Matthew Torre

Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical Students: A Systematic Review and Meta-Analysis

Importance Medical students are at high risk for depression and suicidal ideation. However, the prevalence estimates of these disorders vary between studies. Objective To estimate the prevalence of depression, depressive symptoms, and suicidal ideation in medical students. Data Sources and Study Selection Systematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language restriction for studies on the prevalence of depression, depressive symptoms, or suicidal ideation in medical students published before September 17, 2016. Studies that were published in the peer-reviewed literature and used validated assessment methods were included. Data Extraction and Synthesis Information on study characteristics; prevalence of depression or depressive symptoms and suicidal ideation; and whether students who screened positive for depression sought treatment was extracted independently by 3 investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. Main Outcomes and Measures Point or period prevalence of depression, depressive symptoms, or suicidal ideation as assessed by validated questionnaire or structured interview. Results Depression or depressive symptom prevalence data were extracted from 167 cross-sectional studies (n = 116 628) and 16 longitudinal studies (n = 5728) from 43 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of depression or depressive symptoms was 27.2% (37 933/122 356 individuals; 95% CI, 24.7% to 29.9%, I2 = 98.9%). Summary prevalence estimates ranged across assessment modalities from 9.3% to 55.9%. Depressive symptom prevalence remained relatively constant over the period studied (baseline survey year range of 1982-2015; slope, 0.2% increase per year [95% CI, -0.2% to 0.7%]). In the 9 longitudinal studies that assessed depressive symptoms before and during medical school (n = 2432), the median absolute increase in symptoms was 13.5% (range, 0.6% to 35.3%). Prevalence estimates did not significantly differ between studies of only preclinical students and studies of only clinical students (23.7% [95% CI, 19.5% to 28.5%] vs 22.4% [95% CI, 17.6% to 28.2%]; P = .72). The percentage of medical students screening positive for depression who sought psychiatric treatment was 15.7% (110/954 individuals; 95% CI, 10.2% to 23.4%, I2 = 70.1%). Suicidal ideation prevalence data were extracted from 24 cross-sectional studies (n = 21 002) from 15 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of suicidal ideation was 11.1% (2043/21 002 individuals; 95% CI, 9.0% to 13.7%, I2 = 95.8%). Summary prevalence estimates ranged across assessment modalities from 7.4% to 24.2%. Conclusions and Relevance In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among medical students was 27.2% and that of suicidal ideation was 11.1%. Further research is needed to identify strategies for preventing and treating these disorders in this population.

Osseous and chondromatous metaplasia in calcific aortic valve stenosis

BACKGROUND Aortic valve replacement for calcific aortic valve stenosis is one of the more common cardiac surgical procedures. However, the underlying pathophysiology of calcific aortic valve stenosis is poorly understood. We therefore investigated the histologic findings of aortic valves excised for calcific aortic valve stenosis and correlated these findings with their associated clinical features. RESULTS AND METHODS We performed a retrospective analysis on 6685 native aortic valves excised for calcific stenosis and 312 prosthetic tissue aortic valves with calcific degeneration at a single institution between 1987 and 2013. Patient demographics were correlated with valvular histologic features diagnosed on formalin-fixed, decalcified, and paraffin embedded hematoxylin and eosin stained sections. Of the analyzed aortic valves, 5200 (77.8%) were tricuspid, 1473 (22%) were bicuspid, 11 (0.2%) were unicuspid, and 1 was quadricuspid. The overall prevalence of osseous and/or chondromatous metaplasia was 15.6%. Compared to tricuspid valves, bicuspid valves had a higher prevalence of metaplasia (30.1% vs. 11.5%) and had an earlier mean age of excision (60.2 vs. 75.1 years old). In addition, the frequency of osseous metaplasia and/or chondromatous metaplasia increased with age at time of excision of bicuspid aortic valves, while tricuspid aortic valves showed the same incidence regardless of patient age. Males had a higher prevalence of metaplasia in both bicuspid (33.5% vs. 22.3%) and tricuspid (13.8% vs. 8.6%) aortic valves compared to females. Osseous metaplasia and/or chondromatous metaplasia was also more common in patients with bicuspid aortic valves and concurrent chronic kidney disease or atherosclerosis than in those without (33.6% vs. 28.3%). No osseous or chondromatous metaplasia was observed within the cusps of any of the prosthetic tissue valves. CONCLUSIONS Osseous and chondromatous metaplasia are common findings in native aortic valves but do not occur in prosthetic tissue aortic valves. Bicuspid valves appear to have an inherent proclivity for metaplasia, as demonstrated by their higher rates of osseous metaplasia and/or chondromatous metaplasia both overall and at earlier age compared to tricuspid and prosthetic tissue aortic valves. This predilection could be due to aberrant hemodynamic forces on bicuspid valves, as well as intrinsic genetic changes associated with bicuspid valve formation. Aortic valve interstitial cells may play a central role in this process. Calcification of prosthetic tissue valves is most likely a primarily dystrophic phenomenon.

Cardiac troponin assays in the management of heart failure

Cardiac troponins I and T are established biomarkers of cardiac injury. Testing for either of these two cardiac troponins has long been an essential component of the diagnosis of acute myocardial infarction. In addition, cardiac troponin concentrations after acute myocardial infarction predict future adverse events including development of ischemic heart failure and chronic elevations of cardiac troponin correlate with heart failure severity. These predictions and correlations are particularly obvious when cardiac troponin concentrations are measured using the new high sensitivity cardiac troponin assays. Thus, a growing body of literature suggests that cardiac troponin testing may have important clinical implications for heart failure patients with reduced or preserved ejection fraction. In this review, we explore the prognostic utility of measuring cardiac troponin concentrations in patients with acute or chronic heart failure and in populations at risk of developing heart failure and the relationship between cardiac troponin levels and disease severity. We also summarize the ongoing debates and research on whether serial monitoring of cardiac troponin levels may become a useful tool for guiding therapeutic interventions in patients with heart failure.

Activation of basolateral amygdala in juvenile C57BL/6J mice during social approach behavior.

There is a strong need to better understand the neurobiology of juvenile sociability (tendency to seek social interaction), a phenotype of central relevance to autism spectrum disorders (ASD). Although numerous genetic mouse models of ASD showing reduced sociability have been reported, and certain brain regions, such as the amygdala, have been implicated in sociability, there has been little emphasis on delineating brain structures and circuits activated during social interactions in the critical juvenile period of the mouse strain that serves as the most common genetic background for these models-the highly sociable C57BL/6J (B6) strain. We measured expression of the immediate early genes Fos and Egr-1 to map activation of brain regions following the Social Approach Test (SAT) in juvenile male B6 mice. We hypothesized that juvenile B6 mice would show activation of the amygdala during social interactions. The basolateral amygdala (BLA) was activated by social exposure in highly sociable, 4-week-old B6 mice. In light of these data, and the many lines of evidence indicating alteration of amygdala circuits in human ASD, future studies are warranted to assess structural and functional alterations in the BLA, particularly at BLA synapses, in various mouse models of ASD.

Immune-related fulminant myocarditis in a patient receiving ipilimumab therapy for relapsed chronic myelomonocytic leukaemia

A 66-year-old man with chronic myelomonocytic leukaemia (CMML) presented with myalgias and acute-onset shortness of breath, profound orthopnoea, and bilateral pedal oedema of 1 day’s duration. He had been diagnosed with CMML a year and half before presentation, and after an inadequate response to four cycles of decitabine chemotherapy, he underwent a matched unrelated donor allogeneic haematopoietic stem cell transplant 7 months before presentation. Six months after his transplant, he developed recurrent anaemia and thrombocytopenia, and bone marrow biopsy confirmed relapsed CMML. He was enrolled in an experimental protocol of ipilimumab, a monoclonal antibody (IgG1) that blocks the checkpoint protein cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), to promote anti-tumour immunity. One week after receiving his first infusion, he was admitted to the hospital with abdominal pain and diarrhoea, and was found to have colitis involving the descending and sigmoid colon. He underwent flexible sigmoidoscopy and biopsy of the inflamed tissue showed focal active colitis and ulceration with no diagnostic features of cytomegalovirus infection or graft-vs.-host disease. A diagnosis of ipilimumab-related colitis was made, and he was treated with a 7-day taper of dexamethasone. His presenting cardiopulmonary symptoms began on the day after he completed corticosteroid treatment. At presentation, his temperature was 36.8 ∘C, pulse was 108 b.p.m., blood pressure was 116/59 mmHg, respiratory rate was 24/min, and oxygen saturation was 92% on room air. His breathing was laboured and he was unable to lie flat. His jugular venous pressure was elevated at 12 cmH2O. Auscultation of the heart and lungs revealed a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . rapid and regular heart rate, an S4 gallop, and audible crackles at the bases of both lung fields. His extremities were warm and he had 2+ bilateral symmetric pitting pedal oedema. His complete blood count was near his recent baseline with a white blood cell count of 33×103 cells/mm3 (with 44% monocytes), haematocrit was 28.9%, and platelet count was 7000/μL. Other laboratories measurements of note included a serum sodium of 132 mmol/L, alanine aminotransferase 268 U/L, aspartate aminotransferase 189 U/L, lactate 2.9 mmol/L, troponin-T 1.99 ng/mL (reference range <0.01 ng/mL), creatine kinase 1172 U/L (reference range 39–308 U/L), creatine kinase MB isoenzyme 168.5 ng/ml (reference range 0.0–7.7 mg/ml), and N-terminal-pro-B-type natriuretic peptide 2155 pg/ml (reference range <900 pg/ml). His electrocardiogram showed low voltage, sinus rhythm, and a new right bundle branch block (Figure 1), and chest radiography revealed mild interstitial oedema and small bilateral pleural effusions. Computed tomography angiography of the chest showed no evidence of pulmonary embolism. Transthoracic echocardiography demonstrated preserved left ventricular systolic function (ejection fraction 70%) with evidence of diastolic dysfunction, normal right ventricular size and function, and no significant valvular lesions. He was given intravenous furosemide for decongestion and admitted to the cardiac intensive care unit for closer monitoring. It was recommended that a pulmonary artery catheter be placed for closer haemodynamic assessment; however, the patient declined invasive monitoring. Within hours of presentation, he developed progressive hypotension requiring the initiation of dopamine as well as progressive high-grade atrioventricular block and ultimately complete heart block with a wide ventricular escape (Figure 1). He was started on empirical high-dose methylprednisolone (1000 mg daily), and was offered temporary transvenous pacing and right heart catheterization with endomyocardial biopsy, but again declined all invasive measures. Following extensive discussion between the patient, the treating oncologist, and the intensive care unit team, the patient was transitioned to comfort measures only given . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . his poor oncological prognosis. He expired within 24 h. Post-mortem examination with microscopic evaluation of skeletal muscle biopsies demonstrated inflammatory myositis, characterized by a predominantly CD3+ T-cell inflammatory infiltrate with associated myocyte necrosis (Figure 2). Microscopic evaluation of cardiac muscle was not performed because of the family’s request for a limited post-mortem examination.

Prevalence of Burnout Among Physicians: A Systematic Review

Importance Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout prevalence among physicians would have important health policy implications, but the overall prevalence is unknown. Objective To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout. Data Sources and Study Selection Systematic search of EMBASE, ERIC, MEDLINE/PubMed, psycARTICLES, and psycINFO for studies on the prevalence of burnout in practicing physicians (ie, excluding physicians in training) published before June 1, 2018. Data Extraction and Synthesis Burnout prevalence and study characteristics were extracted independently by 3 investigators. Although meta-analytic pooling was planned, variation in study designs and burnout ascertainment methods, as well as statistical heterogeneity, made quantitative pooling inappropriate. Therefore, studies were summarized descriptively and assessed qualitatively. Main Outcomes and Measures Point or period prevalence of burnout assessed by questionnaire. Results Burnout prevalence data were extracted from 182 studies involving 109 628 individuals in 45 countries published between 1991 and 2018. In all, 85.7% (156/182) of studies used a version of the Maslach Burnout Inventory (MBI) to assess burnout. Studies variably reported prevalence estimates of overall burnout or burnout subcomponents: 67.0% (122/182) on overall burnout, 72.0% (131/182) on emotional exhaustion, 68.1% (124/182) on depersonalization, and 63.2% (115/182) on low personal accomplishment. Studies used at least 142 unique definitions for meeting overall burnout or burnout subscale criteria, indicating substantial disagreement in the literature on what constituted burnout. Studies variably defined burnout based on predefined cutoff scores or sample quantiles and used markedly different cutoff definitions. Among studies using instruments based on the MBI, there were at least 47 distinct definitions of overall burnout prevalence and 29, 26, and 26 definitions of emotional exhaustion, depersonalization, and low personal accomplishment prevalence, respectively. Overall burnout prevalence ranged from 0% to 80.5%. Emotional exhaustion, depersonalization, and low personal accomplishment prevalence ranged from 0% to 86.2%, 0% to 89.9%, and 0% to 87.1%, respectively. Because of inconsistencies in definitions of and assessment methods for burnout across studies, associations between burnout and sex, age, geography, time, specialty, and depressive symptoms could not be reliably determined. Conclusions and Relevance In this systematic review, there was substantial variability in prevalence estimates of burnout among practicing physicians and marked variation in burnout definitions, assessment methods, and study quality. These findings preclude definitive conclusions about the prevalence of burnout and highlight the importance of developing a consensus definition of burnout and of standardizing measurement tools to assess the effects of chronic occupational stress on physicians.

Embolic Foreign Material in the Central Nervous System of Pediatric Autopsy Patients With Instrumented Heart Disease

Upon detection of foreign-body embolization to the central nervous system (CNS) following a specific invasive cardiovascular procedure in 1 autopsied child, we undertook a quality assurance analysis to determine whether other patients had had similar events. Autopsies of all infants and children with history of cardiac catheterization, heart surgery on cardiopulmonary bypass, and/or extracorporeal membrane oxygenation over a 5-year period at a single tertiary care institution were reviewed for light-microscopic evidence of foreign material. Of the 24 patients meeting clinical criteria (13 females, 11 males; ages 6 days to 20 years, median age 7.5 months), 8 (33%) had foreign embolic material to the CNS. The material was associated with a cellular inflammatory reaction in all cases, with a subset associated with infarcts. No embolic foreign material was detected in 14 age-matched patients without history of cardiovascular procedures. Particles acquired from ex vivo manipulation of a catheter type utilized in at least 1 of the affected patients demonstrated similar histologic characteristics. We conclude that, in addition to recognized risks of hypoxic-ischemic brain damage in congenital cardiopulmonary disease, potential brain insult exists in the form of instrumentation-related foreign emboli to the cerebral vasculature. Cardiac catheters are a potential source of foreign embolic material.

Cytopathologic and immunophenotypic changes in NUT midline carcinoma after targeted therapy.

We read with great interest the article by Bishop et al entitled Cytopathologic Features of NUT Midline Carcinoma: A Series of 26 Specimens From 13 Patients, which represents the largest series of NUT midline carcinoma (NMC) cases. Among their observations is the fact that there were variations in several cytomorphologic features, including tumor cell cohesiveness, the appearance of chromatin, and the presence of tumor necrosis and inflammatory infiltrates. However, there is no mention of whether these specimens were collected before or after treatment with chemotherapy and/or with one of the emerging targeted therapies for NMC, such as bromodomain and extraterminal (BET) inhibitors. BET inhibitors, which displace the bromodomain containing 4–nuclear protein in testis (BRD4-NUT) fusion protein from chromatin, have shown promising results in early clinical trials and could possibly become part of the standard of care in the management of NMC. Understanding the microscopic changes that accompany BET inhibitor therapy might, therefore, become of increasing clinical and diagnostic importance. As staff members of one of the largest NMC referral centers, we report that BET inhibitor therapy can be associated with significant cytopathologic and immunophenotypic alterations that could result in potential diagnostic pitfalls in the diagnosis of NMC. Posttreatment alterations that we have observed in a subset of cytology specimens, mainly pleural fluids, include the presence of psammomatous calcifications, a significant reduction in nuclear size, and changes in the immunoprofile (ie, from diffuse p63 expression to absent p63 expression). In some instances, there may be a shift to a more differentiated squamous phenotype with the initiation of BET inhibitor therapy, and this underscores the high variability in posttreatment NMC. The variable degree of squamous differentiation after BET inhibitor therapy might be due to a number of factors, including the duration of therapy and the location of recurrence. Tumor cells present in pleural fluid, for instance, would be exposed to a lower drug concentration than tumor cells in a lymph node. It is also conceivable that the administration of BET inhibitors might select for a more primitive tumor population over time, so clinical recurrences would be expected to consist of more aggressive, dedifferentiated tumor cells. Despite these alterations, positive NUT protein immunohistochemistry staining was retained in all our posttreatment cases. On the basis of our experience, we have several suggestions for the workup of suspected NMC recurrence after BET inhibitor therapy: 1) marked histologic and immunophenotypic differences between pretreatment NMC tumor cells and posttreatment tumor cells do not necessarily rule out recurrence, and 2) NUT protein immunohistochemistry is integral for the diagnosis of persistent/recurrent NMC.

Expanding the spectrum of pediatric NTRK-rearranged fibroblastic tumors to the central nervous system: A case report with RBPMS-NTRK3 fusion: CNS fibroblastic tumor with RBPMS-NTRK3 fusion

We report a case of a 20‐month‐old male presenting with seizures who was found to have a hyperintense lesion on T2‐weighted images of magnetic resonance imaging in the left medial temporal lobe that was initially clinically and radiologically thought to be either low‐grade glioma or focal cortical dysplasia. Histologic, immunohistochemical and molecular evaluation (array comparative genomic hybridization, Archer fusion panel) of the resection specimen demonstrated a highly infiltrative fibroblastic spindle cell neoplasm with mild nuclear atypia and an RBPMS‐NTRK3 fusion. NTRK‐fused mesenchymal tumors are known to involve extracranial sites but, to our knowledge, have not been described within the central nervous system. Accurate and timely diagnosis of this entity has important prognostic and therapeutic implications, as NTRK‐fused tumors may recur locally and may respond to selective kinase inhibitor therapies.

Neuropathology of a Case With Fatal CAR T-Cell-Associated Cerebral Edema.

Chimeric antigen receptor (CAR) T cells are a new and powerful class of cancer immunotherapeutics that have shown potential for the treatment of hematopoietic malignancies. The tremendous promise of this approach is tempered by safety concerns, including potentially fatal neurotoxicity, sometimes but not universally associated with cytokine release syndrome. We describe the postmortem examination of a brain from a 21-year-old patient with relapsed pre-B cell acute lymphoblastic leukemia (ALL) who died from fulminant cerebral edema following CAR T-cell infusion. We found a range of changes that included activation of microglia, expansion of perivascular spaces by proteinaceous exudate, and clasmatodendrosis-a beading of glial fibrillary acidic protein consistent with astrocyte injury. Notably, within the brain parenchyma, we identified only infrequent T cells and did not identify ALL cells or CAR T cells. The overall findings are nonspecific but raise the possibility of astrocyte and blood-brain barrier dysfunction as a potential etiology of fatal CAR T-cell neurotoxicity in this patient.