The inference of gray whale (Eschrichtius robustus) historical population attributes from whole-genome sequences

Commercial whaling caused extensive demographic declines in many great whale species, including gray whales that were extirpated from the Atlantic Ocean and dramatically reduced in the Pacific Ocean. The Eastern Pacific gray whale has recovered since the 1982 ban on commercial whaling, but the Western Pacific gray whale-once considered possibly extinct-consists of only about 200 individuals and is considered critically endangered by some international authorities. Herein, we use whole-genome sequencing to investigate the demographic history of gray whales from the Pacific and use environmental niche modelling to make predictions about future gene flow.Our sequencing efforts and habitat niche modelling indicate that: i) western gray whale effective population sizes have declined since the last glacial maximum; ii) contemporary gray whale genomes, both eastern and western, harbor less autosomal nucleotide diversity than most other marine mammals and megafauna; iii) the extent of inbreeding, as measured by autozygosity, is greater in the Western Pacific than in the Eastern Pacific populations; and iv) future climate change is expected to open new migratory routes for gray whales.Our results indicate that gray whale genomes contain low nucleotide diversity and have been subject to both historical and recent inbreeding. Population sizes over the last million years likely peaked about 25,000 years before present and have declined since then. Our niche modelling suggests that novel migratory routes may develop within the next century and if so this could help retain overall genetic diversity, which is essential for adaption and successful recovery in light of global environmental change and past exploitation

Improving treatment decision-making and survival in elderly patients with end-stage kidney disease

Background: End-stage kidney disease (ESKD) burden is increasing particularly amongst the elderly. For older patients, ESKD treatment decisions involve choosing between dialysis versus supportive (non-dialysis) therapies. Registry data provides information on dialysis survival however no systematic data collection exists for supportive care. Methods: This thesis systematically evaluates treatment decision-making from the perspectives of nephrologists and elderly patients/carers using a discrete choice experiment (DCE) and an in-depth interview study respectively. It then scrutinises one of the important factors, survival through a systematic review and meta-analysis and registry cohort studies. Results: The DCE and interview study demonstrate that quality-of-life is critical in decisions. The interview study reveals that patients/carers consider choices in the context of their sense-of-self. The meta-analysis shows that the survival benefit between therapies cannot be confidently estimated due to data limitations. The cohort studies indicate that patient and practice variables predict elderly dialysis patient survival and that automatic estimated glomerular filtration rate reporting led to positive impacts on elderly late referral rates. Conclusion: This thesis emphasises the need for patient-centred treatment discussions which highlight the impact of therapies on dignity, quality-of-life, relationships and life purpose. Survival with both pathways has also been outlined improving prognostication which further enhances decision-making

Impact of estimated GFR reporting on late referral rates and practice patterns for end-stage kidney disease patients: a multilevel logistic regression analysis using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA)

Background Late referral for renal replacement therapy (RRT) leads to worse outcomes. In 2005, estimated glomerular filtration rate (eGFR) reporting began in Australasia, with an aim of substantially increasing earlier disease detection. Study Design Observational cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data. Setting & Participants All patients commencing RRT in Australasia between January 1, 1999, and December 31, 2010. We excluded the period between December 31, 2004, and January 1, 2007, to allow for practice change. Factor Introduction of eGFR reporting. Outcomes Primary outcome was late referral defined as commencing RRT within 3 months of nephrology referral. Secondary outcomes included initial RRT modality and prepared access at hemodialysis therapy initiation. Measurements Late referral rates per era were determined and multilevel logistic regression was used to identify late referral predictors. Results We included 25,009 patients. Overall, 3,433 (25.3%) patients were referred late in the pre-eGFR era compared with 2,464 (21.6%) in the post-eGFR era, for an absolute reduction of 3.7% (95% CI, 2.7%-4.8%; P < 0.001). After adjustments for age, body mass index, race, comorbid conditions, and primary kidney disease, adjusted late referral rates were 25.8% (95% CI, 23.3%-28.3%) and 21.8% (95% CI, 19.2%-24.4%) in the pre- and post-eGFR eras, respectively, for a difference of 4.0% (95% CI, 1.2%-6.8%; P = 0.005). Late referral risk was attenuated significantly post-eGFR reporting (OR, 1.30; 95% CI, 1.12-1.51) compared to pre-eGFR reporting (OR, 2.15; 95% CI, 1.88-2.46) for indigenous patients. Late referral rates decreased for older patients but increased slightly for younger patients (P = 0.001 for interaction between age and era). There was no impact on initial RRT modality or prepared access rates at hemodialysis therapy initiation between eras. Limitations Residual confounding could not be excluded. Conclusions eGFR reporting was associated with small reductions in late referral, but more than 1 in 5 patients are still referred late. Other initiatives to increase timely referral warrant investigation

