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Background: In addition to the benefits of a diverse faculty, many institutions are under pressure from students and administrators to increase the number of faculty from historically excluded backgrounds. Despite increases in the numbers of engineering PhD earners from these groups, the percentages of Black/African American and Hispanic/Latino tenure-track faculty have not increased, and the percentage of women remains low. Purpose: The purpose of this study is to identify how experiences in graduate school encourage or deter PhD earners from historically excluded groups in pursuing an engineering academic career. Method: We conducted 20 semi-structured interviews with engineering PhD students and recent graduates, with half of participants interested and half disinterested in pursuing an academic career after graduation. Results: Three key factors emerged as strongly influential on participants' desire to pursue an academic career: their relationship with their advisor, their perception of their advisor's work-life balance, and their perception of the culture of academia. Participants extrapolated their experiences in graduate school to their imagined lives as faculty. The results illuminate the reasons why engineering PhD earners from historically underrepresented groups remain in or leave the academic career pathway after graduate school. Conclusions: The findings of this study have important implications for how graduate students' and postdoc's relationships with their advisors as well as perceptions of their advisors' work-life balances and the culture of academia affect future faculty. We make recommendations on what students, faculty, and administrators can do to create a more inclusive environment to encourage students from historically excluded groups to consider academic careers.

Digital methods provide archaeologists with ever-increasing opportunities to collect more data about the past in new formats. These larger evidentiary datasets, in turn, help us to address questions about the human past with increasing precision. To take full advantage of these opportunities, archaeologists must develop digital literacy skills and learn how to lead digital projects. Here, we describe seven digitally-based projects we have undertaken at the University of Pennsylvania in order to create new tools for archaeological data collection and sharing, as well as to test collaborative models for the digital humanities programming process. In these projects, archaeology students work directly with engineering students. Through this interface, the students from both areas gain valuable transdisciplinary experience while experimenting with new ways to accomplish programming goals and to collect archaeological data. The learning potential for these students was a key motivation for our initiative. Our projects have already led to several websites and digital applications that are available as open source downloads. We present our impressions of this collaborative process with the goal of encouraging other archaeologists to form similar digital humanities partnerships.

This study examines how community partners understand reciprocity and co-education in service-learning. Twenty community partners participated in 30-minute telephone interviews. When asked to define reciprocity, participants identified the importance of communication and maintaining a two-way relationship. With regard to co-education, community partners highlighted communication, the back-and-forth nature of the relationship, and their role as a facilitator. This study will help universities and community partners increase the effectiveness and maximize the benefits of their service-learning relationships.

A combination therapy of preproinsulin (PPI) and immunomodulators (TGFβ+IL10) orally delivered via genetically modified Salmonella and anti-CD3 promoted glucose balance in in NOD mice with recent onset diabetes. The Salmonella bacteria were modified to express the diabetes-associated antigen PPI controlled by a bacterial promoter in conjunction with over-expressed immunomodulating molecules. The possible mechanisms of action of this vaccine to limit autoimmune diabetes remained undefined. In mice, the vaccine prevented and reversed ongoing diabetes. The vaccine-mediated beneficial effects were associated with increased numbers of antigen-specific CD4+CD25+Foxp3+ Tregs, CD4+CD49b+LAG3+ Tr1-cells, and tolerogenic dendritic-cells (tol-DCs) in the spleens and lymphatic organs of treated mice. Despite this, the immune response to Salmonella infection was not altered. Furthermore, the vaccine effects were associated with a reduction in islet-infiltrating lymphocytes and an increase in the islet beta-cell mass. This was associated with increased serum levels of the tolerogenic cytokines (IL10, IL2, and IL13) and chemokine ligand 2 (CCL2) and decreased levels of inflammatory cytokines (IFNγ, GM-CSF, IL6, IL12, and TNFα) and chemokines (CXCL1, CXCL2, and CXCL5). Overall, the data suggest that the Salmonella-based vaccine modulates the immune response, reduces inflammation, and promotes tolerance specifically to an antigen involved in autoimmune diabetes.

