Development and validation of a claims-based algorithm to identify moderate exacerbations in patients with asthma treated in the US.

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting ß2-agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted. The objective was to refine current algorithms to identify moderate exacerbations in claims data and assess the refined algorithm's performance. Positive and negative predictive values (PPV and NPV) were assessed via chart review of 150 moderate exacerbations events and 50 patients without exacerbations. Sensitivity analyses assessed alternative algorithms and compared healthcare resource utilization (HRU) between algorithm-identified patients (claims group) and those confirmed by chart review (confirmed group) to have experienced a moderate exacerbation. RESULTS: Algorithm-identified moderate exacerbations were: visit of ≤1 day with an asthma exacerbation diagnosis OR visit of ≤1 day with selected asthma diagnoses AND ≥1 respiratory pharmacy claim, excluding systemic corticosteroids, within 14 days after the first claim. The algorithm's PPV was 42%; the NPV was 78%. HRU was similar for both groups. CONCLUSION: This algorithm identified potential moderate exacerbations from claims data; however, the modest PPV underscores its limitations in identifying moderate exacerbations, although performance was partially due to identification of previously unidentified severe exacerbations. Application of this algorithm in future claims-based studies may help quantify the economic burden of moderate and severe exacerbations in asthma when an algorithm identifying severe exacerbations is applied first.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: A retrospective US claims study.

INTRODUCTION: Despite adherence to inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. METHODS: Retrospective, longitudinal study analyzed data from Optum's de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. RESULTS: In the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p < 0.001]). CONCLUSIONS: This study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

Independent and Combined Effects of Prenatal Alcohol Exposure and Prenatal Stress on Fetal HPA Axis Development.

Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11ß-HSD1, 11ß-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group (p < 0.01). In multivariable modeling, PS was associated with pCRH gene expression (ß = 0.006, p < 0.01), while PAE was associated with 11ß-HSD2 protein expression (ß = 0.56, p < 0.01). A significant alcohol-by-stress interaction was observed with respect to 11ß-HSD2 protein expression (p < 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.

Frequency of Cardiac Valvulopathies in Patients With Marfan Syndrome: A Systematic Review and Meta-Analysis.

Marfan syndrome (MFS) is a progressive connective tissue disease with a broad range of clinical manifestations. We sought to establish the spectrum of structural valvular abnormalities as cardiovascular involvement has been identified as the most life-threatening aspect of the syndrome. This was a systematic review with a meta-analysis of studies indexed in Medline from the inception of the database to November 7, 2022. Using the random-effects model, separate Forest and Galbraith plots were generated for each valvular abnormality assessed. Heterogeneity was assessed using the I2 statistics whilst funnel plots and Egger's test were used to assess for publication bias. From a total of 35 studies, a random-effects meta-analysis approximated the pooled summary estimates for the prevalence of cardiac valve abnormalities as mitral valve prolapse 65% (95% CI: 57%-73%); mitral valve regurgitation 40% (95% CI: 29%-51%); aortic valve regurgitation 40% (95% CI: 28%-53%); tricuspid valve prolapse 35% (95% CI: 15%-55%); and tricuspid valve regurgitation 43% (95% CI: 8%-78%). Only one study reported on the involvement of the pulmonary valve (pulmonary valve prolapse was estimated at 5.3% (95% CI: 1.9%-11.1%) in a cohort of 114 patients with MFS). We believe this study provides a description of the structural valvular disease spectrum and may help inform providers and patients in understanding the clinical history of MFS in the current treatment era with its increased life expectancy.

Potentially modifiable risk and protective factors affecting mental and emotional wellness in pregnancy.

Introduction: Impaired mental and emotional wellness often co-occurs with prenatal substance use, and both affect infant socio-emotional, cognitive, language, motor, and adaptive behavioral outcomes. Guided by the modified biopsychosocial framework, this study examined the role of common substance exposures during pregnancy (i.e., alcohol and cannabis), socio-cultural factors (social support during pregnancy, adverse childhood experiences), and reproductive health factors on maternal mental health (MMH). Methods: Data were obtained from a prospective cohort study-Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-2), and included 202 pregnant persons. Alcohol and cannabis exposures were assessed through repeated prospective interviews and a comprehensive battery of drug and ethanol biomarkers. MMH outcomes were evaluated during the third trimester through the Perceived Stress Scale, Edinburgh Depression Scale, Generalized Anxiety Disorders-7, and Post-traumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders. Univariate and multivariable linear regression models evaluated significant predictors of MMH. Results: Results of multivariable analysis indicate that both maternal adverse childhood experiences and alcohol exposure, even at low-to-moderate levels, during pregnancy were associated with poorer scores for most MMH measures, while higher level of social support and Spanish as the primary language at home (as a proxy of enculturation) had protective effects (all p's < 0.05). Conclusion: These findings highlight the importance of assessing substance use, including periconceptional alcohol exposure, and mental health in pregnant persons as closely related risk factors which cannot be addressed in isolation. Our findings also emphasize a strong protective effect of socio-cultural factors on maternal mental and emotional wellbeing-a strong precursor to maternal-infant bonding and infant neurodevelopment.

