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Rationale: Out-of-hospital coronary heart disease death is a major public health problem, but the association with air pollution is not well understood.Objectives: We evaluated the association between daily ambient air pollution levels (particle number concentration [PNC]--a proxy for ultrafine particles [diameter < 0.1 microm], mass of particles with diameter less than 10 microm [PM[10]; CO, NO[2], and O[3]) and the occurrence of fatal, nonhospitalized coronary events.Methods: Subjects were 5,144 out-of-hospital fatalities (410-414, International Classification of Diseases-9; 1998-2000) who had been residents of Rome. Hospitalizations during the 3 yr before death were considered to identify comorbidities (e.g., diabetes, hypertension, heart failure, dysrhythmia, chronic obstructive pulmonary disease). Statistical analyses were performed using a case-crossover design.Measurements and Main Results: The association with out-of-hospital coronary deaths was statistically significant for PNC, PM[10], and CO. Air pollution on the day of death had the strongest effect (e.g., 7.6% increase [95% confidence interval, 2.0-13.6%]) for an interquartile range of PNC, 27,790 particles/cm[3]. The 65-74- and 75+-yr age groups were at higher risk than the 35-64-yr age group, and there was a suggestion of effect modification for people with hypertension and chronic obstructive pulmonary disease.Conclusions: Air pollutants originating from combustion processes, including ultrafine particles, are related to fatal, nonhospitalized coronary events. The effect is stronger among people over 65 years of age, but is not limited to a group with a specific comorbidity. [ABSTRACT FROM AUTHOR]

There are indications that air pollution is associated with increased hospital admissions for myocardial infarction. Hospital admissions, however, represent only a fraction of all the coronary events (fatal and non-fatal) in the population since acute fatal events are often not hospitalized. Our aim was to evaluate the association of daily air pollution with all acute myocardial infarction events (deaths and first hospital admissions) in the population of Rome. The study is a part of the multi-city HEAPSS project.All hospital admissions of people with a first acute myocardial infarction (AMI; ICD-9: 410) occurring in Rome in 1998-2000 (Rome residents only), were selected from the regional Hospital Information System. AMI was defined as first if there was no AMI hospitalisation during three preceeding years. All out-of-hospital deaths from first AMI (ICD-9: 410) were identified from regional Mortality Register during the same period. Daily air pollution data were taken from five city monitors. To estimate the association of AMI with air pollution, we adopted a time stratified case-crossover design, where control days were all same weekdays occurring within the same month than the index date. Daily weather variables were adjusted for in conditional logistic regression.During the study period, 12,620 cardiac events were observed; 3,821 people died outside of hospitals without a previous hospital admission for AMI, and 8,799 subjects were admitted to hospital for AMI. Odds ratios (OR) are reported in the table for an inter-quartile (IQR) range of each pollutant at lag 0-1 day. Table. No caption available. The study indicates that air pollutants from vehicular traffic increase the risk of fatal and non-fatal coronary events in the population of Rome. Similar analyses in the other HEAPSS cities are in progress. HEAPSS study was funded by European Commission (QLK4-2000-00708). [ABSTRACT FROM AUTHOR]

Pregnant people are vulnerable to air pollution exposure, including risk of preterm birth, low birth weight, and stillbirth. Understanding the infiltration of outdoor wildfire smoke into a residential space is critical for the accurate assessment of wildfire smoke exposure and associated health effects in pregnant people. Relying on ambient measurements of wildfire smoke alone can result in exposure misclassification. In this study, we examine the role of physical housing characteristics in the relationship between smoke exposure and preterm birth. In particular, we examine the effect of home size, year of construction, cooling type, and renovation status, as effect modifiers in the relationship between smoke exposure during pregnancy and preterm birth from 2007 to 2015 in California. To do this, we combined data on home characteristics from the California Tax Assessor, birth outcomes from the California birth records database, and the number of smoke days for each pregnancy from the NOAA (National Oceanic and Atmospheric Administration) Hazard Mapping System (HMS). We estimated the association between smoke day exposures and odds of preterm birth using logistic regression models and stratified by air basin and housing characteristics. Our findings reveal that cooling type and renovation status are key factors modifying the smoke exposure-preterm birth relationship. Notably, we found elevated associations for people living in unrenovated homes, those using evaporative cooling systems, and those using central air conditioning units. While we observed elevated odds of preterm birth associated with increasing smoke day exposure for residents of large and new homes, this effect does not significantly differ across home size and age quartiles. This study highlights the need to further examine the relative roles of housing characteristics as well as factors not