Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

INTRODUCTION: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. METHODS: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. RESULTS: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. CONCLUSION: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Characterization of Adverse Outcomes from Legacy-Contaminated Groundwater Exposure to Early Life Stages of Fathead Minnow.

Complex mixtures of chemicals present in groundwater at legacy-contaminated industrial sites can pose significant risks to adjacent surface waters. The combination of short-term molecular and chronic apical effect assessments is a promising approach to characterize the potential hazard of such complex mixtures. The objectives of this study were to: (1) assess the apical effects (survival, growth, development, and liver histopathology) after chronic exposure of early life stages (ELSs) of fathead minnows (FHM; Pimephales promelas) to contaminated groundwater from a legacy-contaminated pesticide manufacturing and packaging plant, and (2) identify possible molecular mechanisms responsible for these effects by comparing results to mechanistic outcomes previously determined by a short-term reduced transcriptome assay (EcoToxChips). This study revealed a significant increase in mortality and prevalence of spinal curvatures, as well as a significant reduction in the length of FHMs exposed to the groundwater mixtures in a concentration-dependent manner. There was an increasing trend in the prevalence of edema in FHMs, though not significantly different from controls. Additionally, no histopathological effects were observed in the liver of FHMs exposed to the groundwater mixtures. Short-term molecular outcomes determined in a parallel study were found to be informative of chronic apical outcomes, including cardiotoxicity, spinal deformities, and liver toxicity. Overall, the results observed in this study demonstrated that short-term transcriptomics analyses could support the hazard assessment of complex contaminated sites.

Persistence to Basal Insulin: Association With Health Outcomes in a Population With Type 2 Diabetes.

This study examined the association between persistence to basal insulin and clinical and economic health outcomes. The question of whether a persistence measure for basal insulin could be leveraged in quality measurement was also explored. Using the IBM-Truven MarketScan Commercial and Medicare Supplemental Databases from 1 January 2011 to 31 December 2015, a total of 14,126 subjects were included in the analyses, wherein 9,898 (70.1%) were categorized as persistent with basal insulin therapy. Basal insulin persistence was associated with lower A1C, fewer hospitalizations and emergency department visits, and lower health care expenditures. Quality measures based on prescription drug claims for basal insulin are feasible and should be considered for guiding quality improvement efforts.

Evaluating the Variability Between 20-m Multistage Fitness Test Estimating Equations in Law Enforcement Recruits.

ABSTRACT: Campbell, P, Maupin, D, Lockie, RG, Dawes, JJ, Simas, V, Canetti, E, Schram, B, and Orr, R. Evaluating the variability between 20-m multistage fitness test estimating equations in law enforcement recruits. J Strength Cond Res 38(4): 742-748, 2024-The 20-m multistage fitness test (20MSFT) is commonly used by law enforcement agencies to measure aerobic fitness and to estimate maximal aerobic consumption (V̇ o2 max). These measures are an important occupational variable with aerobic fitness levels linked to employment status, occupational performance, and long-term health in law enforcement officers. There are a multitude of predictive equations used to provide an estimate of V̇ o2 max, with the extent of variability in the estimated V̇ o2 max currently unknown in this population. This has consequences for comparisons between, and across, differing agencies, and in capabilities of deriving normative data. The aim of this investigation was to compare the variability in estimated V̇ o2 max scores derived from different 20MSFT predictive equations. The 20-m multistage fitness test data from 1,094 law enforcement recruits (male n = 741, 25.2 ± 6.3 years; female: n = 353, 25.6 ± 5.6 years) from a single agency were retrospectively analyzed. The 20MSFT scores were transformed into estimated V̇ o2 max scores using 6 different predictive equations. Significance was set at p < 0.05. Results demonstrated significantly different V̇ o2 max scores between each predictive equation ( p < 0.001; d = 0.25-1.53) and between male and female recruits ( p < 0.001, r = 0.55). All estimated V̇ o2 max equations showed small to very strong correlations with each other ( p < 0.001; r = 0.32-0.99). The findings indicate considerable dispersion of V̇ o2 max scores when using differing equations, suggesting raw 20MSFT variables (e.g., shuttles or distance completed) should be preferred to measure and apply results from aerobic fitness tests if standardized approaches are not developed within law enforcement.

Determining the Changes in Law Enforcement Recruit Aerobic Fitness Using the 2.4-km Run and 20-m Multistage Fitness Test. Does the Type of Test Matter?

