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BACKGROUND: Refeeding syndrome is the gravest possible medical complication in malnourished patients undergoing refeeding in the hospital. We previously reported that males with malnutrition secondary to eating disorders required more calories and had longer hospital stays than females; however, sex differences in electrolyte abnormalities indicating refeeding syndrome risk remain unknown. The objective of this study was to assess differences in electrolyte abnormalities indicating refeeding syndrome risk among male and female adolescents and young adults with eating disorders hospitalized for medical instability. METHODS: We retrospectively reviewed the electronic medical records of 558 patients aged 9-25 years admitted to the University of California, San Francisco Eating Disorders Program for medical instability between May 2012 and August 2020. Serum was drawn per standard of care between 5 and 7 am each morning and electrolyte abnormalities indicating refeeding syndrome risk were defined as: hypophosphatemia (

OBJECTIVE: The StRONG trial demonstrated the safety and efficacy of higher calorie refeeding (HCR) in hospitalized adolescents and young adults with malnutrition secondary to restrictive eating disorders. Here we compare refeeding outcomes in patients with atypical anorexia nervosa (atypical AN) versus anorexia nervosa (AN) and examine the impact of caloric dose. METHOD: Patients were enrolled upon admission and randomized to meal-based HCR, beginning 2000 kcal/day and advancing 200 kcal/day, or lower calorie refeeding (LCR), beginning 1400 kcal/day and advancing 200 kcal every other day. Atypical AN was defined as %median BMI (mBMI) > 85. Independent t-tests compared groups; multivariable linear and logistic regressions examined caloric dose (kcal/kg body weight). RESULTS: Among n = 111, mean ± SD age was 16.5 ± 2.5 yrs; 43% had atypical AN. Compared to AN, atypical AN had slower heart rate restoration (8.7 ± 4.0 days vs. 6.5 ± 3.9 days, p = .008, Cohens d = -.56), less weight gain (3.1 ± 5.9%mBMI vs. 5.4 ± 2.9%mBMI, p

BackgroundClinical trials using psilocybin therapy to treat anorexia nervosa (AN) are currently underway. The safety and tolerability of psilocybin is of utmost importance in individuals with AN who may present unique medical vulnerabilities. The purpose of this review is to describe how the common physiologic adverse effects of psilocybin may impact medical complications experienced by individuals with AN in clinical trials of psilocybin therapy.Main bodyThe physiologic underpinnings of common adverse effects following psilocybin administration are described, including tachycardia, hypertension, electrocardiogram changes, nausea, headache, and lightheadedness. These anticipated physiologic changes are described in relation to the common medical correlates seen in individuals with AN. Risk mitigation strategies for each adverse effect are proposed.ConclusionEarly evidence suggests that psilocybin therapy is well-tolerated in individuals with AN. Understanding the unique medical complications of AN, and how they may be impacted by common physiologic adverse effects of psilocybin administration, leads to tailored risk mitigation strategies to enhance safety and tolerability of this novel intervention.

ObjectiveParental self-efficacy in the domain of weight restoration for adolescents with restrictive eating disorders is central to success in family-based interventions. We sought to characterize this parental self-efficacy during a brief hospitalization for medical stabilization and follow-up among patients with anorexia nervosa (AN) or atypical AN (AAN) enrolled in the StRONG clinical trial to understand the potential impact of inpatient treatment on caregiver empowerment.MethodsPatients were enrolled upon hospital admission and refed per protocol. We examined correlates of the Parents Versus Anorexia (PVA) scale, a measure of parental self-efficacy in the domain of weight restoration, at admission, discharge, 10-days, 1-month, and 3-months post-discharge. Multi-level models evaluated associations among PVA scores and change in %median BMI and Eating Disorder Examination-Questionnaire (EDE-Q) global scores over 3-months post-discharge.ResultsParents of N = 67 adolescents and young adults M(SD) age 15.79 (2.20) years and 85.00 (11.86) %median BMI participated. PVA scores did not change significantly during hospitalization (p = .053), which lasted on average 10.7 ± 4.5 days. PVA scores increased post-discharge (p = .009), with significant increase between discharge and 1-month post-discharge (p = .045). PVA scores were not associated with subsequent clinical outcomes. Rather, a main effect of time significantly predicted higher %median BMI and improved EDE-Q scores (p

Given the persistence of health inequities in the United States, scholars and health professionals alike have turned to the social determinants of health (SDH) framework to understand the overlapping factors that produce and shape these inequities. However, there is scant empirical literature on how frontline health and social service workers perceive and apply the SDH framework, or related movements such as the right to health, in their daily practice. Our study seeks to bridge this gap by applying constructs from the sociological imagination and structural competency (an emerging paradigm in health professions' education) to understand the perspectives and experiences of social work case managers, community health workers, legal advocates, and mental health counselors at a maternal and child health center in a large US city. This frontline workforce displayed strong sociological imagination, elements of structural competency, and engagement with the principles of the right to health. Workers shared reflections on the SDH framework in ways that signaled promising opportunities for frontline workers to link with the global movement for the right to health. We offer a novel approach to understanding the relationships between frontline worker perspectives on and experiences with the SDH, sociological imagination, structural competency, and the right to health.

To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew (i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.