measured here including behavioral factors, time spent outdoors, window use, and occupational exposures in driving adverse birth outcomes related to wildfire smoke exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Due to their intercellular communication properties and involvement in a wide range of biological processes, extracellular vesicles (EVs) are increasingly being studied and exploited for different applications. Nevertheless, their complex nature and heterogeneity, as well as the challenges related to their purification and characterization procedures, require a cautious assessment of the qualitative and quantitative parameters that need to be monitored. This translates into a multitude of choices and putative solutions that any EV researcher must confront in both research and translational environments. In this respect, decision-making tools may help assess various options, weigh pros and cons, and ultimately arrive at a thought-out decision that considers both the best fit-to-source and fit-to-scope EV application(s). Here, we present a multi-criteria EV decision-making grid (EV-DMG) as a novel, efficient, customizable, and easy-to-use tool to support EV research and innovation. By identifying and weighing key assessment criteria for comparing distinct EV-based preparations and related processes, our EV-DMG may assist any EV community member in making informed, traceable, and reproducible decisions regarding the management of EV sources or samples. Ultimately, this EV-DMG may guide the adoption of the most suitable EV production and analytical pipelines for targeting a defined aim or application., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Background: School physical education is an important population-level health intervention for improving youth fitness. This study estimated the impact of New York City's PE Works program - which included providing PE teachers, training for classroom teachers, and administrative/ teacher support for PE - on student cardiorespiratory fitness as measured by the FitnessGram's 15-meter PACER test for aerobic capacity., Methods: This longitudinal study (2014/15-2018/19) includes 581 elementary schools (n = 315,999 4th /5th -grade students; 84% non-white; 74% who qualify for free or reduced-price meals, a proxy for socioeconomic status). We apply the parametric g-formula to address schools' time-varying exposure to intervention components and time-varying confounding., Results: After four years of staggered PE Works implementation, 49.7% of students/school (95% CI: 42.6%, 54.2%) met age/sex-specific Healthy Fitness Zone (HFZ) aerobic capacity standards set by the FitnessGram. Had PE Works not been implemented, we estimate 45.7% (95% CI: 36.9%, 52.1%) would have met aerobic capacity HFZ standards. Had PE Works been fully implemented in all schools from the program's inception, we estimate 57.4% (95% CI: 49.1%, 63.3%) would have met aerobic capacity HFZ standards. Adding a PE teacher, alone, had the largest impact (6.4% (95% CI: 1.0, 12.0) increase)., Conclusion: PE Works positively impacted student cardiorespiratory fitness. Mandating and funding multicomponent PE programs is an important public health intervention to increase children's cardiorespiratory fitness., Competing Interests: Declarations Ethics approval and consent to participate Informed consent for parents/guardians of participants under the age of 16 was not required as this was a secondary data analysis using de-identified school-level data. Study procedures, including a waiver for consent to participate, were approved by UC Berkeley’s Committee for the Protection of Human Subjects (#202009 − 13643) and NYCDOE’s Institutional Review Board (#3788). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Live donor nephrectomy (LDN) is performed by various specialty surgeons, including urologists, general surgeons, and transplant surgeons. However, national practice patterns and outcomes associated with surgeon specialty have not been previously explored. Here, we investigate surgeon specialty trends, perioperative complications, hospital length of stay, cost, and charge for LDN according to surgeon specialty., Methods: Patients who underwent LDN from 2000 to quarter 1 of 2020 were identified in the Premier Healthcare Database. Associations between physician specialty and 3-month complications, hospital length of stay, institutional cost, and patient charge for LDN procedures were examined using multivariable regression., Results: We identified 11,418 patients who underwent LDN. Of these cases, 3387 (29.7%) were performed by urologists, 3127 (27.4%) by transplant surgeons, 3928 (34.4%) by general surgeons, and 976 (8.5%) by other specialties. In 2000, urologists performed 35.92% of LDNs, decreasing to 18.91% by 2019 ( P < .001 for trend). In the last 5 years, we found no significant difference in complications or length of stay according to surgeon specialty. LDNs performed by a urologist ($57,289, 95% CI $49,292-$66,582) were associated with lower patient charges than those performed by a general surgeon ($68,501, 95% CI $59,090-$79,412) or transplant surgeon ($62,639, 95% CI $53,993-$72,670)., Conclusions: From 2000 to 2019, the proportion of LDNs performed by urologists significantly decreased, while the proportion for transplant surgeons significantly increased, with no significant differences in complications or length of stay across specialties. However, surgeries performed by urologists cost hospitals less and had lower charges for patients.