Dose-response effect of prenatal alcohol exposure on perinatal outcomes.

BACKGROUND: A better understanding of the effects of lower levels of prenatal alcohol exposure (PAE), as a common exposure, is needed. The goal of this study was to examine the effects of mild-moderate PAE and episodic binge drinking on perinatal outcomes. METHODS: The data were obtained from three prospective cohorts with a combined sample of 281 participants: 125 with PAE and 156 without PAE. Alcohol-related measures included the Alcohol Use Disorders Identification Test, timeline follow-back questionnaires (covering the periconceptional period, mid-gestation, and late gestation), and biomarkers. Absolute alcohol per day (AAD) and per drinking day (AADD), number of binge episodes, and maximum number of drinks in a 24-h period were estimated. Perinatal outcomes included gestational age and anthropometric measures. Data were analyzed using correlation and multivariable regression analysis. RESULTS: Among women with PAE, average alcohol consumption across the periconceptional period and pregnancy was 0.37 oz ± 0.74 AA/day (~5 drinks/week). After adjusting for tobacco co-exposure and sociodemographic characteristics, significant associations between all alcohol measures and gestational age at delivery were observed, including cumulative measures of AAD (ß = -0.58; 95% CI: -0.98; -0.17) and AADD (ß = -0.58; 95% CI: -0.90; -0.26) during pregnancy and the periconceptional period. A significant association between the maximum number of drinks in a 24-h period and birth length percentile (ß = -0.70; 95% CI: -1.36; -0.04) was observed in the final model. PAE was associated with lower birth weight percentile in univariate analyses only. CONCLUSIONS: Results of this study demonstrate a negative association between mild-moderate PAE and episodic binge drinking with gestational age at delivery and birth length percentile after controlling for other factors. Robust negative effects of PAE, including in the periconceptional period before pregnancy recognition, on duration of gestation highlight the need for primary prevention efforts aimed at PAE in persons of reproductive age.

Impact of low-level prenatal alcohol exposure and maternal stress on autonomic regulation.

BACKGROUND: Prenatal alcohol exposure (PAE) impacts the neurodevelopment of the fetus, including the infant's ability to self-regulate. Heart rate variability (HRV), that is, the beat-to-beat variability in heart rate, is a non-invasive measurement that can indicate autonomic nervous system (ANS) function/dysfunction. METHODS: The study consisted of a subset of our ENRICH-2 cohort: 80 participants (32 PAE and 48 Controls) who had completed three visits during pregnancy. The participants completed a comprehensive assessment of PAE and other substances throughout pregnancy and assessments for stress, anxiety, and depression in the third trimester. At 24 h of age, infant HRV was assessed in the hospital during the clinically indicated heel lance; 3- to 5-min HRV epochs were obtained during baseline, heel lancing, and recovery episodes. RESULTS: Parameters of HRV differed in infants with PAE compared to Controls during the recovery phase of the heel lance (respiratory sinus arrhythmia (RSA) and high-frequency (HF), p < 0.05). Increased maternal stress was also strongly associated with abnormalities in RSA, HF, and low-frequency / high-frequency (LF/HF, p's < 0.05). CONCLUSIONS: Alterations in ANS regulation associated with PAE and maternal stress may reflect abnormal development of the hypothalamic-pituitary-adrenal axis and have long term implications for infant responsiveness and self-regulation. IMPACT: Previous studies have focused on effects of moderate to heavy prenatal alcohol exposure (PAE) on autonomic dysregulation, but little is known about the effects of lower levels of PAE on infant self-regulation and heart rate variability (HRV). Prenatal stress is another risk factor for autonomic dysregulation. Mild PAE impacts infant self-regulation, which can be assessed using HRV. However, the effect of prenatal stress is stronger than that of mild PAE or other mental health variables on autonomic dysregulation.