ABSTRACT: Campbell, P, Maupin, D, Lockie, RG, Dawes, JJ, Simas, V, Canetti, E, Schram, B, and Orr, R. Determining the changes in law enforcement recruit aerobic fitness using the 2.4-km run and 20-m multistage fitness test. Does the type of test matter? J Strength Cond Res 38(6): 1111-1117, 2024-Aerobic fitness is linked with academy graduation, employment, and the long-term health of law enforcement officers and is often used as a training outcome. However, different tests can be used, and aerobic improvements may differ according to the test used. The aim of this study was to determine whether recruits improved to a greater extent in 1 aerobic test compared with the other. Retrospective data from 5 law enforcement recruit cohorts (males = 741; females = 353) who underwent 18 weeks of academy training were analyzed. Initial 20-m multistage fitness test (20MSFT) and 2.4-km run assessments were completed during weeks 4 and 5 of training, with final testing completed during weeks 16 and 17, respectively. A repeated-measures analysis of variance ( p < 0.05) with a Bonferroni post hoc analysis determined changes in aerobic fitness in the 20MSFT and 2.4-km run between male and female recruits. A mean difference of 9.27 (95% confidence intervals [CI] 14.8-10.9; d = 0.63; p < 0.001) shuttle increase in 20MSFT performance and 20.1 (95% CI 16.0-24.2; d = 0.49; p < 0.001) second improvement in 2.4-km run time were demonstrated when averaged across sex, yielding a larger performance improvement for the 20MSFT compared with the 2.4-km run. Conversely, there was a smaller magnitude of change in aerobic fitness between male recruits and female recruits for the 20MSFT ( d = 0.47) compared with the 2.4-km run ( d = 0.50). The findings indicate that current academy training results in improvements to aerobic fitness and to a greater magnitude in the 20MSFT compared with the 2.4-km run. These results may affect policy considerations for law enforcement agencies regarding aerobic test selection.

Compliance with Uresta (CURE) study; a 12 month follow-up of 40 women.

INTRODUCTION AND HYPOTHESIS: The Uresta bladder support is an effective management option for women with stress urinary incontinence (SUI), however, there is a lack of data assessing long-term compliance. The aim of this study was to assess compliance at 12 month follow-up in women using the Uresta bladder support for exercise related SUI. METHODS: This was a prospective study advertised on social media, running clubs and gyms. Participants were fitted with a Uresta bladder support and followed up over a 12 month period. Power calculation recommended a sample size of 43. Ethical approval was obtained. Outcomes were assessed using the PUQ, ICIQ-FLUTS, UDI-6, IIQ-7, QUID and PGI-I questionnaires. RESULTS: Forty-six women were recruited with an average age, BMI and parity of 42, 24 and 2.3 respectively. The most common activities were running (48%) and CrossFit (22%). Six participants withdrew after 2 weeks. Compliance was 90% at 12 months (n=40). Uresta insertion and removal was 'okay', 'easy' or 'very easy' for 86% and 75% respectively. Leakage was improved (n=13), greatly improved (n=12) or stopped (n=5) for 83% of participants, 75% were 'much better' or 'very much better' on the PGI-I scale, and 94% would recommend Uresta to a friend. There were no adverse events. CONCLUSIONS: The Uresta bladder support is a safe, effective, user-friendly management option for women who experience SUI during exercise with excellent long-term compliance. Further studies are required to identify predictors of successful fitting and efficacy, compare outcomes with different devices, and develop a validated questionnaire assessing SUI with exercise.

A checklist for a consistent, comprehensive medication review.

INTRODUCTION: Medicare Advantage Part D plans and stand-alone Part D prescription drug plans are required by the Centers for Medicare and Medicaid Services to have qualified providers, including pharmacists, and offer annual comprehensive medication reviews (CMRs) for eligible Medicare beneficiaries. Although guidance on the components of a CMR is available, providers have flexibility in how to deliver the CMR to patients and which content to cover. With the variety of patient needs, CMR content is not always consistently delivered in practice. Our research group performed an extensive evaluation to create and test an ideal CMR content coverage checklist for CMR provision. CMR CONTENT CHECKLIST: The CMR Content Checklist can be used for quality improvement purposes to evaluate the comprehensiveness of pharmacist services-to assess either within pharmacist variation across patients or within organization variations between pharmacists or sites. INCORPORATING THE CMR CONTENT CHECKLIST INTO PRACTICE: Testing in a real-world setting demonstrated where gaps in service coverage existed. The CMR Content Checklist could be used as the first step for quality improvement given that it provides details on the key aspects of the service that can inform quality measure development.

