CONTEXT: There is a potential risk that testosterone replacement therapy (TRT) may exacerbate lower urinary tract symptoms (LUTS) among aging men with late-onset hypogonadism (LOH) because of testosterone's growth-promoting effects on the prostate.
OBJECTIVE: To compare the change in LUTS severity as assessed using the International Prostate Symptom Score (IPSS) between men receiving TRT versus placebo for the treatment of LOH.
EVIDENCE ACQUISITION: Systematic search of MEDLINE, Embase, ClinicalTrials.gov, and The Cochrane Library for randomized controlled trials of TRT for LOH published between January 1992 and September 2015. Studies were eligible for inclusion if they were a randomized control trial, used TRT, and assessed LUTS outcomes using the IPSS. Estimates were pooled using random effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression.
EVIDENCE SYNTHESIS: Data were extracted from 14 trials involving 2029 participants. The average age was 64.5 yr and the average follow-up was 34.4 mo. Seven studies used topical, five used injectable, and two used oral testosterone. There was no statistically significant difference in pooled changes in IPSS from baseline to follow up in men treated with TRT compared with those receiving placebo (-0.41 points [95% confidence interval: -0.89 to 0.07; I(2)=0%, p=0.28] vs. 0.12 points [95% confidence interval: -0.32 to 0.55; I(2)=0%, p=0.81], between-group difference p>0.05). No between-group differences were noted in subanalyses that controlled for potential confounders such as type of testosterone, change in testosterone, aging male symptom scale, or prostate-specific antigen levels (p>0.05 for all comparisons).
CONCLUSIONS: In this meta-analysis of 14 clinical trials of TRT for LOH, the change in IPSS was similar among men receiving TRT versus placebo, suggesting that TRT treatment does not worsen LUTS among men with LOH.
PATIENT SUMMARY: In this analysis of 14 clinical trials, testosterone replacement therapy did not worsen lower urinary tract symptoms among men being treated for late-onset hypogonadism.
IMPORTANCE: Physicians in training are at high risk for depression. However, the estimated prevalence of this disorder varies substantially between studies.
OBJECTIVE: To provide a summary estimate of depression or depressive symptom prevalence among resident physicians.
DATA SOURCES AND STUDY SELECTION: 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.
DATA EXTRACTION AND SYNTHESIS: 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.
MAIN OUTCOMES AND MEASURES: Point or period prevalence of depression or depressive symptoms as assessed by structured interview or validated questionnaire.
RESULTS: 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.
CONCLUSIONS AND RELEVANCE: 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.
BACKGROUND: Precursor T-cell acute lymphoblastic leukemia (pre-T-ALL) may cause ocular pathologies such as cotton-wool spots, retinal hemorrhage, and less commonly, retinal detachment or leukemic infiltration of the retina itself. However, these findings are typically accompanied by the pathognomonic hematological signs of acute leukemia.
CASE PRESENTATION: In this case report and review of the literature, we describe a particularly unusual case of a 25-year-old man who presented to our hospital with bilateral exudative retinal detachments associated with posterior pole thickening without any hematological or neurological findings. The patient, who had a history of previously treated pre-T-ALL in complete remission, was found to have leukemia cell infiltration on retinal biopsy.
CONCLUSION: Our case underscores the fact that the ophthalmologist may be the first provider to detect the relapse of previously treated leukemia, and that ophthalmic evaluation is critical for detecting malignant ocular infiltrates.
OBJECTIVE: 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.
DESIGN: Systematic review and meta-analysis.
SETTING: A variety of outpatient academic and private urology clinics.
PATIENTS(S): Men with nonobstructive azoospermia.
INTERVENTION(S): Micro-TESE, cTESE, or TESA.
MAIN OUTCOME MEASURE(S): Sperm retrieval (SR).
RESULT(S): 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.
CONCLUSION(S): 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.
Precision medicine can greatly benefit men's health by helping to prevent, diagnose, and treat prostate cancer, benign prostatic hyperplasia, infertility, hypogonadism, and erectile dysfunction. For example, precision medicine can facilitate the selection of men at high risk for prostate cancer for targeted prostate-specific antigen screening and chemoprevention administration, as well as assist in identifying men who are resistant to medical therapy for prostatic hyperplasia, who may instead require surgery. Precision medicine-trained clinicians can also let couples know whether their specific cause of infertility should be bypassed by sperm extraction and in vitro fertilization to prevent abnormalities in their offspring. Though precision medicine's role in the management of hypogonadism has yet to be defined, it could be used to identify biomarkers associated with individual patients' responses to treatment so that appropriate therapy can be prescribed. Last, precision medicine can improve erectile dysfunction treatment by identifying genetic polymorphisms that regulate response to medical therapies and by aiding in the selection of patients for further cardiovascular disease screening.