BackgroundBinge-eating disorder (BED) is the most common eating disorder phenotype and is linked to several negative health outcomes. Yet, little is known about the social epidemiology of BED, particularly in early adolescence. The objective of this study was to examine the associations between sociodemographic characteristics and BED and binge-eating behaviors in a large, national cohort of 10-14-year-old adolescents in the United States (U.S.) METHODS: We conducted a cross-sectional analysis of two-year follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study (2018 - 2020) that included 10,197 early adolescents (10 - 14 years, mean 12 years) in the U.S. Multivariable logistic regression models were used to assess the associations between sociodemographic characteristics and BED and binge-eating behaviors, defined based on the Kiddie Schedule for Affective Disorders and Schizophrenia.ResultsIn this early adolescent sample (48.8% female, 54.0% White, 19.8% Latino/Hispanic, 16.1% Black, 5.4% Asian, 3.2% Native American, 1.5% Other), the prevalence of BED and binge-eating behaviors were 1.0% and 6.3%, respectively. Identifying as gay or bisexual (compared to heterosexual; adjusted odds ratio [AOR]: 2.25, 95% CI 1.01-5.01) and having a household income of less than $75,000 (AOR: 2.05, 95% CI: 1.21-3.46) were associated with greater odds of BED. Being male (AOR: 1.28, 95% CI: 1.06-1.55), of Native American (AOR: 1.60, 95% CI: 1.01-2.55) descent, having a household income less than $75,000 (AOR: 1.34, 95% CI: 1.08-1.65), or identifying as gay or bisexual (AOR for 'Yes' Response: 1.95, 95% CI: 1.31-2.91 and AOR for 'Maybe' Response: 1.81, 95% CI: 1.19-2.76) were all associated with higher odds of binge-eating behaviors.ConclusionSeveral sociodemographic variables showed significant associations with binge-eating behaviors, which can inform targeted screening, prevention, and education campaigns for BED among early adolescents.

BackgroundNo guidelines currently exist that represent a standardization of care for Avoidant/Restrictive Food Intake Disorder (ARFID) on an inpatient service. Unique features of this diagnosis (e.g., sensory sensitivity contributing to involuntary emesis) suggest that established protocols that were developed for anorexia nervosa might be less effective for adolescents with ARFID. To inform improved inpatient medical stabilization and care for these patients, we first provide an overview of clinical characteristics for patients with ARFID who presented to a pediatric hospital for inpatient eating disorder care. We use these descriptives to outline the rationale for, and executions of, modifications to an inpatient protocol designed to flexibly meet the needs of this clinical population.MethodsChart review with descriptive statistics were conducted for patients who had received an ARFID diagnosis from March 2019 to March 2023 (N = 32, aged 9-23). We then present a case series (n = 3) of adolescents who either transitioned to a novel adjusted protocol from an original standard of care on the inpatient service, or who received only the standard protocol.ResultsThe sample was aged M(SD) = 15.6 (3.3) years, 53% male, and a majority (69%) presented with the ARFID presentation specific to fear of negative consequences. On average, patients had deviated from their growth curve for just over two years and presented with mean 76% of their estimated body weight. Of those requiring nasogastric tube insertion during admission (n = 8, 25%), average duration of tube placement was 15 days. From within this sample, case series data suggest that the adjusted protocol will continue to have a positive impact on care trajectory among adolescents admitted for ARFID including improved weight gain, reduction of emesis, and improved food intake.ConclusionsFindings demonstrate the likely need to tailor established medical inpatient protocols for those with ARFID given different symptom presentation and maintenance factors compared to patients with anorexia nervosa. Further research is warranted to explore the longer-term impact of protocol changes and to inform standardization of care for this high priority clinical population across care sites.

Background: In the setting of widespread COVID-19 vaccination and booster administration, there is an increased incidence of axillary lymphadenopathy identified during breast imaging.Purpose: To investigate how breast imaging radiologists manage unilateral axillary lymphadenopathy (UAL) after a recent ipsilateral COVID-19 vaccination.Methods: A 26-question survey was distributed to 12 California breast imaging facilities in June 2022. Results: There were 10 responses to the survey (83% response rate). All respondents considered recent ipsilateral COVID-19 vaccination relevant to the interpretation of UAL. Seven respondents (70%) also  considered non-COVID-19 vaccinations relevant. All respondents documented recent COVID-19 vaccinations, but 4 (40%) had no information for other vaccines. Eight respondents (80%) delayed screening after COVID-19 vaccination during initial vaccination efforts, and 3 (30%) still required or suggested delaying screening at the time of the survey. Breast Imaging Reporting and Data System (BI-RADS) categorization for UAL with no abnormal findings in the ipsilateral breast varied by facility and modality. BI-RADS categorization for UAL previously assigned to BI-RADS 0 or associated with suspicious ipsilateral breast findings varied, but practices tended to demonstrate a high level of suspicion unless the UAL showed improvement on follow-up imaging. For unchanged UAL on initial follow-up, 7 (70%) assign BI-RADS 3, and 3 (30%) assign BI-RADS 4.Conclusion: Despite available guidelines, there was no consensus approach to managing UAL after vaccination among academic and community-based breast imaging radiologists in California. Management was more uniform for a subset of patients perceived to be at higher risk for lymph node metastases, with most or all respondents recommending biopsy when there was  a suspicious finding in the ipsilateral breast, concurrent ipsilateral breast cancer, or concurrent malignant tumors not in the breast known to metastasize to the axilla.

