International changes in end-of-life practices over time: a systematic review.

BACKGROUND: End-of-life policies are hotly debated in many countries, with international evidence frequently used to support or oppose legal reforms. Existing reviews are limited by their focus on specific practices or selected jurisdictions. The objective is to review international time trends in end-of-life practices. METHODS: We conducted a systematic review of empirical studies on medical end-of-life practices, including treatment withdrawal, the use of drugs for symptom management, and the intentional use of lethal drugs. A search strategy was conducted in MEDLINE, EMBASE, Web of Science, Sociological Abstracts, PAIS International, Worldwide Political Science Abstracts, International Bibliography of the Social Sciences and CINAHL. We included studies that described physicians' actual practices and estimated annual frequency at the jurisdictional level. End-of-life practice frequencies were analyzed for variations over time, using logit regression. RESULTS: Among 8183 references, 39 jurisdiction-wide surveys conducted between 1990 and 2010 were identified. Of those, 22 surveys used sufficiently similar research methods to allow further statistical analysis. Significant differences were found across surveys in the frequency of treatment withdrawal, use of opiates or sedatives and the intentional use of lethal drugs (X 2  > 1000, p < 0.001 for all). Regression analyses showed increased use of opiates and sedatives over time (p < 0.001), which could reflect more intense symptom management at the end of life, or increase in these drugs to intentionally cause patients' death. CONCLUSION: The use of opiates and sedatives appears to have significantly increased over time between 1990 and 2010. Better distinction between practices with different legal status is required to properly interpret the policy significance of these changes. Research on the effects of public policies should take a comprehensive look at trends in end-of-life practice patterns and their associations with policy changes

The Effect of Disease Site (Knee, Hip, Hand, Foot, Lower Back or Neck) on Employment Reduction Due to Osteoarthritis

Osteoarthritis (OA) has a significant impact on individuals' ability to work. Our goal was to investigate the effects of the site of OA (knee, hip, hand, foot, lower back or neck) on employment reduction due to OA (EROA).This study involved a random sample of 6,000 patients with OA selected from the Medical Service Plan database in British Columbia, Canada. A total of 5,491 were alive and had valid addresses, and of these, 2,259 responded (response rate = 41%), from which 2,134 provided usable data. Eligible participants were 19 or older with physician diagnosed OA based on administrative data between 1992 and 2006. Data of 688 residents were used (mean age 62.1 years (27 to 86); 60% women). EROA had three levels: no reduction; reduced hours; and total cessation due to OA. The (log) odds of EROA was regressed on OA sites, adjusting for age, sex, education and comorbidity. Odds ratios (ORs) represented the effect predicting total cessation and reduced hours/total cessation. The strongest effect was found in lower back OA, with OR = 2.08 (95% CI: 1.47, 2.94), followed by neck (OR = 1.59; 95% CI: 1.11, 2.27) and knee (OR = 1.43; 95% CI: 1.02, 2.01). We found an interaction between sex and foot OA (men: OR = 1.94; 95% CI: 1.05, 3.59; women: OR = 0.89; 95% CI = 0.57, 1.39). No significant effect was found for hip OA (OR = 1.33) or hand OA (OR = 1.11). Limitations of this study included a modest response rate, the lack of an OA negative group, the use of administrative databases to identify eligible participants, and the use of patient self-reported data.After adjusting for socio-demographic variables, comorbidity, and other OA disease sites, we find that OA of the lower back, neck and knee are significant predictors for EROA. Foot OA is only significantly associated with EROA in males. For multi-site combinations, ORs are multiplicative. These findings may be used to guide resource allocation for future development/improvement of vocational rehabilitation programs for site-specific OA

GBA mutations are associated with Rapid eye movement sleep behavior disorder

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson’s disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson’s disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson’s disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson’s disease

Case report: Unveiling genetic and phenotypic variability in Nonketotic hyperglycinemia: an atypical early onset case associated with a novel GLRX5 variant

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT, GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3. We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM_016417.3:c.367G&gt;C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH’s genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH

The SISAL database: a global resource to document oxygen and carbon isotope records from speleothems

Stable isotope records from speleothems provide information on past climate changes, most particularly information that can be used to reconstruct past changes in precipitation and atmospheric circulation. These records are increasingly being used to provide “out-of-sample” evaluations of isotope-enabled climate models. SISAL (Speleothem Isotope Synthesis and Analysis) is an international working group of the Past Global Changes (PAGES) project. The working group aims to provide a comprehensive compilation of speleothem isotope records for climate reconstruction and model evaluation. The SISAL database contains data for individual speleothems, grouped by cave system. Stable isotopes of oxygen and carbon (δ 18O, δ 13C) measurements are referenced by distance from the top or bottom of the speleothem. Additional tables provide information on dating, including information on the dates used to construct the original age model and sufficient information to assess the quality of each data set and to erect a standardized chronology across different speleothems. The metadata table provides location information, information on the full range of measurements carried out on each speleothem and information on the cave system that is relevant to the interpretation of the records, as well as citations for both publications and archived data. The compiled data are available at https://doi.org/10.17864/1947.147

Evaluating model outputs using integrated global speleothem records of climate change since the last glacial

Although quantitative isotopic data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to use the speleothem data for data-model comparisons. Here, we illustrate this using 456 globally-distributed speleothem δ18O records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates procuring large numbers of records if data-model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotopic values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model’s ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotopic data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on 18O values, the optimum period for the modern observational baseline, and the selection of an appropriate time-window for creating means of the isotope data for palaeo time slices

Aircraft Numerical "Twin": A Time Series Regression Competition

International audienceThis paper presents the design and analysis of a data science competition on a problem of time series regression from aeronautics data. For the purpose of performing predictive maintenance, aviation companies seek to create aircraft "numerical twins", which are programs capable of accurately predicting strains at strategic positions in various body parts of the aircraft. Given a number of input parameters (sensor data) recorded in sequence during the flight, the competition participants had to predict output values (gauges), also recorded sequentially during test flights, but not recorded during regular flights. The competition data included hundreds of complete flights. It was a code submission competition with complete blind testing of algorithms. The results indicate that such a problem can be effectively solved with gradient boosted trees, after preprocessing and feature engineering. Deep learning methods did not prove as efficient

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie