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Culturally-adapted evidence-based programs (EBPs) are needed to promote healthy behaviors among Native teens and young adults. Little is known about the facilitators and barriers of implementing and sustaining EBPs in Native communities. This paper aims to identify those factors described by educators who implemented the Native Students Together Against Negative Decisions (STAND) curriculum. Methods: We conducted qualitative, semi-structured interviews with 44 Native STAND educators from 48 sites throughout the United States. We used a modified grounded theory approach to explore barriers, facilitators, and sustainability factors related to implementing Native STAND. Results: We learned that disruptions to staffing, coordination, and organizational factors were the most common barriers. Factors that improved implementation success included: tailoring the program to local needs/constraints, having a supportive Project Manager, improved fidelity due to check-in calls, and participation in summer training. Factors that improved sustainability included: access to needed infrastructure, administrative support, community support, and student interest. Discussion: The delivery of Native STAND was further improved by person-to-person communication and resource sharing across sites. Sustaining EBPs in AI/AN settings requires culturally-tailored technical assistance, sufficient implementation funds for materials and staffing, and a community of peer educators to inspire forward progress. Conclusion: EBPs that reflect the needs and experiences of American Indian and Alaska Native (AI/AN) youth are necessary to address systemic inequities in adolescent health outcomes. The Native STAND Dissemination and Implementation study is among the first to assess facilitators and barriers to program delivery in diverse AI/AN settings.

Background: The COVID-19 pandemic negatively affected adolescent mental health due to school closures, isolation, family loss/hardships, and reduced health care access. Methods: We compared adolescent mental health in Rhode Island before versus during the pandemic, separately among middle and high schoolers. This serial cross-sectional study used Youth Risk Behavior Survey data from 2019 and 2021 (N = 7403). Multivariable logistic regression models estimated the association between year and mental health status, adjusting for sociodemographics. Results: Middle schoolers in 2021 had higher odds of ever seriously considering suicide (22.6% vs 16.7%) and ever attempting suicide (9.3% vs 6.1%) compared to 2019. Among high schoolers, those in 2021 had higher odds of experiencing persistent sadness/hopelessness in the past year (37.4% vs 32.0%). However, high schoolers in 2019 and 2021 had similar odds of considering suicide in the past year, while those in 2021 had lower odds of having attempted suicide in the past year (8.5% vs 14.6%). Conclusion: The COVID-19 pandemic may have worsened multiple aspects of adolescent mental health in Rhode Island, particularly among middle schoolers. Implications for school health policy, practice, and equity: Promoting school connectedness, creating supportive environments, and diversifying the mental health workforce may help overcome adverse pandemic effects.

Co-teaching allows educators to take on specific roles and responsibilities in the classroom leading to more effective instruction. With increased expectations to embrace technologies provided during virtual and hybrid instruction, co-teachers are taking on more technology-based responsibilities in face-to-face instruction. In this article, the authors pose a new co-teaching strategy, "One Teach-One Tech," which intentionally delegates technology tasks during co-planning, instruction, and assessment. This strategy can be used with existing co-teaching models to support the effective implementation and innovative use of technology to support students in inclusive, co-taught classrooms. After defining this proposed strategy, the authors present and explore strategies for implementation, benefits, and challenges of this co-teaching strategy.

Background: Communicating with people with severe/profound intellectual disabilities is essential for person-centred, rights-based support. Despite a proliferation of research around COVID-19, there is a dearth of evidence exploring its impact on communication with people with severe/profound intellectual disabilities. This study aimed to explore disability support staff experiences of communicating with people with severe/profound intellectual disabilities through the COVID-19 pandemic. Methods: A qualitative descriptive study was undertaken. A purposive sample of six disability support staff who supported people with severe/profound intellectual disabilities through the pandemic in four Irish residential services participated in online, semistructured interviews. Data were analysed thematically. Findings: Six themes were generated including unwavering commitment; running on empty; being a safe haven; empathic understanding; heightened sensitivity and new insights. Participants discussed the impact of COVID-19 on communicating with people they support, the contextual challenges, how these were managed/overcome and new learning that emerged. Although communication challenges did present because of COVID-19 restrictions, communication remained a priority. Conclusions: Despite the challenges experienced by disability support workers, their unwavering commitment to ensuring the well-being of people with severe/profound intellectual disabilities was identified. This was a small-scale qualitative study but highlights areas warranting further research and makes recommendations for practice and service planning.

The Positive Outcomes With Emotion Regulation (POWER) Program is a transdiagnostic intervention for adolescents at risk of developing emotional disorders. The POWER Program was designed to be implemented in secondary schools, by school personnel with or without specialized mental health training, as a Tier 2 intervention. In this pilot study, the POWER Program was implemented by school psychologists and school psychologists-in-training and evaluated across four focal student participants using a multiple-baseline-across-participants single-case design. Program efficacy was assessed using systematic direct classroom observations of student negative affect and social engagement as well as student and caregiver ratings of emotional and behavioral symptoms. Program usability was assessed through rating scales completed by intervention facilitators and student participants. Overall, results provide evidence of the POWER Program's small- to large-sized effects on students' emotional and behavioral functioning as observed in the classroom and self-reported by students. In addition, results suggest implementation facilitators' and students' positive impressions of the program, evident in ratings of high understanding, feasibility, and acceptability across groups. Study limitations are highlighted with attention to opportunities to further refine and evaluate the POWER Program.

This exploratory study evaluated the effects of self-regulated strategy development (SRSD) on students' written expression when asked to solve a word problem and explain reasoning. A secondary question evaluated potential for differential effects based on determination of having mathematics difficulty (MD). We implemented a quasi-experimental design with 163 students with and without MD in grade 4. Results indicated that students in the treatment group (n = 83) significantly outperformed students in the comparison group (n = 80) on measures of mathematical writing involving subtraction and division word problems. For the subtraction problems, students in the treatment group improved their overall written expression of mathematics scores (g = 0.688), yielding a medium effect. The intervention differentially benefited students without MD. Our findings call for greater integration of systematic writing opportunities in mathematics and highlight the importance of explicitly teaching students how to approach the written expression of their mathematical reasoning.

Autistic youth engage in higher levels of screen time and are more likely to experience mental health problems than their typically developing peers; however, few studies have investigated a potential relationship between daily screen time hours and mental health in autistic youth. This study examined the relations among daily screen time hours and commonly co-occurring psychopathology (i.e., anxiety, depression, conduct/behavioral problems, and attention-deficit/hyperactivity disorder [ADHD]) in autistic youth utilizing data from the 2018-2019 National Survey of Children's Health. Results indicated screen time was significantly related to conduct problems; however, contrary to findings from studies with neurotypical samples, screen time was not significantly related to anxiety, depression, or ADHD diagnoses in autistic children and adolescents.

The use of immersive virtual reality (iVR) technology creates an infinite set of possibilities for language learners both inside and outside the traditional classroom setting. In contributing a deeper understanding of language education with iVR, the present study explored how low-proficiency level English learners perceived iVR and how iVR benefited language learning. This mixed-method study included qualitative data (screen and in-class recordings, post-interviews) and quantitative data (pre-and posttests, post-surveys). Twenty-five 4th graders in a Korean elementary school participated in this study and the study explored their language learning experiences with an iVR platform, Immerse. Findings showed that the students perceived the activities in iVR as motivating, enjoyable, and useful for learning English. Specifically, the current study investigated students' behavioral, affective, and cognitive engagement. The results showed that the iVR learning environment had a positive impact on students' engagement in all three dimensions. The pre- and post-test results indicated that learning outcomes were significantly enhanced after the iVR sessions. The study suggests pedagogical implications to effectively utilize iVR technology for language learning based on the results.

To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

Hard ticks (Acari: Ixodidae) have been historically identified by morphological methods which require highly specialized expertise and more recently by DNA-based molecular assays that involve high costs. Although both approaches provide complementary data for tick identification, each method has limitations which restrict their use on large-scale settings such as regional or national tick surveillance programs. To overcome those obstacles, the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been introduced as a cost-efficient method for the identification of various organisms, as it balances performance, speed, and high data output. Here we describe the use of this technology to validate the distinction of two closely related Dermacentor tick species based on the development of the first nationwide MALDI-TOF MS reference database described to date. The dataset obtained from this protein-based approach confirms that tick specimens collected from United States regions west of the Rocky Mountains and identified previously as Dermacentor variabilis are the recently described species, Dermacentor similis. Therefore, we propose that this integrative taxonomic tool can facilitate vector and vector-borne pathogen surveillance programs in the United States and elsewhere.

Introduction: Program signaling (PS), which enables residency applicants to signal their preference for a specific program, was introduced in emergency medicine (EM) in the 2022–2023 residency application cycle. In this study we evaluated EM program directors’ (PD) utilization of PS in application review and ranking. This study also explores the relationship between program characteristics and number of signals received as well as the relative importance and utilization of signals related to the number of signals received.Methods: This is an institutional review board-approved, cross-sectional study of PDs at Accreditation Council for Graduate Medical Education-accredited EM residency programs. We used descriptive statistics to describe the characteristics of residency programs and practices around PS. Measures of central tendency and dispersion summarized continuous variables. We used chi-square analysis or the Fisher exact test for comparisons between groups for categorical variables. Comparisons for continuous variables were made using the t-test for independent samples or analysis of variance.Results: The response rate was 41% (n = 113/277 EM programs). Most programs participated in PS(n = 261/277 EM programs, 94.2%). Mean number of signals received was 60 (range 2–203). Signals received varied based on program characteristics including geographic location and program type, duration, environment, and longevity. Most used PS in holistic review (52.2%), but other uses varied by proportion of applications that were signaled. The importance of PS in application review (mean 2.9; 1–5scale,1= not important, 5 = extremely important) and rank list preparation (2.1) was relatively low compared to other application elements such as standardized letters of evaluation (4.97 for review, 4.90 for ranking).Conclusion: The study provides insights into PS utilization in EM’s inaugural year. We have identified patterns of signal use based on program characteristics and number of signals received that can inform signal allocation and utilization on an individual applicant and program level. A more nuanced understanding of signal use can provide valuable insight as the specialty of EM grapples with fluctuations in its applicant numbers and shifting demographics of its applicant pool.

