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Socioemotional selectivity theory (Carstensen, 1995) posits a 'positivity effect' in older adults, describing an increasing tendency to attend to, process, interpret, and remember events and others in life in a positive fashion as one ages. Drawing on personal construct theory, Viney (1993) observes increasing integration of constructions of self with others across the lifespan. The current study extends assessment of the positivity effect, integrating it with personal construct theory, by use of Repertory Grid (RepGrid) analysis. Consistent with the positivity effect, older adults (ages 54-86) described others more positively on RepGrid measures in comparison to younger adults (ages 18-25). Older adults also described the self as more similar to others and tended to describe the self more positively. The age groups did not differ in measures of psychological distress or well being with the exception of older adults describing more autonomy. [ABSTRACT FROM AUTHOR]

We investigated associations between neighborhood walkability and physical activity using twins (5477 monozygotic and same-sex dizygotic pairs) as "quasi-experimental" controls of genetic and shared environment (familial) factors that would otherwise confound exposure-outcome associations. Walkability comprised intersection density, population density, and destination accessibility. Outcomes included self-reported weekly minutes of neighborhood walking and moderate-to-vigorous physical activity (MVPA) and days per week using transit services (eg, bus, commuter rail). There was a positive association between walkability and walking, which remained significant after controlling for familial and demographic factors: a 1% increase in walkability was associated with a 0.42% increase in neighborhood walking. There was a positive association between walkability and MVPA, which was not significant after considering familial and demographic factors. In twins with at least 1 day of transit use, a 1-unit increase in log (walkability) was associated with a 6.7% increase in transit use days; this was not significant after considering familial and demographic factors. However, higher walkability reduced the probability of no transit use by 32%, considering familial and demographic factors. Using a twin design to improve causal inference, walkability was associated with walking, whereas walkability and both MVPA and absolute transit use were confounded by familial and demographic factors. This article is part of a Special Collection on Environmental Epidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It is unclear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with Mycobacterium tuberculosis or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk of progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, the characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (replacement, reduction, and refinement) approach we reanalyzed heterogeneous publicly available transcriptional data sets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3, and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes and have been carefully evaluated across several clinical cohorts. These data suggest that in certain experimental designs and in several tissue types, human COR signatures correlate with disease progression as measured by the bacterial burden in the preclinical TB model pipeline. We observed the best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations., Importance: Understanding the strengths or limitations of back-translating human-derived correlate of risk (COR) RNA signatures into the preclinical pipeline may help streamline down-selection of therapeutic vaccine and drug candidates and better align preclinical models with proposed clinical trial efficacy endpoints.

Background: To improve the healthfulness of foods offered while accelerating the use of environmental sustainability practices, it is important to engage hospital food service operators in the adoption of such practices. The purpose of this study was to explore barriers, facilitators and best practices for implementing environmental sustainability standards in food service among veterans affairs (VA) hospitals in the United States., Methods: We conducted an online survey with 14 VA hospital food service directors and then 11 qualitative interviews. The survey assessed motivations for initiating sustainability standards and included a self-rating of implementation for each of five standards: increasing plant-forward dishes, procuring and serving sustainable foods that meet organic/fair trade and other certifications, procuring and serving locally produced foods, reducing food waste and reducing energy consumption. Interviews were transcribed verbatim. Qualitative analysis, including coding of themes and subthemes, was conducted by two coders to determine barriers, facilitators and best practices for each of these five standards. Quantitative methods (counts and frequencies) were used to analyse the survey data., Results: Participants had an average of 5 years of experience implementing sustainability standards. The top three motivators cited were reducing food waste, serving healthier foods and increasing efficiency or cost savings. Barriers revolved around patient preferences, contractual difficulties and costs related to reducing waste. Facilitators included taste testing new recipes that include more sustainable food options and easy access to sustainable products from the prime vendor. Best practices included making familiar dishes plant-forward and plate waste studies to prevent overproduction., Conclusions: Although there were many barriers to implementation, food service directors had solutions for overcoming challenges and implementing food service sustainability standards, which can be tested in future sustainability initiatives., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

At the beginning of the COVID-19 pandemic those with underlying chronic lung conditions, including tuberculosis (TB), were hypothesized to be at higher risk of severe COVID-19 disease. However, there is inconclusive clinical and preclinical data to confirm the specific risk SARS-CoV-2 poses for the millions of individuals infected with Mycobacterium tuberculosis (M.tb). We and others have found that compared to singly infected mice, mice co-infected with M.tb and SARS-CoV-2 leads to reduced SARS-CoV-2 severity compared to mice infected with SARS-CoV-2 alone. Consequently, there is a large interest in identifying the molecular mechanisms responsible for the reduced SARS-CoV-2 infection severity observed in M.tb and SARS-CoV-2 co-infection. To address this, we conducted a comprehensive characterization of a co-infection model and performed mechanistic in vitro modeling to dynamically assess how the innate immune response induced by M.tb restricts viral replication. Our study has successfully identified several cytokines that induce the upregulation of anti-viral genes in lung epithelial cells, thereby providing protection prior to challenge with SARS-CoV-2. In conclusion, our study offers a comprehensive understanding of the key pathways induced by an existing bacterial infection that effectively restricts SARS-CoV-2 activity and identifies candidate therapeutic targets for SARS-CoV-2 infection., Competing Interests: Author BB was employed by HDT Bio Corp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Williams, Ferede, Abdelaal, Berube, Podell, Larsen, Baldwin and Coler.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2 R206H . In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2 R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2 R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2 R206H with high affinity, inhibiting signaling from ALK2 R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2 R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2 R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2 R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Enantioselective C-H amination at a benzylic methylene is a vital disconnection towards chiral benzylamines. Here we disclose that butyric and valeric acid-derived tertiary amides can undergo highly enantioselective benzylic amination using an achiral anionic Rh complex that is ion-paired with a Cinchona alkaloid-derived chiral cation. A broad scope of compounds can be aminated encompassing numerous arene substitutions, amides, and two different chain lengths. Excellent tolerance of ortho substituents was observed, which has not been achieved before in asymmetric intermolecular C-H amination with Rh. We speculate that the tertiary amide group of the substrate engages in hydrogen bonding interactions directly with the chiral cation, enabling a high level of organisation at the transition state for C-H amination. This is in contrast with our previous work where a substrate bearing a hydrogen bond donor was required. Control experiments led to the discovery that methyl ethers also function as proficient directing groups under the optimised conditions, potentially also acting as hydrogen bond acceptors. This finding has the promise to dramatically expand the applicability of our ion-paired chiral catalysts., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The goal of this study is to examine how disaster experience influences local government views on citizen participation in addressing issues of sustainability, such as climate change. This study considers concepts such as wicked problems, the social order, the environment, economic development, and citizen participation where sustainability can be considered a solution to help manage and solve the challenges of disaster, like climate change. The data are taken from a 2015 International City/County Management Association national survey that examines the link between disaster and sustainability. The results show that more than half of the respondents do not view public participation as having much of an impact on sustainability; however, we can expect public participation to increasingly impact sustainability efforts as communities experience more disaster. This suggests that emergency management needs to understand public pressures regarding wicked problems, such as climate change, to collectively address the global influence of environmental, economic, and social issues that have local effects on their communities.

