Analysis of pressure-activated Piezo1 open and subconductance states at a single channel level.

Mechanically activated Piezo1 channels undergo transitions from closed to open-state in response to pressure and other mechanical stimuli. However, the molecular details of these mechanosensitive gating transitions are unknown. Here, we used cell-attached pressure-clamp recordings to acquire single channel data at steady-state conditions (where inactivation has settled down), at various pressures and voltages. Importantly, we identify and analyze subconductance states of the channel which were not reported before. Pressure-dependent activation of Piezo1 increases the occupancy of open and subconductance state at the expense of decreased occupancy of shut-states. No significant change in the mean open time of subconductance states was observed with increasing negative pipette pressure or with varying voltages (ranging from -40 to -100 mV). Using Markov-chain modeling, we identified a minimal four-states kinetic scheme, which recapitulates essential characteristics of the single channel data, including that of the subconductance level. This study advances our understanding of Piezo1-gating mechanism in response to discrete stimuli (such as pressure and voltage) and paves the path to develop cellular and tissue level models to predict Piezo1 function in various cell types.

Benefit-Risk Assessment of mRNA COVID-19 Vaccines in Children Aged 6 Months to 4 Years in the Omicron Era.

BACKGROUND: There is no risk and benefit assessment of COVID-19 vaccination for children younger than 5 years using a single health outcomes scale. The objective of this study is to compare the expected risk and benefits of the mRNA primary series of COVID-19 vaccines for children aged 6 months to 4 years in the United States using a single health outcome scale in the Omicron era. METHODS: The expected benefits and risks of the primary two-dose series of mRNA COVID-19 vaccines for children aged 6 months to 4 years were stratified by sex, the presence of underlying medical conditions, the presence of infection-induced immunity, and the type of mRNA vaccine (BNT162b2 or mRNA-1273). A scoping literature review was conducted to identify the indicators in the decision tree model. The benefit-risk ratio was the outcome of interest. RESULTS: The benefit-risk ratios ranged from 200.4 in BNT162b2 for males aged 6-11 months with underlying medical conditions and without infection-induced immunity to 3.2 in mRNA-1273 for females aged 1-4 years without underlying medical conditions and with infection-induced immunity. CONCLUSIONS: The expected benefit of receiving the primary series of mRNA vaccines outweighed the risk among children ages 6 months to 4 years regardless of sex, presence of underlying medical conditions, presence of infection-induced immunity, or type of mRNA vaccines. However, the continuous monitoring of the COVID-19 epidemiology as well as vaccine effectiveness and safety is important.

Preclinical assessment of drug-drug interaction of fb-PMT, a novel anti-cancer thyrointegrin αvß3 antagonist.

The objective of the current study was to identify potential drug-drug interactions (DDIs) with the drug candidate fb-PMT, a novel anticancer thyrointegrin αvß3 antagonist. This was accomplished by using several in vitro assays to study interactions of fb-PMT with both cytochrome P450 (CYP) enzymes and drug transporters, two common mechanisms leading to adverse drug effects. In vitro experiments showed that fb-PMT exhibited weak reversible inhibition of CYP2C19 and CYP3A4. In addition, fb-PMT did not show time-dependent inhibition with any of the seven CYP isoforms tested, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. Human liver microsomal incubations demonstrated that fb-PMT is stable. Potential transporter-mediated DDIs with fb-PMT were assessed with two ATP binding cassette (ABC) family transporters (P-glycoprotein and breast cancer resistance protein) using Caco2 cells and seven solute carrier family (SLC) transporters (organic cation transporter OCT2, organic anion transporters OAT1 and OAT3, organic anion transporter peptides OATP1B1 and OATP1B3, and the multidrug and toxic extrusion proteins MATE1 and MATE2-K using transfected HEK293 cells). Fb-PMT was not a substrate for any of the nine transporters tested in this study, nor did it inhibit the activity of seven of the transporters tested. However, fb-PMT inhibited the uptake of rosuvastatin by both OATP1B1 and OATP1B3 with half-maximal inhibitory concentrations greater than 3 and less than 10 µM. In summary, data suggest that the systemic administration of fb-PMT is unlikely to lead to DDIs through CYP enzymes or ABC and SLC transporters in humans.

Exercise-based cardiac rehabilitation for coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is the most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people living with CHD may need support to manage their symptoms and prognosis. Exercise-based cardiac rehabilitation (CR) aims to improve the health and outcomes of people with CHD. This is an update of a Cochrane Review previously published in 2016. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of exercise-based CR (exercise training alone or in combination with psychosocial or educational interventions) compared with 'no exercise' control, on mortality, morbidity and health-related quality of life (HRQoL) in people with CHD. SEARCH METHODS: We updated searches from the previous Cochrane Review, by searching CENTRAL, MEDLINE, Embase, and two other databases in September 2020. We also searched two clinical trials registers in June 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of exercise-based interventions with at least six months' follow-up, compared with 'no exercise' control. The study population comprised adult men and women who have had a myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), or have angina pectoris, or coronary artery disease. DATA COLLECTION AND ANALYSIS: We screened all identified references, extracted data and assessed risk of bias according to Cochrane methods. We stratified meta-analysis by duration of follow-up: short-term (6 to 12 months); medium-term (> 12 to 36 months); and long-term ( > 3 years), and used meta-regression to explore potential treatment effect modifiers. We used GRADE for primary outcomes at 6 to 12 months (the most common follow-up time point).  MAIN RESULTS: This review included 85 trials which randomised 23,430 people with CHD. This latest update identified 22 new trials (7795 participants). The population included predominantly post-MI and post-revascularisation patients, with a mean age ranging from 47 to 77 years. In the last decade, the median percentage of women with CHD has increased from 11% to 17%, but females still account for a similarly small percentage of participants recruited overall ( < 15%). Twenty-one of the included trials were performed in low- and middle-income countries (LMICs). Overall trial reporting was poor, although there was evidence of an improvement in quality over the last decade. The median longest follow-up time was 12 months (range 6 months to 19 years). At short-term follow-up (6 to 12 months), exercise-based CR likely results in a slight reduction in all-cause mortality (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.73 to 1.04; 25 trials; moderate certainty evidence), a large reduction in MI (RR 0.72, 95% CI 0.55 to 0.93; 22 trials; number needed to treat for an additional beneficial outcome (NNTB) 75, 95% CI 47 to 298; high certainty evidence), and a large reduction in all-cause hospitalisation (RR 0.58, 95% CI 0.43 to 0.77; 14 trials;  NNTB 12, 95% CI 9 to 21; moderate certainty evidence). Exercise-based CR likely results in little to no difference in risk of cardiovascular mortality (RR 0.88, 95% CI 0.68 to 1.14; 15 trials; moderate certainty evidence), CABG (RR 0.99, 95% CI 0.78 to 1.27; 20 trials; high certainty evidence), and PCI (RR 0.86, 95% CI 0.63 to 1.19; 13 trials; moderate certainty evidence) up to 12 months' follow-up. We are uncertain about the effects of exercise-based CR on cardiovascular hospitalisation, with a wide confidence interval including considerable benefit as well as harm (RR 0.80, 95% CI 0.41 to 1.59; low certainty evidence). There was evidence of substantial heterogeneity across trials for cardiovascular hospitalisations (I2 = 53%), and of small study bias for all-cause hospitalisation, but not for all other outcomes. At medium-term follow-up, although there may be little to no difference in all-cause mortality (RR 0.90, 95% CI 0.80 to 1.02; 15 trials), MI (RR 1.07, 95% CI 0.91 to 1.27; 12 trials), PCI (RR 0.96, 95% CI 0.69 to 1.35; 6 trials), CABG (RR 0.97, 95% CI 0.77 to 1.23; 9 trials), and all-cause hospitalisation (RR 0.92, 95% CI 0.82 to 1.03; 9 trials), a large reduction in cardiovascular mortality was found (RR 0.77, 95% CI 0.63 to 0.93; 5 trials). Evidence is uncertain for difference in risk of cardiovascular hospitalisation (RR 0.92, 95% CI 0.76 to 1.12; 3 trials). At long-term follow-up, although there may be little to no difference in all-cause mortality (RR 0.91, 95% CI 0.75 to 1.10), exercise-based CR may result in a large reduction in cardiovascular mortality (RR 0.58, 95% CI 0.43 to 0.78; 8 trials) and MI (RR 0.67, 95% CI 0.50 to 0.90; 10 trials). Evidence is uncertain for CABG (RR 0.66, 95% CI 0.34 to 1.27; 4 trials), and PCI (RR 0.76, 95% CI 0.48 to 1.20; 3 trials). Meta-regression showed benefits in outcomes were independent of CHD case mix, type of CR, exercise dose, follow-up length, publication year, CR setting, study location, sample size or risk of bias. There was evidence that exercise-based CR may slightly increase HRQoL across several subscales (SF-36 mental component, physical functioning, physical performance, general health, vitality, social functioning and mental health scores) up to 12 months' follow-up; however, these may not be clinically important differences. The eight trial-based economic evaluation studies showed exercise-based CR to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years (QALYs). AUTHORS' CONCLUSIONS: This updated Cochrane Review supports the conclusions of the previous version, that exercise-based CR provides important benefits to people with CHD, including reduced risk of MI, a likely small reduction in all-cause mortality, and a large reduction in all-cause hospitalisation, along with associated healthcare costs, and improved HRQoL up to 12 months' follow-up. Over longer-term follow-up, benefits may include reductions in cardiovascular mortality and MI. In the last decade, trials were more likely to include females, and be undertaken in LMICs, increasing the generalisability of findings. Well-designed, adequately-reported RCTs of CR in people with CHD more representative of usual clinical practice are still needed. Trials should explicitly report clinical outcomes, including mortality and hospital admissions, and include validated HRQoL outcome measures, especially over longer-term follow-up, and assess costs and cost-effectiveness.

The assessment of the impact of induction spatial effects on magnetic flux measurements of toner-printed documents to the detection of forged or altered documents.

Magnetic flux measurements of toners can aid in the rapid differentiation of toner-printed specimens in the context of investigations of forgeries or alterations of printed documents. However, some variables that may impact magnetic flux measurements, including hysteresis effects, are not currently well understood. This study assessed the impact of hysteresis and other induction spatial effects on magnetic flux measurements of toners analyzing five toner-printed samples produced from different devices. The samples were printed with controlled grids of square, rectangular, and elongated rectangular blocks with the same area. Thirty measurements were conducted on each sample, on each grid type. The measurements were repeated in planes of rotation 90°, 180°, and 270° counter to this original position. The values obtained for the square grids were evaluated using one-way ANOVA to assess the presence and impact of hysteresis effects. The values obtained for the rectangular grids were compared with those obtained for the square grids using a two-way ANOVA to determine potential induction current orientation effects. The results of both one-way and two-way ANOVA were significant with p < 0.05, indicating that both hysteresis effects and induction current spatial effects contribute significantly to variations in magnetic flux measurements. Results confirmed that sensor orientation is an important factor that must be accounted for in method protocols for the measurement of magnetic flux of toners. Controlling these variables is a step forward toward the development of a reliable screening method to be deployed in the context of investigations of document forgeries or alterations.

Crowdsourcing and open innovation in drug discovery: recent contributions and future directions.

The past decade has seen significant growth in the use of 'crowdsourcing' and open innovation approaches to engage 'citizen scientists' to perform novel scientific research. Here, we quantify and summarize the current state of adoption of open innovation by major pharmaceutical companies. We also highlight recent crowdsourcing and open innovation research contributions to the field of drug discovery, and interesting future directions.

Correction: Using financial incentives to promote physical activity in American Indian adolescents: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0198390.].

Tobacco Use Patterns among GED Recipients.

U.S. General Educational Development diploma (GED) recipients have the highest smoking prevalence of any education level. This paper describes demographic characteristics and tobacco use patterns and examines effect modification and confounding as potential explanations for higher crude prevalence of smoking. METHODS: The study population included adults aged 25 and older in the 2013 National Health Interview Survey. We estimated adjusted prevalence ratios and 95% CIs for smoking and quitting behaviors using weighted multivariable logistic regression. RESULTS: Among women with a GED, adjusted prevalence of ever use (58.7%) and smoking (32.4%) was 1.50 and 1.52 times the prevalence among high school dropouts (39.1%, 21.3%). Female GED recipients had a significantly higher prevalence of ever smoking compared with dropouts. We found no significant educational differences in smoking prevalence among men or quit behaviors for either sex. CONCLUSIONS: More research is needed to identify targeted interventions to prevent smoking in this disparate population.

Sustained Virologic Response and Costs Associated with Direct-Acting Antivirals for Chronic Hepatitis C Infection in Oklahoma Medicaid.

BACKGROUND: Outcomes involving newer direct-acting antiviral (DAA) hepatitis C virus (HCV) regimens have not been studied extensively among the Medicaid population. OBJECTIVE: To assess clinical (treatment failure) and economic outcomes for chronic HCV-infected Oklahoma Medicaid members following treatment with DAAs and to measure associations with patient, treatment, and clinical characteristics. METHODS: This cross-sectional study used Oklahoma Medicaid pharmacy and medical claims data for adult members who used a newer DAA agent and had reported a successful or failed sustained virological response rate 12 weeks after therapy completion (SVR12) from January 1, 2014, to June 30, 2016. Multivariable logistic and gamma regressions assessed predictors of SVR12 failure and costs controlling for member demographics (i.e., age, sex, race, rural residence); type of DAA and adherence; clinical characteristics (e.g., comorbid conditions, advanced liver disease); and the implementation of changes to a prior authorization program. RESULTS: Of 934 Medicaid members eligible for treatment with DAAs between January 1, 2014, and June 30, 2016, 906 received DAA treatment, 40.6% (368/906) had reported SVR12 outcomes, and 59.4% (n = 538) did not have a reported SVR recorded. Of those with reported SVR12 outcomes, patients were 53.1 ± 9.7 years of age, 51.1% were male, 8.4% had SVR12 failure, and each member had mean costs of $140,283 ± $52,779. Multivariable analyses indicated higher odds of SVR12 failure was independently associated with cirrhosis (OR [decompensated] = 6.69 and OR [compensated] = 3.52, P < 0.001), while males had higher odds of failure than females (OR = 3.34, P < 0.010). No significant difference in SVR12 failure was noted, according to DAA type or a medication adherence threshold of > 95%. Ledipasvir/sofosbuvir was independently associated with lower costs (exp[b] = 0.81; P < 0.001) compared with sofosbuvir, while higher costs were associated with decompensated cirrhosis (exp[b] = 1.22; P < 0.001) and treatment failure (exp[b] = 1.18, P < 0.010). In an analysis including members without reported SVR12 outcomes, decompensated and compensated cirrhosis had lower odds (P < 0.001) of no reported SVR12 from ambulatory clinic settings. CONCLUSIONS: Almost 60% of Medicaid members receiving DAA treatment did not have a final reported SVR12 outcome. Among those with viral load measurements, treatment success was high and both decompensated and compensated cirrhosis were independently associated with significantly higher odds of treatment failure. Addressing a loss to follow-up among HCV patients and curtailing the development of cirrhosis to improve treatment success may warrant interventions that improve access to care and remove barriers that impede treatment initiation and completion. DISCLOSURES: No outside funding supported this study. Pham, Keast, Holderread, Nesser, and Skrepnek disclose either employment by the Oklahoma Health Care Authority or contractual work for this employer. Pham discloses fellowship funding from Purdue Pharma unrelated to this study. Keast and Skrepnek disclose research grant funding from Gilead Sciences and Abbvie. Holderread also reports grant funding from Gilead Sciences and fees from PRIME Education. Thompson, Farmer, and Rathbun have nothing to disclose.

Using financial incentives to promote physical activity in American Indian adolescents: A randomized controlled trial.

American Indians (AI) have high prevalence of diabetes in youth and may benefit from increasing physical activity as a strategy to improve metabolic health. We tested whether financial incentives would elicit greater frequency and/or duration of exercise in AI youth at high risk for developing diabetes. Overweight/obese AI boys and girls, 11-20 years old, were instructed to exercise on 3 days/week for 48 weeks at a tribal wellness center. The program was divided into three, 16-week-long phases to test different financial incentive strategies. Within each phase participants were randomly assigned to one of two groups that received different payments for exercise. Phase 1 was designed to test whether the size of the incentive would affect exercise frequency. In Phase 1, the number of exercise sessions did not differ between the group receiving a modest fixed-value payment per exercise session and the group receiving enhanced incentives to exercise more frequently (26 ± 3 versus 28 ± 2 sessions, respectively, p = 0.568). In Phase 2, the provision of an enhanced financial incentive to increase exercise duration resulted longer sessions, as the incentivized and standard payment groups exercised 38 ± 2 versus 29 ± 1 minutes per session (p = 0.002), respectively. In Phase 3, the effect of reducing the incentives on maintenance of exercise behaviors was inconclusive due to high participant withdrawal. Aerobic fitness increased 10% during Phase 1 but was unchanged thereafter. Insulin sensitivity and body composition were unchanged during the study. In conclusion, enhanced financial incentives increased the duration of exercise sessions, but had minimal effects on exercise participation. These results indicate that financial incentives hold promise in motivating previously sedentary, overweight/obese adolescents to exercise longer, but motivating them to sustain an exercise program remains the major challenge. TRIAL REGISTRATION: ClinicalTrials.gov NCT01848353.

A systems framework for national assessment of climate risks to infrastructure.

