Enasidenib-induced hepatitis in an individual with Type II D2-hydroxyglutaric aciduria.

Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic IDH2 variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2-HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure-free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0-28) and creatine kinase (334 U/L, range 45-198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug-induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.

Hepatomegaly and Splenomegaly: An Approach to the Diagnosis of Lysosomal Storage Diseases.

Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Therapeutic advances, including early diagnosis and disease-targeted management, have improved the life expectancy and quality of life of people affected by certain LSDs. To access these new interventions, LSDs must be considered in patients presenting with hepatomegaly and splenomegaly throughout the lifespan. This review article navigates the diagnostic approach for individuals with hepatosplenomegaly particularly focusing on LSDs. We provide hints in the history, physical exam, laboratories, and imaging that may identify LSDs. Additionally, we discuss molecular testing, arguably the preferred confirmatory test (over biopsy), accompanied by enzymatic testing when feasible.

Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing.

Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years, with intensive care unit (ICU) admissions at the University of Pennsylvania Health System who met inclusion criteria for our study. For each participant, two Medical Genetics and Internal Medicine-trained clinicians reviewed WES reports and patient charts for variant classification, result interpretation, and identification of genetic diagnoses related to their critical illness. Of the 365 individuals in our study, 90 (24.7%) were found to have clearly diagnostic results on WES; an additional 40 (11.0%) had a suspicious variant of uncertain significance (VUS) identified; and an additional 16 (4.4%) had a medically actionable incidental finding. The diagnostic rate of exome sequencing did not decrease with increasing patient age. Affected genes were primarily involved in cardiac function (18.8%), vascular health (16.7%), cancer (16.7%), and pulmonary disease (11.5%). Only half of all diagnostic findings were known and documented in the patient chart at the time of ICU admission. Significant disparities emerged in subgroup analysis by EHR-reported race, with genetic diagnoses known/documented for 63.5% of White patients at the time of ICU admission but only for 28.6% of Black or Hispanic patients. There was a trend towards patients with undocumented genetic diagnoses having a 66% increased mortality rate, making these race-based disparities in genetic diagnosis even more concerning. Altogether, universal exome sequencing in ICU-admitted adult patients was found to yield a new definitive diagnosis in 11.2% of patients. Of these diagnoses, 76.6% conferred specific care-altering medical management recommendations. Our study suggests that the diagnostic utility of exome sequencing in critically ill young adults is similar to that observed in neonatal and pediatric populations and is age-independent. The high diagnostic rate and striking race-based disparities we find in genetic diagnoses argue for broad and universal approaches to genetic testing for critically ill adults. The widespread implementation of comprehensive genetic sequencing in the adult population promises to enhance medical care for all individuals and holds the potential to rectify disparities in genetic testing referrals, ultimately promoting more equitable healthcare delivery.

Unspoken Truths: Mental Health Among Academic Surgeons.

OBJECTIVE: To characterize the current state of mental health within the surgical workforce in the United States. BACKGROUND: Mental illness and suicide is a growing concern in the medical community; however, the current state is largely unknown. METHODS: Cross-sectional survey of the academic surgery community assessing mental health, medical error, and suicidal ideation. The odds of suicidal ideation adjusting for sex, prior mental health diagnosis, and validated scales screening for depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol use disorder were assessed. RESULTS: Of 622 participating medical students, trainees, and surgeons (estimated response rate=11.4%-14.0%), 26.1% (141/539) reported a previous mental health diagnosis. In all, 15.9% (83/523) of respondents screened positive for current depression, 18.4% (98/533) for anxiety, 11.0% (56/510) for alcohol use disorder, and 17.3% (36/208) for PTSD. Medical error was associated with depression (30.7% vs. 13.3%, P <0.001), anxiety (31.6% vs. 16.2%, P =0.001), PTSD (12.8% vs. 5.6%, P =0.018), and hazardous alcohol consumption (18.7% vs. 9.7%, P =0.022). Overall, 13.2% (73/551) of respondents reported suicidal ideation in the past year and 9.6% (51/533) in the past 2 weeks. On adjusted analysis, a previous history of a mental health disorder (aOR: 1.97, 95% CI: 1.04-3.65, P =0.033) and screening positive for depression (aOR: 4.30, 95% CI: 2.21-8.29, P <0.001) or PTSD (aOR: 3.93, 95% CI: 1.61-9.44, P =0.002) were associated with increased odds of suicidal ideation over the past 12 months. CONCLUSIONS: Nearly 1 in 7 respondents reported suicidal ideation in the past year. Mental illness and suicidal ideation are significant problems among the surgical workforce in the United States.

Improving Transparency in the Residency Application Process: Survey Study.

BACKGROUND: Increasing numbers of residency applications create challenges for applicants and residency programs to assess if they are a good fit during the residency application and match process. Applicants face limited or conflicting information as they assess programs, leading to overapplying. A holistic review of residency applications is considered a gold standard for programs, but the current volumes and associated time constraints leave programs relying on numerical filters, which do not predict success in residency. Applicants could benefit from increased transparency in the residency application process. OBJECTIVE: This study aims to determine the information applicants find most beneficial from residency programs when deciding where to apply, by type of medical school education background. METHODS: Match 2023 applicants voluntarily completed an anonymous survey through the Twitter and Instagram social media platforms. We asked the respondents to select 3 top factors from a multiple-choice list of what information they would like from residency programs to help determine if the characteristics of their application align with program values. We examined differences in helpful factors selected by medical school backgrounds using ANOVA. RESULTS: There were 4649 survey respondents. When responses were analyzed by United States-allopathic (US-MD), doctor of osteopathic medicine (DO), and international medical graduate (IMG) educational backgrounds, respondents chose different factors as most helpful: minimum United States Medical Licensing Examination (USMLE) or Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Step 2 scores (565/3042, 18.57% US-MD; 485/3042, 15.9% DO; and 1992/3042, 65.48% IMG; P<.001), resident hometown region (281/1132, 24.82% US-MD; 189/1132, 16.7% DO; and 662/1132, 58.48% IMG; P=.02), resident medical school region (476/2179, 22% US-MD; 250/2179, 11.5% DO; and 1453/2179, 66.7% IMG; P=.002), and percent of residents or attendings underrepresented in medicine (417/1815, 22.98% US-MD; 158/1815, 8.71% DO; and 1240/1815, 68.32% IMG; P<.001). CONCLUSIONS: When applying to residency programs, this study found that the factors that respondents consider most helpful from programs in deciding where to apply differ by educational background. Across all educational groups, respondents want transparency around standardized exam scores, geography, and the racial or ethnic backgrounds of residents and attendings.

Screen Use and Social Media "Addiction" in the Era of TikTok: What Generalists Should Know.

While the term "screen addiction" or "social media addiction" is gaining steam in the popular media, preclinical, clinical, and population health research have not caught up with regards to the diagnosis and treatment of unhealthy screen use. The overarching goal of this article is to provide broad clinical tips to generalists, working outside the mental health specialty, on the evaluation and treatment of unhealthy screen exposure in children and young adults. We will clarify the difference between addiction and overuse, and why this distinction matters. Recognizing that screens are here to stay in the post-COVID era, we will provide guidance on how to reduce potential harms associated with screen exposure without necessarily requiring people to abstain or stop using screens.

Phenotypes of undiagnosed adults with actionable OTC and GLA variants.

Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.

Supporting the Resilience and Mental Health of Missouri Healthcare Workers Through COVID-19 and Beyond: the Gateway2Wellness Program.

The COVID-19 pandemic is over, but US healthcare workers (HCWs) continue to report high levels of work-related exhaustion and burnout but are unlikely to seek help. Digital tools offer a scalable solution. Between February and June 2022, we surveyed Missouri hospital administrators to assess HCW mental health and identify related evidence-based or evidence-informed resources. Simultaneously, we conducted a digital survey and focus groups with HCWs and leaders at Washington University School of Medicine (WUSOM) in St. Louis to evaluate HCW mental health needs, and preferences for digital support. Here, we describe the results and subsequent development of the Gateway to Wellness (G2W) program, a digital precision engagement platform that links HCWs to the most effective tailored resources for their mental health needs.

Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

Comparison of Electronic Health Record Messages to Mental Health Care Professionals Before vs After COVID-19 Pandemic.

This qualitative improvement study examines the change in electronic health record messaging from patients to mental health professionals before vs after the COVID-19 pandemic.

Perspectives of Rare Disease Experts on Newborn Genome Sequencing.

Importance: Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained. Objective: To query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns. Design, Setting, and Participants: This survey study, designed between November 2, 2021, and February 11, 2022, assessed experts' perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US. Exposures: Expert perspectives on newborn screening using genome sequencing. Main Outcomes and Measures: The proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests. Results: Of 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts. Conclusions and Relevance: In this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.

Concordance between electronic health record-recorded race/ethnicity and parental report in hospitalized children.

BACKGROUND: Electronic health records (EHRs) have become an important repository for patient race and ethnicity. Misclassification could negatively affect efforts to monitor and reduce health disparities and structural discrimination. OBJECTIVE: We assessed the concordance of parental reports of race/ethnicity for their hospitalized children with EHR-documented demographics. We also aimed to describe parents' preferences on how race/ethnicity should be captured in the hospital's EHR. DESIGNS, SETTINGS, AND PARTICIPANTS: From December 2021 to May 2022, we conducted a single-center cross-sectional survey of parents of hospitalized children asking to describe their child's race/ethnicity and compared these responses to the race/ethnicity documented in the EHR. MAIN OUTCOME AND MEASURES: Concordance was analyzed with a kappa statistic (κ). Additionally, we queried respondents about their awareness of and preferences for race/ethnicity documentation. RESULTS: Of the 275 participants surveyed (79% response rate), there was 69% agreement (κ = 0.56) for race and 80% agreement (κ = 0.63) for ethnicity between parent report and EHR documentation. Sixty-eight parents (21%) felt that the designated categories poorly represent their child's race/ethnicity. Twenty-two (8%) were uncomfortable with their child's race/ethnicity being displayed on the hospital's EHR. Eighty-nine (32%) preferred a more comprehensive list of race/ethnicity categories. CONCLUSIONS: Nonconcordance between EHR-recorded race/ethnicity and parental report exists in the EHR for our hospitalized patients, which has implications for describing patient populations and for understanding racial and ethnic disparities. Current EHR categories may be limited in their ability to capture the complexity of these constructs. Future efforts should focus on ensuring that demographic information in the EHR is accurately collected and appropriately reflects families' preferences.

Understanding the Use of Program Resources During Virtual Recruitment by Psychiatry Residency Applicants.

OBJECTIVE: This study aims to understand the residency resources used by psychiatry applicants who applied during the first two virtual recruitment seasons, match 2021 and 2022. METHODS: Between January 27, 2022, and February 24, 2022, a non-probabilistic sample of psychiatry residents from the match 2018 through match 2022 cycles were asked to complete a survey via email and social media. Due to the continuation of virtual recruitment post-pandemic, an analysis of psychiatry residents in the match 2021 and 2022 cycles was conducted. Questions assessed the use of recruitment resources, including websites, the Fellowship and Residency Electronic and Interactive Database, virtual open houses, video tours, away rotations, and social media platforms. Descriptive statistics and chi-square analyses were used. RESULTS: Psychiatry residents from the match 2021 and 2022 cycles completed the survey (n = 605), with 288 US allopathic medicine doctors (47.6%), 178 (29.4%) international medical graduates, and 139 (23.0%) osteopathic medicine doctors. More than half of respondents (n = 347, 57.4%) reported that the virtual interview season increased the number of programs they intended to apply to. Most respondents (n = 594, 88.3%) reported attending one or more psychiatry virtual open houses and 84.6% (n = 512) followed psychiatry residency programs on at least one social media platform. Program websites were reported to be the most influential digital platform for both applying and ranking. CONCLUSION: Understanding the influence of recruitment resources is essential for residents and program leadership to optimize time and resources to assist applicants with their decision-making.

The Role of Internal Medicine-Pediatric Programs and Transition Champions in Graduate Medical Trainee Health Care Transition Development.

OBJECTIVE: Transition to adult health care for adolescents and young adults (AYAs), especially those with chronic conditions, is a critical time. Medical trainees lack competency in providing transition care, but little is known about the factors contributing to the development of health care transition (HCT) knowledge, attitudes, and practice. This study examines how Internal Medicine-Pediatrics (Med-Peds) programs and institutional HCT champions influence trainee HCT knowledge, attitudes, and practices. STUDY DESIGN: A 78-item electronic survey regarding the knowledge, attitudes, and practices of caring for AYA patients was sent to trainees from 11 graduate medical institutions. RESULTS: A total of 149 responses were analyzed, including 83 from institutions with Med-Peds programs and 63 from institutions without Med-Peds programs. Trainees with an institutional Med-Peds Program were more likely to identify an institutional HCT champion (odds ratio, 10.67; 95% confidence interval, 2.40-47.44; p = .002). The mean HCT knowledge scores and use of a routine, standardized HCT tools were higher in trainees with an institutional HCT champion. Trainees without an institutional Med-Peds program experienced more barriers to HCT education. Trainees with institutional HCT champions or Med-Peds programs reported greater comfort in providing transition education and using validated, standardized transition tools. DISCUSSION: The presence of a Med-Peds residency program was associated with a greater likelihood of a visible institutional HCT champion. Both factors were associated with increased HCT knowledge, positive attitudes, and HCT practices. Both clinical champions and adoption of Med-Peds program curricula will enhance HCT training within graduate medical education.

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Telemental health policies for college students during COVID-19.

Federal and institutional policy changes have accelerated the use of telemental health to care for college students distant from their mental health providers during the early part of the COVID-19 pandemic. Temporary measures have made telemental health more readily available, including relaxing of regulations related to interstate licensure, controlled substance prescribing, patient privacy, and reimbursement. Though early efforts are underway to sustain these changes during and in the wake of the pandemic, there are important areas in which federal and institutional policy are still lacking. Additional steps are needed to successfully implement and sustain telemental health for college students include ensuring student access to technology and Internet; proactive outreach to optimize the student's home environment, addressing concerns about safety and confidentiality; developing the means to track rapidly shifting telemental health policy changes; and developing centralized resources that enable remote providers to become familiar with involuntary commitment laws and emergency protocols.