Testosterone Therapy is Associated With Depression, Suicidality, and Intentional Self-Harm: Analysis of a National Federated Database.

BACKGROUND: Long-term use of testosterone can be associated with mood destabilizing effects. Most studies investigating psychiatric complications of anabolic steroids have used small samples, but a comprehensive assessment of the risk of developing mental health disorders after testosterone use has not been performed at the population level. AIM: To determine whether testosterone therapy is associated with major depressive disorder or suicide attempts in men. METHODS: We conducted a retrospective cohort study of 70.3 million electronic health records collected from 46 healthcare organizations encompassing flagship hospitals, satellite hospitals, and outpatient clinics since 2008 to determine whether testosterone use is associated with major depressive disorder and suicide attempts in a large population. We included men 18 or older who either used testosterone or did not, defined by reported use, insurance claim, or prescription use of testosterone documented in the electronic health record. We propensity-score matched by age, race, ethnicity, obesity, and alcohol-related disorder. Additionally, a sub-group analysis was performed in testosterone deficient (<300 ng/dL) men comparing those with TD on testosterone therapy to a control group of men with TD who are not using testosterone. OUTCOMES: We determined measures of association with a new diagnosis of major depressive disorder and suicide attempt or intentional self-harm following testosterone use within 5 years. RESULTS: A total of 263,579 men who used testosterone and 17,838,316 men who did not were included in the analysis. Testosterone use was independently associated with both Major Depressive Disorder (OR 1.99, 95% CI 1.94-2.04, P < .0001) and Suicide Attempt/Intentional Self-Harm (OR 1.52, 95% CI 1.40-1.65, P < .0001). Results remained significant in testosterone deficient sub-group analysis. CLINICAL IMPLICATIONS: Men who use testosterone should be screened for and counseled about risks of depression and suicidality. STRENGTHS AND LIMITATIONS: Strengths of this study include a large sample size, the ability to account for chronology of diagnoses, the use of propensity score matching to control for potentially confounding variables, and the consistency of results with sub-group analyses. Limitations include the potential for incorrect coding within the electronic health record, a lack of granular information regarding testosterone therapy adherence, the possibility that unrecorded testosterone or anabolic steroid use were prevalent but not captured within the control group, and a lack of data regarding testosterone withdrawal. CONCLUSION: Testosterone use is independently associated with new-onset mental health disorders. Future studies are necessary to elucidate the role that androgen withdrawal plays and whether a causal relationship exists. Nackeeran S, Patel MS, Nallakumar DT, et al. Testosterone Therapy is Associated With Depression, Suicidality, and Intentional Self-Harm: Analysis of a National Federated Database. J Sex Med 2022;19:933-939.

Mitochondrial dysfunction in airways and quadriceps muscle of patients with chronic obstructive pulmonary disease.

BACKGROUND: Mitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD. METHODS: Bronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function. RESULTS: Decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV1 (% predicted), transfer factor of the lung for carbon monoxide (TLCOC % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression. CONCLUSIONS: Mitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.

Stem cell antigen/Ly6a protects against bladder fibrosis in mice.

We have defined a population of stem cell antigen (Sca)-1+/CD34+/lin- mesenchymal stem cells in the mouse urinary bladder. These cells are reduced after partial bladder outlet obstruction (PO). To test the role of Sca-1 expressed by these cells, we analyzed bladders from Sca-1 knockout (KO) mice in both uninjured male mice and male mice subjected to PO. We found that loss of Sca-1 alone had little effect on bladder development or function but reduced the total number of mesenchymal stem cells by 30%. After PO, bladders from Sca-1-null KO male mice were larger, with more collagen and less muscle, than obstructed wild-type mice. Steady-state levels of caldesmon were significantly reduced and levels of fibroblast-specific protein 1 were significantly increased in Sca-1 KO mice compared with wild-type mice after PO. In investigating the effects of PO on cell proliferation, we found that loss of Sca-1 changed the timing of cell division in CD34+/lin-, collagen-producing, and smooth muscle cells. PO in combination with loss of Sca-1 drastically reduced the ability of CD34+/lin- cells to form colonies in vitro. Our findings therefore support the hypothesis that Sca-1 protects the bladder from fibrotic remodeling after obstruction, in part by influencing the proliferation of cells responding to the injury.

Using laser capture microdissection to study fiber specific signaling in locomotor muscle in COPD: A pilot study.

