Citations

Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results We identified 13 loci that reached genome-wide significance (p<5×10 −8 ) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Background and Aim: Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life. Methods: A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered. Results: We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17–50%), IBS-D (37–62%) and IBS-C (4–25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies). Conclusions: Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.

Abstract Background: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. Methods: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. Results: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10–6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. Conclusions: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. Impact: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

Background: Placement of an intrathecal drug delivery system (IDDS) may provide substantial benefit to certain patients. However, placement of these devices is not without complications, and minimal data exist describing the rates of these complications. Specifically, there is a paucity of data describing the incidence of post dural puncture headache (PDPH) following IDDS placement. Objectives: The aim of this study was to identify the incidence and treatment course of PDPH following placement of an IDDS in a retrospective review. Study Design: Retrospective assessment of medical records. Setting: Department of Pain Medicine and Anesthesiology, Mayo Clinic, Rochester, MN. Methods: Following IRB approval, 319 IDDS surgical reports in 285 patients were identified retrospectively over a 20 year study time period. We report demographic information, number of dural punctures, techniques for sealing dural leak, details, and treatment course of PDPH in this population. Results: Symptoms of PDPH were recognized in 73 individual cases (23% of total procedural volume). Younger patient age was the only statistically significant characteristic in predicting development of a PDPH. There were no statistically significant differences found in regards to other risk factors for PDPH development or treatment strategy employed. Seventy-nine percent of PDPH patients were successfully managed with conservative non-interventional therapies (bedrest, IV fluids, analgesics, antiemetics), while 21% required progression to epidural blood or fibrin glue patch procedures for full resolution of symptoms. Limitations: Limitations include the retrospective design of the study as well as the potential for undocumented or improperly documented surgical techniques and/or events. Conclusion: Though the development of PDPH after IDDS implantation was found to be fairly common (23% incidence), the majority of these patients had self-limited symptoms that resolved with conservative medical management. Epidural blood patch or application of epidural fibrin glue was therapeutically successful for the remainder of PDPH patients who were refractory to conservative measures. Key words: Pain, intrathecal drug delivery system, pain pump, morphine, baclofen, postdural puncture headache, spinal headache

Abtract Background and study aims Endoscopic and surgical techniques have been utilized for palliation of gastric outlet obstruction (GOO). Enteral stenting (ES) is an established technique with high clinical success and low morbidity rate. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a novel approach that aims to provide sustained palliation of GOO. We conducted a comprehensive review and meta-analysis to evaluate the effectiveness in terms of clinical and technical success, as well as the safety profile of EUS-GE and ES. Methods We searched multiple databases from inception through July 2020 to identify studies that reported on safety and effectiveness of EUS-GE in comparison to ES. Pooled rates of technical success, clinical success, and adverse events (AEs) were calculated. Study heterogeneity was assessed using I2% and 95 % confidence interval. Results Five studies including 659 patients were included in our final analysis. Pooled rate of technical and clinical success for EUS-GE was 95.2 % (CI 87.2-.98.3, I2 = 42) and 93.3 % (CI 84.4–97.3, I2 = 59) while for ES it was 96.9 % (CI 90.9–99, I2 = 64) and 85.6 % (CI 73–92.9, I2 = 85), respectively. Pooled rate of re-intervention was significantly lower with EUS-GE i. e. 4 % (CI 1.8–8.7, I2 = 35) compared to ES, where it was 23.6 % (CI 17.5–31, I2 = 35), p = 0.001. Pooled rates of overall and major AEs were comparable between the two techniques. Conclusion EUS-GE is comparable in terms of technical and clinical effectiveness and has a similar safety profile when compared to ES for palliation of GOO.

AbstractFor children with voice disorders, access to care has long been a challenge. Reasons for this include the challenge of qualifying children with isolated voice disorders for services within the public-school system as well as a family's geographic proximity to experienced clinicians who are in the healthcare system. Over the past decade, there have been both formal and informal investigations into the use of telepractice to deliver services to communicatively disordered children and adults, including those with voice disorders. Although barriers and obstacles existed, use of telepractice to deliver such services demonstrated both feasibility and, in some studies, effective outcomes. However, prior to spring of 2020, use of telepractice to deliver speech pathology services was not mainstream. This changed when the nation was forced to shut down many of its in-person healthcare and educational delivery due to the COVID-19 pandemic. This article summarizes select relevant literature pertaining to the use of telepractice in speech language pathology over the past decade and provides a case-based discussion of how it was and is currently being used to deliver pediatric voice care.

AbstractBackgroundPulmonary vein isolation (PVI) with autonomic modulation may be more successful than PVI alone for atrial fibrillation (AF) ablation and may be signaled by changes in sinus rhythm heart rate (HR) post ablation. We sought to determine if a change in sinus rhythm HR predicted AF recurrence post PVI.MethodsPatients who underwent AF ablation from 2000 to 2011 were included if sinus rhythm was noted on ECG within 90 days pre and 7 days post ablation. Basic ECG interval and HR changes were analyzed and outcomes determined.ResultsA total of 1152 patients were identified (74.3% male, mean age 57 ± 11 years). Mean AF duration was 5.2 ± 5.3 years. Paroxysmal AF was noted in 712 (61.8%) of the patients. Mean EF was 61% ± 6%. Sinus rhythm HR was 61 ± 11 pre‐ablation and 76 ± 13 bpm post‐ablation (27% ± 24% increase, p < .001). The ability of relative HR change post‐ablation to predict AF recurrence was borderline (hazard ratio 0.65 [0.41–1.01], p = .067). With patients separated into quartiles based on the relative HR change, the upper quartile with the largest relative increase in HR had a significantly lower rate of AF recurrence compared to the lowest quartile following multi variable modeling (p = .038). There were significant changes in PR (171 ± 28 to 167 ± 30 ms) and QTc (424 ± 25 to 434 ± 29 ms) intervals (both p < .001) but these were not predictive of outcome.ConclusionRelative changes in HR post AF ablation correlates with AF recurrence. Further prospective studies are needed to confirm this relationship.