionnaire score, and cardiovascular-related composite endpoint events. This is the first study to use the non-invasive coronary artery function index, FFRCT, to evaluate the efficacy of EECP in patients with CCS. It comprehensively evaluates the treatment efficacy from multiple dimensions, including exercise capacity, symptom changes, and prognosis. Therefore, this will potentially provide reliable evidence to inform treatment strategies for CCS. Trial registration number: ChiCTR2400079915. Registered on January 16, 2024 (retrospectively registered), https://www.chictr.org.cn/about.html.
Spaceflight-associated neuro-ocular syndrome (SANS) poses significant ocular health risks in long-duration missions, yet its molecular mechanisms remain incompletely understood. Oxidative stress and apoptosis are candidate drivers, but their transcriptomic-phenotypic relationships in spaceflight-exposed retinal tissue have not been systematically characterized. We applied a machine learning ensemble to predict two ocular phenotypes: 4-hydroxynonenal (4-HNE) endothelial cell density as a marker of oxidative damage, and TUNEL endothelial cell density as a marker of apoptosis. In this observational study, we use transcriptomic data from a controlled experiment with ground control and spaceflown mice to predict these phenotypes. Gene Ontology pathway enrichment was performed using the most predictive genes for each phenotype. Genes predicting 4-HNE converge on membrane-associated pathways, photoreceptor modification, synaptic dysfunction, and extracellular matrix dysregulation, including B2m, Trf, Cnga1, mt-Nd1, Snap25, and Efemp1. Genes predicting TUNEL emphasize stress-induced apoptosis, rod photoreceptor degeneration, and endoplasmic reticulum dysfunction, with Ddit4, Nrl, Rom1, Reep6, and Gabarapl1 emerging as central regulators. Oxidative lipid peroxidation and apoptotic cell death represent complementary and molecularly distinct pathological mechanisms in spaceflight-exposed murine retinal tissue. The gene signatures provide a putative molecular framework for developing noninvasive biomarkers and therapeutic targets to monitor and protect astronaut visual health during long-duration and deep-space missions.
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Tumor-infiltrating nerves play critical roles in promoting tumor growth and progression; however, the mechanisms that drive tumor innervation remain unclear. Upon transformation, tumors recruit surrounding peripheral nerves into the tumor microenvironment (TME) to obtain their own innervation, a process called axonogenesis. While in vitro studies suggest tumor cell-derived neurotrophins, such as brain-derived neurotrophic factor (BDNF), drive axonogenesis, this has yet to be demonstrated in vivo. During wound healing, macrophages are the primary source of neurotrophins. Given the critical role of macrophages in breast cancer growth, we investigated whether these immune cells drive tumor axonogenesis in breast tumors in vivo. Syngeneic Py230 mouse triple-negative breast cancer (TNBC) cells were transplanted into intact mice and mice lacking immune-derived BDNF. Bone marrow-derived macrophages from either wild-type or immune-BDNF-deficient mice were transplanted into tumor-bearing recipients to determine if macrophage-derived BDNF was sufficient to restore tumor growth and innervation. We found that transplanted TNBC cannot grow in the absence of immune-derived BDNF, and that depletion of macrophages from the TME compromises tumor innervation. Remarkably, the introduction of wild-type macrophages restores tumor growth and innervation in mice lacking immune-derived BDNF, demonstrating that macrophages are both necessary and sufficient for tumor axonogenesis in vivo. In the absence of sensory tumor innervation, tumor growth was significantly reduced. Moreover, targeting BDNF signaling diminished TNBC growth and innervation. Our findings identify macrophages as the critical source of BDNF driving axonogenesis in breast cancer and suggest that selectively targeting BDNF signaling could provide a novel therapeutic strategy for treating TNBC through compromising tumor innervation.