Background: Increasing evidence suggests an association between third-generation antipsychotics (TGAs) and impulse control disorders (ICDs). This is thought to be due to their partial agonism of dopamine receptors. However, neither the relative nor absolute risks of ICDs in those prescribed TGAs are well established. To inform clinical practice, this systematic review and meta-analysis summarizes and quantifies the current evidence for an association., Methods: An electronic search of Medline, PsychINFO, EMBASE, and the Cochrane Clinical Trials Database was undertaken from database inception to November 2022. Three reviewers screened abstracts and reviewed full texts for inclusion. A random-effects meta-analysis was conducted with eligible studies., Results: A total of 392 abstracts were retrieved, 214 remained after duplicates were removed. Fifteen full texts were reviewed, of which 8 were included. All 8 studies found that TGAs were associated with increased probability of ICDs. Risk of bias was high or critical in 7 of 8 studies. Three studies were included in the pooled analysis for the primary outcome, 2 with data on each of aripiprazole, cariprazine, and brexpiprazole. Exposure to TGAs versus other antipsychotics was associated with an increase in ICDs (pooled odds ratio, 5.54; 2.24-13.68). Cariprazine and brexpiprazole were significantly associated with ICDs when analyzed individually. Aripiprazole trended toward increased risk, but very wide confidence intervals included no effect., Conclusions: Third-generation antipsychotics were associated with increased risk of ICDs in all studies included and pooled analysis. However, the risk of bias is high, confidence intervals are wide, and the quality of evidence is very low for all TGAs examined., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: This research aimed to describe how the characteristics of deaths following drug use changed during the COVID-19 pandemic in England, and how this can inform future strategy to support the health and social care of people who use drugs in future emergency scenarios., Method: All deaths reported to the National Programme on Substance Abuse Deaths which occurred between January 2018 and December 2021 inclusive were extracted for analysis. Exponential smoothing models were constructed to determine any differences between forecasted vs. actual trends., Key Results: Following the first lockdown period in England there were significant increases in the proportion of people who died at home beyond the 95% confidence bounds of the exponential smoothing model and concurrent decreases in the proportion of people who died in hospital. Whilst the overall proportion of deaths attributable to opioids did not significantly deviate from the forecasted trend, there were significant increases in methadone-related deaths and decreases in heroin/morphine-related death beyond the 95% confidence bounds. The proportion of deaths concluded as suicide increased, as did those implicating antidepressant use. There were no changes in the proportion of deaths following use of other drug classes, alcohol use in combination with psychoactive drugs, or on decedent demographics (gender, age, and drug user status). A small number of deaths due to drug use had COVID-19 infection itself listed as a cause of death ( n  = 23)., Conclusion: For people who use drugs, the impact of the restrictions due to the COVID-19 pandemic was greater than that of infection from the virus itself. The health and social care strategy for these people needs to be pre-emptively adapted to mitigate against the specific risk factors for fatal drug overdose associated with future emergency scenarios., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sekeris, Algahtani, Aldabergenov, Rock, Auwal, Aldewaissan, Williams, Kalk and Copeland.)

Early care and education (ECE) environments influence children's lifelong health behaviors, growth, and development. Although the number of interventions to improve health in ECE environments is increasing, few have been designed for and tested in family child care homes (FCCHs). This study reports the process evaluation of two interventions to improve FCCH health environments, both part of Happy Healthy Homes, a matched-attention randomized-controlled intervention trial conducted in Oklahoma FCCHs. Participating child care providers received one of two multicomponent interventions: (a) an intervention focused on enhancing the quality of the nutrition environment, self-efficacy, and practices or (b) an intervention focused on improving providers' environmental health literacy, self-efficacy, and practices. Guided by "Implementation" constructs of the RE-AIM framework (i.e., reach, effectiveness, adoption, implementation, maintenance), intervention report forms and participant tracking were used to assess intervention dose delivered and interventionist-perceived challenges and successes to implementation. Interviews were conducted to obtain participant feedback after the intervention. Dose delivered was high for both interventions overall and across individual sessions, and provider feedback was positive. Implementation challenges and strengths identified for both interventions may be useful for further enhancing intervention appropriateness and success, particularly for interventions with FCCHs. Process evaluation findings indicate that the two Happy Healthy Home interventions can be conducted with high delivery and are well attended and considered to be valuable to FCCH providers.