The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India.

BACKGROUND: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. OBJECTIVE: The aim was to identify genetic risk factors for PD in a South Asian population. METHODS: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO. RESULTS: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. CONCLUSIONS: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Non-calcified plaque in asymptomatic patients with zero coronary artery calcium score: A systematic review and meta-analysis.

BACKGROUND: There is growing interest in understanding the coronary atherosclerotic burden in asymptomatic patients with zero coronary artery calcium score (CACS). In this population, we aimed to investigate the prevalence and severity of non-calcified coronary plaques (NCP) as detected by coronary CT angiography (CCTA), and to analyze the associated clinical predictors. METHODS: This was a systematic review with meta-analysis of studies indexed in PubMed/Medline and Web of Science from inception of the database to March 31st, 2023. Using the random-effects model, separate Forest and Galbraith plots were generated for each effect size assessed. Heterogeneity was assessed using the I2 statistics whilst Funnel plots and Egger's test were used to assess for publication bias. RESULTS: From a total of 14 studies comprising 37808 patients, we approximated the pooled summary estimates for the overall prevalence of NCP to be 10% (95%CI: 6%-13%). Similarly, the pooled prevalence of obstructive NCP was estimated at 1.1% (95%CI: 0.7%-1.5%) from a total of 10 studies involving 21531 patients. Hypertension [OR: 1.46 (95%CI:1.31-1.62)] and diabetes mellitus [OR: 1.69 (95%CI: 1.41-1.97)] were significantly associated with developing any NCP, with male gender being the strongest predictor [OR: 3.22 (95%CI: 2.17-4.27)]. CONCLUSION: There is a low burden of NCP among asymptomatic subjects with zero CACS. In a subset of this population who have clinical predictors of NCP, the addition of CCTA has a potential to provide a better insight about occult coronary atherosclerosis, however, a risk-benefit approach must be factored in prior to CCTA use given the low prevalence of NCP.

Modified Recurrence Quantification Analysis for Objective Assessment of Cerebellar Ataxia.

Cerebellar Ataxia (CA) is a neurological condition that affects coordination, balance and speech. Assessing its severity is important for developing effective treatment and rehabilitation plans. Traditional assessment methods involve a clinician instructing a person with ataxia to perform tests and assigning a severity score based on their performance. However, this approach is subjective as it relies on the clinician's experience, and can vary between clinicians. To address this subjectivity, some researchers have developed automated assessment methods using signal processing and data-driven approaches, such as supervised machine learning. These methods still rely on subjective ground truth and can perform poorly in real-world scenarios. This research proposed an alternative approach that uses signal processing to modify recurrence plots and compare the severity of ataxia in a person with CA to a control cohort. The highest correlation score obtained was 0.782 on the back sensor with the feet-apart and eyes-open test. The contributions of the research include modifying the recurrence plot as a measurement tool for assessing CA severity, proposing a new approach to assess severity by comparing kinematic data between people with CA and a control reference group, and identifying the best subtest and sensor position for practical use in CA assessments.

National and Local Direct Medical Cost Burden of COPD in the United States From 2016 to 2019 and Projections Through 2029.

BACKGROUND: Despite the significant burden posed by COPD to health care systems, there is a lack of up-to-date information quantifying the general COPD burden, costs, and long-term projections to various stakeholders in the United States. RESEARCH QUESTION: What are the updated state-specific and nationwide estimates of the COPD disease burden and direct costs in 2019, along with projections of COPD-attributable medical costs through 2029? STUDY DESIGN AND METHODS: A cross-sectional, retrospective study design using the 2016 to 2019 Medical Expenditure Panel Survey, 2019 American Community Survey, and 2019 Behavioral Risk Factor Surveillance System data was applied to generate COPD-attributable expenditure estimates. Cost projections for the years 2020 to 2029 were based on 2017 national population projections reported by the US Census Bureau, and all costs were adjusted to 2019 US dollars. RESULTS: In total, 4,135 people living with COPD were included; a higher proportion had other concurrent conditions such as cardiovascular-related conditions compared with people without COPD (n = 86,021). Overall, in 2019, COPD-attributable medical costs after adjusting for demographic characteristics and 19 concurrent conditions (including COPD-related and non-COPD-related conditions) were estimated at $31.3 billion, with state-specific cost estimates reporting wide variation, from $44.8 million in Alaska to $3.1 billion in Florida. Nationwide COPD-attributable medical costs borne by payer type were as follows: private insurance, $11.4 billion; Medicare, $10.8 billion; and Medicaid, $3.0 billion. Projections of national medical costs attributable to COPD are reported to increase to $60.5 billion in 2029. INTERPRETATION: Understanding the current disease and economic burden of COPD in the United States, along with the projected costs attributable to COPD in the next decade, will highlight unmet needs and gaps in care that help inform health care decision-makers in planning future actions to alleviate this disease burden.

