Gas7-Deficient Mouse Reveals Roles in Motor Function and Muscle Fiber Composition during Aging

Background: Growth arrest-specific gene 7 (Gas7) has previously been shown to be involved in neurite outgrowth in vitro; however, its actual role has yet to be determined. To investigate the physiological function of Gas7 in vivo, here we generated a Gas7-deficient mouse strain with a labile Gas7 mutant protein whose functions are similar to wild-type Gas7. Methodology/Principal Findings: Our data show that aged Gas7-deficient mice have motor activity defects due to decreases in the number of spinal motor neurons and in muscle strength, of which the latter may be caused by changes in muscle fiber composition as shown in the soleus. In cross sections of the soleus of Gas7-deficient mice, gross morphological features and levels of myosin heavy chain I (MHC I) and MHC II markers revealed significantly fewer fast fibers. In addition, we found that nerve terminal sprouting, which may be associated with slow and fast muscle fiber composition, was considerably reduced at neuromuscular junctions (NMJ) during aging. Conclusions/Significance: These findings indicate that Gas7 is involved in motor neuron function associated with muscle strength maintenance

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Clinical Needs Discovery in Pediatric Urology: Utilizing the Biodesign Process

IntroductionBiodesign innovation processes provide a needs-driven approach to medical innovation, empowering both medical trainees and health care providers to take action in addressing the shortcomings of health care encountered in daily clinical practice. Our objective was to uncover the most pressing unmet clinical needs within a specific clinical setting, pediatric urology at UCLA.MethodsThe biodesign process involves a sequential process of identifying, validating, and prioritizing unmet needs, followed by solution landscaping and prototyping for the most promising needs. Opportunities for medical innovation were first identified through six weeks of clinical immersion, which involved both clinical observation and interview-based insight extraction. Interviews were conducted with 35 stakeholders, including patients, patient families, and health care staff by a medical student participant in Sling Health LA, a program which provides innovation training and incubation for ideas. Follow-up interviews with key stakeholders were performed to validate needs. Priority scores were then assigned to each validated need using a series of pre-determined and weighted criteria. Finally, genealogy maps were constructed and used to guide subsequent solution landscaping for the top three needs.Results33 unmet clinical needs were identified throughout the clinical immersion phase, 27 of which were validated. Following coarse needs prioritization, five needs emerged as top contenders. After fine needs prioritization, three top needs were selected. The first top need arising from this ethnographic study was that “parents and children need a faster (<3 months to resolution) treatment option for resolving nocturnal enuresis that also prevents incontinence during the treatment phase”. Other discovered top needs included “parents and physicians need an accurate method to monitor retractile testes at-home and in the outpatient setting to reduce unnecessary surgical referrals and procedures”, and “a hospital system need to reduce complications and readmissions associated with post-operative catheter obstruction after urologic procedures”. A preliminary solution concept was generated for the top clinical need, nocturnal enuresis treatment.ConclusionBiodesign processes offer a standardized method for identifying pressing unmet clinical needs and informing solution development. The top three needs discovered within pediatric urology through this ethnographic investigation represent promising innovation targets for further solution prototyping and design

A Virtual Cohort Study of Individuals at Genetic Risk for Parkinson's Disease: Study Protocol and Design.

BackgroundThe rise of direct-to-consumer genetic testing has enabled many to learn of their possible increased risk for rare diseases, some of which may be suitable for gene-targeted therapies. However, recruiting a large and representative population for rare diseases or genetically defined sub-populations of common diseases is slow, difficult, and expensive.ObjectiveTo assess the feasibility of recruiting and retaining a cohort of individuals who carry a genetic mutation linked to Parkinson's disease (G2019S variant of LRRK2); to characterize this cohort relative to the characteristics of traditional, in-person studies; and to evaluate this model's ability to create an engaged study cohort interested in future clinical trials of gene-directed therapies.MethodsThis single-site,3-year national longitudinal observational study will recruit between 250 to 350 LRRK2 carriers without Parkinson's disease and approximately 50 with the condition. Participants must have undergone genetic testing by the personal genetics company, 23andMe, Inc., have knowledge of their carrier status, and consent to be contacted for research studies. All participants undergo standardized assessments, including video-based cognitive and motor examination, and complete patient-reported outcomes on an annual basis.Results263 individuals living in 33 states have enrolled. The cohort has a mean (SD) age of 56.0 (15.9) years, 59% are female, and 76% are of Ashkenazi Jewish descent. 233 have completed the baseline visit: 47 with self-reported Parkinson's disease and 186 without.ConclusionsThis study establishes a promising model for developing a geographically dispersed and well-characterized cohort ready for participation in future clinical trials of gene-directed therapies

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Patient outcomes and experiences of an acupuncture and self-care service for persistent low back pain in the NHS: a mixed methods approach

Background Supported self-management, acupuncture and information can help reduce the symptoms of low back pain. These approaches are currently recommended by NICE guidance as treatment options for patients with persistent low back pain. However, there has been no previous evaluation of a service providing them together for this common problem. The purpose of this service evaluation was to report patient outcomes and experiences of the Beating Back Pain Service (BBPS), a pilot service based in a primary and community care setting, delivering acupuncture, self-management and information to patients with chronic low back pain. Methods Patients completed a questionnaire at three time points: pre-BBPS, immediately post-BBPS and three months post-BBPS. Outcome measures included the Bournemouth Questionnaire (measuring musculoskeletal, MSK, problems), EuroQoL-5D (measuring quality of life), Pain and Self-efficacy Questionnaire, and additional questions on medication use, physical activity, understanding of pain and positive well-being. Additionally, the STarT Back (measuring risk of developing chronic pain) was collected at BBPS information sessions. Non-parametric tests were used to evaluate pre- and post- variables. Questionnaires also collected qualitative data (open-text responses) regarding patient views and experiences of the BBPS, which were analysed using thematic analysis. Results 80 (out of 108) patients who attended the initial BBPS information session agreed to participate in the service evaluation (mean age 47 years, 65% female). 65 patients attended subsequent BBPS acupuncture and/or self-management sessions and were asked to complete post-treatment questionnaires; complete datasets were available for 61 patients. There were statistically significant improvements over time for pain (p <0.0001), quality of life (p = 0.006), understanding of pain (p <0.001), physical activity (p = 0.047) and relaxation (p = 0.012). Post-hoc analysis revealed that scores improved between baseline and post-treatment, these improvements were maintained at 3-month follow-up (except relaxation). Patients receiving a combination of acupuncture and self-management sessions produced the most positive results. Patient satisfaction with the BBPS was high. Conclusions The BBPS provided a MSK pain management service that many patients found effective and valuable. Combining self-management with acupuncture was found to be particularly effective, although further consideration is required regarding how best to engage patients in self-management

Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium–score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.</p