INTRODUCTION: Pharmacists focusing on psychotropic medication management and practicing across a wide variety of healthcare settings have significantly improved patient-level outcomes. The Systematic Literature Review Committee of the American Association of Psychiatric Pharmacists was tasked with compiling a comprehensive database of primary literature highlighting the impact of psychiatric pharmacists on patient-level outcomes. METHODS: A systematic search of literature published from January 1, 1961, to December 31, 2022, was conducted using PubMed and search terms based on a prior American Association of Psychiatric Pharmacists literature review. Publications describing patient-level outcome results associated with pharmacist provision of care in psychiatric/neurologic settings and/or in relation to psychotropic medications were included. The search excluded articles for which there was no pharmacist intervention, no psychiatric disorder treatment, no clinical outcomes, no original research, no access to full text, and/or no English-language version. RESULTS: A total of 4270 articles were reviewed via PubMed, with 4072 articles excluded based on title, abstract, and/or full text in the initial pass and 208 articles selected for inclusion. A secondary full-text review excluded 11 additional articles, and 5 excluded articles were ultimately included based on a secondary review, for a final total of 202 articles meeting the inclusion criteria. A comprehensive database of these articles was compiled, including details on their study designs and outcomes. DISCUSSION: The articles included in the final database had a wide range of heterogeneity. While the overall impact of psychiatric pharmacists was positive, the study variability highlights the need for future publications to have more consistent, standardized outcomes with stronger study designs.

Question asked in a preschool/primary teacher PD session on read-alouds: "After our Family Night presentation on home read-alouds, we got so many questions from families and caretakers. How can we give follow-up support?" This teaching guide suggests three simple ideas for supporting parent home-read-alouds with preschool, kindergarten, and first-grade students.

This paper introduces a process of reading, reflection, and discussion used by two white faculty teaching at predominately white institutions to address challenges to equity in their introductory astronomy courses. The conversations focused on the context of large introductory courses, where individual instructors may lack resources and agency to make large-scale structural changes. Six goals to improve the classroom experience for all students are identified. The paper explores the nature of inequities that students face and, through a process of backwards design, identifies actions that begin to address such issues. The ideas discussed are rooted in ongoing conversations around injustice, antiracism, equity and inclusion and this paper describes a process by which individual instructors can make progress in their own classrooms. We write this paper with the hope that it could serve as a model, and that other faculty of introductory courses might consider embracing similar goals as we strive to make our disciplines more welcoming and inclusive.

Motivational interviewing (MI), a therapy strategy used to guide students to help students better understand how to develop their social emotional learning (SEL) skills to make positive choices that resolve social conflict, bodes promising for helping youth to cultivate the social and emotional skills needed to address bullying, peer drama, and other issues affecting their mental, physical, and emotional health. Bulldog Solution, Inc., a Chicago-based organization, utilized MI research-informed approach to increase students' social conflict management and leadership skills through self-awareness and self-discovery, as a mechanism for preventing bullying and supporting the social and emotional growth of young people. This study presents emerging themes resulting from a 9-week, motivational interview and SEL-based program titled, "Peace Over Drama," implemented with middle school students (sixth-seventh-eighth grade) with disabilities and/or at risk for disability-identification (n = 17) in one Chicago middle school on the south side. Implications for school-based prevention models and scaling of similar SEL and MI programing are discussed.

BACKGROUND: Injuries, the leading cause of death in children 1-17 years old, are often preventable. Injury patterns are impacted by changes in the childs environment, shifts in supervision, and caregiver stressors. The objective of this study was to evaluate the incidence and proportion of injuries, mechanisms, and severity seen in Pediatric Emergency Departments (PEDs) during the COVID-19 pandemic. METHODS: This multicenter, cross-sectional study from January 2019 through December 2020 examined visits to 40 PEDs for children

Introduction Immigrants comprised a significant portion of the total population in the United States (US), and a considerable number of children in the US live with at least one immigrant parent, which has continued to increase over the past decades. However, healthcare providers (HPs) in the US report lack of comfort in interacting with immigrant and refugee populations. Methods The authors, in partnership with the Midwest Consortium of Global Health Educators, developed an innovative, interactive ethics curriculum within the Immigrant Partnership Advocacy and Curricular Kit (I-PACK). They sought to increase HPs confidence in navigating complex encounters with immigrant families by teaching a relevant ethical framework, highlighting the importance of cultural humility, and equipping learners with an ethics tool (five-box Method) for use in clinical encounters. They piloted the curriculum during three workshop sessions in 2020-2021, and this curriculum continues to be used nationally as a part of I-PACK. Results Pre- and post-session surveys indicated that all participants (100%, n=22) reported acquisition of new skills/knowledge and 19 (86%) felt confident applying this to their clinical practice. The participants reported appreciation for an ethical framework with which to analyze cases, enjoyment of active participation in small group discussions, and utility of the five-box method tool. Some areas of improvement offered were to have more cases and more time dedicated to small-group discussions. Conclusions Given the success of the I-PACK ethics curriculum pilot, the authors plan to incorporate immigrant health cases in the general ethics training in medical school classes and pediatric residency training. Furthermore, they will advocate for the importance of including immigrant health ethics across graduate medical education, as fluency and competence in navigating the ethics of immigrant health are required to provide patient-centered, culturally informed care to all populations.

This quantitative study was conducted to determine if a relationship exists between former Missouri Career and Technical Education (CTE) concentrators' Technical Skills Assessment (TSA) performance and attaining related placement after high school, specifically analyzing for differences among racial/ethnic and socioeconomic status (SES) groups. The study included data from 65,606 students who graduated over a five year time frame. To investigate these relationships, multiple descriptive models were run and disaggregated by gender, race/ethnicity, and SES. Students who passed their TSA were more likely to attain related placement compared to those not passing, but disadvantaged (lower SES) and Black students across all CTE program areas had reduced odds of attaining related placement compared to not disadvantaged or other racial/ethnic students. Additional analysis to determine the relationship by CTE content areas included multiple binary logistic regression models. The findings demonstrate positive impacts of secondary CTE programs, but equity concerns are raised need further examination.

BackgroundGingivitis is a non-specific inflammatory lesion in response to the accumulation of oral biofilm and is a necessary precursor to periodontitis. Enhanced oral hygiene practices, including utilization of a dentifrice that could significantly improve plaque accumulation and gingival inflammation, is desirable to prevent and treat gingivitis and potentially prevent progression to periodontitis. This clinical study aimed to investigate the effect of a new stannous fluoride-containing dentifrice with 2.6% ethylenediamine tetra acetic acid (EDTA) as an anti-tartar agent to reduce plaque index and gingival index over a 3-month study period compared to other commercially-available fluoride-containing dentifrices.MethodsThis double-blind, randomized controlled clinical study evaluated plaque, gingival inflammation, and sulcular bleeding in patients using one of five commercially available fluoride-containing dentifrices The dentifrices tested contained: 0.454% stannous fluoride and 2.6% EDTA (D1), 0.24% sodium fluoride (C), and 0.454% stannous fluoride (D2-D4). One hundred fifty subjects participated over a 3-month period. Co-primary endpoints were improvements in plaque index (PI) and modified gingival index (mGI) from baseline values. No professional cleaning was performed during the study period.ResultsAll subjects in the study demonstrated statistically significant improvements in all measures of oral hygiene over the 3-month study period. Subjects using dentifrice 1 (D1) showed statistically significantly greater reductions in PI, mGI, and modified sulcular bleeding index (mSBI) compared with all other commercially-available dentifrices tested (p

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.