The skin-penetrating gastrointestinal parasitic nematode Strongyloides stercoralis causes strongyloidiasis, which is a neglected tropical disease that is associated with severe chronic illness and fatalities. Unlike other human-infective nematodes, S. stercoralis cycles through a single free-living generation and thus serves as a genetically tractable model organism for understanding the mechanisms that enable parasitism. Techniques such as CRISPR/Cas9-mediated mutagenesis and transgenesis are now routinely performed in S. stercoralis by introducing exogenous DNA into free-living adults and then screening their F1 progeny for transgenic or mutant larvae. However, transgenesis in S. stercoralis has been severely hindered by the inability to establish stable transgenic lines that can be propagated for multiple generations through a host; to date, studies of transgenic S. stercoralis have been limited to heterogeneous populations of transgenic F1 larvae. Here, we develop an efficient pipeline for the generation of stable transgenic lines in S. stercoralis. We also show that this approach can be used to efficiently generate stable transgenic lines in the rat-infective nematode Strongyloides ratti. The ability to generate stable transgenic lines circumvents the limitations of working with heterogeneous F1 populations, such as variable transgene expression and the inability to generate transgenics of all life stages. Our transgenesis approach will enable novel lines of inquiry into parasite biology, such as transgene-based comparisons between free-living and parasitic generations.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Recapitulating spontaneous metastasis in preclinical models is crucial for understanding mechanisms underlying cancer progression and testing effective therapeutic interventions. We present a protocol for establishing and characterizing the spontaneous metastasis model in mice. We describe steps for generating primary tumors, tumor resection, monitoring metastatic dissemination, and evaluating metastatic burden using histological and imaging techniques. This protocol provides a valuable tool for studying metastasis in vivo and testing therapeutic strategies aimed at preventing or targeting metastatic diseases. For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Huanglongbing (HLB) is a fatal citrus disease that is currently threatening citrus varieties worldwide. One putative causative agent, Candidatus Liberibacter asiaticus (CLas), is vectored by Diaphorina citri, known as the Asian citrus psyllid (ACP). Understanding the details of CLas infection in HLB disease has been hindered by its Candidatus nature and the inability to confidently detect it in diseased trees during the asymptomatic stage. To identify early changes in citrus metabolism in response to inoculation of CLas using its natural psyllid vector, leaves from Madam Vinous sweet orange (Citrus sinensis (L.) Osbeck) trees were exposed to CLas-positive ACP or CLas-negative ACP and longitudinally analyzed using transcriptomics (RNA sequencing), proteomics (liquid chromatography-tandem mass spectrometry; data available in Dryad: 10.25338/B83H1Z), and metabolomics (proton nuclear magnetic resonance). At 4 weeks postexposure (wpe) to psyllids, the initial HLB plant response was primarily to the ACP and, to a lesser extent, the presence or absence of CLas. Additionally, analysis of 4, 8, 12, and 16 wpe identified 17 genes and one protein as consistently differentially expressed between leaves exposed to CLas-positive ACP versus CLas-negative ACP. This study informs identification of early detection molecular targets and contributes to a broader understanding of vector-transmitted plant pathogen interactions.

Phenotypic covariation among suites of traits may constrain or promote diversification both within and between species, yet few studies have empirically tested this relationship. In this study, we investigate whether phenotypic covariation of craniofacial traits is associated with diversification in an adaptive radiation of pupfishes found only on San Salvador Island, Bahamas (SSI). The radiation includes generalist, durophagous, and lepidophagous species. We compared phenotypic variation and covariation (i.e., the P matrix) between (1) allopatric populations of generalist pupfish from neighboring islands and estuaries in the Caribbean, (2) SSI pupfish allopatric lake populations with only generalist pupfish, and (3) SSI lake populations containing the full radiation in sympatry. Additionally, we examine patterns observed in the P matrices of two independent lab-reared F2 hybrid crosses of the two most morphologically distinct members of the radiation to make inferences about the underlying mechanisms contributing to the variation in craniofacial traits in SSI pupfishes. We found that the P matrix of SSI allopatric generalist populations exhibited higher levels of mean trait correlation, constraints, and integration with simultaneously lower levels of flexibility compared to allopatric generalist populations on other Caribbean islands and sympatric populations of all three species on SSI. We also document that while many craniofacial traits appear to result from additive genetic effects, variation in key traits such as head depth, maxilla length, and lower jaw length may be produced via non-additive genetic mechanisms. Ultimately, this study suggests that differences in phenotypic covariation significantly contribute to producing and maintaining organismal diversity.

OBJECTIVE: To evaluate the role of psychosocial well-being on perioperative pain and opioid use among patients with cleft lip and palate (CLP) undergoing alveolar bone grafting (ABG). DESIGN: Retrospective review. SETTING: Tertiary level craniofacial clinic. PARTICIPANTS: 34 patients with CLP (median age: 11.7 years), including 25 (73.5%) unilateral CLP and 9 (26.5%) bilateral CLP, who underwent ABG from 2015 to 2022. INTERVENTIONS: ABG using iliac crest bone graft. Patients were prospectively administered four patient-reported psychosocial instruments from the Patient-Reported Outcomes Measurement Information System. MAIN OUTCOME MEASURES: Perioperative opioid use in morphine equivalent dosage/kilogram, patient-reported pain scores, and length of hospital stay after ABG. RESULTS: Patient-reported anxiety (r = 0.41, p = 0.02) and depressive symptoms (r = 0.35, p = 0.04) correlated to higher perioperative opioid usage. Multivariable regression models including psychosocial scores, total acetaminophen usage, length of surgery, and other simultaneous surgeries were developed for total opioid usage, patient-reported pain, and length of hospital stay. Patient-reported anxiety was independently predictive of higher perioperative opioid use (β=0.36, p = 0.01) and higher pain scores (β=0.39, p = 0.02), but not length of hospital stay. CONCLUSIONS: We identified an association for patient-reported anxiety and perioperative opioid use and pain in a CLP cohort undergoing ABG. Future considerations in preoperative patient and family consultation may be indicated in patients self-reporting higher anxiety in an effort to minimize perioperative opioid usage.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

