Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross‐referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.     

GJB2: the spectrum of deafness-causing allele variants and their phenotype

Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.     

Bolus versus continuous feeding regimens post gastrostomy tube placement in children

Background/purposeOwing to the frequency of gastrostomy tube placement in children and the numerous regimens used to start feeds after placement we attempted to see if it matters if the initial feeds after a gastrostomy tube placement are provided in a bolus or continuous manner.MethodsUsing a prospective randomized trial, children were randomized to initial bolus or continuous chimney feeding after gastrostomy tube placement. Feeding tolerance and complications related to the gastrostomy tube were collected for 4 weeks after placement.ResultsDemographics were similar in the two groups. Times to goal feeds were similar in both groups, but in the first two weeks more feeding modifications were required in the bolus group. Other than the rate of leakage during the second week after placement which occurred more in the bolus group, all other clinical outcomes were similar in the two groups.ConclusionsOther than minor, clinically insignificant differences noted above, the method of initial feeding after a gastrostomy tube placement does not affect feeding tolerance or gastrostomy tube complication in the first month after placement.Level of evidenceTherapeutic, level II.     

Cultural Complications Curriculum: Applicability to Surgical Oncology Programs and Practices

Annals of Surgical Oncology - Recognizing the need to raise awareness of core diversity, equity, and inclusion (DEI) issues in the healthcare system, our previously developed Cultural Complications...     

Implications of the 2018 Canadian Cannabis Act: Should regulation differ for medicinal and non-medicinal cannabis use?⋆

The regulatory framework for access to medical cannabis has been established in Canada since 2001, with the number of patients seeking access growing substantially over the years. With the novel enactment of the Cannabis Act in October 2018, Canada now maintains two distinct mechanisms for accessing cannabis - one for medical cannabis and the other for non-medical cannabis. With two regulatory access mechanisms in place, questions have arisen in the country as to the necessity of maintaining regulatory separation and the integrity of the medical access framework. A single framework would remove the gate-keeping function that the medical profession currently holds, streamlining processes and simplifying the current regulatory landscape. This approach has been advocated for by the Canadian Medical Association, despite objections from multiple stakeholders. Critical questions arise should the medical access framework be dissolved into a single, non medical-based regulatory framework. Insurance coverage, control mechanisms, market incentives, and patient obligations represent some examples of these issues. This paper will expand upon these considerations and highlight why maintaining two separate access mechanismss best serves the Canadian public. As medicinal cannabis continues to be liberated in international jurisdictions, this paper can help to illuminate the current status of medical cannabis in Canada, and provide insights to those from other countries on our current approach and domestic challenges.     

Serial evaluation of segmental esophageal reconstruction using a polyurethane scaffold in a pig model

BackgroundMany esophageal pathologies are clinically treated by resection and reconstruction of the esophagus. Surgical esophagectomy remains a morbid procedure and despite minimally invasive advances, has changed little in decades. Novel approaches to esophageal segmental resection and reconstruction are an unmet need.MethodsCircumferential thoracic esophageal transection was performed in both male and female pigs and the defects reconstructed using 5 or 10 cm polyurethane (PU) tubular grafts and stented. A subset were treated with stent only. Animals were survived to 14, 30, 60, and 399 days. Tissues were evaluated histologically, and via non-invasive serial endoscopy and contrast swallowing studies in long-term animals.ResultsLuminal patency was achieved in all animals with no clinical evidence of leak. In short-term animals, there was healing noted in all cases with a variably sized region of ulceration remaining at the most central part of the repaired tube (between the proximal and distal anastomosis). In four long-term animals following stent removal, two resumed normal diet and thrived, while two animals were euthanized prior to the proposed endpoint because of stricture formation and inability to tolerate a normal diet. Re-epithelialization was observed in all groups, and more complete over time.ConclusionsThe PU scaffold provides a matrix across which formation of new tissue can occur. The mechanisms through which this happens remain unclear, but likely a combination of fibrosis and tissue contraction, in conjunction with new tissue formation.