Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study. Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×$10^{−6}$. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts. Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis

Clinical pearls in hospital nephrology

Hospitalized patients who have established kidney disease and those who have acute kidney injury in the hospital, along with patients with electrolyte disturbances tend to be some of the most complex to care for. Through working closely in nephrology consultation in the hospital with patients and providers, in both private and academic settings, we have come to encounter certain common presentations and recurrent themes that are worthy of emphasis, and of which a good understanding can translate into improved patient care. For the provider who works closely with such patients, many of these aspects are important to recognize and understand. In this review, we present 10 questions that address some of the highly relevant aspects of nephrology for the provider in the hospital. Through a MEDLINE database search, we reviewed the most pertinent studies as we then go through the explanation of management decisions in an evidence-based methodology with an up-to-date approach based on the current literature on the subject

Progress report on a novel in situ 14C extraction scheme at the University of Cologne

We present initial results of in situ14C system blank and calibration sample measurements obtained using the in situ14C extraction scheme developed at the University of Cologne. The 14C extraction scheme specifically exploits the phase transformation of quartz to cristobalite in order to quantitatively extract the carbon as CO2 and follows a scheme that is different to that of existing extraction systems. Features are offline furnace extraction, single pass catalytic oxidation using mixed copper (I,II) oxide as catalyst, the use of UHV-compatible components and of vacuum annealed copper tubing. The design allows a relatively rapid sample throughput - two samples per day as opposed to the current 2 days per sample that can be done on other lines - and can accommodate samples ranging between 0.5 and 4 g of clean quartz. Following extraction and cleaning, the CO2 gas is measured using the gas ion source of the MICADAS AMS facility at ETH Zurich. The extraction system yields low systems blanks (10 +16/−10 x 103 atoms 14C, ±1 σ) and the initial results indicate that further improvements are achievable. Measurements of the CRONUS-A standard sample show a good reproducibility and results are consistent with published values. We also present the first in situ14C results for the CRONUS-R standard material

The ANSTO - University of Wollongong in-situ\u3csup\u3e 14\u3c/sup\u3eC extraction laboratory

We present our first 14 C in-situ results for calibration and system blanks from the recently completed Australian Nuclear Science and Technology Organisation (ANSTO) - University of Wollongong (UOW) in-situ 14 C extraction system. System performance parameters and quality is evidenced by low 14 C blanks and good reproducibility for multiple targets from different reference materials. The 14 C extraction scheme exploits the high temperature phase transformation of quartz to cristobalite in order to quantitatively extract the carbon as CO 2 . The in-situ 14 C extraction system comprises three independently operated and modular units that are used for initial in-vacuo removal of meteoric 14 C, followed by offline high-temperature heating of quartz to release trapped cosmogenic in-situ 14 C, and finally CO 2 gas purification and mass measurement. The design allows for rapid sample throughput of about 6 samples per week with samples masses ranging between 0.5 and 4 g of clean quartz. Other features include single-pass catalytic oxidation using mixed copper (I,II) oxide as catalyst, use of UHV-compatible components and of vacuum annealed copper tubing. We present results for sets of purified quartz samples prepared from CRONUS-A, CRONUS-R and CRONUS-N inter-comparison materials, with final averages consistent with published values. Following extraction and cleaning, CO 2 gas aliquots for some of the samples were analysed using the ETH Zürich CO 2 gas ion source at the ETH MICADAS AMS facility in addition to CO 2 being graphitised using the ANSTO laser-heated graphitisation micro-furnace and then analysed on ANSTO\u27s ANTARES AMS facility. System blanks using either CO 2 or graphite ion-sources at both facilities are on the order of ∼1 x 10 4 atoms

The ANSTO - University of Wollongong in-situ C-14 extraction laboratory

We present our first C-14 in-situ results for calibration and system blanks from the recently completed Australian Nuclear Science and Technology Organisation (ANSTO) University of Wollongong (UOW) in-situ C-14 extraction system. System performance parameters and quality is evidenced by low C-14 blanks and good reproducibility for multiple targets from different reference materials. The C-14 extraction scheme exploits the high temperature phase transformation of quartz to cristobalite in order to quantitatively extract the carbon as CO2. The in-situ C-14 extraction system comprises three independently operated and modular units that are used for initial in-vacuo removal of meteoric C-14, followed by offline high-temperature heating of quartz to release trapped cosmogenic in-situ C-14, and finally CO2 gas purification and mass measurement. The design allows for rapid sample throughput of about 6 samples per week with samples masses ranging between 0.5 and 4 g of clean quartz. Other features include single-pass catalytic oxidation using mixed copper (LII) oxide as catalyst, use of UHV-compatible components and of vacuum annealed copper tubing. We present results for sets of purified quartz samples prepared from CRONUS-A, CRONUS-R and CRONUS-N inter-comparison materials, with final averages consistent with published values. Following extraction and cleaning, CO2 gas aliquots for some of the samples were analysed using the ETH Zurich CO2 gas ion source at the ETH MICADAS AMS facility in addition to CO2 being graphitised using the ANSTO laser-heated graphitisation micro-furnace and then analysed on ANSTO's ANTARES AMS facility. System blanks using either CO2 or graphite ion-sources at both facilities are on the order of similar to 1 x 10(4) atoms

Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater

PURPOSE In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. PATIENTS AND METHODS Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator\u27s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. RESULTS Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). CONCLUSION With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy