Search

Background: Climate change is increasing the frequency of high heat and high humidity days. Whether these conditions can trigger ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation, VT/VF] in susceptible persons is unknown. Objectives: The purpose of this study was to determine the relationship between warm-season weather conditions and risk of VT/VF in individuals with pacemakers and defibrillators. Methods: Baseline clinical and device data from 5,944 patients in North Carolina (2010-2021) were linked to daily weather data geocoded to individuals’ residential addresses. Associations between extreme humidity, temperature, and VT/VF overall and by patient, community, and built environment factors were estimated using a case time-series design with distributed lag nonlinear models, adjusting for temporal trends and individual factors. Results: VT/VF events occurred on 4,486 of the 484,988 person-days. Extreme humidity (95th percentile: 90% relative humidity) increased odds of VT/VF in the 7 days following exposure (aOR 1.23 [95% CI: 1.00-1.51]). Humidity-associated VT/VF risk was highest among those who were male (aOR: 1.38 [95% CI: 1.08-1.76]), age 67 to 75 years (aOR: 1.65 [95% CI: 1.16-2.35]) with coronary artery disease (aOR: 1.79 [95% CI: 1.25-2.57]), heart failure (aOR: 1.72 [95% CI: 1.2-2.46]), diabetes (aOR: 3.01 [95% CI: 1.99-4.56]), hypertension (aOR: 2.06 [95% CI: 1.48-2.88]), and prior myocardial infarction (aOR: 1.75 [95% CI: 1.23-2.48]). Communities with high socioeconomic deprivation (aOR: 1.83 [95% CI: 1.28-2.62]), high income inequality (aOR: 1.56 [95% CI: 1.19-2.04]), and urban areas with less greenspace (aOR: 1.29 [95% CI: 0.93-1.78]) also had increased VT/VF risk. High temperatures were not associated with VT/VF. Conclusions: In patients with preexisting cardiovascular disease, exposure to extreme humidity increased VT/VF risk, especially among vulnerable individuals, disadvantaged communities, and urban areas with less green space. These findings emphasize the need for policies that address environmental risks in susceptible individuals and communities.

Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Abstract CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

Abstract Climate change factors and expanded population growth in the Wildland Urban Interface (transition zone between human structures and undeveloped wildland) contribute to a projected increase in wildfire frequency and smoke exposure. As an unregulated source of air pollution, reducing smoke exposure represents a difficult challenge for health risk communicators. The target audience is broad with unpredictable health impacts due to spatial and temporal variability in exposure. Beyond providing information, agencies face challenges reaching affected populations, motivating behavior change, and overcoming barriers between intentions and actions (recommended health protection). The Smoke Sense citizen science project developed a smartphone app to provide an engagement, learning, and information-sharing platform. Here we draw upon previous trends in behavioral patterns and propose a synergistic approach of citizen and behavioral science that can be applied to increase understanding of health risk and motivate new habits to reduce exposure among impacted individuals. Presentation of the approach proceeds as follows: (1) we identify several core factors that contribute to an intention-action gap, (2) identify applicable social and behavioral science principles that can bridge the gap, (3) propose explicit examples focused on theoretical principles, (4) describe small-scale user preliminary feedback and examples for monitoring and evaluating impact, and (5) provide a look to the future for collaborative citizen engagement. Current health risk communication strategies often lack consideration of behavioral factors that may enhance motivation and encourage behavior change. The proposed approach aims to leverage the strengths of citizen and social science and seeks to encourage a focused ‘digital community’ to implement new habits in the face of unpredictable and dynamic environmental threats.

Abstract In response to increasing wildfire risks, California plans to expand the use of prescribed fire. We characterized the anticipated change in health impacts from exposure to smoke under a future fire‐management scenario relative to a historical period (2008–2016). Using dispersion models, we estimated daily fine particulate matter (PM2.5) emissions from hypothetical future prescribed fires on 500,000‐acres classified as high priority. To evaluate health impacts, we calculated excess daily cardiorespiratory emergency department visit rates attributed to all‐source PM2.5, distinguishing the portion of the burden attributed to prescribed fire. The total burden was differentiated by fire type and by smoke strata‐specific days to calculate strata‐specific burden rates, which were then applied to estimate the burden in the future scenario. This analysis suggests that the exposure to prescribed fire smoke, measured as the number of persons exposed per year, would be 15 times greater in the future. However, these exposures were associated with lower concentrations compared to the historical period. The increased number of exposure days led to an overall increase in the future health burden. Specifically, the northern, central, and southern regions experienced the largest burden increase. This study introduces an approach that integrates spatiotemporal exposure differences, baseline morbidity, and population size to assess the impacts of prescribed fire under a future scenario. The findings highlight the need to consider both the level and frequency of exposure to guide strategies to safeguard public health as well as aid forest management agencies in making informed decisions to protect communities while mitigating wildfire risks.

