Impact of the Early Phase of the COVID-19 Pandemic on Medical Student Well-Being: a Multisite Survey.

BACKGROUND: The COVID-19 pandemic drastically impacted medical student experiences. Little is known about the impact of the pandemic on student well-being and protective factors for burnout. OBJECTIVE: Assess US medical student burnout, stress, and loneliness during the initial phase of the pandemic, compare results to pre-pandemic data, and identify risk factors for distress and protective factors to inform support interventions. DESIGN: Cross-sectional survey of medical students conducted between May and July 2020. PARTICIPANTS: 3826 students from 22 medical schools. MAIN MEASURES: Burnout (MBI-HSS), stress (PSS-10), loneliness (UCLA scale), and student experiences. Compared burnout and stress to pre-pandemic studies (2010-2020). KEY RESULTS: Of 12,389 students, 3826 responded (31%). Compared to pre-pandemic studies, burnout was lower (50% vs. 52%, P = 0.03) while mean stress was higher (18.9 vs. 16.0, P < 0.001). Half (1609/3247) reported high (≥ 6/9) loneliness scores. Significant differences were found in burnout and stress by class year (P = 0.002 and P < 0.001) and race (P = 0.004 and P < 0.001), with the highest levels in second- and third-year students and Black, Asian, or other racial minority students. Students experiencing financial strain or racism had higher burnout and stress (P < 0.001 for all). Respondents with COVID-19 diagnoses in themselves or family members had higher stress (P < 0.001). Nearly half (1756/3569) volunteered during the pandemic, with volunteers reporting lower burnout [48% (782/1639) vs. 52% (853/1656), P = 0.03]. CONCLUSIONS: While stress was higher compared to pre-pandemic data, burnout was significantly lower. Higher burnout and stress among Black, Asian, and other racial minority students and those who experienced financial strain, racism, or COVID-19 diagnoses likely reflect underlying racial and socioeconomic inequalities exacerbated by the pandemic and concurrent national racial injustice events. Volunteer engagement may be protective against burnout. Schools should proactively support vulnerable students during periods of stress.

Electronic cigarette extract induced toxic effect in iPS-derived cardiomyocytes.

BACKGROUND: Cigarette smoking is an important risk factor for cardiac diseases. In the current study, we sought to assess the effect of electronic cigarette extract (ECE) and conventional cigarette smoke extract (CSE) on cardiomyocytes. METHODS: iPSCs-derived cardiomyocytes were used in the study to evaluate cellular toxicities. Cells were exposed to either ECE or CSE for two consecutive days as an acute exposure or every other day for 14 days. Concentration of nicotine in both ECE and CSE were measured by Mass-Spectrometry and Q-Exactive-HF was used to identify other ingredients in both extracts. Fluorescent microscopy was used to measure the oxidative stress after ECE and CSE exposure. Motility and beat frequency of cardiomyocytes were determined using the Sisson-Ammons Video Analysis system. Heart failure target panel genes of exposed cardiomyocytes were compared to control unexposed cells. RESULTS: Despite nicotine concentration in CSE being six-fold higher than ECE (50 µg in CSE and 8 µg in ECE), ECE had similar toxic effect on cardiomyocytes. Both CSE and ECE generate significant cellular reactive oxygen species. The Sisson-Ammons Video Analysis (SAVA) analysis showed significant changes in myocyte function with both CSE and ECE slowing beating and increasing cell death. Chronic exposure of both ECE and CSE significantly decreased cardiomyocytes viability long term at all doses. Target panel gene expression profiles of both ECE and CSE exposed cardiomyocytes were different from controls with distinct pattern of genes that involved cell proliferation, inflammation, and apoptosis. CONCLUSION: ECE and CSE produce similar cardiomyocyte toxicities which include generating oxidative stress, negative chronotropic effects, adverse changes in myocardial gene expression and ultimately cell death.

Otolaryngology Away Subinternships: An Analysis of the Application Process and Survey of Current Applicants' Perspectives.

Objective: To assess the availability and uniformity of application information for away subinternships and survey 4th-year medical students on their experiences obtaining away subinternships in otolaryngology-head and neck surgery (OHNS) during the 2022 to 2023 application cycle. Study Design: Cross-sectional study. Setting: Online survey. Methods: The Association of American Medical College's Visiting Student Learning Opportunities (VSLO) program was queried for information on OHNS away subinternship applications. A survey assessing 4th-year medical students' perceptions of the away subinternship application process was distributed via OHNS residency program directors and Otomatch. Results: Of 129 OHNS residency programs, 103 (80%) offered away subinternship opportunities on VSLO. Variability in application release dates (January 18 to June 3, 2022), offer release dates (January 27 to August 7, 2022), and estimated cost ($22-$5500) were found. The most common application requirements were a transcript (98.1%) and a CV/resume (90.3%). There were 64 survey respondents, for a 13% response rate. The most common concerns include applying to too few programs (80%) and not knowing offer release dates (77%). The most common stressors include choosing a number of programs to which to apply (48%) and cost (35%). The majority (76%) reported difficulty finding updated information on program websites. Among the proposed changes, the greatest support was found for having all applications on VSLO (88%), uniform application release date (84%), and uniform application requirements (82%). Conclusion: The OHNS away subinternship application process is a significant source of anxiety for medical students due to the tremendous variability in application and acceptance procedures. Having all applications on VSLO, uniform application requirements, and uniform application opening and offer release dates would better facilitate this process.

Characterization of a chronic cough in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Objectives: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a common cause of late-onset ataxia that often presents with chronic cough. This study is the first to characterize the CANVAS cough both objectively and subjectively. Methods: A cross-sectional study of 13 patients was conducted. Medical records and available esophagram, modified barium swallow study, esophageal manometry, and video laryngostroboscopy data were reviewed. Leicester cough questionnaire (LCQ) and Eating Assessment Tool-10 were administered to evaluate quality of life (QoL) impairments and dysphagia symptoms, respectively. CANVAS history questionnaire was developed to characterize the clinical course. Results: 92% of patients endorsed chronic cough that preceded gait instability by a median of 16 years. Cough was dry (67%), disturbed sleep (75%), triggered by various factors, including talking, eating, and dry/spicy foods, did not respond to standard reflux therapy, and inconsistently responded to neuromodulators and superior laryngeal nerve injections. Despite perceived cough severity worsening or remaining constant in most patients, no correlation was found between cough duration and total LCQ scores. Patients reported significantly more negative social QoL impacts compared to physical QoL impacts. Ataxia duration and years of cough before ataxia symptoms were directly and inversely correlated with total LCQ scores, respectively. Imaging data revealed esophageal dysmotility (71%), vestibular penetration (57%), vestibular aspiration (14%), supraglottic compression (63%), vocal fold lesions/atrophy (50%), and arytenoid erythema (38%). Conclusion: Chronic cough is a hallmark presenting symptom in CANVAS with predominantly psychosocial QoL effects and unrecognized laryngeal alterations. In cases of idiopathic, refractory chronic cough, genetic testing for CANVAS should be considered, especially in association with sensory, cerebellar, and/or vestibular involvement. Level of evidence: VI.

Systemic Bevacizumab for Severe Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) is the most common benign pediatric laryngeal neoplasm. Various adjuvant medical therapies have failed to reliably decrease surgical frequency in this challenging airway disease. Recently, systemic bevacizumab has shown promise in advanced, treatment-resistant papillomatosis. We describe the use of systemic bevacizumab in two children with severe RRP unresponsive to other therapies. Voice and breathing improved dramatically in both patients with minimal side effects. Both patients have not required surgery in 24 months and 16 months, respectively. Systemic bevacizumab is a promising long-term treatment for severe RRP, with oncology playing an important role in patient care.

The impact of the COVID-19 pandemic on nighttime room entries and sleep disruptions for pediatric patients.

OBJECTIVES/BACKGROUND: Sleep is critical to recovery, but inpatient sleep is often disrupted. During the COVID-19 pandemic, social distancing efforts to minimize spread may have improved hospitalized children's sleep by decreasing unnecessary overnight disruptions. This study aimed to describe the impact of these efforts on pediatric inpatient sleep using objective and subjective metrics. METHODS: Sleep disruptions for pediatric inpatients admitted prior to and during the COVID-19 pandemic were compared. Hand hygiene sensors tracking room entries were utilized to measure objective overnight disruptions for 69 nights pre-pandemic and 154 pandemic nights. Caregiver surveys of overnight disruptions, sleep quantity, and caregiver mood were adopted from validated tools: the Karolinska Sleep Log, Potential Hospital Sleep Disruptions and Noises Questionnaire, and Visual Analog Mood Scale. RESULTS: Nighttime room entries initially decreased 36% (95% CI: 30%, 42%, p < 0.001), then returned towards baseline, mirroring the COVID-19 hospital census. However, surveyed caregivers (n_pre = 293, n_post = 154) reported more disrupted sleep (p < 0.001) due to tests (21% vs. 38%), anxiety (23% vs. 41%), and pain (23% vs. 48%). Caregivers also reported children slept 61 fewer minutes (95% CI: -12 min, -110 min, p < 0.001). Caregivers self-reported feeling more sad, weary, and worse overall (p < 0.001 for all). CONCLUSIONS: Despite a decrease in objective room entries during the pandemic, caregivers reported their children were disrupted more and slept less. Caregivers also self-reported worse mood. This highlights the effects of the COVID-19 pandemic on subjective experiences of hospitalized children and their caregivers. Future work targeting stress and anxiety could improve pediatric inpatient sleep.

Objective Measures of Physical Distancing in the Hospital During the COVID-19 Pandemic.

During the COVID-19 pandemic, hospitals published physical-distancing guidance and created dedicated respiratory isolation units (RIUs) for patients with COVID-19. The degree to which such distancing occurred between clinicians and patients is unknown. In this study, heat sensors from an existing hospital hand-hygiene monitoring system objectively tracked room entries as a proxy for physical distancing in both RIUs and general medicine units before and during the pandemic. The RIUs saw a 60.6% reduction in entries per room per day (from 85.7 to 33.8). General medicine units that cared for patients under investigation for COVID-19 and other patients experienced a 14.7% reduction in entries per room per day (from 76.9 to 65.1). While gradual extinction was observed in both units as COVID-19 cases declined, the RIUs had a higher degree of physical distancing. Although the optimal level of physical distancing is unknown, sustaining physical distancing in the hospital may require re-education and real-time monitoring.

CD56 regulates human NK cell cytotoxicity through Pyk2.

Human natural killer (NK) cells are defined as CD56+CD3-. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.

The immune system deploys different cell types to take out cancer cells. True to their name, one type of immune cell known as natural killer cells kills tumor target cells by releasing toxic proteins that kill the harmful cells. In humans, these immune cells are defined, among other things, by the presence of a protein called CD56 on their cell surface. This protein (which is also known as NCAM) is thought to help cells to stick to their surroundings and control their movements. However, it was not clear whether CD56 also plays a role in the destructive abilities of natural killer cells. Gunesch et al. have now looked to see what would happen if natural killer cells lacked CD56 on their surface. The experiments included deleting the gene for CD56 from two kinds of human natural killer cell that are commonly grown in the laboratory (called NK92 and YTS). In both cases, the cells lacking CD56 killed fewer cancer cells than the unedited natural killer cells. The NK92 cells were much more affected by the loss of CD56 than the YTS cells, and after Gunesch et al. compared the two kinds of cell they identified another protein called Pyk2 as the potential reason behind the difference. The Pyk2 protein is known to help a natural killer cell latch onto target cancer cells and release its toxic proteins. To do this, Pyk2 must first be activated with phosphate groups via a process known as phosphorylation. Gunesch et al. showed that Pyk2 protein in unedited NK92 cells was more highly phosphorylated than those of the YTS cells, and that Pyk2 activation by phosphorylation was greatly decreased in NK92 cells when the gene for CD56 was deleted. Together these and other results suggest that CD56 on natural killer cells helps to promote Pyk2 to activate the cells' cancer-killing abilities through Pyk2 phosphorylation, especially in NK92 cells. These findings open up new lines of investigation into the relationship between sticky surface proteins and the activation of immune cells. They may also have important implications for the use of the immune system to treat cancer via immunotherapy.

Human NK cell deficiency as a result of biallelic mutations in MCM10.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.