Qualitative analysis of telephonic comprehensive medication review content and delivery.

BACKGROUND: Comprehensive medication reviews (CMRs) are offered to eligible Medicare beneficiaries to improve patient medication knowledge, identify, and address medication concerns, and empower medication self-management. However, the specific content of real-world CMRs is unclear. OBJECTIVE: To qualitatively assess CMR content and delivery among telephonic CMR providers. METHODS: This qualitative thematic analysis used transcriptions of audio-recorded patient interactions during CMRs from 3 telephonic medication therapy management provider organizations. Data were qualitatively analyzed using the inductive saturation model to code emergent themes by independent reviewers who met to agree themes through consensus. Intercoder reliability was calculated using Krippendorf alpha. RESULTS: Overall, 32 CMR transcripts from 3 organizations were analyzed in 13 rounds of coding. Intercoder reliability was >95%. A total of 21 themes were identified across 4 stages: call opening (4 themes), medication reconciliation (5 themes), clinical assessments and guidance (8 themes), and call closing (4 themes). The call opening stage included: service explanation; insurance coverage/cost; identity/privacy/recording; and patient's medication management. Medication reconciliation included: drug name, dose, frequency, and indication; medication deletion and addition; over-the-counter and vaccination assessment; drug efficacy assessment; and prescribing provider assessment. Clinical assessments and guidance included 4 core clinical assessments: allergy assessment; drug therapy problem assessment; drug-related adverse events; and medication modification; and 4 additional assessments: clinical/therapeutic guidance; cost savings guidance; diet/exercise/lifestyle guidance; and optional clinical and behavioral assessments. Call closing included: documentation; primary care provider confirmation; patient satisfaction; and call transfer. There were variations among organizations in the depth that CMR components were covered. CONCLUSION: These findings suggest provider organizations are including components that meet Centers for Medicare and Medicaid Services goals for CMRs. Yet, variations among organizations indicate a need for standardization and patient-centered measures to ensure appropriate CMR components are covered, while maintaining flexibility for pharmacists to provide patient-oriented CMRs that meet patients' clinical needs.

Trends in telephonic comprehensive medication review in the United States from 2000 to present: a scoping literature review.

BACKGROUND: Although comprehensive medication review (CMR) services have been shown to provide value to patients and payers, the extent of uniformity in service delivery is unknown. A variety of standards and recommendations are available from academic and professional sources, but variation in service provision is an important consideration when attempting to measure or compare service quality nationally. OBJECTIVE: This study aimed to identify and summarize trends in the peer-reviewed and gray literature describing telephonic CMR delivery and content. METHODS: A scoping review of peer-reviewed and gray literature was conducted to quantify and qualify trends in CMR service. Two independent reviewers screened abstracts from 9 bibliographic databases and selected gray literature sources in accordance with the Joanna Briggs Institute guidelines and an internally developed protocol. Inclusion criteria for the review were English language; discussion of telephonic CMR service in the United States; research, legislation, or guidelines that describe CMR content coverage requirements for payment; and publication from the year 2000 to the present. Data relating to publication type, study design, setting, region, and themes of CMR content were collated into a Microsoft Excel data extraction form. Qualitative thematic analysis was conducted, and key findings and concepts were reported contextually. RESULTS: Of 374 identified documents screened, 15 were included in this scoping review and thematic analysis. The following characteristics of CMRs were identified: content, coverage, eligibility, frequency, process, and responsiveness. All published documents (n = 15, 100%) included a discussion of CMR content, and 14 sources (93%) addressed process elements of providing a CMR. Discussion of other themes varied in frequency across documents, ranging from 3 articles (20%) addressing organizational goals for CMR to 12 articles (80%) including elements of responsiveness. Within-theme variation was also observed for several CMR content areas. CMR process was the most heterogeneous theme with topics ranging from access to patient health records to pharmacist training. CONCLUSIONS: Assessment of telephonic CMR comprised a small but steadily increasing portion of the medication therapy management literature. Publications since 2015 have shown an increasing consensus of CMR content and purpose. Per the identified literature, there is an ongoing demand for higher-quality, more holistic CMRs, but there is no consensus on how to measure CMR quality. Future work should include engaging with CMR experts to understand variability in measures of CMR success.

Psychometric evaluation of a comprehensive medication management service experience instrument.

BACKGROUND: The Health-Systems Alliance for Integrated Medication Management (HAIMM) instrument was developed to estimate patient experience following pharmacist-delivered comprehensive medication management (CMM). OBJECTIVES: The objective of this paper was to assess the psychometric properties and factor structure of the HAIMM instrument. METHODS: Data were collected from 5 members of the HAIMM collaborative. A one-factor confirmatory factor analysis (CFA) model was used to assess instrument dimensionality. A partial-credit item response theory model was used to assess the psychometric properties of the ten-item HAIMM patient experience instrument, consisting of tests for rating scale functioning, person and item fit, and content validity. RESULTS: Among 516 respondents, there was a strong skew toward high satisfaction, including a strong ceiling effect. CFA results suggest a unidimensional construct. Item difficulty was spread across a low range and content redundancies were identified. The mean-square values for both infit and outfit all fell within the recommended range, whereas the z-standard fit was within the recommended range for most items. The 5-point Likert scale used in the HAIMM instrument did not distinguish between participants' level of experience following the pharmacist-delivered CMM service. CONCLUSION: The psychometric analysis showed the HAIMM survey tool does not cover all of the content that should be assessed to fully evaluate CMM experiences. In its current form, the HAIMM instrument should not be used to make comparisons about the quality of CMM services provided, although it may be useful to monitor patient satisfaction for quality improvement purposes. Further research is required to develop an improved instrument that contains expanded content coverage, response options, and aspects of CMM to be useful by health care providers, health systems, and other decision makers.

Key informant perspectives about telephonic comprehensive medication review services in the United States.

BACKGROUND: Comprehensive medication reviews (CMRs) are provided by providers such as pharmacists to eligible beneficiaries. Although CMRs have been shown to provide value to patients, little is known about the service uniformity, quality, and content of CMRs. OBJECTIVE: This study aimed to characterize the current state of CMR services from diverse stakeholder perspectives and describe variation in responses to content and delivery of telephonic CMR services. METHODS: Semistructured interviews were conducted with 10 key informants. The interview guide contained 6 key questions with additional probing questions. Transcripts were analyzed using the inductive saturation model and phenomenological approach to code emergent themes, which were iteratively refined until saturation was achieved. RESULTS: Key informants included CMR payers (n = 3), providers (n = 5), and standards-setting organizations (n = 2). Ten themes about CMRs emerged from qualitative analysis: (1) definition, (2) organizational goals, (3) content, (4) eligibility, (5) frequency, (6) acceptance and completion, (7) process and personnel, (8) quality assurance, (9) preparation, and (10) future directions. CMR content descriptions were consistent across perspectives. Key informants described scenarios appropriate for expanded CMR eligibility criteria, although none were consistently reported. Providers emphasized patient CMR acceptance rates whereas payers and standard-setting organizations emphasized completion rates. Completion rates and adherence to Centers for Medicare and Medicaid Services standards were characterized as core organizational goals (n = 8), whereas patient satisfaction was less frequently identified (n = 4). A lack of incentive for CMR providers to follow-up with patients was a barrier to expanded services. Overall, key informants were dissatisfied with the CMR completion rate measure and would prefer measures focused on service quality and outcomes. CONCLUSIONS: CMR services largely met perceived guidelines, with variation in value-added services. Key informants desired adoption of an actionable measure that is focused on quality rather than completion rate. To inform a quality measure, future research should analyze completed CMRs to determine the extent of variation in content and delivery.

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

BACKGROUND: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. METHODS: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m2 /d) in combination with clofarabine (40 mg/m2 ), etoposide (100 mg/m2 ), and dexamethasone (8 mg/m2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. RESULTS: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m2 /d, 6 were treated at the dose level of 40 mg/m2 /d, and 4 were treated at the dose level of 60 mg/m2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. CONCLUSIONS: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509). LAY SUMMARY: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

US COVID-19 Shutdown Demonstrates Importance of Background NO2 in Inferring NOx Emissions From Satellite NO2 Observations.

Satellite nitrogen dioxide (NO2) measurements are used extensively to infer nitrogen oxide emissions and their trends, but interpretation can be complicated by background contributions to the NO2 column sensed from space. We use the step decrease of US anthropogenic emissions from the COVID-19 shutdown to compare the responses of NO2 concentrations observed at surface network sites and from satellites (Ozone Monitoring Instrument [OMI], Tropospheric Ozone Monitoring Instrument [TROPOMI]). After correcting for differences in meteorology, surface NO2 measurements for 2020 show decreases of 20% in March-April and 10% in May-August compared to 2019. The satellites show much weaker responses in March-June and no decrease in July-August, consistent with a large background contribution to the NO2 column. Inspection of the long-term OMI trend over remote US regions shows a rising summertime NO2 background from 2010 to 2019 potentially attributable to wildfires.