Principal preparation programs use various components to develop candidates, including coursework, core assessments, and field-based internships or practicums. The internship represents an exceptionally high leverage learning opportunity (Lochmiller, 2014). The success of the internship depends highly on the abilities of a mentor via informal instructional supervision. Mette (2020) explains that supervision has a potential transformational quality. This study explores mentorships in a university principal preparation program through the mentor's perspective. We interviewed a sample of mentors nominated as effective by peer and program informants. We learned that mentors were deliberate in developing three specific skills --metacognitive ability, developmental efficacy, and learning-oriented goal setting. Mentor principals described these three elements as paramount to master before becoming a principal. We discuss implications for principal preparation programs to use mentors as informal instructional supervisors and develop highly effective school principals.

Aims: Manual impaction, with a mallet and introducer, remains the standard method of installing cementless acetabular cups during total hip arthroplasty (THA). This study aims to quantify the accuracy and precision of manual impaction strikes during the seating of an acetabular component. This understanding aims to help improve impaction surgical techniques and inform the development of future technologies. Methods: Posterior approach THAs were carried out on three cadavers by an expert orthopaedic surgeon. An instrumented mallet and introducer were used to insert cementless acetabular cups. The motion of the mallet, relative to the introducer, was analyzed for a total of 110 strikes split into low-, medium-, and high-effort strikes. Three parameters were extracted from these data: strike vector, strike offset, and mallet face alignment. Results: The force vector of the mallet strike, relative to the introducer axis, was misaligned by an average of 18.1°, resulting in an average wasted strike energy of 6.1%. Furthermore, the mean strike offset was 19.8 mm from the centre of the introducer axis and the mallet face, relative to the introducer strike face, was misaligned by a mean angle of 15.2° from the introducer strike face. Conclusion: The direction of the impact vector in manual impaction lacks both accuracy and precision. There is an opportunity to improve this through more advanced impaction instruments or surgical training. Cite this article: Bone Joint Res 2024;13(4):193–200.

BackgroundAn urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality.MethodsUsing an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (

Background: Marital status has been shown to have protective effects for married patients with various cancers. We sought to determine effects of marital status on perioperative outcomes after robotic-assisted pulmonary lobectomy (RAPL). Methods: We retrospectively analyzed 709 consecutive patients who underwent RAPL between 2010 and 2022 by one surgeon. Patients were stratified by marital status at time of surgery. The Married group included married, domestically partnered, and co-habitating patients (N = 473). The Unmarried group included never married, divorced, and widowed individuals (N = 236). Demographics, preoperative comorbidities, intraoperative and postoperative complications, estimated blood loss (EBL), chest tube duration, hospital length of stay (LOS), tumor characteristics, and survival data were analyzed utilizing Student's t-test, Wilcoxon rank-sum test, Chi-square, or Fisher's exact test as appropriate, with significance at p≤0.05. Results: Unmarried patients were more likely to be female, while married patients were more likely to experience robotic-associated intraoperative complications and greater intraoperative estimated blood loss. Kaplan-Meier survival analysis revealed no difference in 5-year overall survival based on marital status. Other perioperative outcomes, intraoperative complications (except robotic-associated), postoperative complications, demographic history (except gender), and preoperative comorbidities did not significantly differ between the two groups. Conclusion: This study challenges the existing reports in the literature that marriage confers cancer treatment outcomes advantage and prolonged survival among cancer patients. Social support, in terms of a spouse or domestic partner, may be less protective in early-stage lung cancer and after minimally invasive pulmonary lobectomy compared to other cancer populations.

