Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs, and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Among them are several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research.

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

Racial Socialization and Black Adolescent Mental Health and Developmental Outcomes: A Critical Review and Future Directions.

OBJECTIVE: Black American adolescents are beleaguered with the most frequent and severe experiences of racial discrimination (RD) among their peers. To protect Black adolescents' mental health and developmental outcomes from the pernicious impact of discrimination, parents and other proximal adults and peers often utilize racial socialization (RS), or communications and behaviors emphasizing the importance of race and the harms of racism. While several recent RS reviews have been conducted across ethnicity, a modern review investigating RS practices related to and predictive of Black adolescent psychosocial outcomes is needed. METHOD: To ground our critical systematic review of 45 articles, we first highlighted the ways RD impacts the lives of Black adolescents. Then, drawing from integrative models for Black youth development, we synthesized recent psychological, academic, and sociocultural literatures to describe the role of RS in Black adolescents' wellness. RESULTS: The impact of various tenets of RS was seen most clearly as a protective factor against RD with respect to adolescents' mental health (e.g. depression), academic achievement (e.g. GPA), and sociocultural identity (e.g. public and private racial regard) development. Cultural socialization, a strategy related to extolling pride for one's race, was the most consistent RS protective factor, with novel RS constructs (e.g. parental competency) emerging as a method to buffer youth internalizing and externalizing problems. CONCLUSIONS: Recommendations are made for future research on understudied components of RS and multiple methods and reporters to capture a more holistic depiction of RS practices. We emphasize preventative and intervening approaches to reduce the impetus for RS and its impact, including burgeoning clinical and community-level programs and the importance for provider training to yield positive mental health outcomes for Black adolescents.

Directionality explored: Black Adolescents' awareness of systemic racism and race-based experiences.

Increases in conversations about race and racial discrimination experiences during adolescence make this a critical developmental period to investigate adolescents' awareness of racism. We examined bidirectional associations between race-based experiences and awareness of systemic racism-operationalized as understanding systemic causes of racial disparities in education. Adolescents who self-identified as African American/Black were surveyed in Grade 6 (n = 317; Mage = 11.12; 48% girls) and Grade 8 (n = 247; Mage = 13.15; 56% girls). Cross-lagged panel analyses revealed that racial barrier messages, but not racial discrimination experiences, in Grade 6 positively predicted awareness of systemic racism in Grade 8. Adolescents' awareness of systemic racism in Grade 6 did not predict racial socialization or racial discrimination experiences in Grade 8.

Examining the feasibility of a parental self-help intervention for families awaiting pediatric eating disorder services.

OBJECTIVE: Waitlists for eating disorder (ED) services grew immensely during the COVID-19 pandemic. To address this, we studied the feasibility of a novel parental self-help waitlist intervention. METHOD: Parents of a child/adolescent (7-17 years) awaiting pediatric ED services were provided with our intervention, adapted from the family-based treatment model, and consisting of videos and reading material with no therapist involvement. Parent-reported child/adolescent weight was collected weekly 6 weeks pre-intervention, 2 weeks during the intervention, and 6-week post-intervention. Recruitment and retention rates were calculated. Regression-based interrupted time series analyses were completed to measure changes in the rate of weight gain. RESULTS: Ninety-seven parents were approached, and 30 agreed to participate (31% recruitment rate). All but one completed end-of-study measures (97% retention rate). The average rate of weight gain was 0.24 lbs/week pre-intervention, which increased significantly to 0.78 lbs/week post-intervention (p < .034). DISCUSSION: Our findings provide preliminary evidence that this intervention is feasible. Future research is needed to confirm the efficacy of this intervention on a larger scale. PUBLIC SIGNIFICANCE: The COVID-19 pandemic has resulted in several challenges in providing care for children and adolescents with eating disorders, including long waiting lists and delays in treatment. This study suggests that providing parents on a waitlist with educational videos and reading material is acceptable to parents, and may even help in improving the child's symptoms of an eating disorder.

Reflecting on change: Critical consciousness as a protective factor for Black youth.

OBJECTIVES: The previous decade has seen an abundance of scholarship on the benefits of critical consciousness (CC) for racial and ethnic minority youth. However, it is unclear whether CC is a buffer against the negative effects of racial discrimination on Black adolescents' outcomes. The present study examined whether three CC dimensions buffered against the negative effects of racial discrimination on academic attitudes. METHOD: A total of 205 Black adolescents (Mage = 15.10) reported racial discrimination and CC. We conducted multiple regression analyses for each component of CC to test for their direct and protective effects on academic attitudes. RESULTS: Our results revealed associations between CC dimensions and academic attitudes. Critical reflection and critical action also buffered against racial discrimination's negative effects. CONCLUSIONS: Implications for research on the nature and impact of CC dimensions on racial discrimination and academic attitudes are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The BODY-Q Chest Module: Further Validation in a Canadian Chest Masculinization Surgery Sample.

BACKGROUND: The BODY-Q Chest module is a patient-reported outcome (PRO) instrument that measures satisfaction with how the chest (10 items) and nipples (5 items) look. This PRO instrument was previously field tested in an international sample of people seeking treatment for gynecomastia (n = 174), weight loss (n = 224), and chest masculinization (n = 341). OBJECTIVES: The aim of this study was to examine the psychometric performance of the BODY-Q Chest module in a new chest masculinization surgery sample. METHODS: Data were collected from patients attending a private plastic surgery outpatient clinic in Canada between January 2018 and June 2019. Rasch measurement theory analysis was used to examine how the scales performed psychometrically. RESULTS: The sample provided 266 assessments (115 preoperative, 151 postoperative). All items had ordered thresholds, providing evidence that the 4 response options for each scale worked as expected. Item fit was within ±2.5 for all items, with all Bonferroni adjusted chi-square values nonsignificant. The data for the chest (χ2(20) = 18.72, P = 0.54) and nipples (χ 2(10) = 12.28, P = 0.27) scales fit the requirements of the Rasch model. Reliability was high with person separation index and Cronbach's α values of ≥0.95 for the chest and ≥0.87 for the nipple scales, respectively. More depressive symptoms on the Patient Health Questionnaire-9 and lower health-related quality of life scales were weakly correlated with worse scores on the chest and nipple scales (P < 0.001). CONCLUSIONS: The BODY-Q Chest module was shown to be scientifically sound in an independent sample of patients seeking chest masculinization surgery.

Mini-Clinical Evaluation Exercise in the Era of Milestones and Entrustable Professional Activities in Obstetrics and Gynaecology: Resume or Reform?

OBJECTIVE: The Accreditation Council for Graduate Medical Education (ACGME) milestones and the core Entrustable Professional Activities (EPAs) provide guiding frameworks and requirements for assessing residents' progress. The Mini-Clinical Evaluation Exercise (Mini-CEX) is a formative assessment tool used to provide direct observation after an ambulatory or clinical encounter. This study aimed to investigate the feasibility and reliability of the Mini-CEX in the authors' obstetrics and gynaecology (OB/GYN) residency program and its ability to measure residents' progress and competencies in the frameworks of ACGME milestones and EPAs. METHODS: OB/GYN residents' 5-academic-year Mini-CEX performance was analyzed retrospectively to measure reliability and feasibility. Additionally, realistic evaluation was conducted to assess the usefulness of Mini-CEX in the frameworks of ACGME milestones and EPAs. RESULTS: A total of 395 Mini-CEX evaluations for 49 OB/GYN residents were analyzed. Mini-CEX evaluation data significantly discriminated among residents' training levels (P < 0.003). Residents had an average of 8.1 evaluations per resident completed; 10% of second-year residents and 28% of third-year residents were evaluated 10 or more times per year, whereas no postgraduate year 1 or postgraduate year 4 residents achieved this number. Mini-CEX data could contribute to all 6 primary measurement domains of OB/GYN milestones and 8 of 10 EPAs required for first-year residents. CONCLUSION: The Mini-CEX demonstrated potential for measuring residents' clinical competencies in their ACGME milestones. Faculty time commitment was the main challenge. Reform is necessary for the current feedback structure in Mini-CEX, faculty development, and operational guidelines that help residency programs match residents' clinical competency ratings with ACGME milestones and EPAs.

Comprehensive sexual health assessments for adolescents.

Sexual activity and experimentation are normative parts of adolescent development that may, at the same time, be associated with adverse health outcomes, including the acquisition of sexually transmitted infections, unplanned pregnancy, and teen dating violence. Anticipatory guidance regarding sexual and reproductive health for teens should address normal sexual development issues, such as identity and attractions, safe relationships, safer sex, and contraception. Health care providers can enhance the sexual education of the youth they see and help mitigate negative health outcomes. This practice point offers a '7-P' approach to ensure that health care providers obtain comprehensive sexual health assessments for adolescents. Teen issues such as identity, confidentiality, and consent, and dating violence are discussed, and Canadian Paediatric Society resources are cited to provide more detailed care pathways on related issues: contraception, pregnancy, and sexually transmitted infections.

Tissue protein and lipid alterations in response to metallic impaction.

Tissue response to metallic contact and injury remains poorly understood at the level of proteins and lipid changes. We used corneas as a model system (bovine, porcine [n = 300 each], and human corneas [n = 6]) to characterize proteomic and lipidomic reactions to metallic exposure (impaction with iron). We also made a limited investigation into protein extractability and profile changes due to copper, and lead exposure as well. We identified selected proteins after trypsin digestion using an LCQ Deca XP and lipids using a TSQ Quantum Access Max mass spectrometer, respectively. Our findings indicate that iron impaction to corneal tissue results in cleavage of 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-2 variant (PLCB2; 134 kDa) into a 36 kDa species and presence of the epithelial layer is necessary for this cleavage. Penetration of the cornea with other metals (copper and lead) resulted in lower protein extractability from corneal tissue compared with controls but not distinct changes in PLCB2. The changes in protein profiles were unique to the type of metal used for impaction. The depth of injury negatively affected protein extractability and profile compared with controls. These changes were also dependent on several other factors in a complex manner. Iron impaction of corneal tissue for 24 hours results in cleavage of PLCB2 commensurate with significant changes in phosphatidylinositols but not phosphatidylcholines or other phospholipids.

Learning in a High-Stress Clinical Environment: Stressors Associated with Medical Students' Clerkship Training on Labor and Delivery.

Phenomenon: Obstetrics and gynecology can be a high-stress clinical environment for medical students due to the specialty's fast-paced and unpredictable nature. Little is known about learning stressors for medical students on the obstetrics and gynecology clerkship to inform stress-reducing interventions and improve learning experience. This study investigated (a) which aspects of the learning environment are most stressful for obstetrics and gynecology clerkship students, (b) how perceived learning stressors in this environment differ for medical students and teachers (residents, fellows, and faculty), and (c) what interventions students propose to address these stressors. Approach: From May 2015 to April 2016, we conducted semistructured individual interviews with 3rd-year medical students from obstetrics and gynecology clerkship cohorts (n = 52) as well as clerkship teachers (n = 10) at an academic medical center. Two investigators used a qualitative Framework Method approach to analyze the interview data and agree upon final themes. Findings: We identified labor and delivery as the most stressful learning environment and four labor and delivery-related themes of students' learning stressors: context (pace, logistics, nature of childbirth, and nonroutine schedule), learning tasks (student role and assignments and the amount of new knowledge and skills), communication (terminology used in conversation and interacting with the labor and delivery team), and clinical scenario (crisis, emergency, and patient refusal of student involvement). Whereas students identified context as causing most of the stress, teachers concentrated on stressors related to learning tasks. Insights: Learning stressors associated with students' educational experience in the clinical context of labor and delivery are challenging for medical students. In addition to the specific content of these challenges, the recognition that teachers' assumptions about sources of stressors are different from those of students is an important finding and has implications for changing the learning environment. Clerkship programs are encouraged to provide practical guidelines and embed an introduction of the clinical learning environment into the Obstetrics and Gynecology clerkship orientation curriculum.

Acceptability and tolerability of omega-3 fatty acids as adjunctive treatment for children and adolescents with eating disorders.

The objective of this study was to examine the acceptability and tolerability of omega-3 fatty acids as an adjunctive treatment for children and adolescents with eating disorders (EDs). Children and adolescents with EDs received omega-3 supplements (300 mg eicosapentaenoic acid [EPA] and 200 mg docosahexaenoic acid [DHA]/day) in addition to standard treatment for 8 weeks. Primary outcomes were dropout rate, compliance, and side effects. Secondary outcomes included percent ideal body weight, Eating Disorders Inventory-3 (EDI-3), Children's Depression Inventory-2 (CDI-2), and Multidimensional Anxiety Scale for Children (MASC). There were 21 participants with mean age of 15.29 ± 2.0 years. There were no dropouts. Omega-3 was well tolerated by all participants. Compared to baseline, at week 8 there was a significant increase in mean percent ideal body weight but no significant difference in scores on the EDI-3, CDI-2, and MASC. We conclude that omega-3 supplements are acceptable and well tolerated in the pediatric ED population.

Severe avoidant/restrictive food intake disorder and coexisting stimulant treated attention deficit hyperactivity disorder.

There is a growing body of literature describing the development, clinical course, and treatment of avoidant/restrictive food intake disorder (ARFID), a diagnostic category introduced in the DSM-5. However, information surrounding complex cases of ARFID involving coexisting medical and/or psychiatric disorders remains scarce. Here we report on two cases of young patients diagnosed concurrently with ARFID and attention deficit hyperactivity disorder (ADHD) who both experienced significant growth restriction following initiation of stimulant medication. The appetite suppressant effect of stimulants exacerbated longstanding avoidant and restrictive eating behaviors resulting in growth restriction and admission to an inpatient eating disorders unit. The implications of ARFID exacerbated by stimulant-treated ADHD are explored, as well as the treatment delivered. These cases suggest that further research is needed to explore management options to counteract the appetite suppression effects of stimulants, while simultaneously addressing attention deficit symptoms and oppositional behavior. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1036-1039).

Gas/solid carbon branching ratios in surface-mediated reactions and the incorporation of carbonaceous material into planetesimals.

We report the ratio of the initial carbon available as CO that forms gas-phase compounds compared to the fraction that deposits as a carbonaceous solid (the gas/solid branching ratio) as a function of time and temperature for iron, magnetite, and amorphous iron silicate smoke catalysts during surface-mediated reactions in an excess of hydrogen and in the presence of N2. This fraction varies from more than 99% for an amorphous iron silicate smoke at 673 K to less than 40% for a magnetite catalyst at 873 K. The CO not converted into solids primarily forms methane, ethane, water, and CO2, as well as a very wide range of organic molecules at very low concentration. Carbon deposits do not form continuous coatings on the catalytic surfaces, but instead form extremely high surface area per unit volume "filamentous" structures. While these structures will likely form more slowly but over much longer times in protostellar nebulae than in our experiments due to the much lower partial pressure of CO, such fluffy coatings on the surfaces of chondrules or calcium aluminum inclusions could promote grain-grain sticking during low-velocity collisions.

Anorexia nervosa and gender dysphoria in two adolescents.

Little has been published about the co-occurrence of gender dysphoria (GD) and eating disorders (ED) in adults, with no cases described in the adolescent population. The emphasis on body shape in both conditions suggests that there may be some overlap in symptomatology. We report two adolescent cases initially diagnosed with anorexia nervosa who later met criteria for GD. The drive for thinness for the 16-year-old male was associated with a wish to achieve a feminine physique whereas there was an emphasis for stunted breast growth and a desire for muscularity in the 13-year-old female. Complexities in presentation, evolution of symptoms over time, and the treatment of the two cases are discussed. Clinicians should inquire about sexual issues in the presentation of ED and should monitor for symptoms of GD, not only at initial presentation, but throughout treatment, especially as weight gain progresses.

Cannabis withdrawal syndrome: An important diagnostic consideration in adolescents presenting with disordered eating.

Although previously thought to have no withdrawal symptoms, there is now convergent evidence for a cannabis withdrawal syndrome (CWS), criteria for its diagnosis, and evidence of its impact in the adolescent population. Cannabis withdrawal syndrome represents an important and under-recognized consideration in adolescents with disordered eating. We describe three clinical cases of adolescents presenting to an eating disorders program with primary complaints of gastrointestinal symptoms, food avoidance, and associated weight loss. They did not meet the criteria for an eating disorder, but did fulfill the DSM-5 criteria for CWS. This report emphasizes the importance of considering the impact of heavy cannabis use in adolescents presenting with gastrointestinal complaints, and eating disorder symptoms, including weight loss.

Gynecologic simulation training increases medical student confidence and interest in women's health.

BACKGROUND: Exposure to commonly performed gynecologic procedures via simulation has potential to improve medical student knowledge and foster confidence with procedures. PURPOSES: To implement and evaluate a gynecologic simulation curriculum for 3rd-year medical students during their obstetrics and gynecology core clerkship. METHODS: A gynecologic simulation curriculum was implemented for medical students during their obstetrics and gynecology clerkship. Participants completed pre-and postsurveys to assess learner confidence; effect on interest in a surgical field, women's health, and obstetrics and gynecology as a career; and whether the session met their learning needs. RESULTS: Fifty-nine students participated. Improved confidence in performing the procedures was noted when comparing mean survey scores before and after the simulation for IUD insertion and removal (1.9 pre, 4.3 post, p < .0001), for dilatation and curettage (1.7 pre, 3.8 post, p < .0001), and basic laparoscopy skills (2.1 pre, 4.3 post, p < .0001). An increase in pursuing a surgical field (3.3 pre, 3.6 post, p < .003) and interest in women's health (3.7 pre, 4.9 post, p < .004) was noted among students after the simulation session. The curriculum strongly met the students learning needs with a mean score of 4.54 on the 5-point scale. CONCLUSIONS: Gynecologic simulation training for medical students can increase confidence in procedures, interest in pursuing a surgical field and women's health, and was highly effective in meeting student learning needs.

Use of a simple visual distraction to reduce pain and anxiety in patients undergoing colposcopy.

OBJECTIVE: We hypothesized that a passive visual distraction would reduce pain and anxiety among women undergoing colposcopy. MATERIALS AND METHODS: We assessed the association between exposure to a passive visual distraction during colposcopy and procedure-related pain and anxiety using a nonrandomized intervention design. Women presenting for initial or repeat colposcopy at Brigham and Women's Hospital Colposcopy Clinics were eligible for participation. Women undergoing colposcopy during the first 6 months of the study (n=168) were not exposed to the visual distraction, whereas women undergoing colposcopy during the second 6 months of the study (n=153) were exposed to a pleasing, passive visual distraction consisting of images on a light diffuser installed within the examination room's ceiling light. We used ordinal logistic regression to compare self-reported pain, measured using the visual analog scale, and anxiety, measured using the Spielberger State-Trait Anxiety Inventory-6, among women receiving and not receiving the intervention. RESULTS: Two hundred sixteen women with complete data were included in the final analyses. Women in both groups reported high levels of colposcopy-related anxiety. Compared to women who did not receive the visual distraction, women receiving the visual distraction during colposcopy had a 54% reduction in the odds of experiencing a given level of postexamination pain, holding preprocedure pain constant (odds ratio=0.46, 95% confidence interval=0.28-0.77). Visual distraction was not associated with postexamination anxiety (odds ratio=0.95, 95% confidence interval=0.60-1.51). CONCLUSIONS: A passive visual distraction reduced perceived pain, but not anxiety, after colposcopy.

Top Ten Tips Palliative Care Clinicians Should Know About Caring for Patients with Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are a group of rare chronic progressive blood cancers that vary widely in clinical presentation, yet all patients have a risk of disease progression and thrombotic complications. Diseases include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. With current treatment approaches, most patients live a prolonged life, but many experience a complex of symptoms that negatively influence their functional status and quality of life. Although significant advances have been made in preventing arterial and venous complications while mitigating inflammatory processes, comprehensive palliative care can help address unmet complex physical and psychosocial needs on a long-term basis. This article, created by a multidisciplinary group of providers, offers an overview of MPNs so palliative care clinicians can better support patients with these hematologic cancers.