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Parental involvement in intervention can support intervention efficacy, improve generalization, and increase accessibility. The Preschool Life Skills (PLS) program is designed to teach 13 preschool life skills and prevent problem behavior. The current study explores the utility of the PLS program as delivered by parents. In Experiment 1, 6 parents were taught to use the PLS program at home with their typically developing children (3 years 3 months to 4 years 11 months). This application of the PLS program led to an increase in preschool life skills and a decrease in problem behavior and supported some generalization of the target preschool life skills from the home to preschool settings. In Experiment 2, 7 parents were taught to use the PLS program with their children with autism spectrum disorder (ASD; 3 years 11 months to 6 years 9 months). Results overall supported the parent implementation of the program and highlighted modifications required to support positive outcomes for children with ASD.

Early messages about reproductive and sexual health influence personal identities, health behaviors, and ongoing perceptions of sex and sexuality. Women are often socialized with negatively-valenced messages toward understanding their reproductive and sexual health. However, scholarship emphasizes a communicative approach for socializing intimate health behaviors and needs. The present study addresses the communication that prompts a shift in perception from early, harmful memorable messages to a more comprehensive perspective on sexuality. To do so, we qualitatively analyze open-ended survey responses from 191 women. Findings reinforce previous memorable message literature by revealing messages of shame, sex, abortion, childbearing, and fears of infertility. In addition, we extend the memorable messages construct by exploring how more positively valenced messages and individual moments of intervention redirect women in how they understand their intimate health and sexuality.

This qualitative case study of 20 teachers enrolled in a two-year fellowship, examines the professional development of science teachers during participation in a professional learning community. Our professional development model specifically employs vertical teaming of teachers from elementary, middle, and high school levels to examine the progression of science content in K-12 classrooms. We describe science teachers' perspective on how vertically aligned groups supported their professional development. Through qualitative analysis of five data sources, we found that the fellows showed increased appreciation for vertical articulation of science content in grades K-12 and attributed their professional growth to the experience of working with teachers at diverse grade levels. These findings have implications for professional development as it relates to NGSS.

Abstract To improve the manufacturing of vertical GaN devices for power electronics applications, the effects of defects in GaN substrates need to be better understood. Many non-destructive techniques including photoluminescence, Raman spectroscopy and optical profilometry, can be used to detect defects in the substrate and epitaxial layers. Raman spectroscopy was used to identify points of high crystal stress and non-uniform conductivity in a substrate, while optical profilometry was used to identify bumps and pits in a substrate which could cause catastrophic device failures. The effect of the defects was studied using vertical P-i-N diodes with a single zone junction termination extention (JTE) edge termination and isolation, which were formed via nitrogen implantation. Diodes were fabricated on and off of sample abnormalities to study their effects. From electrical measurements, it was discovered that the devices could consistently block voltages over 1000 V (near the theoretical value of the epitaxial layer design), and the forward bias behavior could consistently produce on-resistance below 2 mΩ cm2, which is an excellent value considering DC biasing was used and no substrate thinning was performed. It was found that high crystal stress increased the probability of device failure from 6 to 20%, while an inhomogeneous carrier concentration had little effect on reverse bias behavior, and slightly (~ 3%) increased the on-resistance (Ron). Optical profilometry was able to detect regions of high surface roughness, bumps, and pits; in which, the majority of the defects detected were benign. However a large bump in the termination region of the JTE or a deep pit can induce a low voltage catastrophic failure, and increased crystal stress detected by the Raman correlated to the optical profilometry with associated surface topography.

We present a method for analysing the lipophilic fraction extracted from ground coffee beans using 60 MHz proton (1H) NMR spectroscopy. In addition to the triglycerides from coffee oil, spectral features are seen from a range of secondary metabolites, such as various diterpenes. We demonstrate quantitation of a peak attributed to one such compound, 16-O-methylcafestol (16-OMC), which is of interest as a coffee species marker. It is present in low concentrations (<