Background: During a routine cadaver dissection, findings led to the recognition of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. MRKH is the second most common cause of primary amenorrhea in females. MRKH, also known as Müllerian aplasia, is a rare congenital disorder that is seen in 1 out of 5000 karyotypic females (46,XX). Patients with MRKH present with agenesis/aplasia of the uterus and the upper two thirds of the vagina. There are two different subtypes of MRKH. In Type I, only uterovaginal agenesis is seen. However, patients with MRKH Type II have uterovaginal agenesis including the absence of one or both fallopian tubes and ovaries, along with abnormalities of the kidney or skeleton. A subgroup of MRKH Type II is termed MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia) because of the severity of malformations seen in multiple extragenital organs including the kidney and skeleton. A patient with Type II is the rarest of the two subtypes occurring in 28–44 % of MRKH patients when compared to the occurrence of Type I, 56–72 %. Methods/results: Routine dissection of embalmed 63-year-old Caucasian female cadaver and inspection of various anatomical systems revealed this donor had MRKH type II with MURCS. Herein, reports the anatomical manifestations of MRKH type II with MURCS. Conclusion: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a rare congenital disorder that is seen in 1 out of 5000 karyotypic females (46, XX). Patients with MRKH present with agenesis/aplasia of the uterus and the upper two thirds of the vagina. The discovery of MRKH in this cadaver was found upon routine dissection. Such findings provide insight into the anatomical implications and organ compensation that can occur over time with this pathology.

Summary: Early caregiving adversity (ECA) is associated with social behavior deficits and later development of psychopathology. However, the infant neural substrates of ECA are poorly understood. The lateral habenula (LHb), a highly conserved brain region with consistent links to adult psychopathology, is understudied in development, when the brain is most vulnerable to environmental impacts. Here, we describe the structural and functional ontogeny of the LHb and its behavioral role in infant and juvenile rat pups. We show that the LHb promotes a developmental transition in social approach behavior under threat as typically reared infants mature. By contrast, we show that ECA disrupts habenular ontogeny, including volume, protein expression, firing properties, and corticohabenular connectivity. Furthermore, inhibiting a specific corticohabenular projection rescues infant social approach deficits following ECA. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.

Background: Patients undergoing hemodialysis are at high risk for healthcare-associated infections; they are at 100 times the risk of Staphylococcus aureus bloodstream infections (BSI) compared with U.S. adults not on hemodialysis. Prior studies found that nasal decolonization with mupirocin prevented S. aureus BSI among hemodialysis patients. We implemented a nasal decolonization intervention in which patients self-administered povidone-iodine (PVI) at each dialysis session. We aimed to assess: 1) hemodialysis patients’ knowledge of their infection risk and their willingness to take an active role in infection prevention; 2) the acceptability of the PVI nasal decolonization intervention. Methods: We performed a stepped wedge cluster randomized trial at 16 outpatient hemodialysis centers. Patients were surveyed: before starting PVI, 1 month after their center started using PVI, and ~6 months after starting PVI. We used a chi-square test to compare results. Results: 469 patients completed at least 1 survey: 400 pre-intervention, 237 at 1 month and 201 at 6 months. Overall, 56% of patients thought that their risk of infection was average or below average compared with an average person in the U.S. (Figure). Over 98% agreed with the statement “One of the most important things I can do for my health is to take an active role in my health care." In the pre-intervention survey, 73% were willing to do “a lot of effort” to prevent an infection. This proportion was similar (73%) in the 2nd survey, but decreased to 63% in the final survey (p < 0 .01). Among 106 patients who reported starting PVI, 85% reported that PVI felt neutral or pleasant, 9.4% reported a side effect, and 79% reported using it during the past 3 dialysis sessions. Among 102 patients who reported using PVI at 6 months, 87% said it felt neutral/pleasant, 3.9% reported a side effect and 75% reported using it during the past 3 dialysis sessions. Side effects included nasal dripping, congestion or burning/stinging, unpleasant smell, headache, yellow tears, and minor nose bleeding. Conclusions: Hemodialysis patients are not aware of their high risk of infection. Although many were willing to expend a lot of effort to prevent an infection, this willingness decreased during an infection prevention intervention. There were few PVI side effects and most patients stated that PVI felt neutral/pleasant, yet many patients chose to not use PVI. Future research should aim to improve patient education on their risk of infection and assess barriers to adherence with infection prevention interventions.