Background: Smoke exposure from wildfires or residential wood burning for heat is a public health problem for many communities. Do-It-Yourself (DIY) portable air cleaners (PACs) are promoted as affordable alternatives to commercial PACs, but evidence of their effect on health outcomes is limited. Objective: Pilot test an evaluation of the effect of DIY PAC usage on self-reported symptoms, and investigate barriers and facilitators of PAC use, among members of a tribal community that routinely experiences elevated concentrations of fine particulate matter (PM2.5) from smoke. Methods: We conducted studies in Fall 2021 (“wildfire study”; N = 10) and Winter 2022 (“wood stove study”; N = 17). Each study included four sequential one-to-two-week phases: 1) initial, 2) DIY PAC usage ≥8 h/day, 3) commercial PAC usage ≥8 h/day, and 4) air sensor with visual display and optional PAC use. We continuously monitored PAC usage and indoor/outdoor PM2.5 concentrations in homes. Concluding each phase, we conducted phone surveys about participants’ symptoms, perceptions, and behaviors. We analyzed symptoms associated with PAC usage and conducted an analysis of indoor PM2.5 concentrations as a mediating pathway using mixed effects multivariate linear regression. We categorized perceptions related to PACs into barriers and facilitators of use. Results: No association was observed between PAC usage and symptoms, and the mediation analysis did not indicate that small observed trends were attributable to changes in indoor PM2.5 concentrations. Small sample sizes hindered the ability to draw conclusions regarding the presence or absence of causal associations. DIY PAC usage was low; loud operating noise was a barrier to use. Discussion: This research is novel in studying health effects of DIY PACs during wildfire and wood smoke exposures. Such research is needed to inform public health guidance. Recommendations for future studies on PAC use during smoke exposure include building flexibility of intervention timing into the study design.

Abstract Wildfire smoke is associated with short-term respiratory outcomes including asthma exacerbation in children. As investigations into developmental wildfire smoke exposure on children’s longer-term respiratory health are sparse, we investigated associations between developmental wildfire smoke exposure and first use of respiratory medications. Prescription claims from IBM MarketScan Commercial Claims and Encounters database were linked with wildfire smoke plume data from NASA satellites based on Metropolitan Statistical Area (MSA). A retrospective cohort of live infants (2010–2016) born into MSAs in six western states (U.S.A.), having prescription insurance, and whose birthdate was estimable from claims data was constructed (N = 184,703); of these, gestational age was estimated for 113,154 infants. The residential MSA, gestational age, and birthdate were used to estimate average weekly smoke exposure days (smoke-day) for each developmental period: three trimesters, and two sequential 12-week periods post-birth. Medications treating respiratory tract inflammation were classified using active ingredient and mode of administration into three categories:: 'upper respiratory', 'lower respiratory', 'systemic anti-inflammatory'. To evaluate associations between wildfire smoke exposure and medication usage, Cox models associating smoke-days with first observed prescription of each medication category were adjusted for infant sex, birth-season, and birthyear with a random intercept for MSA. Smoke exposure during postnatal periods was associated with earlier first use of upper respiratory medications (1–12 weeks: hazard ratio (HR) = 1.094 per 1-day increase in average weekly smoke-day, 95%CI: (1.005,1.191); 13–24 weeks: HR = 1.108, 95%CI: (1.016,1.209)). Protective associations were observed during gestational windows for both lower respiratory and systemic anti-inflammatory medications; it is possible that these associations may be a consequence of live-birth bias. These findings suggest wildfire smoke exposure during early postnatal developmental periods impact subsequent early life respiratory health.

Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.

Abstract Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. Trial registration The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