Anxiety disorders are common and highly distressing mental health conditions. Exposure therapy is a gold-standard treatment for anxiety disorders. Mechanisms of Pavlovian fear learning, and particularly fear extinction, are central to exposure therapy. A growing body of evidence suggests an important role of reward processes during Pavlovian fear extinction. Nonetheless, predominant models of exposure therapy do not currently incorporate reward processes. Herein, we present a theoretical model of reward processes in relation to Pavlovian mechanisms of exposure therapy, including a focus on dopaminergic prediction error signaling, coinciding positive emotional experiences (i.e., relief), and unexpected positive outcomes. We then highlight avenues for further research and discuss potential strategies to leverage reward processes to maximize exposure therapy response, such as pre-exposure interventions to increase reward sensitivity or post-exposure rehearsal (e.g., savoring, imaginal recounting strategies) to enhance retrieval and retention of learned associations.

ObjectivePeople with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown.DesignCross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO  ≥ LLN, N = 9) or abnormal DL CO (DL CO

San Fernando Valley spineflower (Chorizanthe parryi var. fernandina [S. Watson] Jeps.) (Polygonaceae) is an herbaceous annual plant, endemic to California, and until rediscovered in 1999 had been thought to be extinct for almost seven decades. Historically documented at 10 locations, it currently persists at 2, separated by approximately 27 km. State listed as endangered, a description of its genetic diversity and structure is of conservation interest. After determining a lack of variation in ploidy, we examined genetic variation from samples within both populations: a common garden study for potentially adaptive genetic variation in selected growth and phenological traits and analysis of single nucleotide polymorphisms identified through restriction-site associated DNA sequencing. Both measures indicated that this highly restricted taxon nevertheless harbors substantial levels of genetic diversity and has significant between- and within-population genetic structure. Combining approaches from population genomics and common garden studies provided more insight into the patterns and basis of genetic diversity than is typical for studies of non-model species. Although local adaptation was not specifically studied (i.e., via reciprocal transplant studies), the differences determined from these two independent lines of evidence indicate that mixing gene pools between populations is not recommended at this time. Further, with significant differences revealed among subpopulations, we caution against mixing genotypes across subpopulations for the most part, and without much more evidence that this would not pose a risk of outbreeding depression. The importance of supporting pollinator health and diversity is highlighted. With genetic diversity—particularly with an annual species—being dynamic, fluctuating with the usual processes and with contributions from the soil seedbank, we recommend periodic resampling to monitor genetic diversity and structure. Climate change is anticipated to contribute to this variability.

Conventional Li-ion battery intercalation cathodes leverage charge compensation that is formally associated with redox on the transition metal. Employing the anions in the charge compensation mechanism, so-called anion redox, can yield higher capacities beyond the traditional limitations of intercalation chemistry. Here, we aim to understand the structural considerations that enable anion oxidation and focus on processes that result in structural changes, such as the formation of persulfide bonds. Using a Li-rich metal sulfide as a model system, we present both first-principles simulations and experimental data that show that cation vacancies are required for anion oxidation. First-principles simulations show that the oxidation of sulfide to persulfide only occurs when a neighboring vacancy is present. To experimentally probe the role of vacancies in anion redox processes, we introduce vacancies into the Li2TiS3 phase while maintaining a high valency of Ti. When the cation sublattice is fully occupied and no vacancies can be formed through transition metal oxidation, the material is electrochemically inert. Upon introduction of vacancies, the material can support high degrees of anion redox, even in the absence of transition metal oxidation. The model system offers fundamental insights to deepen our understanding of structure-property relationships that govern reversible anion redox in sulfides and demonstrates that cation vacancies are required for anion oxidation, in which persulfides are formed.

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individuals genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

ABSTRACT: A framework for a 2-wk summer research course is presented, with a mindset of discovery and self-advocacy that is interdisciplinary and inclusive. The foundations of the course are built upon 2 pillars: (a) a well-defined educational plan focused on cellular engineering, with a goal to instill an engineering mindset into the cell biology field; and (b) a tailored Dimensions of Mentoring policy, which uses a structured feedback system to define and strengthen mentor attributes and provide multiple opportunities for mentorship and mentorship training. Undergraduate and master’s student participants work with PhD students or postdoctoral/professor team leaders in small teams in discovery-based research projects. Multiple teams work in parallel during the 2-wk period and convene in course-wide meetings to share findings and give feedback. Working in small teams with multiple levels of peer and team lead mentoring, students experience advancement in research and technical skills. Participants also experience gains in their understanding of the overarching educational goals in cellular engineering and science communication skills through course-wide activities. The principles from the Dimensions of Mentoring were also effective, with mentors at different levels building strong inclusive teams, coaching practical skills, and promoting individual advocacy. Meeting basic needs, providing relatable role models, and prioritizing enjoyable team-building activities were found to be critical factors in providing inclusive and productive environments. Overall, participants report high satisfaction with a discovery-based interdisciplinary research experience because of a supported environment. This creation of a strong community benefits individual career development and contributes to sustainable research productivity.