We examined relationships between walkability and health behaviors between and within identical twin pairs, considering both home (neighborhood) walkability and each twin's measured activity space. Continuous activity and location data (via accelerometry and GPS) were obtained in 79 pairs over 2 weeks. Walkability was estimated using Walk Score ® (WS); home WS refers to neighborhood walkability, and GPS WS refers to the mean of individual WSs matched to every GPS point collected by each participant. GPS WS was assessed within (WHN) and out of the neighborhood (OHN), using 1-mile Euclidean (air1mi) and network (net1mi) buffers. Outcomes included walking and moderate-to-vigorous physical activity (MVPA) bouts, dietary energy density (DED), and BMI. Home WS was associated with WHN GPS WS ( b = 0.71, SE = 0.03, p < 0.001 for air1mi; b = 0.79, SE = 0.03, p < 0.001 for net1mi), and OHN GPS WS ( b = 0.18, SE = 0.04, p < 0.001 for air1mi; b = 0.22, SE = 0.04, p < 0.001 for net1mi). Quasi-causal relationships (within-twin) were observed for home and GPS WS with walking ( ps < 0.01), but not MVPA, DED, or BMI. Results support previous literature that neighborhood walkability has a positive influence on walking.

Both natural and manmade disasters have severely impacted the region of Southeast Texas over the past few decades, and this has negatively affected the socio-economic well-being of the region. The state of Texas has suffered 200-250 billion dollars in damages from natural and manmade disasters since 2010. Given the region's strategic importance to the nation's energy and security, developing resilience knowledge and multi-disaster resilience research focused on issues pertaining to the region is needed. This paper describes the structure and process of building a center for multi-disaster resilience at a regional public university. By utilizing a bottom-up approach, the Center's mission and design are broadly democratized through the participation of a variety of scholars and various stakeholders with whom they interact. Resilience needs specific to the Southeast Texas region are examined, as is the relationship between resilience and the academic disciplines of the stakeholders involved. The issues of resilience in the region are discussed as well as the future steps for the Center's continued growth and development for the study of resilience., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: To test for an association between duration of epistaxis and clinically relevant bleeding in the following 12 months in children with immune thrombocytopenia (ITP)., Design: Prospective cohort study., Setting: The national UK Paediatric ITP registry, a multicentre prospective clinical registry of new cases of ITP between 2006 and February 2020., Patients: All children aged between 2 months and 16 years in participating UK centres., Exposure: Epistaxis at presentation defined as none, <10 min, 10-30 min and >30 min., Main Outcome Measures: Incident severe bleeds, combined moderate and severe bleeds and drop in haemoglobin (Hb) by ≥20 g/L., Results: The sample included 1793 patients, of which 334 had epistaxis <10 min, 88 lasting 10-30 min and 97 >30 min. In the 12 months following presentation, 19 had a severe bleed, 140 had a moderate bleed and 54 had a drop in Hb ≥2 g/dL. Epistaxis >30 min duration was associated with increased odds of severe bleeds (OR 1.43-15.67), moderate or severe bleeding (OR 1.33-4.2) and drop in Hb (OR 1.23-6.91). Shorter duration epistaxis was not associated with increased odds of any outcome. A trend for increased odds with longer duration epistaxis was significant for all outcomes., Conclusions: The longer the duration of epistaxis at presentation with ITP, the higher the risk of a clinically significant bleeding event in the 12 months following. This should inform clinical severity ratings and treatment decisions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Family Child Care Homes (FCCHs) are a setting where providers care for children at their own residence. FCCHs face unique challenges and children may not always receive optimal nutrition and have higher risk of obesity compared to other programs. The objective of this study was to determine differences in food service best practices scores between FCCHs who did/did not perceive barriers to serving healthy meals. Methods: FCCHs ( n  = 167) self-reported demographics, and perceived barriers to serving healthy foods. Nutrition and Physical Activity Self-Assessment for Child Care was used to assess food served with 1 (indicating poor practice) to 4 (indicating best practice). Means, standard deviations, and t -tests were conducted to determine differences in scores between FCCHs with and without perceived barriers. Adjusted alpha was 0.013. Results: FCCHs perceiving food waste as a barrier had significantly lower scores for total food and beverage ( p  = 0.006, 3.2 ± 0.3 vs. 3.4 ± 0.3); fruits and vegetables ( p  = 0.003, 3.1 ± 0.5 vs. 3.3 ± 0.5), whole fruits ( p  = 0.048, 3.1 ± 1.2 vs. 3.4 ± 0.9), and nonstarchy vegetables ( p  = 0.007, 2.8 ± 0.9 vs. 3.2 ± 0.9). Providers perceiving food preferences as a barrier had significantly lower scores compared to those who did not ( p  = 0.008, 2.9 ± 0.9 vs. 3.3 ± 0.9). No significant differences found in best practices among providers with vs. without perceived barrier of food costs. Conclusion: Food waste is an understudied barrier in FCCHs to serve healthy meals. Research is needed to explore these perceived barriers in FCCHs to improve best practices around meals.

