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High school graduation is a pivotal milestone that can shape students' future, offering them opportunities for higher education and gainful employment. Because research shows grade point averages and course failures to be predictive of high school graduation, it is important for students' life outcomes that their teachers assign them equitable grades. However, recent research has scrutinized how schools have traditionally graded students, calling for new approaches such as minimum grading. In this analysis, we simulate the economic impacts of implementing a minimum grading policy statewide during the ninth-grade year of the cohort of students who were in ninth grade in 2015-16 in Arkansas. On average, in Arkansas public schools, we estimate that minimum grading would affect about one (narrow bound) to 3%(broad bound) of students, increase cost-effectiveness by 6% (narrow bound) to 23% (broad bound), largely varying across districts, and have essentially no impact on the return on investment. The application of minimum grading shifted 1% of failing course grades to passing, thereby positioning 10% of previously failing students to pass. These findings suggest that minimum grading could serve as a cost-effective strategy to enhance graduation rates in districts with higher rates of affected students, without necessitating additional educational spending.

A posttest-only control group experimental design compared novice Arduino programmers who developed their own programs (self-programming group, n = 17) with novice Arduino programmers who used ChatGPT 3.5 to write their programs (ChatGPT-programming group, n = 16) on the dependent variables of programming scores, interest in Arduino programming, Arduino programming self-efficacy, Arduino programming posttest scores, and types of programming errors. Students were undergraduates in an introductory agricultural systems technology course in Fall 2023. The results indicated no significant (p < 0.10) differences between groups for programming rubric scores (p = 0.50) or interest in Arduino programming (p = 0.50). There were significant differences for Arduino programming self-efficacy, (p = 0.03, Cohen's d = 0.75) and Arduino posttest scores, (p = 0.03, Cohen's d = 0.76); students in the self-programming group scored significantly higher on both measures. Analysis of students' errors indicated the ChatGPT group made significantly (p < 0.01) more program punctuation errors. These results indicated novice students writing their own programs developed greater Arduino programming self-efficacy and programming ability than novice students using ChatGPT. Nevertheless, ChatGPT may still play an important role in assisting novices to write microcontroller programs.

This report presents a new parent-rated outcome measure of insomnia for children with autism spectrum disorder. Parents of 1185 children with autism spectrum disorder (aged 3-12; 80.3% male) completed the first draft of the measure online. Factor and item response theory analyses reduced the set of 40 items to the final 21-item Pediatric Insomnia Autism Rating Scale. In this online sample, Pediatric Insomnia Autism Rating Scale mean was 21.8 ± 15.0 (range 0-63; coefficient alpha = 0.94). Item response theory results indicated excellent reliability across a range of scores. Next, we conducted a telehealth assessment of 134 children with autism spectrum disorder (aged 3-12; 73% male). In this clinical sample, Pediatric Insomnia Autism Rating Scale mean was 28.9 + 14.62 (range 0-61; coefficient alpha = 0.93). Pearson correlations of Pediatric Insomnia Autism Rating Scale with the PROMIS Sleep Disturbance and the modified Children's Sleep Habits Questionnaire was 0.74 for each. This was significantly higher than correlations of parent-rated disruptive behavior, hyperactivity, repetitive behavior, and anxiety measures (range 0.29-0.59)--supporting convergent and divergent validity. Parents of 63 children completed the Pediatric Insomnia Autism Rating Scale three times over 4 weeks. Intraclass correlation was excellent (0.88) over three time points. Pediatric Insomnia Autism Rating Scale is a valid dimensional measure of insomnia in autistic children that produces reliable scores.

Background: Concussions are a prevalent health concern, affecting millions of individuals in the United States yearly. Concussion symptomology overlaps with other conditions making diagnosis and management particularly challenging, particularly among individuals with ADHD. ADHD is a neurodevelopmental disorder that affects a significant portion of the adult population. Objective: To enhance our understanding of symptom resolution and identify factors that could influence concussion care management, the purpose of the current study was to examine the recovery trajectory of adults diagnosed with both ADHD and concussion compared to the trajectory of adults who have experienced a concussion but do not have an ADHD diagnosis. Methods: The study included a retrospective chart review of patients treated for concussion at a concussion specialty clinic. Results: The findings of the study revealed no significant differences in history of concussion or recovery time between patients with and without ADHD. It was observed that patients with ADHD had a higher prevalence of anxiety, depression, and other mental health conditions. Conclusions: The findings of the current study underscore the need for additional research to guide the care of patients diagnosed with both ADHD and concussion.

Background: The shortage of prescription stimulants is an ongoing issue that is impacting the ability of individuals with ADHD to access their medication. Amidst concerns that this shortage may have a substantial impact on individuals' ability to manage their symptoms effectively, this research seeks to understand the experiences and consequences for those affected. Methods: In this study, we interviewed individuals with ADHD who have been directly impacted by the stimulant shortage. Thematic analysis focused on identifying common themes related to challenges with medication access and the resulting effects on daily living. Results: The study uncovered significant difficulties in accessing ADHD medication due to current shortages, leading to disruptions in the management of ADHD symptoms and subsequent detriments to individuals' professional, educational, and personal lives. Systematic controls aimed at reducing nonmedical use were found to exacerbate these access issues, inadvertently compounding the challenges faced by those using medication for legitimate medical needs. Individuals also described ways they coped with the shortage, with some seeking ADHD medication via unofficial channels. Conclusion: Our findings highlight the urgency of addressing stimulant shortages to safeguard the wellbeing of individuals with ADHD. This study also calls for a critical review of policy measures regulating stimulant medication access, and their effectiveness at reducing non-medical use given the unintended consequences these regulations appear to have on individuals prescribed these medications for therapeutic purposes.

In light of the devastating effects of COVID-19 on early childhood care and education (ECCE), with this study we aimed at illuminating the self-efficacy and well-being of ECCE teacher educators, from the perspective of 9 participants in 7 higher education institutions (HEIs) across 5 South African provinces. The study, conducted by 2 ECCE teacher educators, was informed by the feminist ethics of care, combined with Bandura's Social Cognitive Theory, to understand self-efficacy, and Seligman's PERMA (positive emotions, engagement, relationships, meaning and accomplishments) theory of well-being. Semi-structured, online interviews using Microsoft Teams was used to produce the data. The findings reveal aspects that compromised self-efficacy and well-being, as well as aspects that energised them. All the participants reported that their institutions were under-prepared for the pandemic. They recognised that they lacked work-life balance and were at risk of burnout. Despite this, their resilience enabled them to develop a deeper interest and stronger commitment to their work, largely because of the support they had received from their colleagues. From the findings of the study we recognise that strong self-efficacy sustained teacher educators' professional practice despite the pandemic affecting their well-being in a negative way. In the context of building forward better and differently, this study points to the importance of developing responsive well-being programmes for staff in higher education institutions and communities of practice that are responsive to the needs of female teacher educators.

In recent years, young people engaged in political discourse and civic action online. U.S.-based social movements centered on equity issues, such as Black Lives Matter, Dreamers, and March for Our Lives, engaged young people in shaping and publicizing the goals of these movements through digital platforms. Increasingly in communities at the margins, young Americans need digital and media literacy skills to supplement contentious education restrictions within the United States, as with many state bills curtailing the teaching of LGBTQIA+ histories and critical race theory. With these considerations in mind, our team conducted a national study of impactful media literacy in the United States. The study included an extensive literature review, interviews with key stakeholders, and a national survey of educators within the United States. Aimed at understanding the practices in formal and informal learning spaces, the research process inspired the creation of a field guide focused on offering resources for equity-focused media literacy practices that can support educators where professional structures could not, a core finding from our study on impactful media literacy. This paper shares the process for creating the Field Guide for Equitable Media Literacy Practices, developed and published as a form of public-facing scholarship to encourage all media literacy practitioners to undergo a transformative learning process. The field guide offers a series of approaches to equitable media literacy practices centered on equity and inclusion. While the research is U.S.-based, we believe the practices suggested within the field guide apply globally, especially as we see an increase in youth movements that impact beyond geographic and cultural boundaries.

Past research identified various psychosocial indicators of college students' academic success. Using the affordance ecology framework, the present study explored the complex relations among different psychosocial indicators with a Bayesian Gaussian Graphical Model approach. Specifically, this study aims to uncover the general patterns of the psychosocial indicators, central variables, and the network centrality indices (network betweenness, closeness, and strength). The final sample consisted of 997 college students. Results showed that after accounting for the complex covariances of all indicators, sense of belonging, having the highest strength, was one of the most central factors in the network of psychosocial indicators and demonstrated a strong direct link to the rest of the psychosocial indicators. Variables relating to the family background and socioeconomic status, including perceived parental support, perceived family social status, and perceived personal financial situation, demonstrated high betweenness and closeness in the network. Implications for higher education research on the psychosocial experiences of students were discussed.

We center the voice of Dwyan Moore, a Black 12-year-old boy, during his transition of being diagnosed with a learning dis/Ability. We do so to grapple with the problem of disproportionate representation in special education along race and dis/Ability, with particular attention to educational leadership. Disproportionate representation is a reminder of the legacies of slavery and eugenics in United States public schools. We must address this enduring inequity. How we think, feel, and discuss such issues has systemic educational and equity implications for Black, Indigenous, and Youth of Color with dis/Abilities such as Dwyan. We end by promoting critical reflection and activities among educational school leaders on how student voices and agency can be included in dis/Ability transition planning and programming.

Performance conversations are a critical and necessary part of performance management. Feedback is most effective when it is constructive and when it involves a dialogue rather than a monologue, but people often struggle with this skill. This activity includes an experiential exercise that applies a five-part process for performance feedback, appropriate for human resources, conflict management, and/or organizational behavior classes. Students identify performance-based issues, create a plan to address the issues, craft an email to their employee requesting a meeting, meet with and engage in a performance feedback conversation, and develop an improvement plan collaboratively with the employee. "Managers" and "employees" reflect on the effectiveness of the performance conversation. This five-part exercise can be used in an undergraduate- or graduate-level course. Recommendations for adapting the exercise to the online environment are included.

A robust literature is developing around how the stress of discrimination is implicated in individual- and group-level sleep disturbances, and how these disturbances contribute to the development of population-level sleep disparities over time. Although discrimination can be based on many individual and intersecting biases, like gender, sexuality, socioeconomic status, and education, in this article, we focus on discrimination rooted in ethnicity and race because of the well-founded documentation of disparities in sleep by race. Focusing primarily on adolescence and young adulthood, we integrate research linking ethnic and racial discrimination to sleep across a variety of methods and developmental time spans, ending with reflections on interventions. In so doing, we seek to advance research and encourage conversations that cross-fertilize collaborations between those with interests in discrimination, sleep, and population-level health equity.

In this study we explore the longitudinal impact of effective school factors on student achievement over a five-year period in an urban school district. By collecting teacher survey data from urban schools in a Midwest school district and analyzing the survey data alongside student achievement, we identified several factors associated with student achievement growth. Our findings reveal that Shared Vision and Goals is positively associated with student achievement growth in math and reading. Furthermore, Student Behavior Expectations and Behavior Management Practices are positively associated with growth in reading achievement. Our research contributes to the understanding of effective school factors from a longitudinal perspective, particularly in an urban school setting.

We examined early adolescent predictors of later distress and adaptive coping in early adulthood, using data from a prospective longitudinal cohort study (n = 786). In early adolescence (age 13), we assessed indicators of mental health (internalizing symptoms), stressor exposure (cumulative stressful life events), and family socialization (supportive parent-child interactions). In early adulthood (age 22), during the first COVID-19-related Swiss national lockdown, we assessed cumulative pandemic-related stressors, distress (poor well-being, hopelessness, and perceived disruptions to life) and adaptive coping. Early adolescent internalizing symptoms predicted lower well-being, more hopelessness, and perceived lifestyle disruptions in early adulthood, during the pandemic. Cumulative stressful life events during early adolescence moderated the association between cumulative pandemic-related stressors and perceived lifestyle disruptions. Supportive parent-child interactions fostered subsequent engagement in adaptive coping, which, in turn, predicted less hopelessness and better well-being. Findings reveal that early adolescent development is linked with distress and adaptive coping in later periods.

The regulation of cell physiology depends largely upon interactions of functionally distinct proteins and cellular components. These interactions may be transient or long-lived, but often affect protein motion. Measurement of protein dynamics within a cellular environment, particularly while perturbing protein function with small molecules, may enable dissection of key interactions and facilitate drug discovery; however, current approaches are limited by throughput with respect to data acquisition and analysis. As a result, studies using super-resolution imaging are typically drawing conclusions from tens of cells and a few experimental conditions tested. We addressed these limitations by developing a high-throughput single-molecule tracking (htSMT) platform for pharmacologic dissection of protein dynamics in living cells at an unprecedented scale (capable of imaging >106 cells/day and screening >104 compounds). We applied htSMT to measure the cellular dynamics of fluorescently tagged estrogen receptor (ER) and screened a diverse library to identify small molecules that perturbed ER function in real time. With this one experimental modality, we determined the potency, pathway selectivity, target engagement, and mechanism of action for identified hits. Kinetic htSMT experiments were capable of distinguishing between on-target and on-pathway modulators of ER signaling. Integrated pathway analysis recapitulated the network of known ER interaction partners and suggested potentially novel, kinase-mediated regulatory mechanisms. The sensitivity of htSMT revealed a new correlation between ER dynamics and the ability of ER antagonists to suppress cancer cell growth. Therefore, measuring protein motion at scale is a powerful method to investigate dynamic interactions among proteins and may facilitate the identification and characterization of novel therapeutics.

This piece was inspired by a video of a Ukrainian violinist playing this Ukrainian folk melody in a bomb shelter.Nich yaka misyachna (The night is so moonlit) speaks of love and a beautiful starlit night. However, the melody is set here with dissonance, using a tone row to create tension between the beauty and comfort of the folk melody against the war, turmoil and fear of those sheltering underground.The tone row is used in prime and retrograde transpositions, and for harmonic clusters.     Prime Row 0: Eb-A-F-F#-C-E-D-Bb-C#-G-B-Ab

OBJECTIVE: To study the association between dietary patterns and subgingival microbiota. METHODS: Participants (n = 651) who were enrolled in the Oral Infections, Glucose Intolerance, and Insulin Resistance Study (ORIGINS) with subgingival plaque sampling (n = 890 plaques) and a dietary assessment were included. 16S rRNA gene amplicon sequences of subgingival plaque from sites with either probing depth

In June of 2023, the Nevada Legislature passed the state’s 2023-2025 budget. Buoyed by continued increases in the state’s share of the sales taxes and revenue tied to gaming, entertainment, and tourism as well as business activity, the $10.9 billion general fund budget was the largest in Nevada’s history. After four years of unified Democratic control of state government, the 2023 session was the first budget passed under divided government since 2017. While partisan and interbranch tensions were ever present as evidenced by a record 75 vetoed bills, Nevada’s Republican governor and Democratic-controlled legislature supported substantial investments in K-12 education and state employees. Enthusiasm for long-term spending obligations, however, was tempered by the fact that the general fund budget’s two largest revenue drivers—sales and gaming taxes—fluctuate with macroeconomic conditions. The continued reliance on these revenue sources perpetuates Nevada’s history of booms and busts and undermines the state’s ability to make long-term investments in its human capital and physical infrastructure. Consequently, the budget choices adopted by the governor and legislature reflected broad compromises and investments, while other areas, including costly but much needed reforms to state government, went unaddressed.

Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWASs) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWASs) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWASs) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWASs and TWASs can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p values across all the genes, which suggests high-level consistency between proteome-lipid associations and transcriptome-lipid associations.

BackgroundLeadership skills are essential for middle-level healthcare manager efficacy. Capacity-building efforts may attempt behavioural change by filling 'knowledge gaps' while neglecting a sustainable application of that knowledge. Sustainable application of that knowledge, or implementation know-how, must resonate with local cultural patterns. When it is neglected, root issues like unclear decision-making space and local authority to interpret policy during implementation remain unaddressed. Particularly in decentralized healthcare systems, the impact can appear in implementation challenges, subjective decision-making, poor teamwork, and an absence of disseminating best practices.ObjectivesThe SEARCH-IPT trial led a series of mini-collaborative meetings, which provided business leadership and management training for an intervention group of mid-level healthcare system managers in rural Eastern, East-Central, and Southwestern Uganda to see whether this would increase uptake of isoniazid-prevention therapy (IPT) for people living with HIV (PLHIV) in intervention districts. IPT is known to reduce active tuberculosis (TB), a leading cause of death among PLHIV, by 40-60%.MethodsWe performed a thematic analysis of six focus-group discussions from this intervention (held in May 2019, January 2020, September 2021) and 23 key informant interviews with control group participants (between February and August 2019 and September and December 2020).ResultsAnalysis revealed five implementation skill sets District Health Officers (DHOs) and District Tuberculosis and Leprosy Supervisors (DTLSs) deployed to achieve sustainable implementation and realize their decision-making space. The five practices were as follows: data-based decision-making, root-cause analysis, quality assurance, evidence-based empowerment, and sharing best practices with colleagues.ConclusionThese practices reached beyond outcome measures to address root problems around the DHO's range of authority and elicit buy-in from district health workers. For successful capacity building at the mid-manager level, focusing on core practices as part of competency is objectively implementable and measurable at the system level and does not rely on DHO self-assessments.

Bile acids (BA) are among the most abundant metabolites produced by the gut microbiome. Primary BAs produced in the liver are converted by gut bacterial 7-α-dehydroxylation into secondary BAs, which can differentially regulate host health via signaling based on their varying affinity for BA receptors. Despite the importance of secondary BAs in host health, the regulation of 7-α-dehydroxylation and the role of diet in modulating this process is incompletely defined. Understanding this process could lead to dietary guidelines that beneficially shift BA metabolism. Dietary fiber regulates gut microbial composition and metabolite production. We tested the hypothesis that feeding mice a diet rich in a fermentable dietary fiber, resistant starch (RS), would alter gut bacterial BA metabolism. Male and female wild-type mice were fed a diet supplemented with RS or an isocaloric control diet (IC). Metabolic parameters were similar between groups. RS supplementation increased gut luminal deoxycholic acid (DCA) abundance. However, gut luminal cholic acid (CA) abundance, the substrate for 7-α-dehydroxylation in DCA production, was unaltered by RS. Further, RS supplementation did not change the mRNA expression of hepatic BA producing enzymes or ileal BA transporters. Metagenomic assessment of gut bacterial composition revealed no change in the relative abundance of bacteria known to perform 7-α-dehydroxylation. P. ginsenosidimutans and P. multiformis were positively correlated with gut luminal DCA abundance and increased in response to RS supplementation. These data demonstrate that RS supplementation enriches gut luminal DCA abundance without increasing the relative abundance of bacteria known to perform 7-α-dehydroxylation.

Knowledge about seafloor depth, or bathymetry, is crucial for various marine activities, including scientific research, offshore industry, safety of navigation, and ocean exploration. Mapping the central Arctic Ocean is challenging due to the presence of perennial sea ice, which limits data collection to icebreakers, submarines, and drifting ice stations. The International Bathymetric Chart of the Arctic Ocean (IBCAO) was initiated in 1997 with the goal of updating the Arctic Ocean bathymetric portrayal. The project team has since released four versions, each improving resolution and accuracy. Here, we present IBCAO Version 5.0, which offers a resolution four times as high as Version 4.0, with 100 × 100 m grid cells compared to 200 × 200 m. Over 25% of the Arctic Ocean is now mapped with individual depth soundings, based on a criterion that considers water depth. Version 5.0 also represents significant advancements in data compilation and computing techniques. Despite these improvements, challenges such as sea-ice cover and political dynamics still hinder comprehensive mapping.

Rare earth tris(alkyl) complexes such as M(CH2SiMe3)3(sol) n are widely used as precursors for many compounds and as homogeneous catalysts for alkene polymerization and alkane functionalization. However, the thermal instability of those most conveniently made from the commercially available lithium salt of the neosilyl anion, LiCH2SiMe3, Li(r), restricts their utility. We present a new range of synthetically useful, more kinetically stable rare earth neosilyl solvates, derived from a full kinetic study of the various possible decomposition mechanisms of 7 known and 12 new solvated rare earth neosilyl complexes M(CH2SiMe3)3(sol) n M = Sc(iii), Y(iii), Lu(iii), Sm(iii), and sol = THF; TMEDA; DMPE; diglyme ((CH3)2(OCH2CH2)2O, G2), triglyme ((CH3)2(OCH2CH2)3O, G3). Surprisingly, simply using higher-denticity donors to sterically disfavor neosilyl γ-H elimination is not effective. While Sc(r)3((CH3)2(OCH2CH2)2O) has a half-life, t 1/2, of 258.1 h, six times longer than for Sc(r)3(C4H8O)2 (t 1/2 = 43 h), Lu(r)3((CH3)2(OCH2CH2)2O) and Y(r)3((CH3)2(OCH2CH2)2O) do not show the expected, analogous increased t 1/2. This is because new decomposition pathways appear for poorly fitting donors. Finally, kinetic studies demonstrate the impact of small, and increasing amounts of LiCl on the kinetics of the reactivity of the smaller alkyls Y(r)3(THF)2 and Lu(r)3(THF)2; molecules used in hydrocarbon chemistry and catalysis for fifty years. A new route to pure Y(r)3(THF)2, which avoids the traditional use of Li(r), is presented.

PURPOSE: Little is known about serious illness conversations (SIC) conducted during telemedicine visits and their impact on end-of-life (EOL) outcomes for patients with advanced cancer. PATIENTS AND METHODS: We conducted a retrospective analysis telemedicine visits for patients with metastatic lung cancer conducted during the first surge of the COVID-19 pandemic (October 3, 2020-October 6, 2020). We used natural language processing (NLP) to characterize documentation of SIC domains (ie, goals of care [GOC], limitation of life-sustaining treatment [LLST], prognostic awareness [PA], palliative care [PC], and hospice). We used unadjusted logistic regression to evaluate factors associated with SIC documentation and the relationship between SIC documentation and EOL outcomes. RESULTS: The study included 634 telemedicine visits across 360 patients. Documentation of at least one SIC domain was present in 188 (29.7%) visits with GOC and PA being the most discussed domains. Family presence (odds ratio [OR], 1.66; P = .004), progressive or newly diagnosed disease (OR, 5.42; P

BackgroundRapid diagnosis of tuberculosis (TB) is important for improving outcomes and reducing transmission. Previous studies assessing the impact of Xpert MTB/RIF (Xpert), a molecular assay that provides results within 2 h, on mortality have been inconclusive. In this planned analysis of a pragmatic cluster-randomized trial in Uganda, we assessed whether a multicomponent strategy, including decentralized Xpert testing, decreased mortality among adults evaluated for TB.MethodsTen community health centers were randomized, using a computer-generated randomization sequence, to the XPEL-TB intervention (on-site Xpert testing plus implementation supports) and ten to routine TB care without any modifications (on-site smear microscopy and referral-based Xpert testing for selected patients). The trial included all adults ( ≥ 18 years of age) undergoing evaluation for presumptive TB at each trial health center. All-cause mortality was a secondary outcome of the trial. For this analysis, the primary outcome was the mortality rate (censored at 18 months), and the secondary outcome was the six-month mortality risk. We compared the outcomes between trial arms using cluster-level analyses to account for stratified randomization and patient-level covariates. The trial was registered with the US National Institutes of Health (identifier: NCT03044158) and the Pan African Clinical Trials Registry (identifier: PACTR201610001763265).FindingsVital status was ascertained for 8413 of 9563 (88%) XPEL-TB trial participants who presented at the health centers from October 22, 2018 through February 29, 2020. The adjusted rate ratio (aRR) was 0.77 (95% CI: 0.47-1.28), comparing the intervention (145 deaths/3655 person-years) to routine care (154 deaths/3015 person-years). In sub-group analyses, point estimates for mortality were lower in the intervention arm among people without HIV (aRR = 0.50, 95% CI: 0.26-0.96) and among females (aRR = 0.64, 95% CI: 0.33-1.23). The mortality risk analysis yielded similar results.InterpretationConsistent point estimates favoring the intervention in our trial and previous ones suggest that Xpert testing may have an impact on mortality at community health centers. However, the magnitude of effect is small, and statistically significant results are unlikely to be attained within a single trial. Future trials of novel TB diagnostics at community health centers should focus on more proximal outcomes including TB detection and treatment initiation.FundingThis work was supported by the National Heart, Lung, and Blood Institute of the US National Institutes of Health under award number R01HL130192.

BACKGROUND: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the region-level neuroanatomical properties of the orbitofrontal cortex (OFC), but not posteromedial cortex (PMC). Informed by a growing body of research indicating that examining the morphology of specific cortical folds (sulci) can produce unique insights into behavioral outcomes, the present study modeled the association between ERI and the morphology of sulci within OFC and PMC, which is a finer scale than previously conducted. METHODS: Analyses were conducted in a transdiagnostic sample of 118 adult individuals with a broad range of psychiatric syndromes. First, we manually defined over 4,000 sulci across 236 cerebral hemispheres. Second, we implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI. Third, we tested whether effects were specific to OFC sulci, sulcal depth, and ERI (as compared to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity). RESULTS: The LASSO regression revealed bilateral associations of ERI with the depths of eight OFC sulci. These effects were strongest for OFC sulci, sulcal depth, and ERI in comparison to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker. CONCLUSIONS: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.

Few studies have measured components of stress responses in real time-an essential step in designing just-in-time interventions targeting moments of risk. Using ecological momentary assessment (EMA), we characterised stress response components to everyday stressors, including reactivity (the response following a stressor), recovery (the return towards baseline), and pile-up (the accumulation of stressors) (RRPs) by quantifying the dynamics of response indicators (i.e., subjective stress, negative affect, and perseverative cognition). To determine the utility of these novel measures in capturing and characterising acute moments of the stress response, this study evaluated the proportion of variance in RRPs attributed to (1) between-person, (2) between-days, and (3) within-day (momentary) levels. Healthy adults (n = 123; aged 35-65, 79% women, 91% non-Hispanic White) participated in a 14-day study assessing stress response via EMA 6 times a day. RRPs were constructed from 10,065 EMA reports. Multilevel models with moments nested within days nested within persons were used to partition variance in the RRPs. Reactivity and recovery indicators captured the most variation within-days (i.e., across moments; range 76%-80% and 87%-89%, respectively), with small amounts of variance between-person. For pile-up, variation was mostly observed between-days (range 60%-63%) and between-persons (range 27%-31%). In contrast, raw measures of stress response reflected substantial between-person (range 32%-54%) and within-day (range 34%-53%) variance. These results demonstrated that a person-specific approach to measuring stress response components (i.e., RRPs) can capture the dynamic within-person variation in stress response, as it occurs in real time, making it well-suited for use in novel just-in-time interventions targeting moments of risk.

Rab11 family interacting protein 4 (Rab11-FIP4) regulates endocytic trafficking. A possible role for Rab11-FIP4 in the regulation of lysosomal function has been proposed, but its precise function in the regulation of cellular homeostasis is unknown. By mRNA array and protein analysis, we found that Rab11-FIP4 is downregulated in the lysosomal storage disease cystinosis, which is caused by genetic defects in the lysosomal cystine transporter, cystinosin. Rescue of Rab11-FIP4 expression in Ctns-/- fibroblasts re-established normal autophagosome levels and decreased LC3B-II expression in cystinotic cells. Furthermore, Rab11-FIP4 reconstitution increased the localization of the chaperone-mediated autophagy receptor LAMP2A at the lysosomal membrane. Treatment with genistein, a phytoestrogen that upregulates macroautophagy, or the CMA activator QX77 (CA77) restored Rab11-FIP4 expression levels in cystinotic cells supporting a cross-regulation between two independent autophagic mechanisms, lysosomal function and Rab11-FIP4. Improved cellular homeostasis in cystinotic cells rescued by Rab11-FIP4 expression correlated with decreased endoplasmic reticulum stress, an effect that was potentiated by Rab11 and partially blocked by expression of a dominant negative Rab11. Restoring Rab11-FIP4 expression in cystinotic proximal tubule cells increased the localization of the endocytic receptor megalin at the plasma membrane, suggesting that Rab11-FIP4 reconstitution has the potential to improve cellular homeostasis and function in cystinosis.

Illness narratives invite practitioners to understand how biomedical and traditional health information is incorporated, integrated, or otherwise internalized into a patient's own sense of self and social identity. Such narratives also reveal cultural values, underlying patterns in society, and the overall life context of the narrator. Most illness narratives have been examined from the perspective of European-derived genres and literary theory, even though theorists from other parts of the globe have developed locally relevant literary theories. Further, illness narratives typically examine only the experience of illness through acute or chronic suffering (and potential recovery). The advent of biomedical disease prevention methods like post- and pre-exposure prophylaxis (PEP and PrEP) for HIV, which require daily pill consumption or regular injections, complicates the notion of an illness narrative by including illness prevention in narrative accounts. This paper has two aims. First, we aim to rectify the Eurocentrism of existing illness narrative theory by incorporating insights from African literary theorists; second, we complicate the category by examining prevention narratives as a subset of illness narratives. We do this by investigating several narratives of HIV prevention from informants enrolled in an HIV prevention trial in Kenya and Uganda in 2022.

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

Accessible and easy-to-use standardized bioinformatics workflows are necessary to advance microbiome research from observational studies to large-scale, data-driven approaches. Standardized multi-omics data enables comparative studies, data reuse, and applications of machine learning to model biological processes. To advance broad accessibility of standardized multi-omics bioinformatics workflows, the National Microbiome Data Collaborative (NMDC) has developed the Empowering the Development of Genomics Expertise (NMDC EDGE) resource, a user-friendly, open-source web application (https://nmdc-edge.org). Here, we describe the design and main functionality of the NMDC EDGE resource for processing metagenome, metatranscriptome, natural organic matter, and metaproteome data. The architecture relies on three main layers (web application, orchestration, and execution) to ensure flexibility and expansion to future workflows. The orchestration and execution layers leverage best practices in software containers and accommodate high-performance computing and cloud computing services. Further, we have adopted a robust user research process to collect feedback for continuous improvement of the resource. NMDC EDGE provides an accessible interface for researchers to process multi-omics microbiome data using production-quality workflows to facilitate improved data standardization and interoperability.

Fine particulate matter (PM2.5) exposure can induce immune system pathology via epigenetic modification, affecting pregnancy outcomes. Our study investigated the association between PM2.5 exposure and immune response, as well as epigenetic changes using high-dimensional epigenetic landscape profiling using cytometry by time-of-flight (EpiTOF) at the single cell. We found statistically significant associations between PM2.5 exposure and levels of certain cytokines [interleukin-1RA (IL-1RA), IL-8/CXCL8, IL-18, and IL-27)] and histone posttranslational modifications (HPTMs) in immune cells (HPTMs: H3K9ac, H3K23ac, H3K27ac, H2BK120ub, H4K20me1/3, and H3K9me1/2) among pregnant and nonpregnant women. The cord blood of neonates with high maternal PM2.5 exposure showed lower IL-27 than those with low exposure. Furthermore, PM2.5 exposure affects the co-modification profiles of cytokines between pregnant women and their neonates, along with HPTMs in each immune cell type between pregnant and nonpregnant women. These modifications in specific histones and cytokines could indicate the toxicological mechanism of PM2.5 exposure in inflammation, inflammasome pathway, and pregnancy complications.

Many medical conditions impair proprioception but there are few easy-to-deploy technologies for assessing proprioceptive deficits. Here, we developed a method-called OpenPoint-to quantify upper extremity (UE) proprioception using only a webcam as the sensor. OpenPoint automates a classic neurological test: the ability of a person to use one hand to point to a finger on their other hand with vision obscured. Proprioception ability is quantified with pointing error in the frontal plane measured by a deep-learning-based, computer vision library (MediaPipe). In a first experiment with 40 unimpaired adults, pointing error significantly increased when we replaced the target hand with a fake hand, verifying that this task depends on the availability of proprioceptive information from the target hand, and that we can reliably detect this dependence with computer vision. In a second experiment, we quantified UE proprioceptive ability in 16 post-stroke participants. Individuals post stroke exhibited increased pointing error (p < 0.001) that was correlated with finger proprioceptive error measured with an independent, robotic assessment (r = 0.62, p = 0.02). These results validate a novel method to assess UE proprioception ability using affordable computer technology, which provides a potential means to democratize quantitative proprioception testing in clinical and telemedicine environments.

UNLABELLED: This study characterized and compared the fecal and oral microbiota from women with early-stage breast cancer (BC), women with ductal carcinoma in situ (DCIS), and healthy women. Fecal and oral samples were collected from newly diagnosed patients prior to any therapy and characterized using 16S rRNA sequencing. Measures of gut microbial alpha diversity were significantly lower in the BC vs healthy cohort. Beta diversity differed significantly between the BC or DCIS and healthy groups, and several differentially abundant taxa were identified. Clustering (non-negative matrix factorization) of the gut microbiota identified five bacterial guilds dominated by Prevotella, Enterobacteriaceae, Akkermansia, Clostridiales, or Bacteroides. The Bacteroides and Enterobacteriaceae guilds were significantly more abundant in the BC cohort compared to healthy controls, whereas the Clostridiales guild was more abundant in the healthy group. Finally, prediction of functional pathways identified 23 pathways that differed between the BC and healthy gut microbiota including lipopolysaccharide biosynthesis, glycan biosynthesis and metabolism, lipid metabolism, and sphingolipid metabolism. In contrast to the gut microbiomes, there were no significant differences in alpha or beta diversity in the oral microbiomes, and very few differentially abundant taxa were observed. Non-negative matrix factorization analysis of the oral microbiota samples identified seven guilds dominated by Veillonella, Prevotella, Gemellaceae, Haemophilus, Neisseria, Propionibacterium, and Streptococcus; however, none of these guilds were differentially associated with the different cohorts. Our results suggest that alterations in the gut microbiota may provide the basis for interventions targeting the gut microbiome to improve treatment outcomes and long-term prognosis. IMPORTANCE: Emerging evidence suggests that the gut microbiota may play a role in breast cancer. Few studies have evaluated both the gut and oral microbiomes in women with breast cancer (BC), and none have characterized these microbiomes in women with ductal carcinoma in situ (DCIS). We surveyed the gut and oral microbiomes from women with BC or DCIS and healthy women and identified compositional and functional features of the gut microbiota that differed between these cohorts. In contrast, very few differential features were identified in the oral microbiota. Understanding the role of gut bacteria in BC and DCIS may open up new opportunities for the development of novel markers for early detection (or markers of susceptibility) as well as new strategies for prevention and/or treatment.

While the tropical Pacific teleconnection to North America has been studied extensively, the impact of the Indian Ocean on North American climate has received less attention. Here, through observational analysis and hierarchy atmospheric model simulations with different complexity, we find that the Indian Ocean plays a crucial role in North American winter climate through a teleconnection termed the Indian Ocean - North America pattern. We show that in the warm Indian Ocean phase, this teleconnection contributes to anomalously cold winters along the west coast of the United States through advection with increased mountain snowfall, while simultaneously leading to warmer conditions over the Great Lakes region. Snow-albedo feedback amplifies these Rossby wave-induced surface anomalies. Remarkably, this teleconnection pattern is at work on both interannual and multi-decadal time scales, with its climatic impact being slightly less pronounced than that induced by tropical Pacific sea surface temperature anomalies. Our findings underscore the significance of the Indian Ocean in both the prediction and future projection of North American climate.

Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial (MT) Chromosomes. We genotyped the Y and MT Chromosomes in heterogeneous stock (HS) rats (Rattus norvegicus), an outbred population created from 8 inbred strains. We identified 8 distinct Y and 4 distinct MT Chromosomes among the 8 founders. However, only 2 types of each nonrecombinant chromosome were observed in our modern HS rat population (generations 81-97). Despite the relatively large sample size, there were virtually no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and MT Chromosomes were strongly associated with the expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern HS rats there are no Y and MT Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and MT Chromosomes that do not appear in modern HS rats, nor do they address effects that may exist in other rat populations, or in other species.

We describe the development, operation, and application of the 4D Camera-a 576 by 576 pixel active pixel sensor for scanning/transmission electron microscopy which operates at 87,000 Hz. The detector generates data at ∼480 Gbit/s which is captured by dedicated receiver computers with a parallelized software infrastructure that has been implemented to process the resulting 10-700 Gigabyte-sized raw datasets. The back illuminated detector provides the ability to detect single electron events at accelerating voltages from 30 to 300 kV. Through electron counting, the resulting sparse data sets are reduced in size by 10--300× compared to the raw data, and open-source sparsity-based processing algorithms offer rapid data analysis. The high frame rate allows for large and complex scanning diffraction experiments to be accomplished with typical scanning transmission electron microscopy scanning parameters.

INTRODUCTION: Perspectives on long-acting injectable cabotegravir/rilpivirine (CAB/RPV-LA) from HIV health disparity populations are under-represented in current literature yet crucial to optimize delivery. METHODS: Between August 2022 and May 2023, we conducted in-depth interviews with people with HIV (PWH) at four HIV clinics in Atlanta, Chicago and San Francisco. Eligibility criteria were current CAB/RPV-LA use with receipt of ≥3 injections or CAB/RPV-LA discontinuation. We purposefully sampled for PWH who initiated with viraemia (plasma HIV RNA >50 copies/ml) due to adherence challenges, discontinuers, and cis and trans women. Interviews were coded and analysed using thematic methods grounded in descriptive phenomenology. Clinical data were abstracted from the medical record. RESULTS: The sample (San Francisco n = 25, Atlanta n = 20, Chicago n = 14 for total n = 59, median number of injections = 6) consisted of 48 PWH using CAB/RPV-LA and 11 who had discontinued. The median age was 50 (range 25-73) and 40 (68%) identified as racial/ethnic minorities, 19 (32%) cis or trans women, 16 (29%) were experiencing homelessness/unstable housing, 12 (20%) had recently used methamphetamine or opioids and 11 (19%) initiated with viraemia. All participants except one (who discontinued) had evidence of viral suppression at interview. Typical benefits of CAB/RPV-LA included increased convenience, privacy and freedom from being reminded of HIV and reduced anxiety about forgetting pills. However, PWH who became virally suppressed through CAB/RPV-LA use also experienced an amelioration of feelings of shame and negative self-worth related to oral adherence challenges. Regardless of baseline viral suppression status, successful use of CAB/RPV-LA amplified positive provider/clinic relationships, and CAB/RPV-LA was often viewed as less work than oral antiretroviral therapy, which created space to attend to other aspects of health and wellness. For some participants, CAB/RPV-LA remained work, particularly with regard to injection site pain and visit frequency. At times, these burdens outweighed the aforementioned benefits, resulting in discontinuation. CONCLUSIONS: CAB/RPV-LA offers a range of logistical, psychosocial and care engagement benefits, which are experienced maximally by PWH initiating with viraemia due to adherence challenges; however, benefits do not always outweigh treatment burdens and can result in discontinuation. Our findings on rationales for persistence versus discontinuation can inform both initial and follow-up patient counselling.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

The Data Acquisition System (DAQ) for the LUX-ZEPLIN (LZ) dark matter detector is described. The signals from 745 PMTs, distributed across three subsystems, are sampled with 100-MHz 32-channel digitizers (DDC-32s). A basic waveform analysis is carried out on the on-board Field Programmable Gate Arrays (FPGAs) to extract information about the observed scintillation and electroluminescence signals. This information is used to determine if the digitized waveforms should be preserved for offline analysis. The system is designed around the Kintex-7 FPGA. In addition to digitizing the PMT signals and providing basic event selection in real time, the flexibility provided by the use of FPGAs allows us to monitor the performance of the detector and the DAQ in parallel to normal data acquisition. The hardware and software/firmware of this FPGA-based Architecture for Data acquisition and Realtime monitoring (FADR) are discussed and performance measurements are described.

IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

IntroductionVariants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.MethodsWe described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.ResultsANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.DiscussionThis study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.HighlightsANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.