INTRODUCTION: Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signaling may be fiber-specific. Our objective was to develop a method for fiber-specific gene expression analysis. METHODS: 12 COPD and 6 healthy subjects underwent quadriceps biopsy. Cryosections were immunostained for type II fibers, which were separated using laser capture microdissection (LCM). Whole muscle and different fiber populations were subject to quantitative polymerase chain reaction. RESULTS: Levels of muscle-RING-finger-protein-1 and Atrogin-1 were lower in type II fibers of COPD versus healthy subjects (P = 0.02 and P = 0.03, respectively), but differences were not apparent in whole muscle or type I fibers. CONCLUSIONS: We describe a novel method for studying fiber-specific gene expression in optimum cutting temperature compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. Muscle Nerve 55: 902-912, 2017.

Physical activity patterns and clusters in 1001 patients with COPD.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV1], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV1, worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.

The 'anatomic shunt test' in clinical practice; contemporary description of test and in-service evaluation.

The 100% oxygen shunt test for detecting right-to-left anatomical shunting was originally described 70 years ago. However, its clinical value is not yet established. We conducted an audit in 80 patients undergoing the test between 1996 and 2012 in a tertiary referral centre. A significant difference (p=0.02) existed between the median shunt percentages where anatomical shunting was identified (10.2%) and absent (5.0%). The area under the curve for a ROC plot was 0.70. A shunt percentage of 8.3 had a sensitivity of 80% and specificity of 75% for detection of an anatomic shunt. We conclude the test is satisfactory for the first-line investigation for anatomic shunting.

The five-repetition sit-to-stand test as a functional outcome measure in COPD.

BACKGROUND: Moving from sitting to standing is a common activity of daily living. The five-repetition sit-to-stand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking. AIMS: To determine the reliability, validity and responsiveness of the 5STS in patients with COPD. METHODS: Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods. RESULTS: Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=-0.59, -0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s. CONCLUSIONS: The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings.

Reliability and validity of 4-metre gait speed in COPD.

In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George's Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to "slow" (<0.8 m·s(-1)) or "normal" 4MGS (≥0.8 m·s(-1)). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (ρ = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (ρ = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD.

Response of the COPD Assessment Test to pulmonary rehabilitation in unselected chronic respiratory disease.

BACKGROUND AND OBJECTIVE: The COPD Assessment Test (CAT) is a recently introduced, simple-to-use health status instrument that takes less time to complete than better-established health status instruments. In chronic obstructive pulmonary disease (COPD) patients, the CAT improves with pulmonary rehabilitation (PR), and changes correlate with improvements in longer-established health status instruments such as the Chronic Respiratory Questionnaire (CRQ). Increasing numbers of non-COPD patients are referred for PR, but it is not known whether the CAT is responsive to PR in these populations. METHODS: The CAT score was prospectively measured in 365 consecutive patients (255 COPD, 110 non-COPD) before and after an 8-week PR programme. Pre to post change in CAT was calculated for COPD and non-COPD patients, and correlated with change in the CRQ. RESULTS: For both non-COPD and COPD patients, there was a similar and significant improvement in the mean (95% confidence interval) CAT score following PR (non-COPD: -2.1 (-1.0, -3.2) vs COPD: -3.0 (-2.2, -3.8); P = 0.19). Change in CAT was significantly correlated with all domains of the CRQ in non-COPD patients (all P < 0.01). CONCLUSIONS: As in COPD patients, the CAT is immediately responsive to PR in non-COPD patients. Even in unselected chronic respiratory disease patients undergoing PR, the CAT is a practical alternative to longer-established health status questionnaires.

The COPD Assessment Test (CAT): short- and medium-term response to pulmonary rehabilitation.

BACKGROUND: The COPD Assessment Test (CAT) is a recently introduced instrument to assess health-related quality of life in COPD. We aimed to evaluate the longitudinal change in CAT following Pulmonary Rehabilitation (PR), and test the relationship between CAT and CRQ-Self Report (SR) over time. We hypothesised that the CAT would show similar responsiveness to PR as the CRQ-SR both in the short and medium-term. METHODS: 118 COPD patients completed an eight-week outpatient multidisciplinary PR programme. CAT, CRQ-SR and the incremental shuttle walk (ISW) were measured prior to starting PR (T1), completion of PR (T2) and 6 months after completion of PR (T3). RESULTS: There was a significant improvement in CAT, CRQ-SR and ISW immediately following PR (p < 0.001). Although there was decline between T2 and T3, CAT, CRQ-SR and ISW remained significantly better at T3 compared with T1 (ANOVA p < 0.001). Both between T1-T2 and between T2-T3, change in CAT correlated significantly with change in CRQ (both r = -0.44 and p < 0.001). The slope of the relationship between CAT change and CRQ-SR change at T1-T2 and T2-T3 was not significantly different (ANCOVA: intercept p = 0.79, interaction effect p = 0.95). CONCLUSIONS: In COPD, the CAT score is immediately responsive to PR and remains improved at 6 months. There is no significant difference in the short and medium term changes in the CAT and CRQ-SR following PR. We propose that for most clinical indications for assessing health-related quality of life in COPD, the CAT is a robust and practical alternative to longer-established instruments such as the CRQ-SR.

