To investigate the relative differences in outcomes among microdissection testicular sperm extraction (micro-TESE), conventional testicular sperm extraction (cTESE), and testicular sperm aspiration ...(TESA) in men with nonobstructive azoospermia.
Systematic review and meta-analysis.
Outpatient academic and private urology clinics.
Men with nonobstructive azoospermia.
Micro-TESE, cTESE, or TESA.
Sperm retrieval (SR).
Fifteen studies with a total of 1,890 patients were identified. The weighted average age of the patients was 34.4 years, the follicular stimulating hormone level was 20.5 mIU/mL, the T was 373 ng/dL, and the testicular volume was 13.5 mL. In a direct comparison, performance of micro-TESE was 1.5 times more likely (95% confidence interval 1.4-1.6) to result in successful SR as compared with cTESE. Similarly, in a direct comparison, performance of cTESE was 2.0 times more likely (95% confidence interval 1.8-2.2) to result in successful SR as compared with TESA. Because of inconsistent reporting, evaluation of other procedural characteristics and pregnancy outcomes was not possible.
Sperm retrieval was higher for micro-TESE compared with cTESE and for cTESE compared with TESA. Standardization of reported outcomes as well as combining all available SR data would help to further elucidate the SRs of these procedures.
Physicians in training are at high risk for depression. However, the estimated prevalence of this disorder varies substantially between studies.
To provide a summary estimate of depression or ...depressive symptom prevalence among resident physicians.
Systematic search of EMBASE, ERIC, MEDLINE, and PsycINFO for studies with information on the prevalence of depression or depressive symptoms among resident physicians published between January 1963 and September 2015. Studies were eligible for inclusion if they were published in the peer-reviewed literature and used a validated method to assess for depression or depressive symptoms.
Information on study characteristics and depression or depressive symptom prevalence was extracted independently by 2 trained investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression.
Point or period prevalence of depression or depressive symptoms as assessed by structured interview or validated questionnaire.
Data were extracted from 31 cross-sectional studies (9447 individuals) and 23 longitudinal studies (8113 individuals). Three studies used clinical interviews and 51 used self-report instruments. The overall pooled prevalence of depression or depressive symptoms was 28.8% (4969/17,560 individuals, 95% CI, 25.3%-32.5%), with high between-study heterogeneity (Q = 1247, τ2 = 0.39, I2 = 95.8%, P < .001). Prevalence estimates ranged from 20.9% for the 9-item Patient Health Questionnaire with a cutoff of 10 or more (741/3577 individuals, 95% CI, 17.5%-24.7%, Q = 14.4, τ2 = 0.04, I2 = 79.2%) to 43.2% for the 2-item PRIME-MD (1349/2891 individuals, 95% CI, 37.6%-49.0%, Q = 45.6, τ2 = 0.09, I2 = 84.6%). There was an increased prevalence with increasing calendar year (slope = 0.5% increase per year, adjusted for assessment modality; 95% CI, 0.03%-0.9%, P = .04). In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 15.8% (range, 0.3%-26.3%; relative risk, 4.5). No statistically significant differences were observed between cross-sectional vs longitudinal studies, studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents.
In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among resident physicians was 28.8%, ranging from 20.9% to 43.2% depending on the instrument used, and increased with calendar year. Further research is needed to identify effective strategies for preventing and treating depression among physicians in training.
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.
To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout.
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.
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.
Point or period prevalence of burnout assessed by questionnaire.
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.
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.
Medical students are at high risk for depression and suicidal ideation. However, the prevalence estimates of these disorders vary between studies.
To estimate the prevalence of depression, depressive ...symptoms, and suicidal ideation in medical students.
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.
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.
Point or period prevalence of depression, depressive symptoms, or suicidal ideation as assessed by validated questionnaire or structured interview.
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%.
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.
Depression is common among training physicians and may disproportionately affect women. The identification of modifiable risk factors is key to reducing this disease burden and its negative impact on ...patient care and physician career attrition.
To determine the presence and magnitude of a sex difference in depressive symptoms and work-family conflict among training physicians; and if work-family conflict impacts the sex difference in depressive symptoms among training physicians.
A prospective longitudinal cohort study of medical internship in the United States during the 2015 to 2016 academic year in which 3121 interns were recruited across all specialties from 44 medical institutions.
Prior to and during their internship year, participants reported the degree to which work responsibilities interfered with family life using the Work Family Conflict Scale and depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9).
Mean (SD) participant age was 27.5 (2.7) years, and 1571 participants (49.7%) were women. Both men and women experienced a marked increase in depressive symptoms during their internship year, with the increase being statistically significantly greater for women (men: mean increase in PHQ-9, 2.50; 95% CI, 2.26-2.73 vs women: mean increase, 3.20; 95% CI, 2.97-3.43). When work-family conflict was accounted for, the sex disparity in the increase in depressive symptoms decreased by 36%.
Our study demonstrates that depressive symptoms increase substantially during the internship year for men and women, but that this increase is greater for women. The study also identifies work-family conflict as an important potentially modifiable factor that is associated with elevated depressive symptoms in training physicians. Systemic modifications to alleviate conflict between work and family life may improve physician mental health and reduce the disproportionate depression disease burden for female physicians. Given that depression among physicians is associated with poor patient care and career attrition, efforts to alleviate depression among physicians has the potential to reduce the negative consequences associated with this disease.
BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including ...5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.
Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced
fusion-positive lung and thyroid cancer.
fusion testing strategies with rapid and reliable results are ...critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.
Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a
structural variant of unknown significance (SVUS) were present. Canonical DNA-level
fusions and RNA-confirmed
fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.
A total of 171 of 41,869 patients with DNA NGS harbored
structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic
fusions. The most common
fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were
(45%),
(29.1%), and
(13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for
-
(66.7%, 8/12). A total of 87.5% (7/8) of
SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner:
sensitivity was highest (100%, 31/31), followed by
(88.9%, 16/18) and
(50%, 6/12). Specificity of RET IHC was 82% (73/89).
Although DNA sequencing has high sensitivity and specificity, RNA sequencing of
SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for
-
fusions.
Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical ...reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.
Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly ...or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations.
In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 RECIST 1.1), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing.
Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 31% of 127 patients), thrombocytopenia (11 9%), and neutropenia (ten 8%). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths.
Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations.
Pfizer/Medivation.
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