Animals raised in environments that prevent natural foraging opportunities may have difficulty adapting to novelty, such as feeding and management changes. Our objective was to evaluate how early provision and presentation of forage in dairy calves affected response to novel TMR (total mixed ration; grain and alfalfa) at weaning. Holstein heifer calves were housed individually in a covered outdoor hutch with an attached uncovered wire-fenced pen on sand bedding. Calves were fed a diet of starter grain and milk replacer (5.7-8.4L/d step-up) via a bottle (Control, n = 9) or given additional access to mountaingrass hay presented either in a bucket (Bucket, n = 9), or PVC pipe feeder (Pipe, n = 9). Treatments were applied from birth through 50 d of age, when step-down weaning began. All calves had 3 buckets and a pipe feeder provided in their uncovered pen area. On d 50, each calf was briefly blocked inside their hutch. TMR was put in the 3rd bucket that previously contained hay (Bucket) or was empty (Control, Pipe). The calf was released from the hutch and video-recorded for 30 min. Neophobia towards TMR was affected by prior experience with presentation: Bucket calves began eating TMR faster than Pipe and Control (P≤0.012) and showed the fewest number of startle responses (P = 0.004). Intake was similar across groups (P = 0.978), suggesting this apparent neophobia was transient, but Control calves took longer to eat than Bucket (P

BackgroundSexual minority adolescents and young adults are at higher risk of eating disorders compared to heterosexual peers. However, little is known about the clinical and psychiatric presentation of this population requiring inpatient medical stabilization. Given the increased risk for eating disorder behaviors in sexual minority individuals amidst increased rates of medical hospitalizations secondary to eating disorders, it is important to understand presenting characteristics of this population. The objectives of this study were to (1) describe the clinical characteristics of sexual minority adolescents and young adults with eating disorders admitted for medical instability and (2) compare psychiatric co-morbidities and suicidality of sexual minority adolescents and young adults to heterosexual peers.MethodsA retrospective chart review was conducted of 601 patients admitted to a large inpatient eating disorders medical stabilization unit between 2012 and 2020. Data collected included demographics, medical data including vital signs, and psychiatric characteristics. Chi square or t-tests were used to examine potential differences in clinical characteristics and psychiatric co-morbidities between groups. Modified Poisson regression was used to assess associations between sexual orientation and psychiatric co-morbidities.ResultsOver one fifth (21.1%, n = 103) of our inpatient sample identified as a sexual minority individual. The average age of participants was 15.6 years (2.7). Sexual minority adolescents and young adults had higher percent median body mass index compared to heterosexual peers and yet equally severe vital sign instability on admission. Sexual minority adolescents and young adults were almost 1.5 times more likely to have a psychiatric comorbidity with higher rates of depression, anxiety, and post-traumatic stress disorder. Sexual minority adolescents and young adults were approximately two times more likely to have a history of self-injurious behaviors and/or suicidality.ConclusionsSexual minority adolescents and young adults with eating disorders have equally severe vital sign instability despite higher percent median body mass index on admission for medical stabilization. Sexual minority adolescents and young adults hospitalized for medical complications of eating disorders are far more likely to have an additional mental health disorder and a history of self-harm and/or suicidality, which may portend a less favorable long-term prognosis.

PurposeTo determine sex differences in and associations between zinc deficiency and anemia among adolescents and young adults hospitalized for medical complications of eating disorders.MethodsWe retrospectively reviewed electronic medical records of 601 patients aged 9-25 years admitted to the University of California, San Francisco Eating Disorders Program for medical instability, between May 2012 and August 2020. Descriptive statistics, crude, and adjusted logistic regression models were used to assess the association between zinc deficiency (

OBJECTIVE: We developed a novel, nurse practitioner-run Thoracic Survivorship Program to aid in long-term follow-up. Patients with non-small cell lung cancer who were disease-free at least 1 year after resection could be referred to the Thoracic Survivorship Program by their surgeon. Our objectives were to summarize follow-up compliance and assess long-term outcomes between Thoracic Survivorship Program enrollment and non-Thoracic Survivorship Program. METHODS: Patients who underwent R0 resection for stages I to IIIA between 2006 and 2016 were stratified by enrollment in Thoracic Survivorship Program versus surgeon only follow-up (non-Thoracic Survivorship Program). Follow-up included 6-month chest computed tomography scans for 2 years and then annually. Lack of follow-up compliance was defined by 2 or more consecutive delayed annual computed tomography scans/visits ± 90 days. Relationships between Thoracic Survivorship Program and second primary non--small cell lung cancers, extrathoracic cancers, and survival were quantified using multivariable Cox proportional hazards regression with time-varying covariate reflecting timing of enrollment. RESULTS: A total of 1162 of 3940 patients (29.5%) were enrolled in the Thoracic Survivorship Program. The median time to enrollment was 2.3 years; 3279 of 3940 (83%) had complete computed tomography scan data, and 60 of 3279 (1.8%) had 2 or more delayed scans; 323 of 9082 (3.6%) non-Thoracic Survivorship Program visits were noncompliant versus 132 of 4823 (2.7%) of Thoracic Survivorship Program visits (P = .009); 136 of 1146 Thoracic Survivorship Program patients developed second primary non-small cell lung cancer, and 69 of 1123 developed extrathoracic cancer, whereas 322 of 2794 of non-Thoracic Survivorship Program patients developed second primary non-small cell lung cancer and 225 of 2817 patients developed extrathoracic cancer. In multivariable analyses, Thoracic Survivorship Program enrollment was associated with improved disease-free survival (hazard ratio, 0.57; 95% confidence interval, 0.48-0.67; P

BackgroundRigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).MethodsWe first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T cells and evaluated the function of the CART cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208).ResultsBoth RV- and Tg-CART cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII+ and parental EGFRvIII- SB28.ConclusionOur new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.

