Trends in Sexual Harassment Prevalence and Recognition During Intern Year.

This cohort study uses Internal Health Study and Sexual Experiences Questionnaire data to assess changes in sexual harassment prevalence and recognition among training physicians.

Posttraumatic Stress Disorder Symptoms Among First-Year Resident Physicians Working Before and During the COVID-19 Pandemic.

This cohort study investigates differences in posttraumatic stress disorder (PTSD) symptoms among first-year resident physicians training before and during the first wave of the COVID-19 pandemic (March to June 2020).

Polygenic Risk and Social Support in Predicting Depression Under Stress.

OBJECTIVE: Despite substantial progress in identifying genomic variation associated with major depression, the mechanisms by which genomic and environmental factors jointly influence depression risk remain unclear. Genomically conferred sensitivity to the social environment may be one mechanism linking genomic variation and depressive symptoms. The authors assessed whether social support affects the likelihood of depression development differently across the spectrum of genomic risk in two samples that experienced substantial life stress: 1,011 first-year training physicians (interns) in the Intern Health Study (IHS) and 435 recently widowed Health and Retirement Study (HRS) participants. METHODS: Participants' depressive symptoms and social support were assessed with questionnaires that were administered before and after the life stressor. Polygenic risk scores (PRSs) for major depressive disorder were calculated for both samples. RESULTS: Depressive symptom scores increased by 126% after the start of internship in the IHS sample and by 34% after widowing in the HRS sample. There was an interaction between depression PRS and change in social support in the prediction of depressive symptoms in both the IHS sample (incidence rate ratio [IRR]=0.96, 95% CI=0.93, 0.98) and the HRS sample (IRR=0.78, 95% CI=0.66, 0.92), with higher depression PRS associated with greater sensitivity to changes in social support. Johnson-Neyman intervals indicated a crossover effect, with losses and gains in social support moderating the effect of PRS on depressive symptoms. (Johnson-Neyman interval in the IHS sample, -0.02, 0.71; in the HRS sample, -0.49, 1.92). CONCLUSIONS: The study findings suggest that individuals with high genomic risk for developing increased depressive symptoms under adverse social conditions also benefit more from nurturing social environments.

Using machine learning with intensive longitudinal data to predict depression and suicidal ideation among medical interns over time.

BACKGROUND: Use of intensive longitudinal methods (e.g. ecological momentary assessment, passive sensing) and machine learning (ML) models to predict risk for depression and suicide has increased in recent years. However, these studies often vary considerably in length, ML methods used, and sources of data. The present study examined predictive accuracy for depression and suicidal ideation (SI) as a function of time, comparing different combinations of ML methods and data sources. METHODS: Participants were 2459 first-year training physicians (55.1% female; 52.5% White) who were provided with Fitbit wearable devices and assessed daily for mood. Linear [elastic net regression (ENR)] and non-linear (random forest) ML algorithms were used to predict depression and SI at the first-quarter follow-up assessment, using two sets of variables (daily mood features only, daily mood features + passive-sensing features). To assess accuracy over time, models were estimated iteratively for each of the first 92 days of internship, using data available up to that point in time. RESULTS: ENRs using only the daily mood features generally had the best accuracy for predicting mental health outcomes, and predictive accuracy within 1 standard error of the full 92 day models was attained by weeks 7-8. Depression at 92 days could be predicted accurately (area under the curve >0.70) after only 14 days of data collection. CONCLUSIONS: Simpler ML methods may outperform more complex methods until passive-sensing features become better specified. For intensive longitudinal studies, there may be limited predictive value in collecting data for more than 2 months.

A caveat to using wearable sensor data for COVID-19 detection: The role of behavioral change after receipt of test results.

BACKGROUND: Recent studies indicate that wearable sensors can capture subtle within-person changes caused by SARS-CoV-2 infection and play a role in detecting COVID-19 infections. However, in addition to direct effects of infection, wearable sensor data may capture changes in behavior after the receipt of COVID test results. At present, it remains unclear to what extent the observed discriminative performance of the wearable sensor data is affected by behavioral changes upon receipt of the test results. METHODS: We conducted a retrospective study of wearable sensor data in a sample of medical interns who had symptoms and received COVID-19 test results from March to December 2020, and calculated wearable sensor metrics incorporating changes in step, sleep, and resting heart rate for interns who tested positive (cases, n = 22) and negative (controls, n = 83) after symptom onset. All these interns had wearable sensor data available for > 50% of the days in pre- and post-symptom onset periods. We assessed discriminative accuracy of the metrics via area under the curve (AUC) and tested the impact of behavior changes after receiving test results by comparing AUCs of three models: all data, pre-test-result-only data, and post-test-result-only data. RESULTS: Wearable sensor metrics differentiated between symptomatic COVID-19 positive and negative individuals with good accuracy (AUC = 0.75). However, the discriminative capacity of the model with pre-test-result-only data substantially decreased (AUC from 0.75 to 0.63; change = -0.12, p = 0.013). The model with post-test-result-only data did not produce similar reductions in discriminative capacity. CONCLUSIONS: Changes in wearable sensor data, especially physical activity and sleep, are robust indicators of COVID-19 infection, though they may be reflective of a person's behavior change after receiving a positive test result as opposed to a physiological signature of the virus. Thus, wearable sensor data could facilitate the monitoring of COVID-19 prevalence, but not yet replace SARS-CoV-2 testing.

Patterns in Actions Against Physician Licenses Related to Substance Use and Psychological or Physical Impairment in the US From 2004 to 2020.

This cross-sectional study examines the frequency of actions taken against physician licenses in the US because of substance use and psychological or physical impairment from 2004 to 2020.

Assessment of the Prevalence and Trajectory of Depressive Symptoms by Sexual Orientation During Physician Training.

This cohort study uses survey data to assess the prevalence and development of depressive symptoms among sexual minority and heterosexual physicians during residency training.

Motor Unit Recruitment is Altered When Acute Experimental Pain is Induced at a Site Distant to the Contracting Muscle.

Acute pain alters motor unit discharge properties in muscles that are painful or influence loading of painful structures. Less is known about the changes in discharge when pain is induced in distant tissues that are unable or have limited capacity to modify the load of the contracting muscle. We aimed to determine whether acute experimental pain alters quadriceps motor unit discharge when pain is induced in; (i) a muscle that is unlikely to be mechanically influenced by modified quadriceps activity (tibialis anterior: TA), or (ii) the antagonist muscle (biceps femoris: BF). Using a within-subject design, 16 adults performed force-matched isometric knee extension during pain-free control conditions, and trials after painful hypertonic saline injections into TA or BF. Surface and intramuscular electromyography recordings were made. Despite maintained force, discharge rate of quadriceps motor units was lower during Pain than Control conditions for TA and BF trials (both P < 0.001). Redistribution of motor unit activity was observed; some units were recruited in control or pain but not both. As modified quadriceps motor unit discharge has limited/no potential to modify load in the painful tissue to protect the painful part, the findings might support an alternative hypothesis that activity is redistributed to larger motor units.

Interpersonal Correlates of Dementia Caregivers' Emotional Support Networks: Considering Family History.

Caregiving networks of individuals with Alzheimer's disease and related dementias (ADRD) are comprised of family and friends directly involved in caregiving activities and those supporting these activities. The purpose of this study was to investigate whether caregiving-related behaviors and interactions (i.e., uplift, malfeasance, and nonfeasance), kinship tie (i.e., friend, family), and family history of ADRD were associated with caregivers' emotional support networks. Seventy-one caregivers across 30 families provided information about 776 network members. Perceived emotional support and interactions representing uplift, malfeasance, and nonfeasance were assessed. Results indicated that uplift and friendship were associated with increased, whereas nonfeasance was associated with decreased, likelihood of perceived emotional support. Caregivers with a family history of ADRD were particularly more likely to report emotional support from friends and uplifting network members. Findings suggest the need for differential strategies based on families' prior caregiving experience to facilitate positive and minimize negative interactions within caregiving networks.

Trends in Depressive Symptoms and Associated Factors During Residency, 2007 to 2019 : A Repeated Annual Cohort Study.

BACKGROUND: Efforts to address the high depression rates among training physicians have been implemented at various levels of the U.S. medical education system. The cumulative effect of these efforts is unknown. OBJECTIVE: To assess how the increase in depressive symptoms with residency has shifted over time and to identify parallel trends in factors that have previously been associated with resident physician depression. DESIGN: Repeated annual cohort study. SETTING: U.S. health care organizations. PARTICIPANTS: First-year resident physicians (interns) who started training between 2007 and 2019. MEASUREMENTS: Depressive symptoms (9-item Patient Health Questionnaire [PHQ-9]) assessed at baseline and quarterly throughout internship. RESULTS: Among 16 965 interns, baseline depressive symptoms increased from 2007 to 2019 (PHQ-9 score, 2.3 to 2.9; difference, 0.6 [95% CI, 0.3 to 0.8]). The prevalence of baseline predictors of greater increase in depressive symptoms with internship also increased across cohorts. Despite the higher prevalence of baseline risk factors, the average change in depressive symptoms with internship decreased 24.4% from 2007 to 2019 (change in PHQ-9 score, 4.1 to 3.0; difference, -1.0 [CI, -1.5 to -0.6]). This change across cohorts was greater among women (4.7 to 3.3; difference, -1.4 [CI, -1.9 to -0.9]) than men (3.5 to 2.9; difference, -0.6 [CI, -1.2 to -0.05]) and greater among nonsurgical interns (4.1 to 3.0; difference, -1.1 [CI, -1.6 to -0.6]) than surgical interns (4.0 to 3.2; difference, -0.8 [CI, -1.2 to -0.4]). In parallel to the decrease in depressive symptom change, there were increases in sleep hours, quality of faculty feedback, and use of mental health services and a decrease in work hours across cohorts. The decrease in work hours was greater for nonsurgical than surgical interns. Further, the increase in mental health treatment across cohorts was greater for women than men. LIMITATION: Data are observational and subject to biases due to nonrandom sampling, missing data, and unmeasured confounders, limiting causal conclusions. CONCLUSION: Although depression during physician training remains high, the average increase in depressive symptoms associated with internship decreased between 2007 and 2019. PRIMARY FUNDING SOURCE: National Institute of Mental Health.

A Caveat to Using Wearable Sensor Data for COVID-19 Detection: The Role of Behavioral Change after Receipt of Test Results.

Recent studies indicate that wearable sensors have the potential to capture subtle within-person changes that signal SARS-CoV-2 infection. However, it remains unclear the extent to which observed discriminative performance is attributable to behavioral change after receiving test results. We conducted a retrospective study in a sample of medical interns who received COVID-19 test results from March to December 2020. Our data confirmed that sensor data were able to differentiate between symptomatic COVID-19 positive and negative individuals with good accuracy (area under the curve (AUC) = 0.75). However, removing post-result data substantially reduced discriminative capacity (0.75 to 0.63; delta= -0.12, p=0.013). Removing data in the symptomatic period prior to receipt of test results did not produce similar reductions in discriminative capacity. These findings suggest a meaningful proportion of the discriminative capacity of wearable sensor data for SARS-CoV-2 infection may be due to behavior change after receiving test results.

Efficacy of a Stress Management Intervention for Mothers of Children with Cancer.

OBJECTIVE: Mothers of children with cancer confront life stress that can impact their psychological and physical health and, in turn, the health of the family. Recommendations advocate preemptive stress-management interventions; however, few studies have investigated their efficacy. Here, we report results of a parallel randomized pilot trial examining health benefits of a stress management intervention designed to teach coping skills. METHODS: One hundred twenty mothers (age 36 ± 8 years) of children newly diagnosed with cancer were randomized to a 12-session stress management intervention (n = 60) or usual care (n = 60). Sessions took place in the inpatient or outpatient setting of a children's hospital. Primary outcome variables included psychological function and physical health assessed preintervention and postintervention and at 6-month follow-up (∼12 months postdiagnosis). RESULTS: Enrollment, retention, and satisfaction data supported feasibility and acceptability. Latent change score models showed the intervention reduced perceived stress (d = -0.37, p = 0.03), anxiety symptoms (ds = -0.38 and -0.56, ps < .03) and, a nonsignificant effect for depressive symptoms (d = -0.29, p = .11) across the 6 months following diagnosis. Intervention participants also endorsed fewer depressive symptoms than controls ∼12 months after diagnosis. The intervention improved stress management skills, which associated with the psychological benefits of participation. There were no intervention-related changes in perceived health or markers of inflammation. CONCLUSION: Intervention-related improvements in stress management skills may result in better psychological health in the face of caring for a child with cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02022449.

Dietary Management of Propionic Acidemia: Parent Caregiver Perspectives and Practices.

BACKGROUND: Propionic acidemia (PA), an autosomal recessive metabolic disorder, has an estimated incidence of 1:105,000-130,000 in the United States.1,2 Nutrition management is a main intervention for PA. Research in inborn errors of metabolism such as phenylketonuria has identified association of parental perceptions and practices with dietary outcomes. Parental perceptions and practices in the nutrition management of PA have not been investigated. OBJECTIVE: To assess the dietary perceptions and practices of parental caregivers of children affected by PA. METHODS: PA parents were surveyed about perceptions and practices associated with feeding their affected child(ren). The single-page survey was anonymous, and responses to survey items were not identifiable. Parents provided information on how often they followed the prescribed diet and the rationale for any adjustments. RESULTS: Parents "always" or "most of the time" followed the prescribed diet for children 4-20 years of age; yet, open-ended responses indicated that 71.4% made situational adjustments to their child's diet for a variety of reasons, including illness, iatrogenic effects, and social events. CONCLUSIONS: PA parents make situational adjustments to their child's highly specialized diet. Uncertainty exists as to the situational adjustments being within the guidelines used by the metabolic healthcare team who rely on parents to inform them about dietary situational adjustments.

Development of glucocorticoid resistance over one year among mothers of children newly diagnosed with cancer.

Chronic distress associates with peripheral release of cortisol and a parallel upregulation of innate inflammation. Typically, cortisol functions to down-regulate inflammatory processes. However, in the context of chronic stress, it is hypothesized that glucocorticoid receptors within immune cells become less sensitive to the anti-inflammatory effects of cortisol, resulting in increased systemic inflammation. Caring for a child newly diagnosed with cancer is a particularly provocative chronic stressor. Here, we examine evidence for the development of cellular resistance to glucocorticoids among 120 mothers (Aged 18-56 years; 86% Caucasian) across the 12 months following their child's new diagnosis with cancer. Measures of psychological distress, interleukin (IL)-6, and glucocorticoid resistance (GCR) were assessed 1, 6, and 12 months after the diagnosis. A latent factor for distress was derived from the covariation among symptoms of anxiety, depression, and post-traumatic stress. Latent change score models revealed a significant positive association between change in distress and change in GCR from 0 to 6 months, and 6 months-1 year. This finding provides initial evidence for a longitudinal association between change in maternal distress and change in GCR from the onset of a chronic stressor through one year. Although levels of IL-6 increased during the first six months after the child's diagnosis, the magnitude of this change was not related to change in distress or change in GCR. Given the possible health consequences of reduced immune sensitivity to glucocorticoids, future work should further explore this stress response and its clinical significance.

A new lysine derived glyoxal inhibitor of trypsin, its properties and utilization for studying the stabilization of tetrahedral adducts by trypsin.

New trypsin inhibitors Z-Lys-COCHO and Z-Lys-H have been synthesised. Ki values for Z-Lys-COCHO, Z-Lys-COOH, Z-Lys-H and Z-Arg-COOH have been determined. The glyoxal group (-COCHO) of Z-Lys-COCHO increases binding ~300 fold compared to Z-Lys-H. The α-carboxylate of Z-Lys-COOH has no significant effect on inhibitor binding. Z-Arg-COOH is shown to bind ~2 times more tightly than Z-Lys-COOH. Both Z-Lys-13COCHO and Z-Lys-CO13CHO have been synthesized. Using Z-Lys-13COCHO we have observed a signal at 107.4 ppm by 13C NMR which is assigned to a terahedral adduct formed between the hydroxyl group of the catalytic serine residue and the 13C-enriched keto-carbon of the inhibitor glyoxal group. Z-Lys-CO13CHO has been used to show that in this tetrahedral adduct the glyoxal aldehyde carbon is not hydrated and has a chemical shift of 205.3 ppm. Hemiketal stabilization is similar for trypsin, chymotrypsin and subtilisin Carlsberg. For trypsin hemiketal formation is optimal at pH 7.2 but decreases at pHs 5.0 and 10.3. The effective molarity of the active site serine hydroxyl group of trypsin is shown to be 25300 M. At pH 10.3 the free glyoxal inhibitor rapidly (t1/2=0.15 h) forms a Schiff base while at pH 7 Schiff base formation is much slower (t1/2=23 h). Subsequently a free enol species is formed which breaks down to form an alcohol product. These reactions are prevented in the presence of trypsin and when the inhibitor is bound to trypsin it undergoes an internal Cannizzaro reaction via a C2 to C1 alkyl shift producing an α-hydroxycarboxylic acid.

Quantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteases.

Two new papain inhibitors have been synthesized where the terminal α-carboxyl groups of Z-Phe-Ala-COOH and Ac-Phe-Gly-COOH have been replaced by a proton to give Z-Phe-Ala-H and Ac-Phe-Gly-H. We show that for papain, replacing the terminal carboxylate group of a peptide inhibitor with a hydrogen atom decreases binding 3-4 fold while replacing an aldehyde or glyoxal group with a hydrogen atom decreases binding by 300,000-1,000,000 fold. Thiohemiacetal formation by papain with aldehyde or glyoxal inhibitors is shown to be ~10,000 times more effective than hemiacetal or hemiketal formation with chymotrypsin. It is shown using effective molarities, that for papain, thiohemiacetal stabilization is more effective with aldehyde inhibitors than with glyoxal inhibitors. The effective molarity obtained when papain is inhibited by an aldehyde inhibitor is similar to the effective molarity obtained when chymotrypsin is inhibited by glyoxal inhibitors showing that both enzymes can stabilize tetrahedral adducts by similar amounts. Therefore the greater potency of aldehyde and glyoxal inhibitors with papain is not due to greater thiohemiacetal stabilization by papain compared to the hemiketal and hemiacetal stabilization by chymotrypsin, instead it reflects the greater intrinsic reactivity of the catalytic thiol group of papain compared to the catalytic hydroxyl group of chymotrypsin. It is argued that while the hemiacetals and thiohemiacetals formed with the serine and cysteine proteases respectively can mimic the catalytic tetrahedral intermediate they are also analogues of the productive and non-productive acyl intermediates that can be formed with the cysteine and serine proteases.

Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin.

The aldehyde inhibitor Z-Ala-Ala-Phe-CHO has been synthesized and shown by (13)C-NMR to react with the active site serine hydroxyl group of alpha-chymotrypsin to form two diastereomeric hemiacetals. For both hemiacetals oxyanion formation occurs with a pKa value of ~7 showing that chymotrypsin reduces the oxyanion pKa values by ~5.6 pKa units and stabilizes the oxyanions of both diastereoisomers by ~32kJmol(-1). As pH has only a small effect on binding we conclude that oxyanion formation does not have a significant effect on binding the aldehyde inhibitor. By comparing the binding of Z-Ala-Ala-Phe-CHO with that of Z-Ala-Ala-Phe-H we estimate that the aldehyde group increases binding ~100 fold. At pH7.2 the effective molarity of the active site serine hydroxy group is ~6000 which is ~7× less effective than with the corresponding glyoxal inhibitor. Using (1)H-NMR we have shown that at both 4 and 25°C the histidine pKa is ~7.3 in free chymotrypsin and it is raised to ~8 when Z-Ala-Ala-Phe-CHO is bound. We conclude that oxyanion formation only has a minor role in raising the histidine pKa and that the aldehyde hydrogen must be replaced by a larger group to raise the histidine pKa>10 and give stereospecific formation of tetrahedral intermediates. The results show that a large increase in the pKa of the active site histidine is not needed for the active site serine hydroxyl group to have an effective molarity of 6000.

Enteropathogenic Escherichia coli type III effectors EspG and EspG2 disrupt the microtubule network of intestinal epithelial cells.

Enteropathogenic Escherichia coli infection of intestinal epithelial cells leads to localized depletion of the microtubule cytoskeleton, an effect that is dependent on delivery of type III translocated effector proteins EspG and Orf3 (designated EspG2) to the site of depletion. Microtubule depletion involved disruption rather than displacement of microtubules.