Neuromodulation in neurogenic bladder.

While neuromodulation is a well-established treatment option for patients with non-neurogenic overactive bladder and urinary retention, its applicability to the neurogenic bladder population has only recently been examined more in depth. In this article we will discuss the outcomes, contraindications, and special considerations of sacral and percutaneous tibial nerve stimulation (PTNS) in patients with neurogenic lower urinary tract dysfunction

Rapid Effects of Hearing Song on Catecholaminergic Activity in the Songbird Auditory Pathway

Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development

Neuromodulation in neurogenic bladder.

While neuromodulation is a well-established treatment option for patients with non-neurogenic overactive bladder and urinary retention, its applicability to the neurogenic bladder population has only recently been examined more in depth. In this article we will discuss the outcomes, contraindications, and special considerations of sacral and percutaneous tibial nerve stimulation (PTNS) in patients with neurogenic lower urinary tract dysfunction

De novo erectile dysfunction after anterior urethroplasty: a systematic review and meta-analysis.

ObjectiveTo evaluate the likelihood of developing de novo erectile dysfunction (ED) after anterior urethroplasty and to determine if this likelihood is influenced by age, stricture length, number of previous procedures or timing of evaluation.Materials and methodsPubMed, Embase, Cochrane, and Google Scholar databases were searched for the terms 'urethroplasty', 'urethral obstruction', 'urethral stricture', 'sexual function', 'erection', 'erectile function', 'erectile dysfunction', 'impotence' and 'sexual dysfunction'. Two reviewers evaluated articles for inclusion based on predetermined criteria.ResultsIn a meta-analysis of 36 studies with a total of 2323 patients, de novo ED was rare, with an incidence of 1%. In studies that assessed postoperative erectile function at more than one time point, ED was transient and resolved at between 6 and 12 months in 86% of cases.ConclusionsMen should be counselled regarding the possibility of transient or permanent de novo ED after anterior urethroplasty procedures. Increasing mean age was associated with an increased likelihood of de novo ED, but this was not statistically significant

The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis

BACKGROUND: Pelvic fracture urethral injury (PFUI) is associated with a high risk of erectile dysfunction (ED). The effect of the type of posterior urethral disruption repair on erectile function has not been clearly established. We systematically reviewed and conducted a meta-analysis of the proportion of patients with ED at (i) baseline after pelvic fracture with PFUI, (ii) after immediate primary realignment, and (iii) after delayed urethroplasty. METHODS: Using search terms for primary realignment or urethroplasty and urethral disruption, we systematically reviewed PubMed and EMBASE. A meta-analysis of the proportion of patients with ED was conducted assuming a random-effects model. RESULTS: Of 734 articles found, 24 met the inclusion criteria. The estimate of the proportion (95% confidence interval) of patients with ED after (i) PFUI was 34 (25–45)%, after (ii) immediate primary realignment was 16 (8–26)%, and after (iii) delayed urethroplasty was an additional 3 (2–5)% more than the 34% after pelvic fracture in this cohort. CONCLUSIONS: After pelvic fracture, 34% of patients had ED. After primary endoscopic alignment, patients had a lower reported rate of ED (16%). Delayed urethroplasty conferred an additional 3% risk above the 34% associated with PFUI alone, with 37% of patients having de novo ED. The difference in de novo ED after primary endoscopic alignment vs. delayed urethroplasty is probably due to reporting differences in ED and/or patients with less severe injury undergoing primary realignment

The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis.

BACKGROUND:Pelvic fracture urethral injury (PFUI) is associated with a high risk of erectile dysfunction (ED). The effect of the type of posterior urethral disruption repair on erectile function has not been clearly established. We systematically reviewed and conducted a meta-analysis of the proportion of patients with ED at (i) baseline after pelvic fracture with PFUI, (ii) after immediate primary realignment, and (iii) after delayed urethroplasty. METHODS:Using search terms for primary realignment or urethroplasty and urethral disruption, we systematically reviewed PubMed and EMBASE. A meta-analysis of the proportion of patients with ED was conducted assuming a random-effects model. RESULTS:Of 734 articles found, 24 met the inclusion criteria. The estimate of the proportion (95% confidence interval) of patients with ED after (i) PFUI was 34 (25-45)%, after (ii) immediate primary realignment was 16 (8-26)%, and after (iii) delayed urethroplasty was an additional 3 (2-5)% more than the 34% after pelvic fracture in this cohort. CONCLUSIONS:After pelvic fracture, 34% of patients had ED. After primary endoscopic alignment, patients had a lower reported rate of ED (16%). Delayed urethroplasty conferred an additional 3% risk above the 34% associated with PFUI alone, with 37% of patients having de novo ED. The difference in de novo ED after primary endoscopic alignment vs. delayed urethroplasty is probably due to reporting differences in ED and/or patients with less severe injury undergoing primary realignment