The effect of the COVID-19 pandemic on substance use patterns and physiological dysregulation in pregnant and postpartum women.

BACKGROUND: The SARS-CoV-2/COVID-19 pandemic has been associated with increased stress levels and higher alcohol use, including in pregnant and postpartum women. In the general population, alcohol use is associated with dysregulation in the autonomic nervous system (ANS), which is indexed by heart rate variability (HRV). The objectives of this study were to: (1) characterize changes in substance use during the SARS-CoV-2/COVID-19 pandemic via a baseline self-report survey followed by mobile ecological momentary assessment (mEMA) of substance use; and (2) examine the associations between momentary substance use and ambulatory HRV measures in pregnant and postpartum women. METHODS: Pregnant and postpartum women were identified from the ENRICH-2 prospective cohort study. Participants were administered a baseline structured phone interview that included the Coronavirus Perinatal Experiences (COPE) survey and ascertained the prevalence of substance use. Over a 14-day period, momentary substance use was assessed three times daily, and HRV measurements were captured via wearable electronics. Associations between momentary substance use and HRV measures (root mean square of successive differences [RMSSD] and low frequency/high frequency [LF/HF] ratio) were examined using a mixed effects model that included within-subject (WS) and between-subject (BS) effects and adjusted for pregnancy status and participant age. RESULTS: The sample included 49 pregnant and 22 postpartum women. From a combination of a baseline and 14-day mEMA surveys, 21.2% reported alcohol use, 16.9% reported marijuana use, and 8.5% reported nicotine use. WS effects for momentary alcohol use were associated with the RMSSD (ß = -0.14; p = 0.005) and LF/HF ratio (ß = 0.14; p = 0.01) when controlling for pregnancy status and maternal age. No significant associations were observed between HRV measures and instances of marijuana or nicotine use. CONCLUSIONS: These findings highlight the negative effect of the SARS-CoV-2/COVID-19 pandemic on the psychological health of pregnant and postpartum women associated with substance use, and in turn, ANS dysregulation, which potentially puts some women at risk of developing a substance use disorder.

A systematic review and meta-analysis of the prevalence, incidence, and predictors of atrial fibrillation in cardiac sarcoidosis.

BACKGROUND: The occurrence of atrial arrhythmias, in particular, atrial fibrillation (AF) in patients with cardiac sarcoidosis (CS) are of growing interest in the field of infiltrative cardiomyopathies. Via a systematic review with meta-analysis, we sought to synthesize data on the prevalence, incidence, and predictors of atrial arrhythmias as well as outcomes in patients with CS. METHODS: PubMed/Medline, Web of Science, and Scopus were systematically queried from inception until April 26th, 2023. Using the random-effects model, separate plots were generated for each effect size assessed. RESULTS: From a total of 8 studies comprising 978 patients with CS, the pooled summary estimates for the prevalence of AF was 23% (95% CI: 13%-34%). Paroxysmal AF was the most common subtype of AF (83%; 95% CI: 77%-90%), followed by persistent AF (17%; 95% CI: 10%-23%). In 9 studies involving 545 patients with CS, the pooled incidence of AF was estimated at 5%, 13.1%, and 8.9% at <2 years, 2-4 years, and > 4 years of follow-up respectively, with an overall cumulative incidence of 10.6% (95% CI: 4.9%-17.8%) over a 6-year follow-up period. Increased left atrial size and atrial 18F-fluorodeoxyglucose uptake were identified as strong independent predictors for the development of atrial arrhythmias on qualitative synthesis. CONCLUSION: The burden of AF and related arrhythmias in CS patients is considerable. This necessitates close follow-up and predictive risk-stratification tools to guide the initiation of appropriate strategies, including therapeutic interventions for prevention of AF-related embolic phenomenon, especially in those with known clinical predictors.

Impulsivity and Alcohol Use during Pregnancy and Postpartum: Insights from Novel Methodological Approaches within the Context of the COVID-19 Pandemic.