Peripheral nerve injuries (PNIs) are a common cause of long-term motor and sensory disability despite advances in microsurgical repair. Functional recovery following PNI depends not only on axonal regeneration, but also on preservation of distal nerve pathways, maintenance of neuromuscular junction integrity, prevention of irreversible muscle degeneration, and adaptive central nervous system reorganization. Electrical rehabilitation modalities have been proposed as adjunctive strategies to enhance recovery across these domains, yet their clinical utility in PNIs remains incompletely defined. This review summarizes the pathophysiology of peripheral nerve injury and critically evaluates the current evidence for commonly used electrical rehabilitation modalities, including transcutaneous electrical nerve stimulation (TENS), neuromuscular and functional electrical stimulation (NMES/FES), and surface electromyographic (sEMG) biofeedback. Across modalities, the existing literature is heterogeneous and limited by small sample sizes, reliance on animal models, and substantial variability in stimulation parameters and timing. While TENS may play a role in pain management during the acute phase and sEMG biofeedback shows promise for facilitating motor relearning-particularly following nerve transfer surgery-robust evidence supporting routine use of electrical muscle stimulation in PNIs is lacking. Future investigations should prioritize standardized protocols, appropriate patient selection, and adequately powered clinical trials to clarify the role of electrical modalities in peripheral nerve rehabilitation.
Adolescent girls and young women (AGYW) in sub-Saharan Africa are disproportionately affected by Chlamydia trachomatis (CT) infections, a leading cause of pelvic inflammatory disease, infertility and increased HIV susceptibility. CT-induced genital inflammation disrupts mucosal barriers and activates HIV target cells, compounding immunological risks. We investigated CT infection in AGYW from two South African regions, focusing on genital inflammation and immune activation. An observational cohort of 298 sexually active AGYW (aged 16-22 years) from Cape Town and Johannesburg was enrolled. Participants in Johannesburg attended one visit, while those in Cape Town were followed longitudinally (6-8 months). Cytokine profiling of cervicovaginal samples assessed inflammatory responses, while cervical cytobrush-derived CD4+ T cells were analysed for CD38, Ki67 and C-C chemokine receptor type 5 expression. CT ompA genotyping examined strain diversity. CT prevalence was 2.4-times higher in Cape Town (41.6%) than Johannesburg (17.4%). CT infection was associated with upregulated interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α, with responses appearing stronger in Johannesburg, although low CT cases at this site limited regional comparisons. Genotyping suggested regional variation: genovar D, predominant in Cape Town, was associated with lower interferon (IFN)-γ concentrations, whereas genovar E, more common in Johannesburg, was associated with higher IFN-γ concentrations. AGYW with CT infection across multiple visits did not exhibit elevated genital tract cytokine levels compared with those infected at a single visit. However, they showed increased activated cervical CD4+ T cells. CT-associated immune responses in AGYW appear to reflect a combination of pathogen diversity, regional context and host immune history.
With increasing emphasis and awareness of U.S. immigration enforcement actions against immigrant families, there have been contested assertions by political and medical leaders that these actions by government agents constitute a form of child abuse. Substantial research documents the health impacts of U.S. immigration enforcement on children's well-being; however, findings remain scattered across disciplines. This scoping review aims to (1) identify mechanisms through which immigration enforcement produces harm to children and (2) assess whether these harms align with child welfare definitions of child maltreatment, with the goal of developing a typology of government-sanctioned child maltreatment. Following PRISMA-ScR guidelines, we searched academic databases and identified 71 empirical articles. We identified three primary mechanisms of harm: parental detention and deportation, child detention and deportation, and intensified enforcement climate and threat. Of the studies examined, 79% described harms that aligned with federal child maltreatment definitions, and 93% of state-specific articles aligned with at least one component of state-level conceptualizations, including threat/risk of harm, neglect/failure to provide, neglect due to caregiver unavailability, and emotional abuse. While most documented harms align with definitions of child maltreatment, there are challenges in classifying these as such due to legal frameworks not recognizing the government as a potential perpetrator, despite the government's own contradicting acknowledgement of the responsibility for child safety within the child welfare system. These findings support conceptualizing immigration enforcement as government-sanctioned child maltreatment. Future research should build on this typology and develop actionable frameworks to inform policy, practice, and accountability.
Improved understanding of how chimeric antigen receptor (CAR) and endogenous T-cell phenotypes associate with progression-free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1+ cytotoxic T cells and ICOS-TIGIT+ Tregs. At Month 1 after infusion, the presence of >1% CAR-T cells, a CD4/CD8 CAR-T-cell ratio >0.09, and greater abundance of non-activated non-cytolytic CAR-T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T-cell clusters were prognostic at the latest assessment performed after CAR-T infusion. Lower percentages of ICOS+TIGIT- Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti-B-cell maturation antigen (anti-BCMA) CAR-T cells uncovered that the T-cell composition prior to apheresis as well as CAR-T and endogenous T-cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR-T cells in relapsed/refractory MM.