Extreme weather causes substantial adverse socio-economic impacts by damaging and disrupting the infrastructure services that underpin modern society. Globally, $2.5tn a year is spent on infrastructure which is typically designed to last decades, over which period projected changes in the climate will modify infrastructure performance. A systems approach has been developed to assess risks across all infrastructure sectors to guide national policy making and adaptation investment. The method analyses diverse evidence of climate risks and adaptation actions, to assess the urgency and extent of adaptation required. Application to the UK shows that despite recent adaptation efforts, risks to infrastructure outweigh opportunities. Flooding is the greatest risk to all infrastructure sectors: even if the Paris Agreement to limit global warming to 2°C is achieved, the number of users reliant on electricity infrastructure at risk of flooding would double, while a 4°C rise could triple UK flood damage. Other risks are significant, for example 5% and 20% of river catchments would be unable to meet water demand with 2°C and 4°C global warming respectively. Increased interdependence between infrastructure systems, especially from energy and information and communication technology (ICT), are amplifying risks, but adaptation action is limited by lack of clear responsibilities. A programme to build national capability is urgently required to improve infrastructure risk assessment.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

Turning risk assessment and adaptation policy priorities into meaningful interventions and governance processes.

The UK is one of the first countries in the world to have set up a statutory system of national climate risk assessments followed by a national adaptation programme. Having this legal framework has been essential for enabling adaptation at the government level in a challenging political environment. However, using this framework to create an improvement in resilience to climate change across the country requires more than publishing a set of documents; it requires careful thought about what interventions work, how they can be enabled and what level of risk acceptability individuals, organizations and the country should be aiming for.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

A structural equation modeling approach to understanding pathways that connect socioeconomic status and smoking.

The inverse association between socioeconomic status and smoking is well established, yet the mechanisms that drive this relationship are unclear. We developed and tested four theoretical models of the pathways that link socioeconomic status to current smoking prevalence using a structural equation modeling (SEM) approach. Using data from the 2013 National Health Interview Survey, we selected four indicator variables (poverty ratio, personal earnings, educational attainment, and employment status) that we hypothesize underlie a latent variable, socioeconomic status. We measured direct, indirect, and total effects of socioeconomic status on smoking on four pathways through four latent variables representing social cohesion, financial strain, sleep disturbance, and psychological distress. Results of the model indicated that the probability of being a smoker decreased by 26% of a standard deviation for every one standard deviation increase in socioeconomic status. The direct effects of socioeconomic status on smoking accounted for the majority of the total effects, but the overall model also included significant indirect effects. Of the four mediators, sleep disturbance and psychological distress had the largest total effects on current smoking. We explored the use of structural equation modeling in epidemiology to quantify effects of socioeconomic status on smoking through four social and psychological factors to identify potential targets for interventions. A better understanding of the complex relationship between socioeconomic status and smoking is critical as we continue to reduce the burden of tobacco and eliminate health disparities related to smoking.

Mothers' self-reported grocery shopping behaviours with their 2- to 7-year-old children: relationship between feeding practices and mothers' willingness to purchase child-requested nutrient-poor, marketed foods, and fruits and vegetables.

OBJECTIVE: To assess relationships between mothers' feeding practices (food as a reward, food for emotion regulation, modelling of healthy eating) and mothers' willingness to purchase child-marketed foods and fruits/vegetables (F&V) requested by their children during grocery co-shopping. DESIGN: Cross-sectional. Mothers completed an online survey that included questions about feeding practices and willingness (i.e. intentions) to purchase child-requested foods during grocery co-shopping. Feeding practices scores were dichotomized at the median. Foods were grouped as nutrient-poor or nutrient-dense (F&V) based on national nutrition guidelines. Regression models compared mothers with above-the-median v. at-or-below-the-median feeding practices scores on their willingness to purchase child-requested food groupings, adjusting for demographic covariates. SETTING: Participants completed an online survey generated at a public university in the USA. SUBJECTS: Mothers (n 318) of 2- to 7-year-old children. RESULTS: Mothers who scored above-the-median on using food as a reward were more willing to purchase nutrient-poor foods (ß=0·60, P<0·0001), mothers who scored above-the-median on use of food for emotion regulation were more willing to purchase nutrient-poor foods (ß=0·29, P<0·0031) and mothers who scored above-the-median on modelling of healthy eating were more willing to purchase nutrient-dense foods (ß=0·22, P<0·001) than were mothers with at-or-below-the-median scores, adjusting for demographic covariates. CONCLUSIONS: Mothers who reported using food to control children's behaviour were more willing to purchase child-requested, nutrient-poor foods. Parental feeding practices may facilitate or limit children's foods requested in grocery stores. Parent-child food consumer behaviours should be investigated as a route that may contribute to children's eating patterns.