The parametric g-formula is a causal inference method that appropriately adjusts for time-varying confounding affected by prior exposure. Like all parametric methods, it assumes correct model specification, usually assessed by comparing the observed outcome with the simulated outcome under no intervention (natural course). However, it is unclear how to evaluate natural course performance and whether other variables should also be considered. We reviewed current practices for evaluating model misspecification in applications of parametric g-formula. To illustrate the pitfalls of current practices, we then applied the parametric g-formula to examine cardiovascular disease mortality in relation to occupational exposure in the United Autoworkers-General Motors cohort (UAW-GM), comparing 20 parametric model sets and qualitatively assessing natural course performance for all time-varying variables over follow-up. We found that current practices of evaluating model misspecification are often insufficient, increasing risk of bias and statistical cherry picking. Based on our motivational analyses of the UAW-GM cohort, good natural course performance of the outcome does not guarantee good simulations of other covariates; poor predictions of exposures and covariates may still exist. We recommend reporting natural course performance for all time-varying variables at all time-points. Objective criteria for evaluating model misspecification in parametric g-formula need to be developed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: In recent decades, risk of job loss in America after age 50 has been high, potentially causing significant stress during the period preceding retirement. Yet no study has quantified the burden of clinically relevant depressive symptoms attributable to job loss in this age group over this period or identified the most vulnerable populations., Methods: Participants aged 50+ in the Health and Retirement Study (recruited 1992-2016) who were employed and scored <5 on the Center for Epidemiologic Studies-Depression 8-item scale (CESD-8) at baseline (N = 18,571) were followed for depressive symptoms until they first had CESD-8 ≥5 or died, or through the 2018 survey. Parametric g-formula analyses examined the difference in cumulative risk of having CESD-8 ≥5 if there had been no involuntary job loss compared to the observed scenario, adjusting for sex, race/ethnicity, age, and dynamic measures of recent marriage end (divorce or widowhood), having a working spouse, assets/debt, and health changes., Results: We estimated that risk of CESD-8 ≥5 would have been 1.1% (95% confidence interval [0.55, 1.37]) lower if no involuntary job loss had occurred; job loss accounted for 11% of the total burden among those who lost a job. Stronger associations were observed for women (1.2% [0.7, 1.8] vs men 0.5% [0.2, 1.1]), White respondents (1.0% [0.6, 1.5] vs Black respondents 0.5% [-0.1, 1.4]), and those in the lowest quartile of baseline assets (1.1% [0.4, 1.9] vs wealthiest quartile 0.5% [-0.4, 0.9])., Discussion: Involuntary job loss is associated with high depressive symptom burden in older persons, suggesting that screening and intervention soon after job loss may help mitigate depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Extracellular vesicles (EVs) are membrane-enclosed bio-nanoparticles secreted by cells and naturally evolved to transport various bioactive molecules between cells and even organisms. These cellular objects are considered one of the most promising bio-nanovehicles for the delivery of native and exogenous molecular cargo. However, many challenges with state-of-the-art EV-based candidates as drug carriers still exist, including issues with scalability, batch-to-batch reproducibility, and cost-sustainability of the final therapeutic formulation. Microalgal extracellular vesicles, which we named nanoalgosomes, are naturally released by various microalgal species. Here, we evaluate the innate biological properties of nanoalgosomes derived from cultures of the marine microalgae Tetraselmis chuii, using an optimized manufacturing protocol. Our investigation of nanoalgosome biocompatibility in preclinical models includes toxicological analyses, using the invertebrate model organism Caenorhabditis elegans, hematological and immunological evaluations ex vivo and in mice. We evaluate nanoalgosome cellular uptake mechanisms in C. elegans at cellular and subcellular levels, and study their biodistribution in mice with accurate space-time resolution. Further examination highlights the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization demonstrates that they are biocompatible and innate bioactive effectors with unique bone tropism. These findings suggest that nanoalgosomes have significant potential for future therapeutic applications., (© 2024. The Author(s).)

Objective: To determine the prevalence and severity of SpaceOAR-related adverse events using the Manufacturer and User Facility Device Experience (MAUDE) database., Methods: We analyzed SpaceOAR-related adverse event reports in the Manufacturer and User Facility Device Experience (MAUDE) database from January 2015 to May 2023. For each report, the event type, associated device and patient problems, event description, event timing, and event severity stratified by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) grading system were recorded., Results: From 2015 to 2022, 206,619 SpaceOAR devices were sold. From January 2015 to May 2023, we identified 981 reports describing 990 SpaceOAR-related adverse events. Malfunctions were the most common event type (N = 626), followed by patient injuries (N = 350) with few reported deaths (N = 5). Device positioning problems were the most frequent device issue (N = 686). Pain was the most reported patient problem (N = 216). Abscesses and fistulas related to the device were each reported in 91 events. A noteworthy portion of relevant adverse events occurred before the initiation of radiation (N = 35, 22.4%), suggesting the device, rather than the radiation, was responsible. In total, 470 (50.2%) and 344 (36.7%) of the adverse events were CTCAE grade 1 and 2, respectively. There were 123 (13.1%) events that were CTCAE grade ≥3., Conclusion: We identified multiple reports of SpaceOAR-related adverse events, many of which are more serious than have been reported in clinical trials. While SpaceOAR use is common, suggesting these events are rare, these data highlight the need for continued postmarket surveillance., Competing Interests: Declaration of Competing Interest Daniel E. Spratt receives research funding from the National Institutes of Health and the Prostate Cancer Foundation and personal fees from Astellas, AstraZeneca, Bayer, BlueEarth, Boston Scientific, Elekta, GT Medical Technologies Inc, Myovant, Pfizer, Janssen, Novartis, and Varian. Elisha T. Fredman serves as a consultant to Boston Scientific for the SpaceOAR product. The other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases 1,2 . Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired 3,4 . However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes., Significance: Lipid nanoparticle-encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity., (©2024 The Authors; Published by the American Association for Cancer Research.)