IMPORTANCE:. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has evolved through multiple phases in the United States, with significant differences in patient centered outcomes with improvements in hospital strain, medical countermeasures, and overall understanding of the disease. We describe how patient characteristics changed and care progressed over the various pandemic phases; we also emphasize the need for an ongoing clinical network to improve the understanding of known and novel respiratory viral diseases. OBJECTIVES:. To describe how patient characteristics and care evolved across the various COVID-19 pandemic periods in those hospitalized with viral severe acute respiratory infection (SARI). DESIGN:. Severe Acute Respiratory Infection-Preparedness (SARI-PREP) is a Centers for Disease Control and Prevention Foundation-funded, Society of Critical Care Medicine Discovery-housed, longitudinal multicenter cohort study of viral pneumonia. We defined SARI patients as those hospitalized with laboratory-confirmed respiratory viral infection and an acute syndrome of fever, cough, and radiographic infiltrates or hypoxemia. We collected patient-level data including demographic characteristics, comorbidities, acute physiologic measures, serum and respiratory specimens, therapeutics, and outcomes. Outcomes were described across four pandemic variant periods based on a SARS-CoV-2 sequenced subsample: pre-Delta, Delta, Omicron BA.1, and Omicron post-BA.1. SETTING:. Multicenter cohort of adult patients admitted to an acute care ward or ICU from seven hospitals representing diverse geographic regions across the United States. PARTICIPANTS:. Patients with SARI caused by infection with respiratory viruses. MAIN OUTCOMES AND RESULTS:. Eight hundred seventy-four adult patients with SARI were enrolled at seven study hospitals between March 2020 and April 2023. Most patients (780, 89%) had SARS-CoV-2 infection. Across the COVID-19 cohort, median age was 60 years (interquartile range, 48.0–71.0 yr) and 66% were male. Almost half (430, 49%) of the study population belonged to underserved communities. Most patients (76.5%) were admitted to the ICU, 52.5% received mechanical ventilation, and observed hospital mortality was 25.5%. As the pandemic progressed, we observed decreases in ICU utilization (94% to 58%), hospital length of stay (median, 26.0 to 8.5 d), and hospital mortality (32% to 12%), while the number of comorbid conditions increased. CONCLUSIONS AND RELEVANCE:. We describe increasing comorbidities but improved outcomes across pandemic variant periods, in the setting of multiple factors, including evolving care delivery, countermeasures, and viral variants. An understanding of patient-level factors may inform treatment options for subsequent variants and future novel pathogens.

Studies suggest that religion is a protective factor for substance misuse and mental health concerns among Black/African American youth despite reported declines in their religious involvement. However, few studies have investigated the associations among religion, substance misuse, and mental health among Black youth. Informed by Critical Race Theory, we evaluated the correlations between gender, depression, substance misuse, and unprotected sex on mental health. Using multiple linear regression, we assessed self-reported measures of drug use and sex, condom use, belief in God, and religiosity on mental health among a sample of Black youth (N = 638) living in a large midwestern city. Results indicated drug use, and sex while on drugs and alcohol, were significant and positively associated with mental health symptoms. Belief in God was negatively associated with having sex while on drugs and alcohol. The studys findings suggest that despite the many structural inequalities that Black youth face, religion continues to be protective for Black youth against a myriad of prevalent problem behaviors.

IntroductionEGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.MethodsPatients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.ResultsA total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.ConclusionsOsimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

AbstractNeuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomical likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7849 abstracts of experiments published between January 1, 1990, and April 26, 2021, were identified from 8 databases and evaluated by 2 independent reviewers. Overall, 103 experiments with a total of 5075 participants met the preregistered inclusion criteria. After correction for multiple comparisons using the gold-standard family-wise error correction ( P < 0.05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. Most of the clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex, and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.