BackgroundAedes aegypti is a primary vector of dengue, chikungunya, Zika, and urban yellow fever viruses. Indoor, ultra low volume (ULV) space spraying with pyrethroid insecticides is the main approach used for Ae. aegypti emergency control in many countries. Given the widespread use of this method, the lack of large-scale experiments or detailed evaluations of municipal spray programs is problematic.Methodology/principal findingsTwo experimental evaluations of non-residual, indoor ULV pyrethroid spraying were conducted in Iquitos, Peru. In each, a central sprayed sector was surrounded by an unsprayed buffer sector. In 2013, spray and buffer sectors included 398 and 765 houses, respectively. Spraying reduced the mean number of adults captured per house by ~83 percent relative to the pre-spray baseline survey. In the 2014 experiment, sprayed and buffer sectors included 1,117 and 1,049 houses, respectively. Here, the sprayed sector's number of adults per house was reduced ~64 percent relative to baseline. Parity surveys in the sprayed sector during the 2014 spray period indicated an increase in the proportion of very young females. We also evaluated impacts of a 2014 citywide spray program by the local Ministry of Health, which reduced adult populations by ~60 percent. In all cases, adult densities returned to near-baseline levels within one month.Conclusions/significanceOur results demonstrate that densities of adult Ae. aegypti can be reduced by experimental and municipal spraying programs. The finding that adult densities return to approximately pre-spray densities in less than a month is similar to results from previous, smaller scale experiments. Our results demonstrate that ULV spraying is best viewed as having a short-term entomological effect. The epidemiological impact of ULV spraying will need evaluation in future trials that measure capacity of insecticide spraying to reduce human infection or disease.

Abstract Neural recordings made to date through various approaches—both in-vitro or in-vivo—lack high spatial resolution and a high signal-to-noise ratio (SNR) required for detailed understanding of brain function, synaptic plasticity, and dysfunction. These shortcomings in turn deter the ability to further design diagnostic, therapeutic strategies and the fabrication of neuro-modulatory devices with various feedback loop systems. We report here on the simulation and fabrication of fully configurable neural micro-electrodes that can be used for both in vitro and in vivo applications, with three-dimensional semi-insulated structures patterned onto custom, fine-pitch, high density arrays. These microelectrodes were interfaced with isolated brain slices as well as implanted in brains of freely behaving rats to demonstrate their ability to maintain a high SNR. Moreover, the electrodes enabled the detection of epileptiform events and high frequency oscillations in an epilepsy model thus offering a diagnostic potential for neurological disorders such as epilepsy. These microelectrodes provide unique opportunities to study brain activity under normal and various pathological conditions, both in-vivo and in in-vitro, thus furthering the ability to develop drug screening and neuromodulation systems that could accurately record and map the activity of large neural networks over an extended time period.

The importance of mosquitoes in human pathogen transmission has motivated major research efforts into mosquito biology in pursuit of more effective vector control measures. Aedes aegypti is a particular concern in tropical urban areas, where it is the primary vector of numerous flaviviruses, including the yellow fever, Zika, and dengue viruses. With an anthropophilic habit, Ae. aegypti prefers houses, human blood meals, and ovipositioning in water-filled containers. We hypothesized that this relatively simple ecological niche should allow us to predict the impacts of insecticidal control measures on mosquito populations. To do this, we use Skeeter Buster 2 (SB2), a stochastic, spatially explicit, mechanistic model of Ae. aegypti population biology. SB2 builds on Skeeter Buster, which reproduced equilibrium dynamics of Ae. aegypti in Iquitos, Peru. Our goal was to validate SB2 by predicting the response of mosquito populations to perturbations by indoor insecticidal spraying and widespread destructive insect surveys. To evaluate SB2, we conducted two field experiments in Iquitos, Peru: a smaller pilot study in 2013 (S-2013) followed by a larger experiment in 2014 (L-2014). Here, we compare model predictions with (previously reported) empirical results from these experiments. In both simulated and empirical populations, repeated spraying yielded substantial yet temporary reductions in adult densities. The proportional effects of spraying were broadly comparable between simulated and empirical results, but we found noteworthy differences. In particular, SB2 consistently over-estimated the proportion of nulliparous females and the proportion of containers holding immature mosquitoes. We also observed less temporal variation in simulated surveys of adult abundance relative to corresponding empirical observations. Our results indicate the presence of ecological heterogeneities or sampling processes not effectively represented by SB2. Although additional empirical research could further improve the accuracy and precision of SB2, our results underscore the importance of non-linear dynamics in the response of Ae. aegypti populations to perturbations, and suggest general limits to the fine-grained predictability of its population dynamics over space and time.

Abstract Leukemic cutaneous T‐cell lymphomas (L‐CTCL) are lymphoproliferative disorders of skin‐homing mature T‐cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L‐CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L‐CTCL, which correlated with the increased clonal T‐cell count in the blood. Dual inhibition of STAT3/5 using small‐molecule degraders and multi‐kinase blockers abolished L‐CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L‐CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti‐leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L‐CTCL.

Introduction: We re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease. Methods: Expanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression. Results: At the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (p = 0.023). Logistic regression indicated a significant association between delay and odds of progression (p = 0.045): an individual with 3 regions at least 1 SD (40 ms) slower than the mean in 2009 had 2.05× (±SE: 1.43× to 2.95×) the odds of progression by 2019. A 1 SD shorter delay was associated with 2.05× lower odds of progression. Amplitude changes were not predictive of progression. Significance: mfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

Mulavana S Parvathy,1,2 Aditee Parab,3 Balakrishnan Kichu R Nair,1– 3 Carl Matheson,4 Kathy Ingham,1 Lynette Gunning1 1Centre for Medical Professional Development, Hunter New England Local Health District, Newcastle, NSW, Australia; 2School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; 3John Hunter Hospital, Hunter New England Local Health District, Newcastle, NSW, Australia; 4The Australian Medical Council, Canberra, ACT, AustraliaCorrespondence: Mulavana S Parvathy Email usha.parvathy@newcastle.edu.auIntroduction: Australia depends on international medical graduates (IMGs) to meet workforce shortages. The current standard assessment for IMGs is by clinical examination in observed structured clinical encounter (OSCE) format lasting 200 minutes. There are concerns about adequateness of this assessment as it does not test the qualities required to practice in a new country. We introduced a programmatic performance-based assessment for IMGs to prepare them to meet these challenges. The workplace-based assessment (WBA) program involves six-month longitudinal programmatic assessments comprising of 12 mini-clinical evaluation exercises (Mini-CEX), five case-based discussions (CBD), two in-training assessments (ITAs) and two sets of multisource feedback (MSF) assessments. We assessed 254 IMGs since 2010. We conducted a survey to evaluate the satisfaction with the program and the outcomes of these doctors.Methods: We surveyed 254 candidates from 2010 to 2020. The survey used “SelectSurvey” tool with 12 questions and free-text comments. All candidates were sent the survey link to their last registered mobile phone using “Telstra Instant Messaging Service”. We analysed the data using Microsoft “Excel”.Results: We received 153 (60%) responses. Amongst them, 141 (92%) candidates did not require further supervised practice for general registration and 129 (84%) candidates hold general/specialist registration. The candidates found the program useful and felt well supported. They appreciated real patient encounters. The feedback with positive critiquing was helpful in improving their clinical practice. The negative themes were program costs and frustration with the length of the program.Conclusion: Upon completion of the WBA program and obtaining the AMC certificate, most of the doctors were able to gain general registration. Seventy-eight (50%) candidates chose to continue their careers within the local area with 124 (80%) of them within the state. Our survey shows a comprehensive assessment program with immediate constructive feedback produces competent doctors to fill the medical workforce shortages.Keywords: programmatic assessment, workplace based assessment, feedback, international medical graduates, foreign medical graduates

Abstract This study describes the evolution of knockdown resistance (kdr) haplotypes in Aedes aegypti in response to pyrethroid insecticide use over the course of 18 years in Iquitos, Peru. Based on the duration and intensiveness of sampling (~10,000 samples), this is the most thorough study of kdr population genetics in Ae. aegypti to date within a city. We provide evidence for the direct connection between programmatic citywide pyrethroid spraying and the increase in frequency of specific kdr haplotypes by identifying two evolutionary events in the population. The relatively high selection coefficients, even under infrequent insecticide pressure, emphasize how quickly Ae. aegypti populations can evolve. In our examination of the literature on mosquitoes and other insect pests, we could find no cases where a pest evolved so quickly to so few exposures to low or nonresidual insecticide applications. The observed rapid increase in frequency of resistance alleles might have been aided by the incomplete dominance of resistance‐conferring alleles over corresponding susceptibility alleles. In addition to dramatic temporal shifts, spatial suppression experiments reveal that genetic heterogeneity existed not only at the citywide scale, but also on a very fine scale within the city.

Abstract Discovering genes involved in complex human genetic disorders is a major challenge. Many have suggested that machine learning (ML) algorithms using gene networks can be used to supplement traditional genetic association-based approaches to predict or prioritize disease genes. However, questions have been raised about the utility of ML methods for this type of task due to biases within the data, and poor real-world performance. Using autism spectrum disorder (ASD) as a test case, we sought to investigate the question: can machine learning aid in the discovery of disease genes? We collected 13 published ASD gene prioritization studies and evaluated their performance using known and novel high-confidence ASD genes. We also investigated their biases towards generic gene annotations, like number of association publications. We found that ML methods which do not incorporate genetics information have limited utility for prioritization of ASD risk genes. These studies perform at a comparable level to generic measures of likelihood for the involvement of genes in any condition, and do not out-perform genetic association studies. Future efforts to discover disease genes should be focused on developing and validating statistical models for genetic association, specifically for association between rare variants and disease, rather than developing complex machine learning methods using complex heterogeneous biological data with unknown reliability.

Abstract Predictive brain markers promise a number of important scientific, clinical, and societal applications. Over 600 predictive brain markers have been described in published reports, but very few have been tested in independent replication attempts. Here, we conducted an independent replication of a previously published marker predicting treatment response to cognitive-behavioral therapy for social anxiety disorder from patterns of resting-state fMRI amygdala connectivity1. The replication attempt was conducted in an existing dataset similar to the dataset used in the original report, by a team of independent investigators in consultation with the original authors. The precise model described in the original report positively predicted treatment outcomes in the replication dataset, but with marginal statistical significance, permutation test p = 0.1. The effect size was substantially smaller in the replication dataset, with the model explaining 2% of the variance in treatment outcomes, as compared to 21% in the original report. Several lines of evidence, including the current replication attempt, suggest that features of amygdala function or structure may be able to predict treatment response in anxiety disorders. However, predictive models that explain a substantial amount of variance in independent datasets will be needed for scientific and clinical applications.

Abstract Nonpharmacological interventions targeting putative network mechanisms of major depressive disorder (MDD) may represent novel treatments. This mechanistic study investigates how a video game-like intervention, designed to improve cognitive control network (CCN) functioning by targeting multitasking, influences the CCN of middle-aged and older adults with MDD. The sample consisted of 34 adults aged 45–75 with SCID-defined diagnosis of MDD, Hamilton depression rating scale scores ≥20, and a deficit in cognitive control. Participants were instructed to play at home for 20–25 min per day, at least 5 times per week, for 4 weeks. Evidence of target engagement was defined a priori as >2/3 of participants showing CCN improvement. CCN engagement was defined as a change in a Z score of ≥0.5 on functional magnetic resonance imaging (fMRI) in activation and functional connectivity of the CCN during task-based and resting-state fMRI, respectively. 74% of participants showed a change in activation of the CCN, and 72% showed an increase in resting-state functional connectivity. Sixty-eight percent demonstrated improved cognitive control function, measured as either improvement on sustained attention or working memory performance or reduced self-reported symptoms of apathy on the frontal systems behavioral scale (FrsBe). Participants also reported a significant reduction in mood symptoms measured by PHQ-9. A remotely deployed neuroscience-informed video game-like intervention improves both CCN functions and mood in middle-aged and older adults with MDD. This easily-disseminated intervention may rescue CCN dysfunction present in a substantial subset of middle-aged and older adults with MDD.

BackgroundExisting treatments for depression are known to have only modest effects, are insufficiently targeted, and are inconsistently utilized, particularly in older adults. Indeed, older adults with impaired cognitive control networks tend to demonstrate poor response to a majority of existing depression interventions. Cognitive control interventions delivered using entertainment software have the potential to not only target the underlying cerebral dysfunction associated with depression, but to do so in a manner that is engaging and engenders adherence to treatment protocol.MethodsIn this proof-of-concept trial (Clinicaltrials.gov #: NCT02229188), individuals with late life depression (LLD) (22; 60+ years old) were randomized to either problem solving therapy (PST, n = 10) or a neurobiologically inspired digital platform designed to enhance cognitive control faculties (Project: EVO™, n = 12). Given the overlapping functional neuroanatomy of mood disturbances and executive dysfunction, we explored the impact of an intervention targeting cognitive control abilities, functional disability, and mood in older adults suffering from LLD, and how those outcomes compare to a therapeutic gold standard.ResultsEVO participants demonstrated similar improvements in mood and self-reported function after 4 weeks of treatment to PST participants. The EVO participants also showed generalization to untrained measures of working memory and attention, as well as negativity bias, a finding not evident in the PST condition. Individuals assigned to EVO demonstrated 100% adherence.ConclusionsThis study provides preliminary findings that this therapeutic video game targeting cognitive control deficits may be an efficacious LLD intervention. Future research is needed to confirm these findings.

Abstract Background ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. Methods To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. Results We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. Conclusion Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

Abstract Meta-analyses have shown that digital mental health apps can be efficacious in reducing symptoms of depression and anxiety. However, real-world usage of apps is typically not sustained over time, and no studies systematically examine which features increase sustained engagement with apps or the relationship between engagement features and clinical efficacy. We conducted a systematic search of the literature to identify empirical studies that (1) investigate standalone apps for depression and/or anxiety in symptomatic participants and (2) report at least one measure of engagement. Features intended to increase engagement were categorized using the persuasive system design (PSD) framework and principles of behavioral economics. Twenty-five studies with 4159 participants were included in the analysis. PSD features were commonly used, whereas behavioral economics techniques were not. Smartphone apps were efficacious in treating symptoms of anxiety and depression in randomized controlled trials, with overall small-to-medium effects (g = 0.2888, SE = 0.0999, z(15) = 2.89, p = 0.0119, Q(df = 14) = 41.93, p

Generalization and maintenance of intervention outcomes are of paramount importance in achieving socially significant outcomes within applied behavior analysis. Social skills interventions for young children with autism spectrum disorders (ASD) are widely represented within the empirical literature; however, generalization and maintenance outcomes are often under reported. While recognition of the importance of generalization and maintenance is increasing, there is a lack of research systematically evaluating these outcomes and the factors that support successful generalization and maintenance. The current review aimed to investigate the status of generalization and maintenance within the social skills intervention literature for preschool age children with ASD. A total of 57 studies which measured generalization and/or maintenance of social skills intervention outcomes were included in the current review and evaluated regarding generalization and maintenance data collection and assessment, generalization-promotion strategies employed, generalization and maintenance outcomes, and factors posited to influence these outcomes.

Communication deficits in children with Autism Spectrum Disorder (ASD) can manifest in a myriad of lifelong social and educational challenges. Many children with ASD fail to learn vocal verbal behavior and may require intensive individualized intervention to learn early verbal operants. The current research aimed to evaluate the effects of a parent delivered stimulus-stimulus pairing (SSP) procedure on target vocalizations of two young children with ASD who did not present with vocal verbal behavior. Results indicated the intervention was successful in increasing the frequency of the target vocalizations for both participants. Social validity results indicated that parents were satisfied with the intervention and their own implementation of these procedures. These results are discussed in terms of their implications for parent delivered interventions.

Peer-mediated interventions (PMI) are implemented for skills teaching for children with autism spectrum disorder (ASD), particularly within the context of early learning environments. PMI have several potential advantages in comparison to adult-led intervention; however, there is a lack of research evaluating the use of PMI with younger populations. This review aims to synthesize the literature regarding the use of PMI in skills teaching for children with ASD in preschool settings. A systematic search of the literature spanning 1980-2018 was conducted, and 31 articles were identified for inclusion. Results are discussed in relation to participant and peer characteristics, PMI procedures, target skills, intervention outcomes, and research strength. The effectiveness of PMI is discussed along with directions for future research.

The NavDx® blood test analyzes tumor tissue modified viral (TTMV)-HPV DNA to provide a reliable means of detecting and monitoring HPV-driven cancers. The test has been clinically validated in a large number of independent studies and has been integrated into clinical practice by over 1000 healthcare providers at over 400 medical sites in the US. This Clinical Laboratory Improvement Amendments (CLIA), high complexity laboratory developed test, has also been accredited by the College of American Pathologists (CAP) and the New York State Department of Health. Here, we report a detailed analytical validation of the NavDx assay, including sample stability, specificity as measured by limits of blank (LOBs), and sensitivity illustrated via limits of detection and quantitation (LODs and LOQs). LOBs were 0–0.32 copies/μL, LODs were 0–1.10 copies/μL, and LOQs were 2 = 1) across a broad range of analyte concentrations. These results demonstrate that NavDx accurately and reproducibly detects circulating TTMV-HPV DNA, which has been shown to aid in the diagnosis and surveillance of HPV-driven cancers.

Summary: Background: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. Interpretation: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. Funding: UK National Institute for Health Research and UK Medical Research Council.

Impact ionization coefficients play a critical role in semiconductors. In addition to silicon, silicon carbide and gallium nitride are important semiconductors that are being seen more as mainstream semiconductor technologies. As a reflection of the maturity of these semiconductors, predictive modeling has become essential to device and circuit designers, and impact ionization coefficients play a key role here. Recently, several studies have measured impact ionization coefficients. We dedicated the first part of our study to comparing three experimental methods to estimate impact ionization coefficients in GaN, which are all based on photomultiplication but feature characteristic differences. The first method inserts an InGaN hole-injection layer, the accuracy of which is challenged by the dominance of ionization in InGaN, leading to possible overestimation of the coefficients. The second method utilizes the Franz–Keldysh effect for hole injection but not for electrons, where the mixed injection of induced carriers would require a margin of error. The third method uses complementary p–n and n–p structures that have been at the basis of this estimation in Si and SiC and leans on the assumption of a constant electric field, and any deviation would require a margin of error. In the second part of our study, we evaluated the models using recent experimental data from diodes demonstrating avalanche breakdown.

As life expectancy continues to increase, clinicians are challenged by age-related renal impairment that involves podocyte senescence and glomerulosclerosis. There is now compelling evidence that lithium has a potent antiaging activity that ameliorates brain aging and increases longevity in Drosophila and Caenorhabditis elegans. As the major molecular target of lithium action and a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates. In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.

BACKGROUND: Preimplantation balloon aortic valvuloplasty (BAV) is considered a routine procedure during transcatheter aortic valve implantation (TAVI) to facilitate prosthesis implantation and expansion; however, it has been speculated that fewer embolic events and/or less hemodynamic instability may occur if TAVI is performed without preimplantation BAV. The aim of this study was to systematically review the clinical outcomes associated with TAVI undertaken without preimplantation BAV. METHODS AND RESULTS: We conducted a search of Medline and Embase to identify studies that evaluated patients who underwent TAVI with or without preimplantation BAV for predilation. Pooled analysis and random-effects meta-analyses were used to estimate the rate and risk of adverse outcomes. Sixteen studies involving 1395 patients (674 with and 721 without preimplantation BAV) fulfilled the inclusion criteria. Crude device success was achieved in 94% (1311 of 1395), and 30-day all-cause mortality occurred in 6% (72 of 1282) of patients. Meta-analyses evaluating outcomes of strategies with and without preimplantation BAV showed no statistically significant differences in terms of mortality (relative risk [RR] 0.61, 95% CI 0.32-1.14, P=0.12), safety composite end point (RR 0.85, 95% CI 0.62-1.18, P=0.34), moderate to severe paravalvular leaks (RR 0.68, 95% CI 0.23-1.99, P=0.48), need for postdilation (RR 0.86, 95% CI 0.66-1.13, P=0.58), stroke and/or transient ischemic attack (RR 0.72, 95% CI 0.30-1.71, P=0.45), and permanent pacemaker implantation (RR 0.80, 95% CI 0.49-1.30, P=0.37). CONCLUSIONS: Our analysis suggests that TAVI procedures with or without preimplantation BAV were associated with similar outcomes for a number of clinically relevant end points. Further studies including a large number of patients are needed to ascertain the impact of TAVI without preimplantation BAV as a standard practice.

BackgroundThe UK government is pursuing policies to improve primary care access, as many patients visit accident and emergency (A and E) departments after being unable to get suitable general practice appointments. Direct admission to hospital via a general practitioner (GP) averts A and E use, and may reduce total hospital costs. It could also enhance the continuity of information between GPs and hospital doctors, possibly improving healthcare outcomes.ObjectiveTo determine whether primary care access is associated with the route of emergency admission-via a GP versus via an A and E department.MethodsRetrospective analysis of national administrative data from English hospitals for 2011-2012. Adults admitted in an emergency (unscheduled) for ≥1 night via a GP or an A and E department formed the study population. The measure of primary care access-the percentage of patients able to get a general practice appointment on their last attempt-was derived from a large, nationally representative patient survey. Multilevel logistic regression was used to estimate associations, adjusting for patient and admission characteristics.ResultsThe analysis included 2 322 112 emergency admissions (81.9% via an A and E department). With a 5 unit increase in the percentage of patients able to get a general practice appointment on their last attempt, the adjusted odds of GP admission (vs A and E admission) was estimated to increase by 15% (OR 1.15, 95% CI 1.12 to 1.17). The probability of GP admission if ≥95% of appointment attempts were successful in each general practice was estimated to be 19.6%. This probability reduced to 13.6% when

The mean-variance framework coupled with the Sharpe ratio identifies optimal portfolios under the passive investment style. Optimal portfolio identification under active investment approaches, where performance is measured relative to a benchmark, is less well-known. Active portfolios subject to tracking error (TE) constraints lie on distorted elliptical frontiers in return/risk space. Identifying optimal active portfolios, however defined, have only recently begun to be explored. The Ω – ratio considers both down and upside portfolio potential. Recent work has established a technique to determine optimal Ω – ratio portfolios under the passive investment approach. The authors apply the identification of optimal Ω – ratio portfolios to the active arena (i.e., to portfolios constrained by a TE) and find that while passive managers should always invest in maximum Ω – ratio portfolios, active managers should first establish market conditions (which determine the sign of the main axis slope of the constant TE frontier). Maximum Sharpe ratio portfolios should be engaged when this slope is > 0 and maximum Ω – ratios when < 0.

Abstract Objectives We ascertained the prevalence of ictal arrhythmias to explain the high rate of sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome (DS). Methods We selected cases with clinical DS, ≥6 years, SCN1A mutation, and ≥1 seizure/week. Home‐based ECG recordings were performed for 20 days continuously. Cases were matched for age and sex to two epilepsy controls with no DS and ≥1 major motor seizure during video‐EEG. We determined the prevalence of peri‐ictal asystole, bradycardia, QTc changes, and effects of convulsive seizures (CS) on heart rate, heart rate variability (HRV), and PR/QRS. Generalized estimating equations were used to account for multiple seizures within subjects, seizure type, and sleep/wakefulness. Results We included 59 cases. Ictal recordings were obtained in 45 cases and compared to 90 controls. We analyzed 547 seizures in DS (300 CS) and 169 in controls (120 CS). No asystole occurred. Postictal bradycardia was more common in controls (n = 11, 6.5%) than cases (n = 4, 0.7%; P = 0.002). Peri‐ictal QTc‐lengthening (≥60ms) occurred more frequently in DS (n = 64, 12%) than controls (n = 8, 4.7%, P = 0.048); pathologically prolonged QTc was rare (once in each group). In DS, interictal HRV was lower compared to controls (RMSSD P = 0.029); peri‐ictal values did not differ between the groups. Prolonged QRS/PR was rare and more common in controls (QRS: one vs. none; PR: three vs. one). Interpretation We did not identify major arrhythmias in DS which can directly explain high SUDEP rates. Peri‐ictal QTc‐lengthening was, however, more common in DS. This may reflect unstable repolarization and an increased propensity for arrhythmias.