Background: Guidelines promoting healthy lifestyles are cornerstones of chronic disease prevention and treatment. The purpose of this study is to investigate independent and joint associations of five key health behaviors with health outcomes (body mass index (BMI kg/m 2 ) and depressive symptoms) in adult twins., Methods: We included 6,048 twin pairs from a community-based registry. Five key health behaviors were: (1) ≥ 8 h of sleep per night, (2) ≥ 5 servings of fruits and vegetables daily, (3) ≤ 2 h sedentary time per day, (4) ≥ 150 min of moderate-to-vigorous physical activity (MVPA) per week, and (5) no smoking. We analyzed phenotypic associations between behaviors and outcomes; whether phenotypic associations were confounded by additive genetic and shared environmental factors within twin pairs ("quasi-causal" associations); and which behaviors, considered simultaneously, had the largest associations with outcomes., Results: We found negative phenotypic associations between number of behaviors achieved with BMI and depressive symptoms score (ps < 0.05). Associations remained significant, though attenuated, when controlling for genetic and shared environmental factors, and demographics, for depressive symptoms score but not BMI (p < 0.05). Quantitative variable importance measures derived from regression tree models showed sedentary time and MVPA were the most important variables in partitioning twins with different BMI, and smoking and sedentary time for partitioning twins with different depressive symptoms score., Conclusions: Achievement of commonly endorsed health behaviors is associated with lower BMI (especially sedentary and MVPA targets) and depressive symptoms score (especially sedentary and smoking targets). This provides further support of health behavior promotion to improve health outcomes., (© 2022. The Author(s).)

Objective: Describe nutrition and physical activity practices, nutrition self-efficacy and barriers and food programme knowledge within Family Child Care Homes (FCCH) and differences by staffing., Design: Baseline, cross-sectional analyses of the Happy Healthy Homes randomised trial (NCT03560050)., Setting: FCCH in Oklahoma, USA., Participants: FCCH providers ( n 49, 100 % women, 30·6 % Non-Hispanic Black, 2·0 % Hispanic, 4·1 % American Indian/Alaska Native, 51·0 % Non-Hispanic white, 44·2 ± 14·2 years of age. 53·1 % had additional staff) self-reported nutrition and physical activity practices and policies, nutrition self-efficacy and barriers and food programme knowledge. Differences between providers with and without additional staff were adjusted for multiple comparisons ( P < 0·01)., Results: The prevalence of meeting all nutrition and physical activity best practices ranged from 0·0-43·8 % to 4·1-16·7 %, respectively. Average nutrition and physical activity scores were 3·2 ± 0·3 and 3·0 ± 0·5 (max 4·0), respectively. Sum nutrition and physical activity scores were 137·5 ± 12·6 (max 172·0) and 48·4 ± 7·5 (max 64·0), respectively. Providers reported high nutrition self-efficacy and few barriers. The majority of providers (73·9-84·7 %) felt that they could meet food programme best practices; however, knowledge of food programme best practices was lower than anticipated (median 63-67 % accuracy). More providers with additional staff had higher self-efficacy in family-style meal service than did those who did not ( P = 0·006)., Conclusions: Providers had high self-efficacy in meeting nutrition best practices and reported few barriers. While providers were successfully meeting some individual best practices, few met all. Few differences were observed between FCCH providers with and without additional staff. FCCH providers need additional nutrition training on implementation of best practices.