Status epilepticus (SE) treatment is more effective when benzodiazepines (BZDs) are given soon after SE diagnosis. The Quality Improvement in Time to Treat Status Epilepticus (QuITT-SE) trial is a multicenter, randomized, stepped-wedge effectiveness-implementation hybrid study aimed at improving time to SE treatment. We report the QuITT-SE baseline cohort and test the hypothesis that acute seizure emergency episodes treated promptly differ in clinical and demographic features from those with delayed treatment. Data were summarized from 371 consecutive acute seizures episodes treated with a BZD in the inpatient, non-intensive care unit (ICU) setting from 207 individual patients across eight centers per the QuITT-SE protocol. To test our hypothesis, we utilized a multivariable negative binomial mixed effects model with random intercepts to estimate the incidence rate ratios for variables of interest for time to BZD treatment. The median age was 7 years (IQR = 3-12). Nonelective ICU transfers occurred with 26% of episodes, including 13% within 6 h of the episode. The median time from seizure onset to BZD treatment was 6 min (IQR = 4-10), with 74% of all episodes and 63% of SE treated within 10 min. BZD administration was faster when nurses made the treatment decision, when the intranasal (IN) route was used, when the patient received prior rescue medication within 24 h, or with certain elective admission types. Seizures were shorter when BZD administration was faster or when treatment was with IN midazolam versus intravenous lorazepam (median = 8 min [IQR = 6-15] vs. 10 min [IQR = 7-17], p = .04). Patients were less likely to be transferred to the ICU if they received IN midazolam (odds ratio = .3, p = .007). Delayed BZD administration occurs in one third of SE treatment. Prolonged seizures and ICU transfers are associated with modifiable risk factors. Baseline drivers of delayed acute seizure treatment may be addressed using the QuITT-SE interventions, the study of which is currently ongoing.
Evidence linking different B vitamins to stroke risk remains sparse, particularly regarding long-term intake and dose-response thresholds in populations fortified with folic acids. To prospectively investigate the associations of long-term intake of B vitamins and their circulating levels with incident stroke. Using a validated food frequency questionnaire, we assessed intake of B vitamins among 121,565 participants in the Women's Health Initiative (WHI). We also examined circulating levels of B vitamins in relation to stroke risk among 99,660 All of Us Research Program (AoU) participants. Multivariable Cox models estimated hazard ratios (HRs) and their 95 % confidence intervals (CIs). In WHI (6803 incident stroke cases; median follow-up: 18.4 years), higher long-term intakes of thiamin, riboflavin, niacin, pyridoxine, and folate were significantly associated with lower stroke risk, with HRs (95 % CI) of 0.84 (0.76, 0.92), 0.90 (0.81, 0.99), 0.80 (0.72, 0.88), 0.88 (0.80, 0.96), and 0.88 (0.80, 0.97) comparing the highest to the lowest quintiles, respectively. Most B vitamins exhibited reverse J-shaped associations, whereas folate showed a linear inverse relationship up to at least 2000 dietary folate equivalent (DFE)/day. In AoU (5163 incident stroke cases; median follow-up: 5.7 years), higher plasma folate and pyridoxine were associated with lower risk (HRs: 0.86 and 0.50, respectively). In two large prospective cohorts of US adults, higher intake of thiamin, riboflavin, niacin, pyridoxine, and folate, as well as higher circulating concentrations of pyridoxine and folate, were associated with a lower risk of stroke, even after folic acid fortification.
To assess changes in marriage and family therapist (MFT) and mental health counselor (MHC) workforce distribution from April 2022 to October 2024, evaluating early impacts of Medicare's coverage expansion on provider participation in underserved rural communities. This repeat cross-sectional study used Medicare Fee-for-Service Public Provider Enrollment Files and National Provider Identifier Registry data. Counties were categorized as metropolitan and rural (micropolitan or noncore) using Urban Influence Codes. We analyzed quarterly changes in Medicare participation and the proportion of counties with at least one participating provider across geographic categories. From April 2022 to October 2024, MFTs participating in Medicare increased from 111 to 9394, and MHCs increased from 4013 to 24013. Initially, participation rates were low and did not differ significantly by rurality. By October 2024, participation rates were higher in rural versus metropolitan counties for both provider types (MFTs: 16.4% rural vs. 11.0% metropolitan; MHCs: 12.1% vs. 9.2%; both p < 0.001). The percentage of counties with at least one Medicare-participating MFT increased from 2.5% to 26.5%, and from 27.2% to 55.8% for MHCs. However, only 7.4% of noncore counties had at least one Medicare-participating MFT in October 2024, and 32.2% had at least one MHC. Medicare participation among MFTs and MHCs increased dramatically following the 2024 coverage expansion, especially among rural providers. However, absolute provider availability in rural counties remains low, underscoring the need for additional strategies to translate participation gains into meaningful improvements in rural mental health access.
Hearing protection devices (HPDs) are essential safety equipment for workers in noisy settings but can also degrade auditory perception. Some reports have suggested that HPDs can affect speech intelligibility, particularly at low levels, while others reported no effect for normal-hearing listeners. Here, we investigated the effects of different HPDs on speech intelligibility at various signal-to-noise ratios (SNRs) using the Quick Speech-In-Noise (QuickSIN) test and the Modified Rhyme Test (MRT). 124 audiometrically normal subjects were tested across 2 study sites in Open Ear and 6 HPD listening conditions. Target levels were fixed at 70 dBA, while noise levels varied (QuickSIN: multi-talker babble co-located with the target; MRT: spatially distributed pink noise). Subject performance was comparable to Open Ear for most HPD conditions; however, performance was degraded in both tasks by a high insertion-loss passive earplug, and modestly improved in MRT by a pair of electronic earmuffs. Behavioral performance was compared to predictions using the Speech Intelligibility Index (SII) calculated in two ways: first, using average speech and noise stimulus levels, second, by filtering those stimulus levels with appropriate head-related transfer functions (HRTFs) of a GRAS 45CB acoustic manikin to incorporate the spatial dependence of each sound source in the ear canal (sSII). Comparisons to subject performance reveal a substantial increase in predictive performance with sSII (R2=0.497) over SII (R2=0.212) for MRT. Results suggest speech perception with most HPDs is comparable to Open Ear, and that incorporating spatial information improves acoustical predictions.
Colorectal cancer (CRC) is an important cause of cancer-related morbidity and mortality in both Sub-Saharan Africa (SSA) and Uganda. Despite national progress in cancer awareness and policy development, CRC care remains limited by resource constraints. CRC serves as an ideal lens for assessing health system resiliency, as it spans the care continuum. This review searched PubMed from inception through December 2025 for Uganda specific articles on CRC and analyzed 13 peer-reviewed articles to describe the current state of CRC care in Uganda, with insights from a health needs assessment (HNA) conducted at Mbarara Regional Referral Hospital (MRRH).Across Uganda, CRC diagnosis and treatment are hindered by insufficient endoscopic and pathology capacity, medication stockouts, and inconsistent access to immunohistochemistry and molecular testing. Screening programs remain underdeveloped due to inadequate resources for follow-up diagnostics. At MRRH, chemotherapy and surgery are available but constrained by equipment shortages, long wait times, and limited workforce despite rising patient volumes. Palliative care remains a strength, supported by national morphine availability and the efforts of Hospice Africa Uganda, though integration within oncology clinics remains incomplete. Improvement to CRC care will require expanding diagnostic infrastructure, digitizing health records, workforce development, and strengthening supply-chain management. Addressing chemotherapy and medication stockouts represents a tangible, near-term step toward improving quality of care. Experience from MRRH demonstrates both the challenges and opportunities to scaling cancer care in resource-limited settings and provides an illustrative example, albeit limited as a single-institution review, for addressing CRC systems across Uganda. Main findings: Colorectal cancer care in Uganda remains limited by inadequate diagnostic capacity, medication stockouts, and workforce shortages, although palliative care integration and national policy support represent key strengths.Added knowledge: This narrative review synthesizes Uganda’s colorectal cancer evidence through a health-systems lens, combining published literature from Uganda and an institutional health needs assessment to identify feasible, context-specific interventions.Global health impact for policy and action: Expanding endoscopic and pathology capacity, digitizing health records, and strengthening supply-chain management are actionable strategies to improve equity and quality of cancer care in low-resource settings.
Urine drug testing for tetrahydrocannabinol (THC) is widely performed using lateral flow immunoassay (LFI) kits. However, these tests are vulnerable to adulteration by benzalkonium chloride (BAK), a cationic surfactant that is a common ingredient in consumer products, such as eyedrops and antiseptics, which can produce false-negative THC results. BAK is believed to act by forming micelles around the THC metabolite 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH), blocking detection. Because BAK is not routinely included in specimen validity testing panels, it remains a significant potential masking agent in urine drug screening. This study evaluated BAK-containing products and confirmed that readily available commercial formulations can effectively mask THC in the urine. For example, when 25 mL of an antiseptic liquid containing BAK at a nominal concentration of 1300 ppm was added to 75 mL of urine, the LFI test was found to flip from true positive to false negative. Consumer products containing lower concentrations of BAK, such as eye drops, typically mask THC detection when added to urine at an equal volume. To address the vulnerability of LFI-based THC testing to BAK addition, a rapid, low-cost, noninstrumental screening approach based on the standard addition method was developed to distinguish true negatives from BAK-induced false negatives. In blinded testing of 45 urine samples, consisting of 15 true positives, 15 true negatives, and 15 false negatives, the method correctly identified all of the adulterated samples. These findings highlight a practical strategy for improving the reliability of THC urine drug screening in settings where LFI kits are routinely used.
Waterborne diseases are caused by pathogens that are transmitted via ingestion of contaminated water and remain a leading cause of death particularly in young children. Climate change threatens to undermine the progress that has been made in reducing waterborne diseases. In this Review, we explore how meteorological conditions that are influenced by climate change, including temperature, heavy rainfall and flooding, drought, and extreme weather, affect the biology and transmission of waterborne pathogens, with a focus on those that spread via the faecal-oral route. We discuss evidence that these impacts vary across pathogens and consider how such information is used to project disease risks under future climatic conditions, including incorporating social vulnerability and pathogen-specific outcomes to more accurately estimate future disease burden. We also review strategies to blunt climate-related increases in waterborne diseases, including vaccination; water, sanitation and hygiene interventions; and enhanced surveillance. As climate change continues to alter our global environment, understanding its impacts on waterborne diseases can improve our ability to reduce climate harms, identify and protect vulnerable populations, and develop evidence-based approaches to promote population health.
Minor histocompatibility antigens (MiHA) are polymorphic peptides presented by HLA molecules on recipient cells in allogeneic hematopoietic cell transplantation (allo-HCT) and are derived from proteins with genetic variants that differ between recipient and donor. Following allo-HCT, hematopoietic-restricted MiHA enable selective targeting of residual recipient-derived hematopoiesis, including malignant cells. Advances in engineering T cells with high-affinity MiHA-specific T-cell receptors (TCR; TCR-T) are enabling clinical translation of MiHA T cell immunotherapy. Early-phase trials of HA-1 and HA-2-specific TCR-T demonstrate safety, persistence, and durable anti-leukemic activity in high-risk or relapsed disease. To accelerate translation, the field should expand TCR-T development to additional MiHA targets to broaden HLA and population coverage, integrate MiHA genotyping into donor selection, and devise platform trials to include patients with various MiHA/HLA genotypes and to efficiently test combination therapies. MiHA-directed TCR-T represents a genetically precise, potentially routine HCT adjunct that promises to fortify graft-versus-leukemia effects and improve relapse-free survival.