Many United States (US) cities are experiencing urban heat islands (UHIs) and climate change-driven temperature increases. Extreme heat increases cardiovascular disease (CVD) risk, yet little is known about how this association varies with UHI intensity (UHII) within and between cities. We aimed to identify the urban populations most at-risk of and burdened by heat-related CVD morbidity in UHI-affected areas compared to unaffected areas. ZIP code-level daily counts of CVD hospitalizations among Medicare enrollees, aged 65–114, were obtained for 120 US metropolitan statistical areas (MSAs) between 2000 and 2017. Mean ambient temperature exposure was estimated by interpolating daily weather station observations. ZIP codes were classified as low and high UHII using the first and fourth quartiles of an existing surface UHII metric, weighted to each have 25% of all CVD hospitalizations. MSA-specific associations between ambient temperature and CVD hospitalization were estimated using quasi-Poisson regression with distributed lag non-linear models and pooled via multivariate meta-analyses. Across the US, extreme heat (MSA-specific 99th percentile, on average 28.6 °C) increased the risk of CVD hospitalization by 1.5% (95% CI: 0.4%, 2.6%), with considerable variation among MSAs. Extreme heat-related CVD hospitalization risk in high UHII areas (2.4% [95% CI: 0.4%, 4.3%]) exceeded that in low UHII areas (1.0% [95% CI: −0.8%, 2.8%]), with upwards of a 10% difference in some MSAs. During the 18-year study period, there were an estimated 37,028 (95% CI: 35,741, 37,988) heat-attributable CVD admissions. High UHII areas accounted for 35% of the total heat-related CVD burden, while low UHII areas accounted for 4%. High UHII disproportionately impacted already heat-vulnerable populations; females, individuals aged 75–114, and those with chronic conditions living in high UHII areas experienced the largest heat-related CVD impacts. Overall, extreme heat increased cardiovascular morbidity risk and burden in older urban populations, with UHIs exacerbating these impacts among those with existing vulnerabilities.

SHOX2 is a homeobox transcription factor associated with atrial fibrillation (AF) and sinus node dysfunction. Here, we generated two homozygous SHOX2 knock-out hiPSC lines from a healthy control line and a corrected AF patient line (disease-specific SHOX2 mutation corrected to WT) using CRISPR/Cas9. These cell lines maintained pluripotency, an ability to differentiate into all three germlayers and a normal karyotype, presenting a valuable tool to investigate the impact of a full SHOX2 knock-out with respect to arrhythmogenic diseases on a cellular level.

As wildfire frequency and severity increases, smoke exposures will cause increasingly more adverse respiratory effects. While acute respiratory effects of smoke exposure have been documented in children, longer term sequelae are largely unstudied. Our objective here was to examine the association between gestational and postnatal exposure to wildfire smoke and prolonged use of prescription medication for respiratory conditions in early childhood. Using Merative MarketScan claims data, we created cohorts of term children born in western states between 1 January 2010–31 December 2014 followed for at least three years. Using NOAA Hazard Mapping System data, we determined the average number of days a week that >25% of the population in a metropolitan statistical area (MSA) was covered by smoke within each exposure period. The exposure periods were defined by trimester and two 12 week postnatal periods. Medication use was based on respiratory indication (upper respiratory, lower respiratory, or any respiratory condition) and categorized into outcomes of prolonged use (⩾30 d use) (PU) and multiple prolonged uses (at least two prolonged uses) (MPU). We used logistic regression models with random intercepts for MSAs adjusted for child sex, birth season, and birth year. Associations differed by exposure period and respiratory outcome, with elevated risk of MPU of lower respiratory medications following exposure in the third trimester and the first 12 postnatal weeks (RR 1.15, 95% CI 0.98, 1.35; RR 1.21, 95% CI 1.05, 1.40, respectively). Exposure in the third trimester was associated with an increase in MPU of any respiratory among males infants only (male RR 1.22, 95% CI 1.00, 1.50; female RR 0.93, 95% CI 0.66, 1.31). Through novel use of prescription claims data, this work identifies critical developmental windows in the 3rd trimester and first 12 postnatal weeks during which environmental inhalational disaster events may impact longer-term respiratory health.

Abstract Background Ambient PM2.5 is a ubiquitous air pollutant with demonstrated adverse health impacts in population. Hemodialysis patients are a highly vulnerable population and may be particularly susceptible to the effects of PM2.5 exposure. This study examines associations between short-term PM2.5 exposure and cardiovascular disease (CVD) and mortality among patients receiving maintenance in-center hemodialysis. Methods Using the United State Renal Data System (USRDS) registry, we enumerated a cohort of all US adult kidney failure patients who initiated in-center hemodialysis between 1/1/2011 and 12/31/2016. Daily ambient PM2.5 exposure estimates were assigned to cohort members based on the ZIP code of the dialysis clinic. CVD incidence and mortality were ascertained through 2016 based on USRDS records. Discrete time hazards regression was used to estimate the association between lagged PM2.5 exposure and CVD incidence, CVD-specific mortality, and all-cause mortality 1 t adjusting for temperature, humidity, day of the week, season, age at baseline, race, employment status, and geographic region. Effect measure modification was assessed for age, sex, race, and comorbidities. Results Among 314,079 hemodialysis patients, a 10 µg/m3 increase in the average lag 0–1 daily PM2.5 exposure was associated with CVD incidence (HR: 1.03 (95% CI: 1.02, 1.04)), CVD mortality (1.05 (95% CI: 1.03, 1.08)), and all-cause mortality (1.04 (95% CI: 1.03, 1.06)). The association was larger for people who initiated dialysis at an older age, while minimal evidence of effect modification was observed across levels of sex, race, or baseline comorbidities. Conclusions Short-term ambient PM2.5 exposure was positively associated with incident CVD events and mortality among patients receiving in-center hemodialysis. Older patients appeared to be more susceptible to PM2.5-associated CVD events than younger hemodialysis patients.

Abstract Background Exposure to air pollution is associated with elevated cardiovascular risk. Evidence shows that omega-3 polyunsaturated fatty acids (omega-3 PUFA) may attenuate the adverse cardiovascular effects of exposure to fine particulate matter (PM2.5). However, it is unclear whether habitual dietary intake of omega-3 PUFA protects against the cardiovascular effects of short-term exposure to low-level ambient air pollution in healthy participants. In the present study, sixty-two adults with low or high dietary omega-3 PUFA intake were enrolled. Blood lipids, markers of vascular inflammation, coagulation and fibrinolysis, and heart rate variability (HRV) and repolarization were repeatedly assessed in 5 sessions separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily PM2.5 and maximum 8-h ozone (O3) concentrations were obtained from nearby air quality monitoring stations. Linear mixed-effects models were used to assess the associations between air pollutant concentrations and cardiovascular responses stratified by the omega-3 intake levels. Results The average concentrations of ambient PM2.5 and O3 were well below the U.S. National Ambient Air Quality Standards during the study period. Significant associations between exposure to PM2.5 and changes in total cholesterol, von Willebrand factor (vWF), tissue plasminogen activator, D-dimer, and very-low frequency HRV were observed in the low omega-3 group, but not in the high group. Similarly, O3-associated adverse changes in cardiovascular biomarkers (total cholesterol, high-density lipoprotein, serum amyloid A, soluable intracellular adhesion molecule 1, and vWF) were mainly observed in the low omega-3 group. Lag-time-dependent biphasic changes were observed for some biomarkers. Conclusions This study demonstrates associations between short-term exposure to PM2.5 and O3, at concentrations below regulatory standard, and subclinical cardiovascular responses, and that dietary omega-3 PUFA consumption may provide protection against such cardiovascular effects in healthy adults.

Introduction In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary.Methods Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley’s K analysis, a methodology adapted from ecology.Results Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor–stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR −0.5 to 5.1); stage III: 1.4 (IQR −0.3 to 3.5); stage IV: 0.6 (IQR −2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS–hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p

Abstract Background Short-term exposure to ambient nitrogen dioxide (NO2) is associated with adverse respiratory and cardiovascular outcomes. Supplementation of omega-3 polyunsaturated fatty acids (PUFA) has shown protection against exposure to fine particulate matter. This study aims to investigate whether habitual omega-3 PUFA intake differentially modify the associations between respiratory and cardiovascular responses and short-term exposure to ambient NO2. Methods Sixty-two healthy participants were enrolled into low or high omega-3 groups based on their habitual omega-3 PUFA intake. Each participant was repeatedly assessed for lung function, blood lipids, markers of coagulation and fibrinolysis, vascular function, and heart rate variability (HRV) in up to five sessions, each separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily ambient NO2 concentrations were obtained from an area air quality monitoring station on the day of outcome assessment (Lag0), 4 days prior (Lag1-4), as well as 5-day moving average (5dMA). The associations between short-term exposure to NO2 and the measured indices were evaluated using linear mixed-effects models stratified by omega-3 levels and adjusted by covariates including relative humidity and temperature. Results The average concentration of ambient NO2 during the study periods was 5.3±3.8 ppb which was below the National Ambient Air Quality Standards (NAAQS). In the high omega-3 group, an interquartile range (IQR) increase in short-term NO2 concentrations was significantly associated with increased lung function [e.g. 1.2% (95%CI: 0.2%, 2.2%) in FVC at lag1, 2.6% (95%CI: 0.4%, 4.8%) in FEV1 at 5dMA], decreased blood lipids [e.g. -2.6% (95%CI: -4.4%, -0.9%) in total cholesterol at lag2, -3.1% (95%CI: -6.1%, 0.0%) in HDL at 5dMA, and -3.1% (95%CI: -5.5%, -0.7%) in LDL at lag2], improved vascular function [e.g. 8.9% (95%CI: 0.6%, 17.2%) increase in FMD and 43.1% (95%CI: -79.8%, -6.3%) decrease in endothelin-1 at 5dMA], and changed HRV parameters [e.g. -7.2% (95%CI: -13.6%, -0.8%) in HFn and 13.4% (95%CI: 0.2%, 28.3%) in LF/HF ratio at lag3]. In the low omega-3 group, an IQR increase in ambient NO2 was associated with elevations in coagulation markers (von Willebrand Factor, D-dimer) and a decrease in HRV (very-low frequency); however, null associations were observed between short-term NO2 exposure and changes in lung function, blood lipids, and vascular function. Conclusions The results in this study imply that dietary omega-3 PUFA consumption may offer respiratory and vascular benefits in response to short-term exposure of healthy adults to NO2 levels below the NAAQS. Trial registration ClinicalTrials.gov ( NCT02921048 ).

Background. Successful execution of invasive procedures in acute care settings, including tracheal intubation, requires careful coordination of an interprofessional team. The stress inherent to the intensive care unit (ICU) environment may threaten the optimal communication and planning necessary for the safe execution of this complex procedure. The objective of this study is to characterize the perceptions of interprofessional team members surrounding tracheal intubations in the pediatric ICU (PICU). Methods. This is a single-center survey-based study of staff involved in the intubation of pediatric patients admitted to a tertiary level academic PICU. Physicians, nurses, and respiratory therapists (RT) involved in tracheal intubations were queried via standardized, discipline-specific electronic surveys regarding their involvement in procedural planning and overall awareness of and comfort with the intubation plan. Qualitative variables were assessed by both Likert scales and free-text comments that were grouped and analyzed thematically. Results. One hundred and eleven intubation encounters were included during the study time period, of which 93 (84%) had survey responses from at least 2 professional teams. Among those included in the analysis, the survey was completed 244 times by members of the PICU teams including 86 responses from physicians, 76 from nurses, and 82 from RTs. Survey response rates were >80% from each provider team. There were significant differences in interprofessional team comfort with nurses feeling less well informed and comfortable with the intubation plan and process compared to physicians and RTs (p

Future projection of the temperature-related health burden, including mortality and hospital admissions, is a growing field of research. These studies aim to provide crucial information for decision-makers considering existing health policies as well as integrating targeted adaptation strategies to evade the health burden. However, this field of research is still overshadowed by large uncertainties. These uncertainties exist to an extent in the future climate and population models used by such studies but largely in the disparities in underlying assumptions. Existing studies differ in the factors incorporated for projection and strategies for considering the future adaptation of the population to temperature. These differences exist to a great degree because of a lack of robust evidence as well as gaps in the field of climate epidemiology that still require extensive input from the research community. This narrative review summarizes the current status of projection studies of temperature-attributable health burden, the guiding assumptions behind them, the common grounds, as well as the differences. Overall, the review aims to highlight existing evidence and knowledge gaps as a basis for designing future studies on temperature-attributable health burden estimation. Finding a robust methodology for projecting the future health burden could be a milestone for climate epidemiologists as this would largely benefit the world when applying this technique to project the climate-attributable cause-specific health burden and adapt our existing health policies accordingly.

The escalating frequency and severity of global wildfires necessitate an in-depth understanding and monitoring of wildfire smoke impacts, specifically its contribution to fine particulate matter (PM2.5). We propose a data-fusion method to study wildfire contribution to PM2.5 using satellite-derived smoke plume indicators and PM2.5 monitoring data. Our study incorporates two types of monitoring data, the high-quality but sparse Air Quality System (AQS) stations and the abundant but less accurate PurpleAir (PA) sensors that are gaining popularity among citizen scientists. We propose a multi-resolution spatiotemporal model specified in the spectral domain to calibrate the PA sensors against accurate AQS measurements, and leverage the two networks to estimate wildfire contribution to PM2.5 in California in 2020 and 2021. A Bayesian approach is taken to incorporate all uncertainties and our prior intuition that the dependence between networks, as well as the accuracy of PA network, vary by frequency. We find that 1% to 3% increase in PM2.5 concentration due to wildfire smoke, and that leveraging PA sensors improves accuracy.

Exposure to ozone (O3) is associated with adverse respiratory and cardiovascular outcomes. Alterations in circulating microRNAs (miRNAs) may contribute to the adverse vascular effects of O3 exposure through inter-cellular communication resulting in post-transcriptional regulation of messenger RNAs by miRNAs. In this study, we investigated whether O3 exposure induces alterations in circulating miRNAs that can mediate effects on downstream vascular and coagulation biomarkers. Twenty-three healthy male adults were exposed on successive days to filtered air and 300 ppb O3 for 2 h. Circulating miRNA and protein biomarkers were quantified after each exposure session. The data were subjected to mixed-effects model and mediation analyses for the statistical analyses. The results showed that the expression level of multiple circulating miRNAs (e.g., miR-19a-3p, miR-34a-5p) was significantly associated with O3 exposure. Pathway analysis showed that these miRNAs were predictive of changing levels of downstream biomarkers [e.g., D-dimer, C-reactive protein, tumor necrosis factor α (TNFα)]. Mediation analysis showed that miR-19a-3p may be a significant mediator of O3-exposure-induced changes in blood TNFα levels [0.08 (0.01, 0.15), p = 0.02]. In conclusion, this preliminary study showed that O3 exposure of healthy male adults resulted in changes in circulating miRNAs, some of which may mediate vascular effects of O3 exposure.