Asexuality is a sexual orientation in which someone may experience little, situational, or nosexual attraction. From its complicated existence in queer spaces to its complete invisibility insociety and media representation, why does it continue to lack an understanding even as queertopics continue to enter the mainstream conversation? How is this orientation, seeminglystraightforward, shrouded in confusion, mystification, and false stereotypes? As an asexual andaromantic woman, I believe that the cultural obsession with glamorizing sex and romance andportraying it as essential to a fulfilling life plays a part in confusing the general public on howone could live without the desire to participate fully or at all with these cultural norms andexpectations. To better represent these points and how they affect the lives of asexual people ofvarying intersecting identities, I intend to use an ethnographic approach in this study to betterunderstand these shared experiences and the diversity of the asexual subjectivity. My researchengages with an individual method, including descriptive survey, interview, interaction, andobservation, especially participant observation. My aim in this research is to establish a dialogueon asexuality for a better understanding of an orientation underdeveloped in theory. I identifythis as an opportunity to examine and better understand the spectrum of sexuality. In general, Iintend to interrogate the ways the mainstream norm of sexuality itself still seeps into media andqueer spaces and how to further encourage new forms of asexual inclusivity and acceptance invarious areas of society.

BACKGROUND: Paediatric laceration repair procedures are common in the ED; however, post-discharge recovery remains understudied. Perioperative research demonstrates that children exhibit maladaptive behavioural changes following stressful and painful medical procedures. This study examined post-discharge recovery following paediatric laceration repair in the ED. METHODS: This prospective observational study included a convenience sample of 173 children 2-12 years old undergoing laceration repair in a paediatric ED in Orange, California, USA between April 2022 and August 2023. Demographics, laceration and treatment data (eg, anxiolytic medication), and caregiver-reported child pre-procedural and procedural pain (Numerical Rating Scale (NRS)) were collected. On days 1, 3, 7 and 14 post-discharge, caregivers reported childrens pain and new-onset maladaptive behavioural changes (eg, separation anxiety) via the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery. Univariate and logistic regression analyses were conducted to identify variables associated with the incidence of post-discharge maladaptive behavioural change. RESULTS: Post-discharge maladaptive behavioural changes were reported in 43.9% (n=69) of children. At 1 week post-discharge, approximately 20% (n=27) of children exhibited maladaptive behavioural changes and 10% (n=13) displayed behavioural changes 2 weeks post-discharge. Mild levels of pain (NRS ≥2) were reported in 46.7% (n=70) of children on post-discharge day 1, 10.3% (n=14) on day 7 and 3.1% (n=4) on day 14. An extremity laceration (p=0.029), pre-procedural midazolam (p=0.020), longer length of stay (p=0.043) and post-discharge pain on day 1 (p

Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.

BACKGROUND:  Telemedicine expanded rapidly during the COVID-19 pandemic, as key policy changes, financial support, and pandemic fears tipped the balance toward internet-based care. Despite this increased support and benefits to patients and clinicians, telemedicine uptake was variable across clinicians and practices. Little is known regarding physician and institutional characteristics underlying this variability. OBJECTIVE:  This study aimed to evaluate factors influencing telemedicine uptake among frontline physicians in the early pandemic response. METHODS:  We surveyed a national stratified sample of frontline clinicians drawn from the American Medical Association Physician Professional Data in June or July 2020. The survey inquired about the first month and most recent month (June 2020) of pandemic telemedicine use; sample data included clinician gender, specialty, census region, and years in practice. Local pandemic conditions were estimated from county-level data on COVID-19 rates at the time of survey response. Data were analyzed in a weighted logistic regression, controlling for county-specific pandemic data, and weighted to account for survey data stratification and nonresponse. RESULTS:  Over the first 3-4 months of the pandemic, the proportion of physicians reporting use of telemedicine in >30% of visits increased from 29.2% (70/239) to 35.7% (85/238). Relative to primary care, odds of substantial telemedicine use (>30%) both during the first month of the pandemic and in June 2020 were increased among infectious disease and critical care physicians and decreased among hospitalists and emergency medicine physicians. At least minimal prepandemic telemedicine use (odds ratio [OR] 11.41, 95% CI 1.34-97.04) and a high 2-week moving average of local COVID-19 cases (OR 10.16, 95% CI 2.07-49.97) were also associated with substantial telemedicine use in June 2020. There were no significant differences according to clinician gender, census region, or years in practice. CONCLUSIONS:  Prepandemic telemedicine use, high local COVID-19 case counts, and clinician specialty were associated with higher levels of substantial telemedicine use during the early pandemic response. These results suggest that telemedicine uptake in the face of the pandemic may have been heavily influenced by the level of perceived threat and the resources available for implementation. Such understanding has important implications for reducing burnout and preparation for future public health emergencies.

The University of California San Diego (UCSD) School of Medicine (SOM) is transitioning its third-year primary care curriculum from a year-long longitudinal primary care course to a three-week clerkship in Family Medicine (FM). Additionally, there is a lack of FM physicians in the US, and limited information on what factors affect students’ decisions to enter FM. The aim of this pilot study is to analyze the effects of introducing sub-specialty tracks within an FM clerkship on student attitudes towards FM. A limiting factor for students within FM clerkships is that often they are not exposed to the full spectrum of FM. The aim of the tracks is to demonstrate that there are many FM clinicians practicing what may be considered more specialized aspects of primary care, including sports, sexual and reproductive health, and lifestyle and integrative medicine. There is a pre-existing family medicine clerkship for fourth-year medical students (FPM 426), which will serve as the pilot program. Three subspecialty tracks (sports medicine, sexual and reproductive health, and lifestyle and integrative medicine) will be introduced. Students will be assigned a track based on interest. A student will not be assigned a track if they did not express interest or if there was insufficient space to accommodate. Students not assigned a track will serve as the control group for this study. At the end of the clerkship, students will be emailed an anonymous survey to complete, and time will be provided during the course to complete the survey. The post-clerkship survey will collect data on students’ experience of the clerkship and perceptions of FM. We hypothesize that students placed in the subspecialty tracks will report a better experience during their clerkship and an expanded understanding of the scope of practice of family physicians. Comparisons will be made between students within tracks and those not in a track, who will serve as the control.

Congestive heart failure (CHF) is a fatal disease with progressive severity and no cure; the hearts inability to adequately pump blood leads to fluid accumulation and frequent hospital readmissions after initial treatments. Therefore, it is imperative to continuously monitor CHF patients during its early stages to slow its progression and enable timely medical interventions for optimal treatment. An increase in interstitial fluid pressure (IFP) is indicative of acute CHF exacerbation, making IFP a viable biomarker for predicting upcoming CHF if continuously monitored. In this paper, we present an inductor-capacitor (LC) sensor for subcutaneous wireless and continuous IFP monitoring. The sensor is composed of inexpensive planar copper coils defined by a simple craft cutter, which serves as both the inductor and capacitor. Because of its sensing mechanism, the sensor does not require batteries and can wirelessly transmit pressure information. The sensor has a low-profile form factor for subcutaneous implantation and can communicate with a readout device through 4 layers of skin (12.7 mm thick in total). With a soft silicone rubber as the dielectric material between the copper coils, the sensor demonstrates an average sensitivity as high as -8.03 MHz/mmHg during in vitro simulations.

This study compares how English-speaking adults and children from the United States adapt their speech when talking to a real person and a smart speaker (Amazon Alexa) in a psycholinguistic experiment. Overall, participants produced more effortful speech when talking to a device (longer duration and higher pitch). These differences also varied by age: children produced even higher pitch in device-directed speech, suggesting a stronger expectation to be misunderstood by the system. In support of this, we see that after a staged recognition error by the device, children increased pitch even more. Furthermore, both adults and children displayed the same degree of variation in their responses for whether Alexa seems like a real person or not, further indicating that childrens conceptualization of the systems competence shaped their register adjustments, rather than an increased anthropomorphism response. This work speaks to models on the mechanisms underlying speech production, and human-computer interaction frameworks, providing support for routinized theories of spoken interaction with technology.

BackgroundPavlovian fear paradigms involve learning to associate cues with threat or safety. Aberrances in Pavlovian fear learning correlate with psychopathology, especially anxiety disorders. This study evaluated symptom dimensions of anxiety and depression in relation to Pavlovian fear acquisition and generalization.Methods256 participants (70.31 % female) completed a Pavlovian fear acquisition and generalization paradigm at ages 18-19 and 21-22 years. Analyses focused on indices of learning (self-reported US expectancy, skin conductance). Multilevel models tested associations with orthogonal symptom dimensions (Anhedonia-Apprehension, Fears, General Distress) at each timepoint.ResultsAll dimensions were associated with weaker acquisition of US expectancies at each timepoint. Fears was associated with overgeneralization only at age 21-22. General Distress was associated with overgeneralization only at age 18-19. Anhedonia-Apprehension was associated with overgeneralization at ages 18-19 and 21-22.ConclusionsAnhedonia-Apprehension disrupts Pavlovian fear acquisition and increases overgeneralization of fear. These effects may emerge during adolescence and remain into young adulthood. General Distress and Fears also contribute to overgeneralization of fear, but these effects may vary as prefrontal mechanisms of fear inhibition continue to develop during late adolescence. Targeting specific symptom dimensions, particularly Anhedonia-Apprehension, may decrease fear generalization and augment interventions built on Pavlovian principles, such as exposure therapy.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 childrens hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions1,2. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores3. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms4,5.

RATIONALE & OBJECTIVE: The diagnosis and prognostication of chronic kidney disease (CKD) largely rely on glomerular measures that may not reflect tubular damage. We investigated the associations of urine kidney tubule biomarkers with estimated glomerular filtration rate (eGFR) change among middle-aged adults, when chronic diseases typically emerge. STUDY DESIGN: An observational cohort study. SETTING & PARTICIPANTS: A total of 1,145 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study without CKD, hypertension, or cardiovascular disease at the year 20 visit. EXPOSURES: Seven different biomarkers of tubular health: urine epidermal growth factor (EGF), alpha-1-microglobulin (α1m), interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, uromodulin, and chitinase-3-like protein 1. OUTCOMES: Ten-year eGFR change and incident reduced eGFR (new onset of eGFR

Populations may adapt to similar environments via parallel or non-parallel genetic changes, but the frequency of these alternative mechanisms and underlying contributing factors are still poorly understood outside model systems. We used QTL mapping to investigate the genetic basis of highly divergent craniofacial traits between the scale-eater (Cyprinodon desquamator) and molluscivore (C. brontotheroides) pupfish adapting to two different hypersaline lake environments on San Salvador Island, Bahamas. We lab-reared F2 scale-eater x molluscivore intercrosses from two different lake populations, estimated linkage maps, scanned for significant QTL for 29 skeletal and craniofacial traits, female mate preference, and sex. We compared the location of QTL between lakes to quantify parallel and non-parallel genetic changes. We detected significant QTL for six craniofacial traits in at least one lake. However, nearly all shared QTL loci were associated with a different craniofacial trait within each lake. Therefore, our estimate of parallel evolution of craniofacial genetic architecture could range from one out of six identical trait QTL (low parallelism) to five out of six integrated trait QTL (high parallelism). We suggest that pleiotropy and trait integration can affect estimates of parallel evolution, particularly within rapid radiations. We also observed increased adaptive introgression in shared QTL regions, suggesting that gene flow contributed to parallel evolution. Overall, our results suggest that the same genomic regions may contribute to parallel adaptation across integrated suites of craniofacial traits, rather than specific traits, and highlight the need for a more expansive definition of parallel evolution.