Impaired emotion regulation and impulsivity have been linked to substance use. This study evaluated the association between emotion regulation difficulties-specifically impulsivity-and substance use within the context of the COVID-19 pandemic among pregnant (n = 49) and postpartum (n = 20) women. Participants from a prospective cohort ENRICH-2 completed a baseline phone survey of COVID-19-related experiences and impulsivity followed by a 14-day (3x/day) mobile ecological momentary assessment (mEMA) of impulsivity and substance use. Between-subject (BS) and within-subject (WS) associations for baseline impulsivity and momentary impulsivity with respect to substance use were examined using mixed effects models. At the BS level, momentary impulsivity scores that were higher than the overall group average were positively associated with subsequent momentary reports of marijuana use (ß = 1.25; p = 0.04) when controlling for pregnancy status and COVID-19-related stress. At the WS level, momentary impulsivity scores that were higher than an individual's average score were positively associated with subsequent reports of momentary alcohol use (ß = 0.08; p = 0.04). This research supports the idea that impulsivity varies based on individual situations, such as stress associated with the COVID-19 pandemic, and may be an important correlate of substance use in pregnant and postpartum women. Future research might consider investigation of additional factors, which may serve to moderate or mediate the relationship between impulsivity and substance use.

Barriers to Adoption of Digital Therapeutics (DTx) into Audiology Clinical Practice: Acknowledging the Challenges, Adapting to the Future.

The continuous advancements in technologies supporting digital health and digital therapeutics (DTx) bring new possibilities to the field of audiology. This study considers a new DTx for tinnitus called Tinnibot and the willingness of a group of Australian university audiology students to consider this new DTx in their future careers as practicing audiologists. A single-group case-series design (pretest/posttest) was used to examine the opinions of 10 university audiology students before and after participating in a 2-hour information workshop on the topics of tinnitus, DTx, cognitive behavioral therapy, and a new digital therapy tool for tinnitus called Tinnibot. Student knowledge levels of the main topic areas increased from poor (before the workshop) to moderate to high after the workshop, with 40% of participants reporting they would very likely use digital therapies for future patients. A common barrier to improving this rating was the need for direct hands-on training on the DTx before the students would be confident to recommend the DTx to patients. Incorporating direct training on DTx into university audiology programs would allow greater uptake of DTx by students as they begin their careers as practicing audiologists.

Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.

Despite the key roles of perilipin-2 (PLIN2) in governing lipid droplet (LD) metabolism, the mechanisms that regulate PLIN2 levels remain incompletely understood. Here, we leverage a set of genome-edited human PLIN2 reporter cell lines in a series of CRISPR-Cas9 loss-of-function screens, identifying genetic modifiers that influence PLIN2 expression and post-translational stability under different metabolic conditions and in different cell types. These regulators include canonical genes that control lipid metabolism as well as genes involved in ubiquitination, transcription, and mitochondrial function. We further demonstrate a role for the E3 ligase MARCH6 in regulating triacylglycerol biosynthesis, thereby influencing LD abundance and PLIN2 stability. Finally, our CRISPR screens and several published screens provide the foundation for CRISPRlipid (http://crisprlipid.org), an online data commons for lipid-related functional genomics data. Our study identifies mechanisms of PLIN2 and LD regulation and provides an extensive resource for the exploration of LD biology and lipid metabolism.

Interrater Reliability of the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Functional Independence Measure Motor Domain in Individuals With Hereditary Cerebellar Ataxia.

OBJECTIVE: To determine the interrater reliability of the Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), and motor domain of the FIM (m-FIM) administered by physiotherapists in individuals with a hereditary cerebellar ataxia (HCA). DESIGN: Participants were assessed by 1 of 4 physiotherapists. Assessments were video-recorded and the remaining 3 physiotherapists scored the scales for each participant. Raters were blinded to each other's scores. SETTING: Assessments were administered at 3 clinical locations in separate states in Australia. PARTICIPANTS: Twenty-one individuals (mean age=47.63 years; SD=18.42; 13 male and 8 female) living in the community with an HCA were recruited (N=21). MAIN OUTCOME MEASURES: Total and single-item scores of the SARA, BBS, and m-FIM were examined. The m-FIM was conducted by interview. RESULTS: Intraclass coefficients (2,1) for the total scores of the m-FIM (0.92; 95% confidence interval [CI], 0.85-0.96), SARA (0.92; 95% CI, 0.86-0.96), and BBS (0.99; 95% CI, 0.98-0.99) indicated excellent interrater reliability. However, there was inconsistent agreement with the individual items, with SARA item 5 (right side) and item 7 (both sides) demonstrating poor interrater reliability and items 1 and 2 demonstrating excellent reliability. CONCLUSIONS: The m-FIM (by interview), SARA, and BBS have excellent interrater reliability for use when assessing individuals with an HCA. Physiotherapists could be considered for administration of the SARA in clinical trials. However, further work is required to improve the agreement of the single-item scores and to examine the other psychometric properties of these scales.