The gabapentinoids were reclassified as Schedule II medications and Class C drugs in the UK in 2019 due to their potential misuse. In this study we examined deaths following gabapentinoid use in England reported to the National Programme on Substance Abuse Deaths. A total of 3051 deaths were reported (gabapentin: 913 cases; pregabalin: 2322 cases [both detected in 184 cases]). Prescribed and illicitly obtained gabapentinoids accounted for similar proportions of deaths (gabapentin illicit 38.0%, prescribed 37.1%; pregabalin illicit 41.0%, prescribed 34.6%). Opioids were co-detected in most cases (92.0%), and co-prescribed in a quarter (25.3%). Postmortem blood gabapentinoid concentrations were commonly (sub)therapeutic (65.0% of gabapentin cases; 50.8% of pregabalin cases). In only two cases was gabapentinoid toxicity alone attributed in causing death. Gabapentinoids alone rarely cause death. Clinically relevant doses can, however, prove fatal, possibly by reducing tolerance to opioids. Doctors and patients should be aware of this interaction. Gabapentinoid-opioid co-prescribing needs urgent revision., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30 ) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

The study purpose was to determine associations between proximity to grocery stores and Early Care and Education programs' (i.e., ECEs) classroom nutrition practices and barriers, by ECE context (Head Start, community-based childcare [CBC], and family child care homes [FCCHs]). A statewide cross-sectional survey was implemented in Oklahoma ECEs. Directors reported classroom nutrition practices with the Nutrition and Physical Activity Self-Assessment tool, and barriers to implementation. Locations of 457 grocery stores statewide were determined by in-person audit. Geocoded ECEs were considered within a "low proximity" area if no grocery stores were available within a 0.25-mile radius for urban, or 10-mile radius for rural, ECEs. From November 2019 to February 2020, 54 Head Starts, 159 CBCs, and 160 FCCHs participated. 31.0 % were considered as low proximity. Head Starts demonstrated the highest classroom nutrition scores for mealtime practices, and nutrition education and policy. While proximity to grocery stores was not related to classroom nutrition practices for any ECE context (p > 0.05), FCCHs located within a low proximity area reported barriers to implementing those practices more often compared to FCCHs in an area within accessible proximity of grocery store. Thus, proximity to grocery stores was related to barriers in FCCHs only; those provider's experiences and perceptions may be most susceptible to influence of the community nutrition environment, compared to other ECE contexts. Contrary to studies in residential areas and schools, nutrition environments were not related to nutrition practices in ECEs. ECEs may serve as protective micro-environments supporting health for children residing in nearby low-access communities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

The interaction between radionuclides and cementitious material phases is crucial in the prediction of the long-term disposal behavior of cementitious waste forms. This work focuses on the behavior of technetium-99 (Tc) within a hydrated-lime based waste form developed as a candidate to immobilize high-sulphate containing liquid wastes known to inhibit cement solidification when using a fly ash based formulation. In leach testing, the hydrated-lime based formulation demonstrated improvement in Tc retention over a fly ash containing formulation beginning after 14 d leaching. The mineralogical evolution of the hydrated-lime samples during leach testing showed a decrease in portlandite content and reduction capacity at the onset of the Tc retention improvement. Leach testing upwards of 400 days showed the improved Tc retention was sustained. Samples cured for different lengths of time (28 days vs 60 days) confirmed that the improved Tc retention and mineralogic change was caused by cement - leachant interactions and not the sample curing time. The Tc observed diffusivities in the hydrated-lime samples are amongst the lowest measured in a cement waste form tested for development at the US Department of Energy Hanford site, leading to a possible pathway to improved cement conditioning where contaminants can be retained for long disposal times., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Larsen, Williams, Rais, Coler and Baldwin.)

