Citations

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Background: Mucinous pancreatic cysts are well reported to transform into pancreatic adenocarcinoma, whereas nonmucinous cysts are mostly benign with low risk for malignant transformation. Nonsurgical methods of differentiating mucinous and nonmucinous pancreatic cysts are challenging and entail a multi investigational approach. Low intracystic glucose levels have been evaluated in multiple studies for its accuracy in differentiating mucinous from nonmucinous cysts of the pancreas. Methods: Multiple databases were searched and studies that reported on the utility of intracystic glucose levels in diagnosing mucinous pancreatic cysts were analyzed. Meta-analysis was conducted using the random-effects model, heterogeneity was assessed by I 2%, and pooled diagnostic test accuracy values were calculated. Results: Seven studies were included in the analysis from an initial total of 375 citations. The pooled sensitivity of low glucose in differentiating mucinous pancreatic cyst was 90.5% [95% confidence interval (CI): 88.1-92.5; I 2=0%] and the pooled specificity was 88% (95% CI: 80.8-92.7; I 2=79%). The sensitivity at a glucose cut-off of 50 was 90.1% (95% CI: 87.2-92.5; I 2=0%) and the specificity was 85.3% (95% CI: 76.8-91.1; I 2=76%). The sensitivity of glucose levels in pancreatic cyst fluid taken by endoscopic ultrasound guided fine-needle aspiration was 90.8% (95% CI: 87.9-93.1; I 2=0%) and the specificity was 90.5% (95% CI: 81.7-95.3; I 2=83%). The sensitivity of point-of-care glucometers was 89.5% (95% CI: 87.9-93.1; I 2=0%) and specificity was 83.9% (95% CI: 68.5-92.6; I 2=43%). Conclusions: Low glucose level at a cut-off of 50 mg/dL on fluid samples collected by endoscopic ultrasound guided fine-needle aspiration and analyzed by point-of-care glucometer achieves excellent diagnostic accuracy in differentiating mucinous pancreatic cysts.

Background and Aim: Extrahepatic unresectable cholangiocarcinoma carries a dismal prognosis. In addition to biliary drainage by stent placement; photodynamic therapy (PDT) and radiofrequency ablation (RFA) have been tried to prolong survival. In this meta-analysis, we appraise the current known data on the use of PDT, RFA in the palliative treatment of extrahepatic unresectable cholangiocarcinoma. Methods: We searched multiple databases from inception through July 2020 to identify studies that reported on PDT and RFA. Pooled rates of survival, stent patency, 30-, 90-day mortality, and adverse events were calculated. Study heterogeneity was assessed using I 2% and 95% prediction interval. Results: A total of 55 studies (2146 patients) were included. A total of 1149 patients underwent treatment with PDT (33 studies), 545 with RFA (22 studies), and 452 patients with stent-only strategy. The pooled survival rate with PDT, RFA, and stent-only groups was 11.9 [95% confidence interval (CI): 10.7-13.1] months, 8.1 (95% CI: 6.4-9.9) months, and 6.7 (95% CI: 4.9-8.4) months, respectively. The pooled time of stent patency with PDT, RFA, and stent-only groups was 6.1 (95% CI: 4.2-8) months, 5.5 (95% CI: 4.2-6.7) months, and 4.7 (95% CI: 2.6-6.7) months, respectively. The pooled rate of 30-day mortality with PDT was 3.3% (95% CI: 1.6%-6.7%), with RFA was 7% (95% CI: 4.1%-11.7%) and with stent-only was 4.9% (95% CI: 1.7%-13.1%). The pooled rate of 90-day mortality with PDT was 10.4% (95% CI: 5.4%-19.2%) and with RFA was 16.3% (95% CI: 8.7%-28.6%). Conclusion: PDT seemed to demonstrate better overall survival and 30-day mortality rates than RFA and/or stent-only palliation.

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