Management of decompensated cirrhosis (DC) can be challenging for the surgical intensivist. Management of DC is often complicated by ascites, coagulopathy, hepatic encephalopathy, gastrointestinal bleeding, hepatorenal syndrome, and difficulty assessing volume status. This Clinical Consensus Document created by the American Association for the Surgery of Trauma Critical Care Committee reviews practical clinical questions about the critical care management of patients with DC to facilitate best practices by the bedside provider.

Das vergangene Jahrzehnt zeichnete sich durch eine Fülle von Entdeckungen aus, die zur Aufklärung und zum Verständnis von Neuroentwicklungsstörungen führten, darunter geistige Retardierung und Autismus-Spektrum-Störung. Diese Erfolge waren durch methodische Weiterentwicklungen in der Array-Diagnostik und durch Next-Generation-Sequenzierung möglich geworden. Über die Hälfte aller Neuroentwicklungsstörungen konnte dadurch ursächlich aufgeklärt werden. Eine Früherkennung dieser tiefgreifenden Entwicklungsstörungen in den frühen Stadien der Gehirnentwicklung ist von großer Bedeutung, um wirksame Behandlungsschritte einzuleiten. Ein vertieftes Verständnis der neurobiologischen Prozesse der identifizierten Gene und ihrer Stoffwechselwege ist auch notwendig, um die Entwicklung und Funktion der neuronalen Netzwerke und Verschaltungen besser zu verstehen.

Introduction: Fitted filtration performance of an N95 respirator may benefit from differing levels of instructions. Methods: Using a modified Occupational Safety and Health Administration fit test protocol, we measured fitted filtration efficiency for an N95 respirator in 21 screened, healthy participants given 4 levels of escalating instruction: (1) uninstructed (baseline), (2) written/pictorial manufacturer instructions, (3) step-by-step video demonstration, and (4) staff instruction (visual inspection of respirator fit and verbal suggestions to adjust when applicable). Results: Baseline fitted filtration efficiency was not significantly different between participants with or without previous experience of N95 use. Clear improvements in fitted filtration efficiency were observed progressing from baseline (average=86.1%) to manufacturer paper instructions (93.3%), video instructions (97.5%), and post staff intervention (98.3%). Baseline fitted filtration efficiency values were significantly lower than those after video instruction (p

Disposable facemasks are a primary tool to prevent the transmission of SARS-COV-2 during the COVID-19 pandemic. However, plastic waste generated from their disposal represents a significant environmental problem that can be reduced by maximizing the service life of disposable masks. We evaluated the effect of repeated wearing on the fitted filtration efficiency (FFE) of N95, KF94, KN95, and procedure/surgical masks. The FFEs of masks were compared following extended wearing with and without washing. Results reveal that most disposable facemasks can retain a high level of their baseline FFE after extended wearing, even after 40 h of wearing. Laundering disposable masks degraded FFE in some instances. We conclude that the durability of disposable facemask performance is considerably longer than their intended single use indication, suggesting that reusing disposable masks is a safe means of reducing plastic waste in the environment.

Background: Over one-third of the U.S. population is exposed to unsafe levels of ozone (O3). Dietary supplementation with fish oil (FO) or olive oil (OO) has shown protection against other air pollutants. This study evaluates potential cardiopulmonary benefits of FO or OO supplementation against acute O3 exposure in young healthy adults. Methods: Forty-three participants (26 ± 4 years old; 47% female) were randomized to receive 3 g/day of FO, 3 g/day OO, or no supplementation (CTL) for 4 weeks prior to undergoing 2-hour exposures to filtered air and 300 ppb O3 with intermittent exercise on two consecutive days. Outcome measurements included spirometry, sputum neutrophil percentage, blood markers of inflammation, tissue injury and coagulation, vascular function, and heart rate variability. The effects of dietary supplementation and O3 on these outcomes were evaluated with linear mixed-effect models. Results: Compared with filtered air, O3 exposure decreased FVC, FEV1, and FEV1/FVC immediately post exposure regardless of supplementation status. Relative to that in the CTL group, the lung function response to O3 exposure in the FO group was blunted, as evidenced by O3-induced decreases in FEV1 (Normalized CTL −0.40 ± 0.34 L, Normalized FO −0.21 ± 0.27 L) and FEV1/FVC (Normalized CTL −4.67 ± 5.0 %, Normalized FO −1.4 ± 3.18 %) values that were on average 48% and 70% smaller, respectively. Inflammatory responses measured in the sputum immediately post O3 exposure were not different among the three supplementation groups. Systolic blood pressure elevations 20-h post O3 exposure were blunted by OO supplementation. Conclusion: FO supplementation appears to offer protective effects against lung function decrements caused by acute O3 exposure in healthy adults.

