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The maternal mortality rate in the United States is unacceptably high. However, the relative contribution of pregnancy to these outcomes is unknown. Studies comparing outcomes among pregnant vs nonpregnant critically ill patients show mixed results and are limited by small sample sizes.

IMPORTANCE: Many studies have evaluated whether in utero cannabis exposure is associated with fetal and neonatal outcomes, yet little is known about whether prenatal cannabis use is associated with maternal health outcomes during pregnancy. OBJECTIVE: To evaluate whether prenatal cannabis use is associated with maternal health outcomes during pregnancy. DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study included pregnancies in Northern California from January 2011 to December 2019 that lasted 20 weeks or longer and were screened for prenatal cannabis use. EXPOSURES: Prenatal cannabis use was defined as any self-reported use during early pregnancy or a positive toxicology test result based on universal screening at entrance to prenatal care (approximately 8-10 weeks’ gestation). Self-reported frequency of use (daily, weekly, monthly or less, never, unknown), use defined only by self-report, and use defined only by toxicology test results were examined. MAIN OUTCOMES AND MEASURES: Electronic health record data were used to define the following outcomes: gestational hypertension, preeclampsia, eclampsia, gestational diabetes, gestational weight gain greater and less than guidelines, placenta previa, placental abruption, placenta accreta, and severe maternal morbidity. Adjusted risk ratios (aRRs) were calculated using a modified Poisson regression. RESULTS: The sample (n = 316 722 pregnancies; 250 221 unique individuals) included 84 039 (26.5%) Asian/Pacific Islander, 20 053 (6.3%) Black, 83 145 (26.3%) Hispanic, and 118 333 (37.4%) White individuals; the mean (SD) age was 30.6 (5.4) years. Overall, 20 053 (6.3%) screened positive for prenatal cannabis use; 2.9% were positive by self-report, 5.3% by toxicology testing, and 1.8% by both. The frequency of cannabis use was 1930 (0.6%) daily, 2345 (0.7%) weekly, 4892 (1.5%) monthly or less, and 10 886 (3.4%) unknown. Prenatal cannabis use was associated with greater risk of gestational hypertension (aRR, 1.17; 95% CI, 1.13-1.21), preeclampsia (aRR, 1.08; 95% CI, 1.01-1.15), weight gain less than (aRR, 1.05; 95% CI, 1.01-1.08) and greater than (aRR, 1.09; 95% CI, 1.08-1.10) guidelines, and placental abruption (aRR, 1.19; 95% CI, 1.05-1.36). The pattern of results was similar when defining prenatal cannabis use only by self-report or only by toxicology testing, and associations between the frequency of prenatal cannabis use and outcomes varied with outcome. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that prenatal cannabis use was associated with several adverse maternal health outcomes during pregnancy. Continued research is needed to understand whether characteristics of prenatal cannabis use (eg, dose, mode, and timing) moderate these associations.

Despite increased recognition of the importance and need for pedagogical training for public health and health promotion instructors in best-practices and inclusivity, formal training is often overlooked. This disregard for pedagogical training necessitates exploration of alternative and innovative approaches to enhance teaching and learning such as generative AI. This paper describes applied uses of generative AI, specifically ChatGPT, to enhance pedagogy in public health and health promotion education in the areas of curriculum design, instructional strategies, assessment and feedback, and diversity, equity, and inclusion. Generative AI as a supplemental tool shows immense promise for improving teaching and learning, however, inherent limitations and ethical considerations require caution and continued scrutiny.

Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations.

Achilles tendinopathy is a common overuse injury that is traditionally managed with activity modification and a progressive eccentric strengthening program. This narrative review describes the available evidence for adjunctive procedural interventions in the management of midportion and insertional AT, specifically in the athletic population. Safety and efficacy data from available literature on extracorporeal shockwave therapy, platelet-rich plasma, high-volume injectate with or without tendon scraping, and percutaneous needle tenotomy are used to propose an algorithm for treatment of Achilles tendinopathy for the in-season athlete.

Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic morbidity after coronary heart disease and stroke yet is widely underdiagnosed and undertreated. Treatment of risk factors such as diabetes and cigarette smoking can benefit patients with PAD. Patients should have adequate blood pressure and lipid control to decrease clinical manifestations and symptoms of PAD. Use of antithrombotic medications should be individualized to the patient depending on the presence of symptoms, revascularization, and comorbidities. All patient care providers, including physicians, pharmacists, nurse practitioners, and physician assistants, should incorporate PAD screening in their at-risk patients to improve access for appropriate earlier diagnosis, initiation of guideline directed therapy, and risk factor modification to reduce both major adverse CV and limb outcomes. The purpose of this narrative review is to provide an overview of PAD and summarize clinical trial evidence and guideline recommendations for screening and treatment to increase awareness among health care providers to ultimately have a positive impact on patient care.

Schizophrenia (SZ) is a serious mental illness and neuropsychiatric brain disorder with behavioral symptoms that include hallucinations, delusions, disorganized behavior, and cognitive impairment. Regulation of such behaviors requires utilization of neurotransmitters released to mediate cell-cell communication which are essential to brain functions in health and disease. We hypothesized that SZ may involve dysregulation of neurotransmitters secreted from neurons. To gain an understanding of human SZ, induced neurons (iNs) were derived from SZ patients and healthy control subjects to investigate peptide neurotransmitters, known as neuropeptides, which represent the major class of transmitters. The iNs were subjected to depolarization by high KCl in the culture medium and the secreted neuropeptides were identified and quantitated by nano-LC-MS/MS tandem mass spectrometry. Several neuropeptides were identified from schizophrenia patient-derived neurons, including chromogranin B (CHGB), neurotensin, and natriuretic peptide. Focusing on the main secreted CHGB neuropeptides, results revealed differences in SZ iNs compared to control iN neurons. Lower numbers of distinct CHGB peptides were found in the SZ secretion media compared to controls. Mapping of the peptides to the CHGB precursor revealed peptides unique to either SZ or control, and peptides common to both conditions. Also, the iNs secreted neuropeptides under both KCl and basal (no KCl) conditions. These findings are consistent with reports that chromogranin B levels are reduced in the cerebrospinal fluid and specific brain regions of SZ patients. These findings suggest that iNs derived from SZ patients can model the decreased CHGB neuropeptides observed in human SZ.

Complement-mediated diseases can be treated using systemic inhibitors. However, complement components are abundant in circulation, affecting systemic inhibitors’ exposure and efficacy. Furthermore, because of complement’s essential role in immunity, systemic treatments raise infection risk in patients. To address these challenges, we developed antibody fusion proteins combining the alternative-pathway complement inhibitor factor H (fH1–5) with an anti-C3d monoclonal antibody (C3d-mAb-2fH). Because C3d is deposited at sites of complement activity, this molecule localizes to tissue complement while minimizing circulating complement engagement. These fusion proteins bind to deposited complement in diseased human skin sections and localize to activated complement in a primate skin injury model. We further explored the pharmacology of C3d-mAb-2fH proteins in rodent models with robust tissue complement activation. Doses of C3d-mAb-2fH >1 mg/kg achieved >75% tissue complement inhibition in mouse and rat injury models while avoiding circulating complement blockade. Glomerular-specific complement inhibition reduced proteinuria and preserved podocyte foot-process architecture in rat membranous nephropathy, indicating disease-modifying efficacy. These data indicate that targeting local tissue complement results in durable and efficacious complement blockade in skin and kidney while avoiding systemic inhibition, suggesting broad applicability of this approach in treating a range of complement-mediated diseases.