We evaluated pre-operative and intraoperative factors associated with successful patency following bilateral microsurgical vasovasostomy (VV). We retrospectively reviewed the charts of 1331 men who underwent bilateral VV by two surgeons between 2006 and 2013. Vasal fluid was examined intraoperatively for gross quality (i.e., clear or opaque and creamy/thick) and for the presence of spermatozoa on microscopy (i.e., whole spermatozoa, sperm fragments, or azoospermia). Post-operative patency was assessed by semen analysis or patient report of conception. Perioperative factors were explored using descriptive statistics and examined in logistic regression models for associations with post-operative patency. The median age at VV was 39 years [interquartile range (IQR): 35-44] and the median obstructive interval (OI) was 7 years (IQR: 4-11). Overall, 1307 patients achieved post-operative patency (98%) while 24 remained obstructed (2%). Among those who became patent, 410 reported conception. After adjustment for potential confounders, only microscopic examination of the intravasal fluid for the presence of spermatozoa (bilateral or unilateral whole spermatozoa vs. sperm parts/azoospermia) at the time of VV was significantly associated with post-operative patency with an odds ratio (OR) of 14.2 (95% CI: 5.8-34.9; p = <1 × 10(-8) ). Identification of bilateral or unilateral sperm fragments vs. azoospermia was also associated with increased odds of post-operative patency with an OR of 3.5 (95% CI: 0.9-13.6; p = 0.08). There was no statistically significant association between age at VV, OI, presence of granuloma, gross fluid quality, or surgeon and post-operative patency after controlling for potential confounders. Identification of whole spermatozoa in the vasal fluid at the time of VV was positively associated with post-operative patency. Our findings stress the need for intraoperative microscopy to aid in post-operative patient counseling.
OBJECTIVE: To investigate the association between the presence of sperm in the vasal fluid during vasectomy reversal (VR) and postoperative patency.
METHODS: We performed a systematic review and meta-analysis of the English-language literature reporting on the association between the presence of sperm in the intraoperative vasal fluid (ie, whole or parts vs none) and patency (ie, patent or not) after microsurgical vasovasostomy for men with obstructive azoospermia due to vasectomy. Odds ratios (OR) and 95% confidence intervals were calculated to quantify the strength of the association reported by each study. Meta-analysis was performed using a random-effects model.
RESULTS: Four case series and 2 retrospective cohort studies of a total of 1293 eligible patients were identified. The mean age at VR was 37.8 years, and the mean obstructive interval was 7.1 years. The unadjusted OR of postoperative patency was 4.1 times higher (95% confidence interval, 2.3-7.3) given the presence of intravasal sperm or sperm parts as opposed to their absence at the time of VR (Q = 3.4; df = 5; P = .6; I(2) = 22%). The pooled OR should be interpreted with caution as only the 2 retrospective cohort studies reported meaningful data on this association. Because of inconsistent reporting, analysis of other vasal fluid characteristics (eg, consistency) and outcomes (eg, pregnancy) was not possible.
CONCLUSION: The presence of whole sperm or sperm parts in the vasal fluid during VR is positively associated with postoperative patency. Our review highlights the poor methodological quality of existing evidence and underscores the need for more thorough follow up and higher standards of reporting in future studies.
Coward RM, Mata DA, Smith RP, Kovac JR, Lipshultz LI. Reply. Urology. 2014;84 (6) :1341.
OBJECTIVES: • To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post-hoc analysis of a prospective clinical trial. • To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumors exhibited LVI.
PATIENTS AND METHODS: • Surgical and tumor factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (SWOG 4B951/NCT00005047). • The presence or absence of LVI was determined by pathologic examination of transurethral resection or RC specimens. • Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS).
RESULTS: • Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumors. Of these, 34 patients had pT1 and 68 had pT2 disease. • LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 (95% confidence interval [CI]: 1.15 to 2.77; number of events [EV] = 95; p = 0.01) and with OS with a HR of 2.02 (95% CI: 1.31 to 3.11; EV = 98; p = 0.001) after adjustment for pathologic stage. • Among 27 patients with LVI-positive tumors who were randomized to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70; 95% CI: 0.16 to 3.17; EV = 7; p = 0.65) or with OS (HR: 0.45; 95% CI: 0.11 to 1.83; EV = 9; p = 0.26).
CONCLUSIONS: • Our post-hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. • The analysis did not demonstrate a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not ruled out.
OBJECTIVE: To report considerations for preoperative management and outcomes of vasectomy reversal (VR) in men with a history of testosterone supplementation therapy (TST).
METHODS: A retrospective review of men on TST before VR from 2010 to 2013 was performed. For inclusion, patients were required to have baseline and follow-up hormone levels as well as postoperative semen analyses. Preoperative use of medical testicular salvage therapy and testicular sperm aspiration (TESA), intraoperative findings, and pregnancies were also analyzed.
RESULTS: Six of 265 men who underwent VR had prior TST and met inclusion criteria. Median age was 39 years with a median obstructive interval of 7.5 years. Median duration of TST was 9 months before discontinuation and transition to testicular salvage therapy with clomiphene citrate with or without human chorionic gonadotropin for a median of 2.8 months. At baseline, decreased luteinizing hormone (median, 2 mIU/mL), follicle stimulating hormone (median, 5 mIU/mL), and total testosterone (median, 249 ng/dL) were observed. Two men (33%) with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Nine vasovasostomies and 3 epididymovasostomies were performed. Patency was 83% after a median follow-up of 6.4 months and was 100% in men undergoing at least 1 vasovasostomy. Spontaneous pregnancy was achieved by 50% during the follow-up period.
CONCLUSION: Testicular salvage medical therapy may play a role in the preoperative management of VR in men with prior TST. VR after TST can have outcomes comparable to those in the general population.
Influenza A virions contain eight ribonucleoproteins (RNPs), each comprised of a negative-strand viral RNA, the viral polymerase, and multiple nucleoproteins (NPs) that coat the viral RNA. NP oligomerization along the viral RNA is mediated largely by a 28-amino-acid tail loop. Influenza viral RNPs, which serve as the templates for viral RNA synthesis in the nuclei of infected cells, are not linear but rather are organized in hairpin-like double-helical structures. Here we present results that strongly support a coherent model for the assembly of the double-helical influenza virus RNP structure. First, we show that NP self-associates much more weakly in the absence of RNA than in its presence, indicating that oligomerization is very limited in the cytoplasm. We also show that once NP has oligomerized, it can dissociate in the absence of bound RNA, but only at a very slow rate, indicating that the NP scaffold remains intact when viral RNA dissociates from NPs to interact with the polymerase during viral RNA synthesis. In addition, we identify a previously unknown NP-NP interface that is likely responsible for organizing the double-helical viral RNP structure. This identification stemmed from our observation that NP lacking the oligomerization tail loop forms monomers and dimers. We determined the crystal structure of this NP dimer, which reveals this new NP-NP interface. Mutation of residues that disrupt this dimer interface does not affect oligomerization of NPs containing the tail loop but does inactivate the ability of NPs containing the tail loop to support viral RNA synthesis in minigenome assays. IMPORTANCE: Influenza A virus, the causative agent of human pandemics and annual epidemics, contains eight RNA gene segments. Each RNA segment assumes the form of a rod-shaped, double-helical ribonucleoprotein (RNP) that contains multiple copies of a viral protein, the nucleoprotein (NP), which coats the RNA segment along its entire length. Previous studies showed that NP molecules can polymerize via a structural element called the tail loop, but the RNP assembly process is poorly understood. Here we show that influenza virus RNPs are likely assembled from NP monomers, which polymerize through the tail loop only in the presence of viral RNA. Using X-ray crystallography, we identified an additional way that NP molecules interact with each other. We hypothesize that this new interaction is responsible for organizing linear, single-stranded influenza virus RNPs into double-helical structures. Our results thus provide a coherent model for the assembly of the double-helical influenza virus RNP structure.
Between February 29th and March 7th, 2012, a group of 37 American Fulbright Scholars based in Europe participated in a week-long conference on the European Union and NATO held in Luxembourg and Belgium. The primary purpose of the seminar was to educate American Fulbright grantees on the structure and functions of European institutions. By exposing grantees to these institutions firsthand, the seminar served to encourage grantees to think about how their future careers might relate to international diplomacy, law, and policy.