Understanding how residents feel about neighborhood changes due to new development along transit corridors (often referred to as transit-oriented development) remains understudied despite growing concerns over displacement and gentrification. Studies that examined these concerns are largely based on analyzing land use, housing values, and socio-economic shifts (i.e., who is moving in and out of neighborhoods), and do not provide conclusive evidence that transit-oriented development (TOD) is linked to neighborhood gentrification and displacement. Prior surveys of residents living near transit indicate a generally positive assessment of TOD in terms of improved walkability and accessibility but also express concerns over pedestrian safety and parking related to increased traffic and new commercial development. However, recent studies counter this relatively positive assessment of TOD, particularly among activists and community organizers in low-income communities of color.

Research Question: The goal of this study is to assess the impact of a required, quarter-long preparatory course on medical students’ ability to effectively participate in a student-run free clinic and grapple with its ethical nuances. Methods: A one-time, cross-sectional survey was administered to all 55 students in the UCSD Student-Run Free Clinic Project’s (SRFCP) quarter-long introductory course. A Linkert 5-point scale was used to survey student’s impressions of how the course impacted 1) clinical skills, 2) understanding of ethics, 3) social and community issues, 4) sense of community, and 5) future motivation to work with the underserved. Mean scores (with standard deviations) were generated for each topic. Results: Students found the course useful for building a variety of clinical skills (3.97), including newly designed sessions such as working with interpreters (4.18) or effectively pre-charting (3.95). The course also deepened students’ awareness of social issues (4.08) and connectedness to peers (3.76), particularly through an MS1-MS4 teaching model (4.38). Students had mixed perceptions (3.55) on the ethical nuances of SRFCP. A majority felt prepared to work with SRFCP (4.16) and underserved groups (4.29) in the future. Significance: This required didactic helped students feel more prepared to work in SRFCP and strengthened long-term motivation to work with the underserved. A breadth of discussion on ethics, community resources, and health equity helped students define their role in an imperfect system. This study is a call to thoughtfully prepare students to work in free clinics in order to provide the highest quality patient care.

The COVID-19 pandemic has introduced and worsened many barriers to accessing healthcare, especially in the management of diabetes. To no surprise, this resulted in poorer glycemic control and delays in routine screening in patients with diabetes. While a prior study has shown the high-quality diabetes care that patients receive at the UC San Diego Student Run Free Clinic Project (SRFCP), this project examined the effects of the COVID-19 pandemic on diabetes management in this unique population. Diabetes outcome measures were analyzed within the two years prior to, and the two years immediately following the start of the pandemic and compared to previously published outcomes of the SRFCP. For many of the process measures and diabetes clinical outcome measures, there was no difference to or even an improvement during the pandemic. During the pandemic, patients with diabetes recorded higher systolic blood pressures and lower triglyceride values. Female patients with diabetes also saw improvements in their HDL levels. Unsurprisingly, the pandemic saw fewer patients receiving blood pressure measurements compared to prior to the pandemic. The maintenance of high-quality diabetes care for SRFCP patients despite barriers erected during the pandemic is a reflection of the tireless efforts of the providers and staff at the SRFCP.

Introduction: In this study we aimed to investigate the effects of incorporating Swedish-style fika (coffee) breaks into the didactic schedule of emergency medicine residents on their sleepiness levels during didactic sessions. Fika is a Swedish tradition that involves a deliberate decision to take a break during the workday and usually involves pastries and coffee. We used the Karolinska Sleepiness Scale to assess changes in sleepiness levels before and after the implementation of fika breaks.Methods: The study design involved a randomized crossover trial approach, with data collected from emergency medicine residents over a specific period. This approach was done to minimize confounding and to be statistically efficient.Results: Results revealed the average sleepiness scale was 4.6 and 5.5 on fika and control days, respectively (P = 0.004).Conclusion: Integration of fika breaks positively influenced sleepiness levels, thus potentially enhancing the educational experience during residency didactics.

Since the start of the COVID-19 pandemic, in a short span of 3 years, vaccination against SARS-CoV-2 has resulted in the end of the pandemic. Patients with inborn errors of immunity (IEI) are at an increased risk for SARS-CoV-2 infection; however, serious illnesses and mortality, especially in primary antibody deficiencies (PADs), have been lower than expected and lower than other high-risk groups. This suggests that PAD patients may mount a reasonable effective response to the SARS-CoV-2 vaccine. Several studies have been published regarding antibody responses, with contradictory reports. The current study is, perhaps, the most comprehensive study of phenotypically defined various lymphocyte populations in PAD patients following the SARS-CoV-2 vaccine. In this study, we examined, following two vaccinations and, in a few cases, prior to and following the 1st and 2nd vaccinations, subsets of CD4 and CD8 T cells (Naïve, TCM, TEM, TEMRA), T follicular helper cells (TFH1, TFH2, TFH17, TFH1/17), B cells (naïve, transitional, marginal zone, germinal center, IgM memory, switched memory, plasmablasts, CD21low), regulatory lymphocytes (CD4Treg, CD8Treg, TFR, Breg), and SARS-CoV-2-specific activation of CD4 T cells and CD8 T cells (CD69, CD137), SARS-CoV-2 tetramer-positive CD8 T cells, and CD8 CTL. Our data show significant alterations in various B cell subsets including Breg, whereas only a few subsets of various T cells revealed alterations. These data suggest that large proportions of PAD patients may mount significant responses to the vaccine.

BACKGROUND: Despite research that has shown that the presence of support persons during maternity care is associated with more respectful care, support persons are frequently excluded due to facility practices or negative attitudes of providers. Little quantitative research has examined how integrating support persons in maternity care has implications for the quality of care received by women, a potential pathway for improving maternal and neonatal health outcomes. This study aimed to investigate how integrating support persons in maternity care is associated with multiple dimensions of the quality of maternity care. METHODS: We used facility-based cross-sectional survey data from women (n = 1,138) who gave birth at six high-volume facilities in Nairobi and Kiambu counties in Kenya and their support persons (n = 606) present during the immediate postpartum period. Integration was measured by the Person-Centered Integration of Support Persons (PC-ISP) items. We investigated quality of care outcomes including person-centered care outcomes (i.e., Person-Centered Maternity Care (PCMC) and Satisfaction with care) and clinical outcomes (i.e., Implementation of WHO-recommended clinical practices). We used fractional regression with robust standard errors to estimate associations between PC-ISP and care outcomes. RESULTS: Compared to low integration, high integration (≥four woman-reported PC-ISP experiences vs.

New school transitions can be challenging for students on the autism spectrum. No published, evidence-based interventions exist to support families and teachers of students transitioning to elementary and secondary school during this critical period. Using Community Partnered Participatory Research, we developed Building Better Bridges (BBB), a caregiver coaching intervention that includes training on effective school communication, educational rights, advocacy, and child preparation strategies. We compared BBB (n = 83) to a module/resources-only comparison (n = 87) in a four-site randomized controlled trial in racially and ethnically diverse, under-resourced communities. In our intent-to-treat analysis, caregivers and teachers in BBB rated students' transitions to the new classroom as more positive, relative to the comparison group. Results suggest this low-cost intervention can improve the transition process for families and students at high risk of poor transitions.

Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.

BACKGROUND: Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDSTs feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDSTs effectiveness in comparison with an active control and further evaluate implementation feasibility. METHODS: The planned RCT is a hybrid type 1 trial, which will use mixed methods to systematically evaluate the effectiveness and implementation feasibility of CDST among veterans participating in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) in Southern California. The first aim is to assess the effectiveness of CDST in comparison with the active control via the primary outcome, collaborative decision-making behavior during usual care appointments between veterans and their VA mental health clinicians, and secondary outcomes (i.e., treatment engagement, satisfaction, and outcome). The second aim is to characterize the implementation feasibility of CDST within the VA PRRC using the Practical Robust Implementation and Sustainability Model framework, including barriers and facilitators within the PRRC context to support future implementation. DISCUSSION: If CDST is found to be effective and feasible, implementation determinants gathered throughout the study can be used to ensure sustained and successful implementation at this PRRC and other PRRCs and similar settings nationally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324944. Registered on March 27, 2020. Trial registration data can be found in Appendix 1.

Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an in vitro GABA uptake assay for 213 unique variants, including 24 control variants. De novo variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent de novo missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential SLC6A1 missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type SLC6A1 allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

PurposeTo develop a patient-reported outcome measure to assess the impact of glaucoma and treatment, including minimally invasive glaucoma surgery (MIGS).DesignObservational study before and after concomitant cataract and Food and Drug Administration-approved implantable MIGS device surgery.SettingSurvey administration was on a computer, iPad, or similar device.Patient population184 adults completed the baseline survey, 124 a survey 3 months after surgery, and 106 the 1-month test-retest reliability survey. The age range was 37 to 89 (average age = 72). Most were female (57%), non-Hispanic White (81%), and had a college degree (56%).Main outcome measuresThe Glaucoma Outcomes Survey (GOS) assesses functional limitations (27 items), vision-related symptoms (7 items), psychosocial issues (7 items), and satisfaction with microinvasive glaucoma surgery (1 item). These multiple-item scales were scored on a 0 to 100 range, with a higher score indicating worse health.ResultsInternal consistency reliability estimates ranged from 0.75 to 0.93, and 1-month test-retest intraclass correlations ranged from 0.83 to 0.92 for the GOS scales. Product-moment correlations among the scales ranged from 0.56 to 0.60. Improvement in visual acuity in the study eye from baseline to the 3-month follow-up was significantly related to improvements in GOS functional limitations (r = 0.18, P = .0485), vision-related symptoms (r = 0.19, P = .0386), and psychosocial concerns (r = 0.18, P = .0503). Responders to treatment ranged from 17% for vision-related symptoms to 48% for functional limitations.ConclusionsThis study supports using the GOS for ophthalmic procedures such as MIGS. Further evaluation of the GOS in different patient subgroups and clinical settings is needed.