Comparison of MRI- and TRUS-Informed Prostate Biopsy for Prostate Cancer Diagnosis in Biopsy-Naive Men: A Systematic Review and Meta-Analysis.

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) with informed targeted biopsies (TGBX) has changed the paradigm of prostate cancer (PCa) diagnosis. Randomized studies have demonstrated a diagnostic benefit of Clinically significant (CS) for TGBX compared to standard systematic biopsies (SBX). We aimed to evaluate whether mpMRI-informed TGBX has superior diagnosis rates of any-, CS-, high-grade (HG)-, and clinically insignificant (CI)-PCa compared to SBX in biopsy-naive men. METHODS: Data was searched in Medline, Embase, Web of Science, and Evidence-based medicine reviews-Cochrane Database of systematic reviews from database inception until 2019. Studies were selected by two authors independently, with disagreements resolved by consensus with a third author. Overall 1951 unique references were identified, and 100 manuscripts underwent full-text review. Data were pooled using random-effects models. The meta-analysis is reported according to the PRISMA statement. The study protocol is registered with PROSPERO (CRD42019128468). RESULTS: Overall 29 studies (13,845 patients) were analyzed. Compared to SBX, use of mpMRI-informed TGBX was associated with a 15% higher rate of any PCa diagnosis (95% CI 10-20%, p\u3c0.00001). This relationship was not affected by the study methodology (p=0.11). Diagnosis of CS and HG PCa were more common in the mpMRI-informed TGBX group (risk difference of 11%, 95% CI 0-20%, p=0.05, and 2%, 95% CI 1-4%; p=0.005, respectively) while there was no difference in diagnosis of CI PCa (risk difference of 0, 95% CI -3-3%, p=0.96). Notably, the exclusion of SBX in the mpMRI-informed TGBX arm significantly modified the association between a mpMRI strategy and lower rates of CI PCa diagnosis (p=0.01) without affecting the diagnosis rates of CS- or HG-PCa. CONCLUSIONS: In comparison to SBX, a mpMRI-informed TGBX strategy results in a significantly higher diagnosis rate of any-, CS-, and HG-PCa. Excluding SBX from mpMRI-informed TGBX was associated with decreased rates of CI-PCa diagnosis without affecting diagnosis of CS- or HG-PCa

cGMP-Dependent Protein Kinase Type I Is Implicated in the Regulation of the Timing and Quality of Sleep and Wakefulness

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1–4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep

Reporting bias in medical research - a narrative review

Reporting bias represents a major problem in the assessment of health care interventions. Several prominent cases have been described in the literature, for example, in the reporting of trials of antidepressants, Class I anti-arrhythmic drugs, and selective COX-2 inhibitors. The aim of this narrative review is to gain an overview of reporting bias in the medical literature, focussing on publication bias and selective outcome reporting. We explore whether these types of bias have been shown in areas beyond the well-known cases noted above, in order to gain an impression of how widespread the problem is. For this purpose, we screened relevant articles on reporting bias that had previously been obtained by the German Institute for Quality and Efficiency in Health Care in the context of its health technology assessment reports and other research work, together with the reference lists of these articles

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Developing the Bladder Utility Symptom Scale: A Multiattribute Health State Classification System for Bladder Cancer

Disease-specific (e.g. urinary) and generic problems (e.g. fatigue) impact health-related quality of life (HRQOL) of patients with bladder cancer (BC). A questionnaire addressing both sets of problems and generating utilities, a measure of overall HRQOL, is needed for this population. In consultation with 47 BC patients and 12 BC experts we created a novel HRQOL questionnaire for BC in a stepwise, iterative fashion with conceptual framework development, item generation, item reduction, question design and pilot testing. Patients and experts identified urinary problems, bowel problems, sexual problems, body image, pain, and decreased vigor as domains, which impact daily activities and impair HRQOL. Support from patients’ family and friends and their medical team were also paramount to HRQOL. The Bladder Utility Symptom Scale is a comprehensible instrument that was created to facilitate patient-oriented care and guide clinical policy by grounding guidelines, health resource allocation, and policy decisions in the expressed preferences of BC patients.MAS

Treatment of Advanced Renal Cell Carcinoma : Immunotherapies Have Demonstrated Overall Survival Benefits While Targeted Therapies Have Not

Context: Current guidelines suggest several targeted therapies (TTs) and immunotherapies (ITs) in the treatment of advanced or metastatic renal cell carcinoma (mRCC). Ideal sequencing of these treatments is unclear. Objective: The primary objective was to evaluate the overall survival (OS) data of the treatments approved for mRCC. Secondary objectives included evaluating other signs of efficacy and adverse events. Evidence acquisition: We reviewed the current Food and Drug Administration-approved treatments for mRCC. Trials associated with approval were reviewed. We also included pre- and postapproval publications when appropriate. Evidence synthesis: There is minimal evidence supporting OS benefit for the nine approved TTs. They result in adverse events and are a considerable economic burden. For these reasons, their future role in mRCC treatment should be reevaluated, given the emergence of IT that have demonstrated OS benefits. Accumulating long-term survival data with high-dose interleukin-2 treatment suggests that this older treatment could still be considered for eligible patients. Checkpoint inhibitors have shown promising OS and durable responses; as such, the high cost of treatment might be justified. However, the available evidence does not suggest that adding TT to IT would increase efficacy over IT alone, but would add toxicity. Conclusions: Trial data supporting OS benefit are much stronger for ITs than for TTs. Combining checkpoint inhibitors with TTs has not been shown to produce better OS than checkpoint inhibitors alone, while more adverse events are present. Granting drug approvals based on efficacy without demonstrated OS benefit should be revisited. Patient summary: Approved treatments for metastatic kidney cancer include targeted and immune-based therapies. The former commonly produces temporary tumour shrinkage, but survival benefits are unclear. All approved immunotherapies have increased survival, and a proportion of patients appear cured. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.Peer reviewe

Upper urinary tract and urethral recurrences following radical cystectomy: review of risk factors and outcomes between centres with different follow-up protocols

To examine which patient-related and tumour-related characteristics predict upper urinary tract recurrence (UUTR) and urethral recurrence (UR) of bladder cancer post-radical cystectomy (RC). Secondary objective is to evaluate whether or not recurrence patterns are similar between two centres with different post-RC follow-up (F/U) protocols. A retrospective cohort study of 574 consecutive patients undergoing radical cystectomy for urothelial carcinoma of the bladder at two tertiary centres was performed. Clinicopathological factors associated with bladder cancer recurrence and patient-related outcomes, including time to recurrence and death, were collected. Risk factors for recurrences were examined using univariate and multivariable regression analyses. Likelihood of recurrence, time to recurrence, and survival were compared. There was a 3.7 % risk of UUTR (21/574) and a 3.6 % risk of UR (18/503) for the combined cohort at a median F/U of 45 months. When controlling for the effects of all variables modelled, female gender was a significant risk factor for UUT recurrence (OR 3.2, 95 % CI 1.0-9.5, p = 0.03) and prostatic urethral involvement was a significant risk factor for urethral recurrence (OR 7.8, 95 % CI 2.2-27.6, p = 0.001). UUTR were similar (p = 0.82) between Turku (8/205) and Toronto (12/369). Urethral recurrences trended (p = 0.06) towards being more common in Turku (9/151, 6.0 %) versus Toronto (9/352, 2.6 %), but no difference in overall survival was demonstrated between sites. The frequency of UUT and urethral recurrences post-cystectomy is relatively low and remained stable for the past 15 years. The ideal F/U protocol to maximize patient-survival remains unknown