Child care environments foster children's healthy eating habits by providing exposure to healthy foods and feeding practices. We assessed the healthfulness of nutrition environments, menu/meal quality, and the achievement of Child and Adult Care Food Program (CACFP) guidelines and best practices in Oklahoma CACFP-enrolled family child care homes (FCCHs) ( n = 51). Two-day classroom observations were conducted. Healthfulness of classroom nutrition environments was assessed using the Environment and Policy Assessment and Observation (EPAO). Foods served to and consumed by children were quantified using the Dietary Observations in Child Care (DOCC) tool. Nutrient analysis was performed to determine total energy for foods listed on menus, served to, and consumed by children. Menu and meal food variety and CACFP Guideline Achievement Scores were determined. Average nutrition environment score was 11.7 ± 1.2 (61.5% of maximum possible score). Energy (kcals) from menus and consumed by children was insufficient to meet two-thirds of their daily reference intake. Children were exposed to 1.7 vegetables and 1.3 fruits per meal. CACFP Guideline Achievement Scores were 66.3% ± 7.8 for menus and 59.3% ± 7.6 for mealtimes. Similar to previous research, our findings indicate a need for improved FCCH nutrition practices. Tailored interventions for FCCHs are needed.

In response to the SARS-CoV-2 pandemic many vaccines have been developed and evaluated in human clinical trials. The humoral immune response magnitude, composition and efficacy of neutralizing SARS-CoV-2 are essential endpoints for these trials. Robust assays that are reproducibly precise, linear, and specific for SARS-CoV-2 antigens would be beneficial for the vaccine pipeline. In this work we describe the methodologies and clinical qualification of three SARS-CoV-2 endpoint assays. We developed and qualified Endpoint titer ELISAs for total IgG, IgG1, IgG3, IgG4, IgM and IgA to evaluate the magnitude of specific responses to the trimeric spike (S) antigen and total IgG specific to the spike receptor binding domain (RBD) of SARS-CoV-2. We also qualified a pseudovirus neutralization assay which evaluates functional antibody titers capable of inhibiting the entry and replication of a lentivirus containing the Spike antigen of SARS-CoV-2. To complete the suite of assays we qualified a plaque reduction neutralization test (PRNT) methodology using the 2019-nCoV/USA-WA1/2020 isolate of SARS-CoV-2 to assess neutralizing titers of antibodies in plasma from normal healthy donors and convalescent COVID-19 individuals., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Determine the impact of family child care home providers' nutrition knowledge, confidence, and perceived barriers on program nutrition best practices and written nutrition policies., Methods: Cross-sectional analysis of self-reported surveys of 49 female providers in Oklahoma City analyzed with Spearman correlation, multivariate linear and logistic regression (α < 0.05)., Results: Confidence and barriers were significantly correlated (r s (47) = -0.4, P = 0.004). Independent variables explained 36% of practices (r 2 = 0.357). Nutrition knowledge (standard β = 0.442, P = 0.001) and confidence (standard β = 0.358, P = 0.008) were significantly associated with practices; barriers were not. No significant association between independent variables and written policies resulted., Conclusions and Implications: Provider nutrition knowledge and confidence appear to be suitable targets to improve nutrition practices. Further research can evaluate possible influences on the presence and quality of family child care home written nutrition policies and specific nutrition policy topics associated with healthier nutrition practices., (Copyright © 2021 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)