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis.

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of phospholipid hydroperoxides. Inducing ferroptosis is a promising approach to treat therapy-resistant cancer. Ferroptosis suppressor protein 1 (FSP1) promotes ferroptosis resistance in cancer by generating the antioxidant form of coenzyme Q10 (CoQ). Despite the important role of FSP1, few molecular tools exist that target the CoQ-FSP1 pathway. Through a series of chemical screens, we identify several structurally diverse FSP1 inhibitors. The most potent of these compounds, ferroptosis sensitizer 1 (FSEN1), is an uncompetitive inhibitor that acts selectively through on-target inhibition of FSP1 to sensitize cancer cells to ferroptosis. Furthermore, a synthetic lethality screen reveals that FSEN1 synergizes with endoperoxide-containing ferroptosis inducers, including dihydroartemisinin, to trigger ferroptosis. These results provide new tools that catalyze the exploration of FSP1 as a therapeutic target and highlight the value of combinatorial therapeutic regimes targeting FSP1 and additional ferroptosis defense pathways.

Effects of medications for opioid use disorder (MOUD) on fetal brain and cranial measurements.

BACKGROUND: The use and misuse of opioids, as well as opioid use disorder (OUD) have increased remarkably among reproductive-aged and pregnant women. As many as 25% of pregnant women who report non-medical opioid use in the past month also report concurrent alcohol use. While teratogenic effects of alcohol are well established, there are limited studies evaluating fetal intracranial effects associated with medications for OUD (MOUD) and concurrent use of MOUD and alcohol during pregnancy. The objective of this study was to determine the effect of MOUD, with and without concomitant alcohol use, on fetal intracranial measurements. The type of maternal MOUD therapy (methadone vs. buprenorphine) was also examined. METHODS: This study was a secondary analysis of a prospective cohort study among participants (n = 196) assigned into three groups (MOUD [n = 94], MOUD+Alcohol [n = 47], and unexposed controls [n = 55]). Co-exposure with either methamphetamines or cocaine were exclusionary criteria; other co-exposures were carefully characterized with prospective repeated self-report measures and biomarkers. Fetal ultrasound measurements at 18-22 weeks (2nd trimester) and 28-32 weeks (early 3rd trimester) were compared among study groups. In addition to standard morphometrics, we performed specialized intracranial measurements of caval-calvarial distance (CCD), frontal lobe width (FLW), frontal lobe length (FLL), and fronto-thalamic distance (FTD). RESULTS: Brain and cranial measurements between MOUD, with or without alcohol co-exposure, and unexposed controls were generally not significantly different in multivariable analyses. Subjects in the MOUD groups had earlier gestational age at delivery and lower birth weight and birth weight percentile compared to unexposed controls with differences driven primarily by the methadone subgroup. Significant differences in standard and specialized intracranial indices at both second and third trimester as well as differences in the change of HC percentile over time were observed in the methadone subgroup compared to controls, while no differences between buprenorphine subgroup and controls were observed for any measures. CONCLUSION: Patients receiving methadone therapy might require closer monitoring during pregnancy; however, detailed imaging of the fetal brain other than the standard measurements might not be warranted.

Protocol for performing pooled CRISPR-Cas9 loss-of-function screens.

Phenotypic screens involving pooled CRISPR-Cas9 libraries offer a powerful, rapid yet affordable approach to evaluate gene functions on a global scale. Here, we present a protocol for performing pooled CRISPR-Cas9 loss-of-function screens to identify genetic modifiers using either fluorescence-based or cell death phenotypic readouts. We describe steps for designing and amplifying the library and generating and screening cells. We then detail deep sequencing and statistical analysis using cas9 High Throughput maximum Likelihood Estimator. For complete details on the use and execution of this protocol, please refer to Bersuker et al. (2019),1 Li et al. (2022),2 and Roberts et al. (2022).3.