Abstract Introduction Intermittent hypoxia is a key mechanism linking Obstructive Sleep Apnoea (OSA) to cardiovascular disease (CVD). Oximetry analysis could enhance understanding of which OSA phenotypes are associated with CVD risk. We investigated if traditional clinical and novel oximetry measures including hypoxic burden (HB) calculated from the polysomnogram SpO2 signal can predict CVD outcomes in all-comers and OSA subsample cohorts from the Sleep Heart Health Study (SHHS). Methods CVD mortality outcome and complete covariate information was used. We implemented 31 oximetry measures and assessed the performance of the parameters in predicting CVD outcomes (CVD death or incident CVD) in the all-comers and sleep apnoea subsamples. The performance of each measure was assessed using an adjusted Cox proportional hazard ratio (HR) analysis. Results In the general subsample, HB successfully predicted CVD death (HR>1.8, p<0.05) but did not predict incident CVD. In the sleep apnoea subsample (AHI>5) with no CVD at baseline, none of the SpO2 measures we considered predicted incident CVD. Discussion The ability of HB to predict CVD outcomes depends on the cohort and the CVD outcome. Our analysis of the selected SpO2 measures in an OSA subsample did not find strong links between any oximetry measures and incident CVD, and therefore no strong candidates for CVD risk phenotyping in the sleep clinic. Further work is needed to understand the complex relationship between OSA-related intermittent hypoxia patterns and development of CVD to further understanding of OSA phenotypes at risk of CVD consequences.
Abstract INTRODUCTION Animal and cellular models suggest that obstructive sleep apnoea (OSA) plays a role in the development of cancer. Epidemiological studies have found inconsistent associations and typically lack control for lifestyle risk factors contributing to both OSA and cancer. We examined associations between OSA and common cancers in a case-control study. METHODS We analysed data from the New South Wales CLEAR Study which recruited adults with newly diagnosed cancer (n=8551 cases) and cancer-free controls (n=2230). Self-reported OSA was compared in women and men with a verified cancer diagnosis and controls of the same gender. Covariates included age, body mass index, smoking, passive smoking, alcohol intake, physical activity, skin colour, and time spent outdoors. RESULTS OSA was more common in cancer cases than controls: 2.9% vs. 1.9% in women and 7.9% vs. 5.9% in men. For women, OSA was not significantly associated with melanoma (AOR 1.58, 95% CI 0.76-3.29), lung (1.54; 0.59 - 3.99), breast (1.35; 0.79-2.31), or bowel cancer (1.26, 0.61 - 2.59) after adjustment for potential confounders. For men, OSA was not significantly associated with bowel (1.37; 0.92-2.03), prostate (1.31; 0.94 -1.82), lung (0.96; 0.45-2.01), or melanoma (0.92; 0.58-1.48) after control for covariates. DISCUSSION Further analysis will consider rarer cancers and the role of shiftwork, sleep duration, and napping. Preliminary results support a link between OSA and common cancers only through shared risk factors. Information on OSA treatment is missing from this study. OSA treatment together with self-reported OSA may lead to under-estimation of any OSA-cancer association.
Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual’s genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.
The risk of severe adverse events related to thiopurine therapy can be reduced by personalizing dosing based on TPMT and NUDT15 genetic polymorphisms. However, the optimal genetic testing platform has not yet been established. In this study, we report on the TPMT and NUDT15 genotypes and phenotypes generated from 320 patients from a multicenter pediatric healthcare system using both Sanger sequencing and polymerase chain reaction genotyping (hereafter: genotyping) methods to determine the appropriateness of genotyping in our patient population. Sanger sequencing identified variant TPMT alleles including *3A (8, 3.2% of alleles), *3C (4, 1.6%), and *2 (1, 0.4%), and NUDT15 alleles including *2 (5, 3.6%) and *3 (1, 0.7%). For genotyped patients, variants identified in TPMT included *3A (12, 3.1%), *3C (4, 1%), *2 (2, 0.5%), and *8 (1, 0.25%), whereas NUDT15 included *4 (2, 1.9%) and *2 or *3 (1, 1%). Between Sanger sequencing and genotyping, no significant difference in allele, genotype, or phenotype frequency was identified for either TPMT or NUDT15. All patients who were tested using Sanger sequencing would have been accurately phenotyped for either TPMT (124/124), NUDT15 (69/69), or both genes (68/68) if they were assayed using the genotyping method. Considering 193 total TPMT and NUDT15 Sanger Sequencing tests reviewed, all tests would have resulted in an appropriate clinical recommendation if the test had instead been conducted using the comparison genotyping platforms. These results suggest that, in this study population, genotyping would be sufficient to provide accurate phenotype calls and clinical recommendations.
Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges.In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorporate the ability for users to create targeted implementation guides. This expansion was led by a multidisciplinary team that developed an evidence-based, structured framework for the guides, oversaw the technical process/build, and pilot tested the first guide, CYP2C19-Clopidogrel Testing Implementation.Sixty-five resources were collected from 12 institutions and categorized according to a seven-step implementation framework for the pilot CYP2C19-Clopidogrel Testing Implementation Guide. Five months after its launch, 96 CYP2C19-Clopidogrel Testing Implementation Guides had been created. Eighty percent of the resources most frequently selected by users were created by IGNITE to fill an identified resource gap. Resources most often included in guides were from the test reimbursement (22%), Implementation support gathering (22%), EHR integration (17%), and genetic testing workflow steps (17%).Lessons learned from this implementation guide development process provide insight for prioritizing development of future resources and support the value of collaborative efforts to create resources for genomic medicine implementation.
Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.
Introduction: Dysphagia occurs in roughly 30 to 67% of stroke patients and can lead to significant complications, including aspiration with subsequent pneumonia. There has been a lack of agreement on a single effective dysphagia screening tool. The tool used in our institution was developed internally based on extensive literature review, and includes dysphagia screening items followed by a water challenge. Hypothesis: We suspected this dysphagia screening tool was performing well based on low rates of aspiration pneumonia in our stroke patients. The purpose of this study was to validate the dysphagia screening tool against gold standard video fluoroscopy (VF). Methods: This was a prospective study to determine the sensitivity and specificity of the dysphagia screening tool. Our enrollment goal was 300 patients with suspected ischemic stroke between December 2016 and January 2018. The primary nurse completed the routine dysphagia screen, and the sub-investigator performed a blinded simultaneous screen, followed by VF evaluation. We used a group sequential design with interim analyses every 30 patients to allow for early stopping. The primary hypothesis was sensitivity >85%, evaluated using a one-sided test of proportion at a study alpha level of 0.025. Results: At the second interim analysis, 34/61 patients were positive for dysphagia on VF, while only 19 were positive on the screening tool. Estimated sensitivity was 55.9% (95% CI 39.5-71.1%), with a p-value below the second-stage threshold of 0.000002. Therefore, we terminated the study at this point. Estimated specificity was 51.9% (95% CI 34.0-69.3%), and the concordance between examiners for dysphagia screening as 91.8%. Conclusions: This is a routinely used screening tool across multiple hospitals within this organization. The tool did not show adequate sensitivity or specificity compared against the gold standard. Despite the results, we continue to have low rates of aspiration pneumonia. It is possible that VF may overestimate dysphagia, or that subjective interpretation of dysphagia criteria with VF may complicate the results. In conclusion, due to inadequate sensitivity and specificity of the dysphagia screening tool, we terminated the study and recommended modification of the tool.