Success of Prostate and Testicular Cancer Awareness Campaigns Compared to Breast Cancer Awareness Month According to Internet Search Volumes: A Google Trends Analysis.

OBJECTIVE: To compare the efficacy of men's and women's cancer awareness campaigns using internet relative search volume (RSV) as a surrogate for public interest. METHODS: We utilized Google Trends to determine the RSV for "breast cancer," "prostate cancer," and "testicular cancer" from 2010 to 2017. Baseline annual RSV for each cancer was calculated as the median annual RSV, exclusive of the awareness month period. RSV was then determined for each cancer-specific awareness month and compared to baseline. The primary outcome was 2-fold rise in RSV above baseline. RESULTS: Breast Cancer Awareness Month led to a significant increase in cancer-specific RSV in October each year during the study period (mean increase 180.1%). In contrast, none of the men's cancer awareness campaigns led to a significant increase in cancer-specific RSV in any year during the study period. RSV for prostate cancer increased by 2.4% and 4.1% in September and November, respectively. RSV for testicular cancer increased by 9.3% and 6.2% in April and November, respectively. CONCLUSION: Men's cancer awareness campaigns did not increase cancer-specific RSV, whereas Breast Cancer Awareness Month consistently increased RSV. While additional metrics are needed to evaluate the efficacy of public health campaigns, the current data suggest the need for new approaches to generate public interest in male-specific malignancies.

Anaemia and iron dysregulation: untapped therapeutic targets in chronic lung disease?

Hypoxia is common in many chronic lung diseases. Beyond pulmonary considerations, delivery of oxygen (O2) to the tissues and subsequent O2 utilisation is also determined by other factors including red blood cell mass and iron status; consequently, disruption to these mechanisms provides further physiological strains on an already stressed system. O2 availability influences ventilation, regulates pulmonary blood flow and impacts gene expression throughout the body. Deleterious effects of poor tissue oxygenation include decreased exercise tolerance, increased cardiac strain and pulmonary hypertension in addition to pathophysiological involvement of multiple other organs resulting in progressive frailty. Increasing inspired O2 is expensive, disliked by patients and does not normalise tissue oxygenation; thus, other strategies that improve O2 delivery and utilisation may provide novel therapeutic opportunities in patients with lung disease. In this review, we focus on the rationale and possibilities for doing this by increasing haemoglobin availability or improving iron regulation.

The Homeodomain Transcription Factor NKX3.1 Modulates Bladder Outlet Obstruction Induced Fibrosis in Mice.

Fibrosis is an irreversible remodeling process characterized by the deposition of collagen in the extracellular matrix of various organs through a variety of pathologies in children, leading to the stiffening of healthy tissues and organ dysfunction. Despite the prevalence of fibrotic disease in children, large gaps exist in our understanding of the mechanisms that lead to fibrosis, and there are currently no therapies to treat or reverse it. We previously observed that castration significantly reduces fibrosis in the bladders of male mice that have been partially obstructed. Here, we investigated if the expression of androgen response genes were altered in mouse bladders after partial bladder outlet obstruction (PO). Using a QPCR microarray and QRTPCR we found that PO was sufficient to increase expression of the androgen response gene Nkx3.1. Consistent with this was an increase in the expression of NKX3.1 protein. Immunofluorescent antibody localization demonstrated nuclear NKX3.1 in most bladder cells after PO. We tested if genetic deletion of Nkx3.1 alters remodeling of the bladder wall after PO. After PO, Nkx3.1 KO/KO bladders underwent remodeling, demonstrating smaller bladder area, thickness, and bladder: body weight ratios than obstructed, wild type controls. Remarkably, Nkx3.1 KO/KO specifically affected histological parameters of fibrosis, including reduced collagen to muscle ratio. Loss of Nkx3.1 altered collagen and smooth muscle cytoskeletal gene expression following PO which supported our histologic findings. Together these findings indicated that after PO, Nkx3.1 expression is induced in the bladder and that it mediates important pathways that lead to tissue fibrosis. As Nkx3.1 is an androgen response gene, our data suggest a possible mechanism by which fibrosis is mediated in male mice and opens the possibility of a molecular pathway mediated by NKX3.1 that could explain sexual dimorphism in bladder fibrosis.