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In emergency care, clinicians currently have scarce evidence-based guidance on whether to order diagnostic tests for suspected pulmonary embolism in children. We aimed to test whether the Pulmonary Embolism Rule-Out Criteria in Children (PERC-Peds) can safely rule out pulmonary embolism in children. This multicentre, prospective, observational, diagnostic accuracy study was done in 21 paediatric emergency departments across the USA. We enrolled children aged 4-17 years who presented with symptoms prompting the emergency physician to order, or strongly consider ordering, a diagnostic test for pulmonary embolism. Participants formed a consecutive series. At the point of care, clinicians completed a case report form to record the components of the PERC-Peds rule. Diagnostic testing, including D-dimer testing, was done at clinician discretion. Trained research personnel collected patient-reported demographic data, symptoms, medications, and past medical histories prospectively and cross-checked patient-reported past medical histories and medications against data in the electronic health record. Follow-up was done 45 days after enrolment with a standardised, automated SMS message to caregivers. The criterion standard for pulmonary embolism was the outcome of any venous thromboembolism (VTE; including image-proven pulmonary embolism or proximal deep vein thrombosis [DVT; above knee or elbow, but not including isolated saphenous, brachial, or calf vein clots]) within 45 days, as adjudicated by an independent committee of three board-certified paediatric emergency physicians. Adjudicators viewed all imaging reports, information from the 45-day follow-up, and outside medical records. The primary endpoint was safe exclusion by use of PERC-Peds in all participants who were adjudicated, defined as the upper limit of the 95% CI for the false-negative rate not crossing 1·5%. Between July 29, 2020, and Sept 29, 2024, 4039 children were enrolled, with 4011 participants adjudicated for pulmonary embolism or proximal DVT. Date of last follow-up was Sept 18, 2025. The median age of the adjudicated population was 15 years (IQR 13-16); 2567 (64·0%) were female and 1444 (36·0%) were male. 3988 participants had complete data, and 253 (6·3%, 95% CI 5·6-7·2) were diagnosed with pulmonary embolism or proximal DVT within 45 days. The sensitivity of the PERC-Peds rule was 99·6% (95% CI 97·8-100·0), specificity was 19·6% (18·4-20·9), and false-negative rate was 0·1% (0·0-0·8). D-dimer test was ordered in 3161 (78·8%) of 4011 participants. Sequential use of PERC-Peds followed by D-dimer test ruled out pulmonary embolism or proximal DVT in 2167 (54·3%) with a false-negative rate of 0·9% (0·6-1·4). In this multicentre, prospective, observational, diagnostic accuracy study of children with suspected pulmonary embolism in the emergency department, we found a 6·3% prevalence of pulmonary embolism or proximal DVT; in this population, the PERC-Peds negative rule can safely rule out pulmonary embolism. Use of PERC-Peds might reduce low-value diagnostic testing for pulmonary embolism in children and adolescents. US National Institutes of Health.
Cardiovascular disease remains the leading cause of global morbidity and mortality. The original My Heart Counts smartphone application demonstrated the feasibility of large-scale, fully digital recruitment and trial conduct, but was limited by platform exclusivity and the need for human experts to create text-based behavioral interventions. The next-generation My Heart Counts smartphone application is a prospective, observational cohort study with an embedded randomized crossover trial, evaluating personalized text-based coaching prompts, available in both English and Spanish. All study and trial operations will be conducted via the My Heart Counts smartphone application, re-designed using the open-source Stanford Spezi framework to support iOS, with a planned Android release in 2027. The target enrollment is N = 15,000 adults across the United States and United Kingdom. The study establishes a comprehensive digital biobank by synthesizing passive mobile health data (steps, flights climbed, heart rate, sleep, workouts), raw sensor data (e.g., accelerometry), longitudinal clinical surveys, active tasks (6-minute walk test and 12-minute Cooper run test), electrocardiograms (ECG), and electronic health record (EHR) data integrated via HL7 FHIR protocols. The embedded trial evaluates the effect of text-based coaching prompts generated by a large language model (LLM) grounded in the Transtheoretical Model of Change on daily physical activity, as compared to generic prompts. The primary endpoint of the randomized crossover trial is change in daily step count between LLM-driven and generic text-based intervention arms, analyzed using mixed-effects models. Secondary endpoints include change in mean active minutes and calorie burn over each intervention week. Other exploratory analyses include the changes in submaximal (6-minute walk test) and maximal (Cooper 12-minute run test) cardiorespiratory fitness, changes to sensor-derived biomarkers (e.g., sleep quality, resting heart rate, and heart rate variability), and association of sensor-derived biomarkers with EHR-confirmed clinical outcomes. By utilizing autonomous, LLM-driven coaching, modular software design, and cross-platform accessibility, our smartphone application-based study will provide a scalable model for inclusive and decentralized preventive care of patients with cardiovascular disease. Recruitment commenced in March 2026 and is ongoing.