BackgroundDespite the high prevalence of eating disorders in gender diverse adolescents, little is known about the characteristics of gender diverse youth with eating disorders who require inpatient medical stabilization. The primary objective of this study was to describe the medical, anthropometric, and psychiatric characteristics of gender diverse adolescents hospitalized for eating disorders and compare these characteristics to cisgender peers hospitalized for eating disorders. The secondary objective was to evaluate percent median body mass index as one marker of malnutrition and treatment goal body mass index as a recovery metric between patients' birth-assigned sex and affirmed gender using standardized clinical growth charts.MethodsA retrospective chart review was conducted of 463 patients admitted to an inpatient eating disorders medical unit between 2012 and 2020. To compare medical, anthropometric, and psychiatric data between gender diverse and cisgender patients, chi-square/Fisher's exact and t-tests were used. Clinical growth charts matching the patients' birth-assigned sex and affirmed gender identity were used to assess percent of median body mass index and treatment goal body mass index.ResultsTen patients (2.2%) identified as gender diverse and were younger than cisgender patients [13.6 (1.5) years vs. 15.6 (2.7) years, p = 0.017]. Gender diverse patients were hospitalized with a higher percent median body mass index compared to cisgender peers [97.1% (14.8) vs. 87.9% (13.7), p = 0.037], yet demonstrated equally severe vital sign instability such as bradycardia [44 (8.8) beats per minute vs. 46 (10.6) beats per minute, p = 0.501], systolic hypotension [84 (7.1) mmHg vs. 84 (9.7) mmHg, p = 0.995], and diastolic hypotension [46 (5.8) mmHg vs. 45 (7.3) mmHg, p = 0.884]. Gender diverse patients had a higher prevalence of reported anxiety symptoms compared to cisgender patients (60% vs. 28%, p = 0.037).ConclusionsGender diverse patients demonstrated complications of malnutrition including vital sign instability despite presenting with a higher weight. This is consistent with a greater proportion of gender diverse patients diagnosed with atypical anorexia nervosa compared to cisgender peers. Additionally, psychiatric comorbidities were present among both groups, with a larger percentage of gender diverse patients endorsing anxiety compared to cisgender patients.

PurposeMedical complications of eating disorders in males are understudied compared to females, as is the case of vitamin D deficiency. The aim of this study was to assess vitamin D levels among male and female adolescents and young adults hospitalized for medical complications of eating disorders.MethodsWe retrospectively reviewed electronic medical records of patients aged 9-25 years (N = 565) admitted to the University of California, San Francisco Eating Disorders Program for medical instability, between May 2012 and August 2020. Serum vitamin D (25-hydroxy) level was assessed at admission as was history of prior calcium, vitamin D, or multivitamin supplementation. Linear regression was used to assess factors associated with vitamin D levels.ResultsA total of 93 males and 472 females met eligibility criteria (age 15.5 ± 2.8, 58.8% anorexia nervosa; admission body mass index 17.6 ± 2.91). Among male participants, 44.1% had 25-hydroxyvitamin D levels

ObjectivesThe purpose of this agreement was to establish evidence-based consensus statements on imaging of scapholunate joint (SLJ) instability by an expert group using the Delphi technique.MethodsNineteen hand surgeons developed a preliminary list of questions on SLJ instability. Radiologists created statements based on the literature and the authors' clinical experience. Questions and statements were revised during three iterative Delphi rounds. Delphi panellists consisted of twenty-seven musculoskeletal radiologists. The panellists scored their degree of agreement to each statement on an eleven-item numeric scale. Scores of '0', '5' and '10' reflected complete disagreement, indeterminate agreement and complete agreement, respectively. Group consensus was defined as a score of '8' or higher for 80% or more of the panellists.ResultsTen of fifteen statements achieved group consensus in the second Delphi round. The remaining five statements achieved group consensus in the third Delphi round. It was agreed that dorsopalmar and lateral radiographs should be acquired as routine imaging work-up in patients with suspected SLJ instability. Radiographic stress views and dynamic fluoroscopy allow accurate diagnosis of dynamic SLJ instability. MR arthrography and CT arthrography are accurate for detecting scapholunate interosseous ligament tears and articular cartilage defects. Ultrasonography and MRI can delineate most extrinsic carpal ligaments, although validated scientific evidence on accurate differentiation between partially or completely torn or incompetent ligaments is not available.ConclusionsDelphi-based agreements suggest that standardized radiographs, radiographic stress views, dynamic fluoroscopy, MR arthrography and CT arthrography are the most useful and accurate imaging techniques for the work-up of SLJ instability.Key points• Dorsopalmar and lateral wrist radiographs remain the basic imaging modality for routine imaging work-up in patients with suspected scapholunate joint instability. • Radiographic stress views and dynamic fluoroscopy of the wrist allow accurate diagnosis of dynamic scapholunate joint instability. • Wrist MR arthrography and CT arthrography are accurate for determination of scapholunate interosseous ligament tears and cartilage defects.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

ObjectivePatient-reported outcomes (PROs) are an integral part of treat-to-target approaches in managing rheumatoid arthritis (RA). In clinical practice, however, routine collection, documentation, and discussion of PROs with patients are highly variable. The RISE LC (Rheumatology Informatics System for Effectiveness Learning Collaborative) was established to develop and share best practices in PRO collection and use across adult rheumatology practices in the United States METHODS: The goals of the RISE LC were developed through site surveys and in-person meetings. Participants completed a baseline survey on PRO collection and use in their practices. RISE LC learning sessions focused on improving communication around PROs with patients and enhancing shared decision-making in treatment plans. During the coronavirus disease 2019 (COVID-19) pandemic, the RISE LC pivoted to adapt PRO tools for telehealth.ResultsAt baseline, all responding sites (n = 15) had established workflows for collecting PROs. Most sites used paper forms alone. PRO documentation in electronic health records was variable, with only half of the sites using structured data fields. To standardize and improve the use of PROs, participants iteratively developed a Clinical Disease Activity Index-based RA Disease Activity Communication Tool to solicit treatment goals and improve shared decision-making across sites. The COVID-19 pandemic necessitated developing a tool to gauge PROs via telehealth.ConclusionThe RISE LC is a continuous, structured method for implementing strategies to improve PRO collection and use in rheumatological care, initially adapting from the Learning Collaborative model and extending to include features of a learning network. Future directions include measuring the impact of standardized PRO collection and discussion on shared decision-making and RA outcomes.

Background and objectivesOlder adults with cognitive impairment often experience poor oral health outcomes due to inadequate oral hygiene practices. This pilot study aimed to evaluate the feasibility of a care partner-assisted intervention to improve the oral hygiene of community-dwelling older adults with cognitive impairment.Material and methodsThe 6-month intervention included 25 older adults with mild dementia or mild cognitive impairment, who were randomly assigned to Treatment Group 1 or Treatment Group 2. Treatment Group 1 (n = 7) received an educational booklet. Treatment Group 2 (n = 18) received a booklet, a tailored care plan for the participants with cognitive impairment and the care partner received four coaching sessions to learn to facilitate good oral hygiene. Both groups received electric toothbrushes. The study consisted of a 3-month active intervention and 3-month maintenance phase. The outcomes of gingival index, plaque index and overall oral health status based on the Oral Health Assessment Tool were measured at baseline, 3 months (end of active intervention) and 6 months of the study.ResultsThis study had very low dropout rate. Participants' oral hygiene improved in this study. In comparison to Treatment Group 1, participants in Treatment Group 2 had a greater reduction in plaque level and gingival inflammation, and greater improvement in overall oral health status.ConclusionThis study demonstrates the feasibility of this intervention designed to improve the oral health of persons with cognitive impairment and it lays the foundation for using this protocol in a future large randomised clinical trial.

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

OBJECTIVE: To determine the early impact of the COVID-19 pandemic on breast imaging centers in California and Texas and compare regional differences. METHODS: An 11-item survey was emailed to American College of Radiology accredited breast imaging facilities in California and Texas in August 2020. A question subset addressed March-April government restrictions on elective services (during the shutdown and after reopening). Comparisons were made between states with chi-square and Fishers tests, and timeframes with McNemars and paired t-tests. RESULTS: There were 54 respondents (54/240, 23%, 26 California, 28 Texas). Imaging volumes fell during the shutdown and remained below pre-pandemic levels after reopening, with reduction in screening greatest (ultrasound 12% of baseline, mammography 13%, MRI 23%), followed by diagnostic MRI (43%), procedures (44%), and diagnostics (45%). California reported higher volumes during the shutdown (procedures, MRI) and after reopening (diagnostics, procedures, MRI) versus Texas (P = 0.001-0.02). Most screened patients (52/54, 96% symptoms and 42/54, 78% temperatures), and 100% (53/53) modified check-in and check-out. Reading rooms or physician work were altered for social distancing (31/54, 57%). Physician mask (45/48, 94%), gown (15/48, 31%), eyewear (22/48, 46%), and face shield (22/48, 46%) use during procedures increased after reopening versus pre-pandemic (P

ObjectiveTo determine the impact of the COVID-19 pandemic on breast imaging education.MethodsA 22-item survey addressing four themes during the early pandemic (time on service, structured education, clinical training, future plans) was emailed to Society of Breast Imaging members and members-in-training in July 2020. Responses were compared using McNemar's and Mann-Whitney U tests; a general linear model was used for multivariate analysis.ResultsOf 136 responses (136/2824, 4.8%), 96 U.S. responses from radiologists with trainees, residents, and fellows were included. Clinical exposure declined during the early pandemic, with almost no medical students on service (66/67, 99%) and fewer clinical days for residents (78/89, 88%) and fellows (48/68, 71%). Conferences shifted to remote live format (57/78, 73%), with some canceled (15/78, 19%). Compared to pre-pandemic, resident diagnostic (75/78, 96% vs 26/78, 33%) (P < 0.001) and procedural (73/78, 94% vs 21/78, 27%) (P < 0.001) participation fell, as did fellow diagnostic (60/61, 98% vs 47/61, 77%) (P = 0.001) and procedural (60/61, 98% vs 43/61, 70%) (P < 0.001) participation. Most thought that the pandemic negatively influenced resident and fellow screening (64/77, 83% and 43/60, 72%, respectively), diagnostic (66/77, 86% and 37/60, 62%), and procedural (71/77, 92% and 37/61, 61%) education. However, a majority thought that decreased time on service (36/67, 54%) and patient contact (46/79, 58%) would not change residents' pursuit of a breast imaging fellowship.ConclusionThe pandemic has had a largely negative impact on breast imaging education, with reduction in exposure to all aspects of breast imaging. However, this may not affect career decisions.

Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.

Reproductive justice is an intersectional social movement, theory, and praxis well aligned with social work's mission and values. Yet, advancing reproductive justice-the right to have children, to not have children, to parent with safety and dignity, and to sexual and bodily autonomy-has not been a signature area of scholarship and practice for the field. This article argues that it is critical for social work to advance reproductive justice to truly achieve the grand challenge of closing the health gap. The article starts by discussing the history and tenets of reproductive justice and how it overlaps with social work ethics. The authors then highlight some of the ways by which social workers have been disruptors of and complicit in the oppression of individuals, families, and communities with regard to their reproductive rights and outcomes. The article concludes with a call to action and recommendations for social work to foreground reproductive justice in research, practice, and education efforts by centering marginalized voices while reimagining the field's pursuit of health equity.

IntroductionChildren with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.Areas coveredThe authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.Expert opinionAdequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.

IntroductionMicrobial residents of the human oral cavity have long been a major focus of microbiology due to their influence on host health and intriguing patterns of site specificity amidst the lack of dispersal limitation. However, the determinants of niche partitioning in this habitat are yet to be fully understood, especially among taxa that belong to recently discovered branches of microbial life.ResultsHere, we assemble metagenomes from tongue and dental plaque samples from multiple individuals and reconstruct 790 non-redundant genomes, 43 of which resolve to TM7, a member of the Candidate Phyla Radiation, forming six monophyletic clades that distinctly associate with either plaque or tongue. Both pangenomic and phylogenomic analyses group tongue-specific clades with other host-associated TM7 genomes. In contrast, plaque-specific TM7 group with environmental TM7 genomes. Besides offering deeper insights into the ecology, evolution, and mobilome of cryptic members of the oral microbiome, our study reveals an intriguing resemblance between dental plaque and non-host environments indicated by the TM7 evolution, suggesting that plaque may have served as a stepping stone for environmental microbes to adapt to host environments for some clades of microbes. Additionally, we report that prophages are widespread among oral-associated TM7, while absent from environmental TM7, suggesting that prophages may have played a role in adaptation of TM7 to the host environment.ConclusionsOur data illuminate niche partitioning of enigmatic members of the oral cavity, including TM7, SR1, and GN02, and provide genomes for poorly characterized yet prevalent members of this biome, such as uncultivated Flavobacteriaceae.

ObjectivesTo characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality.DesignMulticenter prospective cohort study between September 2017 and February 2018.SettingsThirty-four hospitals in the United States and Jordan.PatientsConsecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor.InterventionsNone.Measurement and main resultsOf 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18).ConclusionsThe use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290.

CONTEXT: The literature on reproductive decision making often focuses on women and neglects the role of men and the importance of relationship context. Research with couples is vital to understanding joint decision making regarding having children at various stages of a couples relationship and an individuals life course. METHODS: In-depth, individual interviews were conducted with a socioeconomically, racially and ethnically diverse sample of 50 young heterosexual women and their male partners in northern California in 2015-2016. A dyadic, thematic analytic approach was used to examine whether and how prospective pregnancy intentions and current pregnancy desires are negotiated at the couple level, and how relationship dynamics influence any negotiation and decision-making processes. RESULTS: Twenty-three couples described engaging in joint pregnancy decision making, which required purposeful communication and, for some, compromise and acceptance. For nearly all of these couples, these processes led to aligned prospective pregnancy intentions, even when current pregnancy desires differed. The remaining 27 couples described individual pregnancy decision-making processes; many respondents reported intentions that aligned with their partners by happenstance, despite some respondents having avoided communicating their desires to their partner. Some of these couples faced relationship difficulties, including poor communication, leading some participants to misinterpret or be unaware of their partners pregnancy intentions and desires. CONCLUSIONS: The relationship context is important in the formulation of prospective pregnancy intentions among young people. Counseling protocols, interventions and policies that attend to the complex factors that influence young couples pregnancy decision making are needed to better help couples attain their reproductive goals.

BACKGROUND: Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade. METHODS: An IDH1R132H glioma model was created in syngeneic HLA-A2/HLA-DR1-transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1R132H peptide vaccination or anti-PD-1 immune checkpoint blockade. RESULTS: The HLA-A2/HLA-DR1-syngeneic IDH1R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1R132H gliomas in a CD4+ and CD8+ cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4+ tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1R132H and DR1-IDH1R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone. CONCLUSION: The development of effective IDH1R132H-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1-syngeneic IDH1R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.

Abstract Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.

Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs), enzymes that contribute to cancer and many inflammatory and degenerative diseases. The TIMP N-terminal domain binds and inhibits an MMP catalytic domain, but the role of the TIMP C-terminal domain in MMP inhibition is poorly understood. Here, we employed yeast surface display for directed evolution of full-length human TIMP-1 to develop MMP-3-targeting ultrabinders. By simultaneously incorporating diversity into both domains, we identified TIMP-1 variants that were up to 10-fold improved in binding MMP-3 compared with WT TIMP-1, with inhibition constants (Ki ) in the low picomolar range. Analysis of individual and paired mutations from the selected TIMP-1 variants revealed cooperative effects between distant residues located on the N- and C-terminal TIMP domains, positioned on opposite sides of the interaction interface with MMP-3. Crystal structures of MMP-3 complexes with TIMP-1 variants revealed conformational changes in TIMP-1 near the cooperative mutation sites. Affinity was strengthened by cinching of a reciprocal "tyrosine clasp" formed between the N-terminal domain of TIMP-1 and proximal MMP-3 interface and by changes in secondary structure within the TIMP-1 C-terminal domain that stabilize interdomain interactions and improve complementarity to MMP-3. Our protein engineering and structural studies provide critical insight into the cooperative function of TIMP domains and the significance of peripheral TIMP epitopes in MMP recognition. Our findings suggest new strategies to engineer TIMP proteins for therapeutic applications, and our directed evolution approach may also enable exploration of functional domain interactions in other protein systems.

ObjectivesTo identify the top priority areas for research to optimize pharmacotherapy in older adults with cardiovascular disease (CVD).DesignConsensus meeting.SettingMultidisciplinary workshop supported by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society, February 6-7, 2017.ParticipantsLeaders in the Cardiology and Geriatrics communities, (officers in professional societies, journal editors, clinical trialists, Division chiefs), representatives from the NIA; National Heart, Lung, and Blood Institute; Food and Drug Administration; Centers for Medicare and Medicaid Services, Alliance for Academic Internal Medicine, Patient-Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, pharmaceutical industry, and trainees and early career faculty with interests in geriatric cardiology.MeasurementsSummary of workshop proceedings and recommendations.ResultsTo better align older adults' healthcare preferences with their care, research is needed to improve skills in patient engagement and communication. Similarly, to coordinate and meet the needs of older adults with multiple comorbidities encountering multiple healthcare providers and systems, systems and disciplines must be integrated. The lack of data from efficacy trials of CVD medications relevant to the majority of older adults creates uncertainty in determining the risks and benefits of many CVD therapies; thus, developing evidence-based guidelines for older adults with CVD is a top research priority. Polypharmacy and medication nonadherence lead to poor outcomes in older people, making research on appropriate prescribing and deprescribing to reduce polypharmacy and methods to improve adherence to beneficial therapies a priority.ConclusionThe needs and circumstances of older adults with CVD differ from those that the current medical system has been designed to meet. Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person-centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices. J Am Geriatr Soc 67:371-380, 2019.

Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers.

Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule's efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. Graphical Abstract.

ObjectiveTo determine if chikungunya virus persists in synovial fluid after infection, potentially acting as a causative mechanism of persistent arthritis.MethodsWe conducted a cross-sectional study of 38 Colombian participants with clinical chikungunya virus infection during the 2014-2015 epidemic who reported chronic arthritis and 10 location-matched controls without chikungunya virus or arthritis. Prior chikungunya virus infection status was serologically confirmed, and the presence of synovial fluid chikungunya virus, viral RNA, and viral proteins was determined by viral culture, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and mass spectrometry, respectively. Biomarkers were assessed by multiplex analysis.ResultsPatients with serologically confirmed chikungunya arthritis (33 of 38 [87%]) were predominantly female (82%) and African Colombian (55%) or white Colombian (33%), with moderate disease activity (mean ± SD Disease Activity Score in 28 joints 4.52 ± 0.77) a median of 22 months after infection (interquartile range 21-23 months). Initial symptoms of chikungunya virus infection included joint pain (97%), swelling (97%), stiffness (91%), and fever (91%). The most commonly affected joints were the knees (87%), elbows (76%), wrists (75%), ankles (56%), fingers (56%), and toes (56%). Synovial fluid samples from all patients with chikungunya arthritis were negative for chikungunya virus on qRT-PCR, showed no viral proteins on mass spectrometry, and cultures were negative. Case and control plasma cytokine and chemokine concentrations did not differ significantly.ConclusionThis is one of the largest observational studies involving analysis of the synovial fluid of chikungunya arthritis patients. Synovial fluid analysis revealed no detectable chikungunya virus. This finding suggests that chikungunya virus may cause arthritis through induction of potential host autoimmunity, suggesting a role for immunomodulating agents in the treatment of chikungunya arthritis, or that low-level viral persistence exists in synovial tissue only and is undetectable in synovial fluid.

Reproductive health disparities-particularly those experienced by racial and ethnic minority groups-are considered a persistent public health issue in the United States. Frameworks that focus on social determinants of health seek to identify the forces producing these disparities, particularly social conditions that create vulnerability to premature death and disease. Such frameworks pose challenges to health care provision, as structural factors can seem immutable to health care professionals trained to treat individual patients. Here, we discuss the links between reproductive health disparities and social determinants of health. We then apply to reproductive health care the structural competency framework, developed by physician-scholars to encourage health care professionals to address health disparities by analyzing and intervening upon sociopolitical forces.