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted Pvalue < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

The COVID-19 pandemic led to a suspension of visiting student rotations across the United States. For senior medical students applying into surgical subspecialties, such as otolaryngology, these away rotations serve a vital role in the residency application process. Prior to the pandemic, there was not a virtual alternative to in-person visiting student rotations for applicants. We developed a replicable and expandable program focused on helping prospective otolaryngology applicants (fourth-year medical students) gain exposure to the experiences typically offered via in-person rotations. The goal was to improve otolaryngology-specific knowledge and to help applicants demonstrate specific program interest, without the financial and logistical challenges associated with in-person away rotations.

This work aimed to evaluate the lipases from Yarrowia lipolyticaas a biocatalyst for synthesizing fatty acid ethyl esters (FAEE). The Yarrowia lipolyticalipases were evaluated in three distinct forms: firstly, as the crude enzymatic liquid extract derived from the submerged fermentation process of Y. lipolytica(YLL); secondly, as YLL immobilized on silica-alumina (YLL-S40); and thirdly, as the fermented solid material obtained from solid-state fermentation of Y. lipolytica(SEP-YLL). The highest FAEE content (54 wt.%) was obtained after 240 h in transesterification reactions using SEP-YLL. The influence of temperature, biocatalyst concentration, and reaction time was studied in the ethyl oleate synthesis. The SEP-YLL also showed better results compared to YLL and YLL-S40. The reaction catalyzed by SEP-YLL achieved 81% conversion at 30 °C. The SEP-YLL was evaluated in a batch-stirred reactor (BSTR) and a continuous packed-bed reactor (PBR), obtaining an oleic acid conversion of 80% and 70%, respectively. The low-cost biocatalyst (SEP-YLL) demonstrated potential for application in biodiesel production by reducing free fatty acids from an acid oil source through PBR and BSTR.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Purpose of Review: This scoping review maps recent literature on dermatology provider-to-provider asynchronous store-and-forward (SAF) electronic consult (eConsult) platforms with dermoscopy. It offers a descriptive overview, highlighting benefits and challenges. Recent Findings: Incorporating dermoscopy into SAF eConsults improves diagnostic accuracy for benign and malignant skin neoplasms. Diagnostic and treatment concordance with traditional face-to-face (FTF) visits is high. SAF eConsults with dermoscopy enhance access to dermatological care by improving triage and reducing wait times for FTF visits. Pediatric patients benefit with improved evaluation of melanocytic and vascular growths. eConsult platforms with dermoscopy serve as a telementoring opportunity for clinicians interested in improving their dermoscopy skills. Summary: Adding dermoscopy to SAF eConsults is valuable and results in improved diagnostic accuracy and reduced need for FTF visits. Implementation barriers can be overcome through collaboration between primary care and dermatology. Dermoscopy in SAF eConsults has significant potential for managing skin conditions and reducing the burden caused by unnecessary FTF visits and biopsies.

The Case A 35-year-old woman noticed a mass in her right breast and underwent a diagnostic workup, including a mammogram that revealed a 2.4-cm mass (Figure) and ultrasound that showed [...]

IMPORTANCE: The gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression. OBJECTIVE: To characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma. DESIGN, SETTING, AND PARTICIPANTS: This single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment−naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021. MAIN OUTCOMES AND MEASURES: Fecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups. RESULTS: A total of 228 participants were enrolled (126 men [55.3%]; median age, 59 [range, 21-90] years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P &lt; .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 [IQR, 9.8-23.0] vs 10.8 [IQR, 7.2-16.8]; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P &lt; .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy. CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention.

Wireworms (Coleoptera: Elateridae) are economically significant pests of potatoes (Solanum tuberosum), damaging the marketable portion of the crop by feeding and tunneling into tubers. While conventional potato growers use the few registered synthetic insecticides to control wireworms, certified organic growers are left with less options due to the limited effectiveness of the available insecticides. Biologically derived pesticides provide an additional alternative for both systems. Certain gram-negative proteobacteria, such as Burkholderiaspp., possess insecticidal compounds. However, very little is known about their efficacy on wireworms. From 2018 to 2021, we conducted experiments in Virginia to assess the efficacy of a Burkholderiaspp.-based commercial pesticide, Majestene, as a wireworm control in potatoes. In a lab experiment, soil drench application of this insecticide at a rate of 66 g a.i. per 1 liter resulted in 30% wireworm mortality and significantly reduced wireworm feeding damage on potato tubers. In the field, in-furrow applications of Burkholderiaspp. at a rate of 17.66 kg a.i. per ha significantly reduced wireworm damage to tubers in 2 of 7 field experiments conducted. By comparison, the commercial standard insecticide, bifenthrin, significantly reduced tuber damage in 3 of the 7 field experiments. Our study demonstrates the prospect for proteobacteria-derived insecticides for control of wireworms and potentially other soil-dwelling insects. In conclusion, findings present growers with another option to combat wireworm pressure, especially in organic systems.

Background: Social media is an important tool for networking, recruitment, and promoting clinical practice. No study has specifically assessed which FPRS practitioners have professional social media accounts, how they utilize them, and what barriers or resources exist to their use.Objectives: This study aims to examine differences in social media use based on provider demographics and practice setting, and identify resources and barriers to professional social media use.Methods: This cross-sectional analysis was an anonymous survey sent to AAFPRS members. Data collected included demographics, practice setting, resources, and barriers encountered to use of professional social media.Results: Most facial plastic surgeons (80%) use professional social media, notably Instagram and Facebook, and mostly post patient photos and stories (67.9%). Social media is more commonly utilized in private practice (56% vs 23%, P= .0016), where there are less institutional barriers (10% vs 40%, P= .02) and more resources available (82.5% vs 12.5%, P= .01).Conclusions: Social media is widely used in FPRS. Working in private practice is associated with increased availability of resources for support, and a reduction in institutional barriers to maintaining a social media presence. With this understanding, facial plastic surgeons can be better equipped for networking, marketing, and promoting the field of FPRS.

When in-person experiences were taken away from medical students and residency applicants during the COVID-19 pandemic, institutions had to pivot to virtual experiences. We present here a comprehensive overview of virtual engagement for medical students. As we increasingly embrace virtual opportunities, it may be possible to continue utilizing these programs for many years to come.

Ammonia monooxygenase and analogous oxygenase enzymes contribute to pharmaceutical biotransformation in activated sludge. In this study, we hypothesized that methane monooxygenase can enhance pharmaceutical biotransformation within the benthic, diffuse periphytic sediments (i.e., “biomat”) of a shallow, open-water constructed wetland. To test this hypothesis, we combined field-scale metatranscriptomics, porewater geochemistry, and methane gas fluxes to inform microcosms targeting methane monooxygenase activity and its potential role in pharmaceutical biotransformation. In the field, sulfamethoxazole concentrations decreased within surficial biomat layers where genes encoding for the particulate methane monooxygenase (pMMO) were transcribed by a novel methanotroph classified as Methylotetracoccus. Inhibition microcosms provided independent confirmation that methane oxidation was mediated by the pMMO. In these same incubations, sulfamethoxazole biotransformation was stimulated proportional to aerobic methane-oxidizing activity and exhibited negligible removal in the absence of methane, in the presence of methane and pMMO inhibitors, and under anoxia. Nitrate reduction was similarly enhanced under aerobic methane-oxidizing conditions with rates several times faster than for canonical denitrification. Collectively, our results provide convergent in situ and laboratory evidence that methane-oxidizing activity can enhance sulfamethoxazole biotransformation, with possible implications for the combined removal of nitrogen and trace organic contaminants in wetland sediments.

Telehealth (TH) broadly encompasses remote activities of clinical care (telemedicine), provider and patient education, and general health services. The use of synchronous video for TH first occurred in 1964 and then catapulted to the forefront in 2020 during the coronavirus disease 2019 public health emergency. Due to the sudden need for increased TH utilization by nearly all health care providers at that time, TH became essential to clinical practice. However, its sustainable future is unclear in part given that best practices for TH in pediatric gastroenterology (GI), hepatology, and nutrition remain undefined and non-standardized. Key areas for review include historical perspective, general and subspeciality usage, health care disparities, quality of care and the provider-patient interaction, logistics and operations, licensure and liability, reimbursement and insurance coverage, research and quality improvement (QI) priorities, and future use of TH in pediatric GI with a call for advocacy. This position paper from the Telehealth Special Interest Group of North American Society of Gastroenterology, Hepatology and Nutrition provides recommendations for pediatric GI-focused TH best practices, reviews areas for research and QI growth, and presents advocacy opportunities.

In this article, the authors analyze the ways literacy integration evolved in a multi‐year interdisciplinary after‐school program that supports youth through a focus on literacy, physical activity, and health. To deviate from the increasingly siloed assumptions around literacy education and attend to a more interdisciplinary, integrated perspective, the authors theorized literacy across multiple theoretical perspectives to examine 5 years of program implementation in three different sites (New York City, Los Angeles, and Paraguay) with culturally and linguistically diverse youth (ages 9–14), program leaders, and researchers. Drawing on assemblage theory to guide the analysis, the authors sought to identify the multidimensional (im)materialities that converged to produce evolutions of literacy integration in an after‐school program. Analyzing data for assemblaging factors that produced youths' literacy engagement differently throughout program years led to identifying three emergent assemblages that frame the findings: (1) Well‐intentioned literacy integration but more complex than expected, (2) Imprints of schooled literacy with sociocultural emergence, and (3) Community‐ and youth‐centered literacy integration. The authors conclude with implications for educators and after‐school leaders seeking to integrate literacy with interdisciplinary aims.

IMPORTANCE: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. OBJECTIVE: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. EVIDENCE REVIEW: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). FINDINGS: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. CONCLUSIONS AND RELEVANCE: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

AbstractPatients with Duchenne muscular dystrophy have multiple risk factors for lower extremity oedema. This study sought to define the frequency and predictors of oedema. Patients aged 15 years and older were screened by patient questionnaire, and the presence of oedema was confirmed by subsequent physical exam. Twenty-four of 52 patients (46%) had oedema, 12 of whom had swelling extending above the foot and two with sores/skin breakdown. There was no significant difference in age, frequency, or duration of glucocorticoid use, non-invasive respiratory support use, forced vital capacity, cardiac medication use, or ejection fraction between patients with and without oedema (all p > 0.2). Those with oedema had a greater time since the loss of ambulation (8.4 years versus 3.5 years; p = 0.004), higher body mass index (28.3 versus 24.8; p = 0.014), and lower frequency of deflazacort use (67% versus 89%; p = 0.008). Multivariate analysis revealed a longer duration of loss of ambulation (p = 0.02) and higher body mass index (p = 0.009) as predictors of oedema. Lower extremity oedema is common in Duchenne muscular dystrophy but independent of cardiac function. Interventions focused on minimising body mass index increases over time may be a therapeutic target.

At the International Literacy Association (ILA) 2019 Conference in October, the theme 'Creating a Culture of Literacy' brought issues of equity front and center. Keynote and session presenters advocated for [...]

Neuroblastomas harbor ALKaberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45–115 mg/m2/dose in children and 100–150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib’s rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988.

ABSTRACTSynaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system. Among the mechanisms that control Rho-GTPase activity and signalling are cell surface receptors, GEF/GAP complexes that tightly regulate single Rho-GTPase dynamics, GEF/GAP and GEF/GEF functional complexes that coordinate multiple Rho-family GTPase activities, effector positive feedback loops, and mutual antagonism of opposing Rho-GTPase pathways. These complex regulatory mechanisms are employed by the cells of the nervous system in almost every step of development, and prominently figure into the processes of synaptic plasticity that underlie learning and memory. Finally, misregulation of Rho-GTPases plays critical roles in responses to neuronal injury, such as traumatic brain injury and neuropathic pain, and in neurodevelopmental and neurodegenerative disorders, including intellectual disability, autism spectrum disorder, schizophrenia, and Alzheimer’s Disease. Thus, decoding the mechanisms of Rho-GTPase regulation and function at excitatory synapses has great potential for combatting many of the biggest current challenges in mental health.

Commonly held beliefs about sleep unsupported by scientific evidence (ie, myths) among adolescents and their parents/caregivers may adversely influence sleep-related attitudes and behaviors among adolescents. Thus, identifying such myths with the goal of developing effective evidence-based counter-messages has the potential to improve sleep health in adolescents.

The past decade witnessed an explosion of public health/public safety collaborations. Many emerged as pragmatic responses to the opioid epidemic, where communities struggled to help individuals at risk of fatal and nonfatal overdoses. Multidisciplinary programs formed to actively engage people with services, including harm reduction, treatment, and peer support, instead of arrest. These initiatives blur traditional lines between public safety, health, treatment, and services. Novel applications of HIPAA and 42 CFR Part 2 created confusion, sometimes discouraging new ways of doing business and other times leading to a disregard for individual privacy protections in the interest of “doing the right thing.” Neither is ideal. In this article, the authors present a framework for collaborations to navigate issues related to privacy, review relevant laws, provide a practical application to public health/public safety partnerships, and offer practice pointers. With this resource, stakeholders are empowered to create effective and compliant overdose response programs.

To describe the development of an innovative prepharmacy underrepresented mentorship program (PUMP) to provide guidance and support to prepharmacy students who are committed to serving underrepresented communities with health disparities.

Hepatic sinusoidal disorders often manifest with characteristic imaging features, such as mosaic enhancement of liver parenchyma, reticular hypointensity in a peripheral distribution at hepatobiliary MRI, splenomegaly, and diffuse tiny foci of restricted diffusion, which facilitates early diagnosis, detection of subclinical disease, and identification of the cause.

The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood.

Objective: To evaluate the impact of otolaryngology programs’ social media on residency candidates in the 2020 to 2021 application cycle.Methods: An anonymous survey was distributed via Otomatch, Headmirror, and word of mouth to otolaryngology residency applicants in the 2021 Match. Survey items included demographics, social media usage, and impact of programs’ social media on applicant perception and ranking. Descriptive statistics were performed, and responses based on demographic variables were compared using Fisher’s exact and Mann-Whitney Utests.Results: Of 64 included respondents, nearly all (61/64, 95%) used Facebook, Instagram, and/or Twitter for personal and/or professional purposes. Applicants (59/64, 92%) most commonly researched otolaryngology residency programs on Instagram (55/59, 93%) and Twitter (36/59, 61%), with younger (P= .023) and female (P= .043) applicants being more likely to engage with programs on Instagram. Program accounts were most helpful in showcasing program culture (50/59, 85%) and highlighting its location (34/59, 58%). Nearly one third (19/59, 32%) reported that social media impacted their rank list. Age, gender, reapplication, home program status, or time taken off before and/or during medical school did not significantly influence social media’s usefulness in the application cycle.Conclusion: Social media platforms like Instagram and Twitter are frequently used by applicants to assess otolaryngology residency programs. Programs’ social media accounts effectively demonstrate program culture and affect applicants’ rank lists. As social media usage continues to rise in the medical community, these findings can help otolaryngology residency programs craft a beneficial online presence that aids in recruitment, networking, and education.

The COVID-19 pandemic has strained health care systems and has resulted in widespread critical care staffing shortages, negatively impacting the quality of care delivered.

Because mental health professionals are susceptible to impairment and burnout that may negatively affect clinical work, it is ethically imperative that they engage in self-care. Previous research has found direct [...]