Abstract Background There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest. Methods Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS. Results A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model. Conclusions These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.

Background: Exposure to ambient air pollution is associated with increased cardiovascular morbidity and mortality. Circulating microRNAs (miRNAs) may mediate cardiovascular effects of exposure to air pollution. This study aims to investigate whether circulating miRNAs mediate the associations between short-term human exposure to ambient air pollution and cardiovascular biomarkers. Methods: Twenty-four healthy adults residing in the Research Triangle area of North Carolina, USA were enrolled between December 2016 and July 2019. Circulating miRNAs, protein, and lipid biomarkers were assessed repeatedly for 3 sessions separated by at least 7 days. Linear mixed-effects models were used to assess the associations between air pollutant concentrations obtained from nearby air quality monitoring stations and miRNAs controlling for covariates including omega-3 index, relative humidity, and temperature. miRNAs that were significantly altered were then matched with protein or blood lipid biomarkers using either Ingenuity Pathway Analysis or a literature search. A mediation analysis was performed to test the statistical significance of miRNA’s mediating effects between exposure to air pollution and cardiovascular biomarkers. Results: Short-term exposure to ambient fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) was associated with changes in 11, 9, and 24 circulating miRNAs, respectively. Pathway analysis showed that several miRNAs including miR-125b-5p, miR-144–5p, miR-26a-5p, and miR-34a-5p may mediate the effects of air pollutant exposure on the changes of downstream protein / lipid biomarkers including serum amyloid A (SAA), C-reactive protein (CRP), soluble vascular adhesive molecules 1 (sICAM1), total cholesterol, and high-density lipoproteins (HDL). Mediation analysis showed that only miR-26a-5p significantly mediated air pollutant (PM2.5 and NO2)-induced effects on blood CRP and total cholesterol levels. For example, 34.1% of PM2.5–associated changes in CRP were significantly mediated by miR-26a-5p at lag4 [indirect effects, 0.06 (0.02, 0.10), P = 0.005]. Similarly, the proportions of indirect effects of miR-26a-5p on the association between NO2 exposure and CRP were 46.8% at lag2 [0.06 (0.02, 0.11), P = 0.003], 61.2% at lag3 [0.05 (0.00, 0.09), P = 0.04], and 30.8% at 5-day moving average [0.06 (0.02, 0.10), P = 0.01]. In addition, omega-3 index may be a significant modifying factor of the mediated effects of miRNAs. Conclusions: This study demonstrates that short-term exposure to ambient PM2.5, O3, and NO2 was associated with specific circulating miRNAs, and some of which may mediate their effects on the downstream inflammation and blood lipid markers.

Abstract SHANK2 mutations have been identified in individuals with neurodevelopmental disorders, including intellectual disability and autism spectrum disorders (ASD). Using CRISPR/Cas9 genome editing, we obtained SH-SY5Y cell lines with frameshift mutations on one or both SHANK2 alleles. We investigated the effects of the different SHANK2 mutations on cell morphology, cell proliferation and differentiation potential during early neuronal differentiation. All mutant cell lines showed impaired neuronal differentiation marker expression. Cells with bi-allelic SHANK2 mutations revealed diminished apoptosis and increased proliferation, as well as decreased neurite outgrowth during early neuronal differentiation. Bi-allelic SHANK2 mutations resulted in an increase in p-AKT levels, suggesting that SHANK2 mutations impair downstream signaling of tyrosine kinase receptors. Additionally, cells with bi-allelic SHANK2 mutations had lower amyloid precursor protein (APP) expression compared to controls, suggesting a molecular link between SHANK2 and APP. Together, we can show that frameshift mutations on one or both SHANK2 alleles lead to an alteration of neuronal differentiation in SH-SY5Y cells, characterized by changes in cell growth and pre- and postsynaptic protein expression. We also provide first evidence that downstream signaling of tyrosine kinase receptors and amyloid precursor protein expression are affected.