Voided volumes predict degree of partial bladder outlet obstruction in a murine model.

The partial bladder outlet obstruction animal model (pBOO) is commonly used as a model for obstructive uropathy. Unfortunately, pBOO demonstrates variable degrees of obstruction requiring bladder weight (BW) or urodynamic studies to determine true obstruction. Our objective is to identify extent of obstruction by correlating early post-operative Void Stains on Paper (VSOP) assays with ultimate BW in mice. pBOO was performed on 32 mice 1- and 4-week VSOPs were quantified for mean voided volume (mVV). At 4 weeks, bladders were harvested and weighed. Correlation was evaluated through bivariate kernel density estimation and a Pearson correlation coefficient (SAS). Single variable histogram of the data established groups based on BWs and mVV. mVV's and bladder weights within group pairings were averaged and plotted to render a non-linear regression model. A significant correlation was found between 1-week mVVs and 4-week BWs upon bivariate analysis with a correlation coefficient of -0.758 (p = 0.0294). A non-linear regression of plotted data defined a statistically significant fit equation correlating 1-week mVV to 4-week BW. We demonstrate a novel method for forecasting degree of obstruction in pBOO based on 1-week post-operative VSOP mVV.

Percutaneous microwave ablation of T1a and T1b renal cell carcinoma: short-term efficacy and complications with emphasis on tumor complexity and single session treatment.

PURPOSE: To update the oncologic outcomes and safety for microwave (MW) ablation of T1a (≤4.0 cm) and T1b (4.1-7.0 cm) renal cell carcinoma (RCC) with emphasis on tumor complexity and single session treatment. MATERIALS AND METHODS: Retrospective review of 29 consecutive patients (30 tumors) with localized (NOMO) RCC (23 T1a; 7 T1b) treated with percutaneous MW ablation between 3/2013 and 6/2014. Primary outcomes investigated were technical success, local tumor progression (LTP), and complications. Technical success was assessed with contrast-enhanced computed tomography (CECT) immediately after MW ablation. Presence of LTP was assessed with CECT or contrast-enhanced magnetic resonance at 6-month target intervals for the first two years and annually thereafter. Complications were categorized using the Clavien-Dindo classification system. RESULTS: Median tumor diameter was 2.8 cm [IQR 2.1-3.3] for T1a and 4.7 cm [IQR 4.1-5.7] for T1b tumors. Median RENAL nephrometry score was 7 [IQR 4-8] for T1a tumors and 9 [IQR 6.25-9.75] for T1b tumors. Technical success was achieved for 22 T1a (96%) and 7 T1b (100%) tumors. There were no LTP during a median imaging follow-up of 12.0 months [IQR 6-18] for the 23 patients (24 tumors) with greater than 6 months of follow-up. There were three Clavien-Dindo grade I-II complication (10%) and no Clavien-Dindo grade III-V complications (0%). All but two patients (93%) are alive without metastatic disease; two patients died after 12-month follow-up of causes unrelated to the MW ablation. CONCLUSION: Percutaneous MW ablation appears to be a safe and effective treatment option for low, moderate, and highly complex T1a and T1b RCC in early follow-up.

Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo.

BACKGROUND: Loss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD. METHODS: We determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation. RESULTS: Growth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001). CONCLUSIONS: Together, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.

Persistent Müllerian duct structures presenting as hematuria in an adult: Case report of robotic surgical removal and review of the literature.

Persistent Müllerian duct syndrome is a rare genetic disorder characterized by a male with retained Müllerian structures. Remnant excision must be considered due to the possibility of malignant degeneration. We review a case of delayed diagnosis in a 25-year-old man presenting with hematuria. Preoperative counseling must emphasize the risk of malignancy versus the risks to fertility. The da Vinci robot offers a novel, safe approach for excision of the relevant Müllerian structures. Dissection should be limited to structures superior to the cavernosal neurovascular bundles to preserve the continence and erectile function. A semen analysis is recommended preoperatively to determine effects on fertility.