Impacts of the COVID-19 economic slowdown on ozone pollution in the U.S.

In this work, we use observations and experimental emissions in a version of NOAA's National Air Quality Forecasting Capability to show that the COVID-19 economic slowdown led to disproportionate impacts on near-surface ozone concentrations across the contiguous U.S. (CONUS). The data-fusion methodology used here includes both U.S. EPA Air Quality System ground and the NASA Aura satellite Ozone Monitoring Instrument (OMI) NO2 observations to infer the representative emissions changes due to the COVID-19 economic slowdown in the U.S. Results show that there were widespread decreases in anthropogenic (e.g., NOx) emissions in the U.S. during March-June 2020, which led to widespread decreases in ozone concentrations in the rural regions that are NOx-limited, but also some localized increases near urban centers that are VOC-limited. Later in June-September, there were smaller decreases, and potentially some relative increases in NOx emissions for many areas of the U.S. (e.g., south-southeast) that led to more extensive increases in ozone concentrations that are partly in agreement with observations. The widespread NOx emissions changes also alters the O3 photochemical formation regimes, most notably the NOx emissions decreases in March-April, which can enhance (mitigate) the NOx-limited (VOC-limited) regimes in different regions of CONUS. The average of all AirNow hourly O3 changes for 2020-2019 range from about +1 to -4 ppb during March-September, and are associated with predominantly urban monitoring sites that demonstrate considerable spatiotemporal variability for the 2020 ozone changes compared to the previous five years individually (2015-2019). The simulated maximum values of the average O3 changes for March-September range from about +8 to -4 ppb (or +40 to -10%). Results of this work have implications for the use of widespread controls of anthropogenic emissions, particularly those from mobile sources, used to curb ozone pollution under the current meteorological and climate conditions in the U.S.

Analysing the predictive capacity and dose-response of wellness in load monitoring.

This study aimed to identify the predictive capacity of wellness questionnaires on measures of training load using machine learning methods. The distributions of, and dose-response between, wellness and other load measures were also examined, offering insights into response patterns. Data (n= 14,109) were collated from an athlete management systems platform (Catapult Sports, Melbourne, Australia) and were split across three sports (cricket, rugby league and football) with data analysis conducted in R (Version 3.4.3). Wellness (sleep quality, readiness to train, general muscular soreness, fatigue, stress, mood, recovery rating and motivation) as the dependent variable, and sRPE, sRPE-TL and markers of external load (total distance and m.min-1) as independent variables were included for analysis. Classification and regression tree models showed high cross-validated error rates across all sports (i.e., > 0.89) and low model accuracy (i.e., < 5% of variance explained by each model) with similar results demonstrated using random forest models. These results suggest wellness items have limited predictive capacity in relation to internal and external load measures. This result was consistent despite varying statistical approaches (regression, classification and random forest models) and transformation of wellness scores. These findings indicate practitioners should exercise caution when interpreting and applying wellness responses.

Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue.

BACKGROUND: Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. METHODS: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. RESULTS: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. CONCLUSIONS: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.

Blood pressure control according to clinical practice guidelines is associated with decreased mortality and cardiovascular events among liver transplant recipients.

Data for liver transplant recipients (LTRs) regarding the benefit of care concordant with clinical practice guidelines for management of blood pressure (BP) are sparse. This paper reports on clinician adherence with BP clinical practice guideline recommendations and whether BP control is associated with mortality and cardiovascular events (CVEs) among LTRs. We conducted a longitudinal cohort study of adult LTRs who survived to hospital discharge at a large tertiary care network between 2010 and 2016. The primary exposure was a BP of <140/<90 mm Hg within year 1 of LT. Among 602 LTRs (mean age 56.7 years, 64% men), 92% had hypertension and 38% had new onset hypertension. Less than 30% of LTRs achieved a BP of <140/<90 mm Hg over a mean of 43.2 months. In multivariable models, adjusted for key confounders, BP control post-LT compared with lack of control was associated with a significantly lower hazard of mortality (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.39, 0.87) and of CVEs (HR 0.65, 95% CI 0.43, 0.97). The association between BP control of <140/<90 mm Hg with improved survival and decreased CVEs in LTRs suggests that efforts to improve clinician adherence to BP clinical practice recommendations should be intensified.