The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector. TCR-transduced HLA-A2+ T cells efficiently killed HLA-A2+H3.3K27M+ glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR-transduced T cells significantly suppressed the progression of glioma xenografts in mice. Alanine-scanning assays suggested the absence of known human proteins sharing the key amino acid residues required for recognition by the TCR, suggesting that the TCR could be safely used in patients. These data provide us with a strong basis for developing T cell-based therapy targeting this shared neoepitope.

Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers.

BackgroundContraceptive use is widely recognized as a means of reducing adverse health-related outcomes. However, dominant paradigms of contraceptive counseling may rely on a narrow definition of "evidence" (i.e., scientifically accurate but exclusive of individual women's experiences). Given increased enthusiasm for long-acting, reversible contraceptive methods, such paradigms may reinforce counseling that overprivileges effectiveness, particularly for groups considered at high risk of unintended pregnancy. This study investigates where and how women's experiences fit into the definition of evidence these counseling protocols use.MethodsUsing a qualitative approach, this analysis draws on semistructured interviews with 38 young (ages 18-24) Black and Latina women. We use a qualitative content analysis approach, with coding categories derived directly from the textual data.FindingsOur analysis suggests that contraceptive decision making is an iterative, relational, reflective journey. Throughout contraceptive histories, participants described experiences evolving to create a foundation from which decision-making power was drawn. The same contraceptive-related decisions were revisited repeatedly, with knowledge accrued along the way. The cumulative experience of using, assigning meanings to, and developing values around contraception meant that young women experienced contraceptive decision making as a dynamic process.Implications for practiceThis journey creates a rich body of evidence that informs contraceptive decision making. To provide appropriate, acceptable, patient-centered family planning care, providers must engage with evidence grounded in women's expertise on their contraceptive use in addition to medically accurate data on method effectiveness, side effects, and contraindications.

This article explores doctoral student satisfaction as related to interest in the professoriate and as influenced by issues of social justice, according to a national student survey. Results indicate that 85% of respondents were satisfied or very satisfied with their doctoral education. Most satisfying aspects were individualization or independence, collegiality or collaboration, praxis or translation, and reaching or achieving milestones. Least satisfying aspects were educational environments or climates, course quality, mentorship quality, and finances. Eighty percent reported that satisfaction was “explained by social justice training opportunities and a sense of a socially just institution.” At research-intensive universities, satisfaction predicted interest in the professoriate. Understanding student satisfaction may improve doctoral education and the faculty pipeline.

Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors. Given these findings, we have investigated the impact of IDH mutations on the immunological milieu in LGG. In immortalized normal human astrocytes (NHAs) and syngeneic mouse glioma models, the introduction of mutant IDH1 or treatment with 2HG reduced levels of CXCL10, which was associated with decreased production of STAT1, a regulator of CXCL10. Expression of mutant IDH1 also suppressed the accumulation of T cells in tumor sites. Reductions in CXCL10 and T cell accumulation were reversed by IDH-C35, a specific inhibitor of mutant IDH1. Furthermore, IDH-C35 enhanced the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. Our findings demonstrate a mechanism of immune evasion in IDH-MUT gliomas and suggest that specific inhibitors of mutant IDH may improve the efficacy of immunotherapy in patients with IDH-MUT gliomas.

School shootings tear the fabric of society. In the wake of a school shooting, parents, pediatricians, policymakers, politicians, and the public search for "the" cause of the shooting. But there is no single cause. The causes of school shootings are extremely complex. After the Sandy Hook Elementary School rampage shooting in Newtown, Connecticut, we wrote a report for the National Science Foundation on what is known and not known about youth violence. This article summarizes and updates that report. After distinguishing violent behavior from aggressive behavior, we describe the prevalence of gun violence in the United States and age-related risks for violence. We delineate important differences between violence in the context of rare rampage school shootings, and much more common urban street violence. Acts of violence are influenced by multiple factors, often acting together. We summarize evidence on some major risk factors and protective factors for youth violence, highlighting individual and contextual factors, which often interact. We consider new quantitative "data mining" procedures that can be used to predict youth violence perpetrated by groups and individuals, recognizing critical issues of privacy and ethical concerns that arise in the prediction of violence. We also discuss implications of the current evidence for reducing youth violence, and we offer suggestions for future research. We conclude by arguing that the prevention of youth violence should be a national priority. (PsycINFO Database Record

In human athletes significant changes in cytokine concentrations secondary to exercise have been observed. This prospective study evaluated the effect of a multi-day stage sled dog race on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10). Samples from 20 dogs were harvested prior to and on days 2 and 8 of an 8-day race. Exercise resulted in significantly decreased TNF-α and IL-8 as well as increases of MCP-1, IL-6, and IL-10 concentrations (P-value between 0.01 and < 0.0001 for all parameters). The proportion of values for IL-2 that were below the detection limit increased from 40% on day 0 to 75% on day 2 and decreased on day 8 to 40% (P = 0.04). Racing sled dogs show cytokine-concentration changes that are different from those in humans.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.