Abstract Background Fine particulate matter (PM2.5) related mild inflammation, altered autonomic control of cardiovascular function, and changes to cell function have been observed in controlled human exposure studies. Methods To measure the systemic and cardiopulmonary impacts of low-level PM exposure, we exposed 20 healthy, young volunteers to PM2.5, in the form of concentrated ambient particles (mean: 37.8 μg/m3, SD 6.5), and filtered air (mean: 2.1 μg/m3, SD 2.6). In this double-blind, crossover study the exposure order was randomized. During the 4 h exposure, volunteers (7 females and 13 males) underwent light intensity exercise to regulate ventilation rate. We measured pulmonary, cardiac, and hematologic end points before exposure, 1 h after exposure, and again 20 h after exposure. Results Low-level PM2.5 resulted in both pulmonary and extra-pulmonary changes characterized by alterations in systematic inflammation markers, cardiac repolarization, and decreased pulmonary function. A mean increase in PM2.5 concentration (37.8 μg/m3) significantly increased serum amyloid A (SAA), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), 1 h after exposure by 8.7, 9.1, 10.7, and 6.6%, respectively, relative to the filtered air control. SAA remained significantly elevated (34.6%) 20 h after PM2.5 exposure which was accompanied by a 5.7% decrease in percent neutrophils. Decreased pulmonary function was observed 1 h after exposure through a 0.8 and 1.2% decrease in forced expiratory volume in 1 s (FEV1) and FEV1/ forced vital capacity (FEV1/FVC) respectively. Additionally, sex specific changes were observed in repolarization outcomes following PM2.5 exposure. In males, P-wave and QRS complex were increased by 15.4 and 5.4% 1 h after exposure. Conclusions This study is the first controlled human exposure study to demonstrate biological effects in response to exposure to concentrated ambient air PM2.5 particles at levels near the PM2.5 US NAAQS standard. Clinical trial registration information clinicaltrials.gov ; Identifier: NCT03232086 . The study was registered retrospectively on July 25, 2017, prior to final data collection on October 25, 2017 and data analysis.

Objective: To compare tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Over a consecutive 2-year period, 824 adult cardiac surgery patients who received TXA during an EACA shortage were compared with 778 patients who received EACA postshortage. Patient characteristics and process and outcome variables were collected through chart review and database queries. This retrospective analysis used inverse probability of treatment weighting to control for confounding by indication, and propensity scores were calculated using a logistic regression model. Results: In adjusted models, overall transfusion rates for the TXA cohort (odds ratio [OR], 0.94; 95% confidence interval [95% CI], 0.81-1.10) and administration of platelets (OR, 1.04; 95% CI, 0.85-1.27), red blood cells (OR, 0.93; 95% CI, 0.80-1.09), fresh frozen plasma (OR, 1.00; 95% CI, 0.79-1.25), and cryoprecipitate (OR, 1.08; 95% CI, 0.71-1.64) were equivalent to the EACA cohort. In addition, there was no statistical difference with respect to stroke, seizure, mortality, reoperation for bleeding, chest tube drainage, and acute kidney injury. Patients who received TXA had shorter ventilator times (difference in medians −1.33 hours [95% CI, −1.86 to −0.80]) and lower postsurgical charges (difference of medians −$2913 [95% CI, −5147 to −679]). Conclusions: Substituting TXA for EACA during cardiac surgery with cardiopulmonary bypass did not change transfusion rate or amount, nor was there a significant difference in chest tube drainage. Patients who received TXA had a statistically significant but not clinically significant lower postoperative ventilator times and charges without an increase in mortality, stroke, reoperation for bleeding, acute kidney injury, or seizures.

RIT Online Learning courses have an overall course completion rate of 94%. For lower-division courses the rate is 92%, undergraduate 93%, and graduate 96%. In this case study we will share additional measurements we have used to monitor student success and describe strategies we have used to promote online discussion as a key component of effective online courses. We will share results from a large survey of our online students that shows the most interactive courses receive the most positive responses from students. The demographics of our online students have shifted to where almost half our online students are campus-based now. We believe our historical emphasis on interaction in our online courses is serving these new online students equally well, which suggests an important opportunity exists to expand online discussion to more campus-based courses. (Contains 6 figures.)

Venous thromboembolism (VTE) is a potential sequela of injury, surgery, and critical illness. Patients in the Trauma Intensive Care Unit are at risk for this condition, prompting daily discussions during patient care rounds and routine use of mechanical and/or pharmacologic prophylaxis measures. While VTE rightfully garners much attention in clinical patient care and in the medical literature, optimal strategies for VTE prevention are still evolving. Furthermore, trauma and surgical patients often have real or perceived contraindications to prophylaxis that affect the timing of preventive measures and the consistency with which they can be applied. In this Clinical Consensus Document, the American Association for the Surgery of Trauma Critical Care Committee addresses several practical clinical questions pertaining to specific or unique aspects of VTE prophylaxis in critically ill and injured patients.