Impact of estimated GFR reporting on late referral rates and practice patterns for end-stage kidney disease patients: a multilevel logistic regression analysis using the Australia and New Zealand dialysis and transplant registry (ANZDATA)

BackgroundLate referral for renal replacement therapy (RRT) leads to worse outcomes. In 2005, estimated glomerular filtration rate (eGFR) reporting began in Australasia, with an aim of substantially increasing earlier disease detection.Study DesignObservational cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data.Setting &amp; ParticipantsAll patients commencing RRT in Australasia between January 1, 1999, and December 31, 2010. We excluded the period between December 31, 2004, and January 1, 2007, to allow for practice change.FactorIntroduction of eGFR reporting.OutcomesPrimary outcome was late referral defined as commencing RRT within 3 months of nephrology referral. Secondary outcomes included initial RRT modality and prepared access at hemodialysis therapy initiation.MeasurementsLate referral rates per era were determined and multilevel logistic regression was used to identify late referral predictors.ResultsWe included 25,009 patients. Overall, 3,433 (25.3%) patients were referred late in the pre-eGFR era compared with 2,464 (21.6%) in the post-eGFR era, for an absolute reduction of 3.7% (95% CI, 2.7%-4.8%; P &lt; 0.001). After adjustments for age, body mass index, race, comorbid conditions, and primary kidney disease, adjusted late referral rates were 25.8% (95% CI, 23.3%-28.3%) and 21.8% (95% CI, 19.2%-24.4%) in the pre- and post-eGFR eras, respectively, for a difference of 4.0% (95% CI, 1.2%-6.8%; P = 0.005). Late referral risk was attenuated significantly post-eGFR reporting (OR, 1.30; 95% CI, 1.12-1.51) compared to pre-eGFR reporting (OR, 2.15; 95% CI, 1.88-2.46) for indigenous patients. Late referral rates decreased for older patients but increased slightly for younger patients (P = 0.001 for interaction between age and era). There was no impact on initial RRT modality or prepared access rates at hemodialysis therapy initiation between eras.LimitationsResidual confounding could not be excluded.ConclusionseGFR reporting was associated with small reductions in late referral, but more than 1 in 5 patients are still referred late. Other initiatives to increase timely referral warrant investigation

COnsiderations of Nephrologists when SuggestIng Dialysis in Elderly patients with Renal failure (CONSIDER): a discrete choice experiment

Background Nephrologists often face difficult decisions when recommending dialysis or non-dialysis (supportive) care for elderly patients, given the uncertainty around survival and the burden of dialysis. Discrete choice experiments (DCEs) mimic real-world decisions through simultaneous consideration of multiple variables. We aimed to determine the relative influence of patient characteristics on dialysis recommendations.Methods We conducted a DCE among Australasian nephrologists consisting of 12 scenarios of two patients (described in terms of age, gender, cognition, comorbidity, life expectancy, current quality of life (QOL), expected QOL with dialysis, social support, patient and family inclination). Nephrologists indicated which patient they preferred recommending dialysis for, or whether they preferred &lsquo;neither&rsquo;. Mixed logit models determined the odds of recommending dialysis over no dialysis. Trade-offs between QOL and survival were calculated.Results A total of 159 nephrologists participated (34% aged 40&ndash;49 years, 62% male and 69% Caucasian). All patient characteristics except gender significantly affected the likelihood of dialysis recommendation. Nephrologists were more likely to recommend dialysis for patients with preserved cognition (odds ratio [OR]: 68.3; 95% confidence interval [CI]: 33.4&ndash;140.0), lower comorbidity (OR: 2.1; 95% CI: 1.1&ndash;4.1), increased life expectancy (OR: 2.8; 95% CI: 2.1&ndash;3.7), high current QOL (OR: 2.8; 95% CI: 2.0&ndash;3.8) and positive patient and family dialysis inclination (OR: 27.5; 95% CI: 16.2&ndash;46.8 and OR: 2.0; 95% CI: 1.3&ndash;3.3, respectively). Nephrologists aged &gt;65 were more likely (OR: 11.7; 95% CI: 1.8&ndash;77.2) to recommend dialysis. Nephrologists were willing to forgo 12 months of patient survival to avoid substantial QOL decrease with dialysis.Conclusion Nephrologists avoided dialysis recommendation if it was expected to considerably reduce QOL. To inform elderly patients\u27 dialysis decisions, systematic and longitudinal cognition and QOL evaluations are needed as well as better research into understanding patient preferences

Burden of care and quality of life among caregivers for adults receiving maintenance dialysis: a systematic review

Rationale & Objective: Dialysis is a burdensome and complex treatment for which many recipients require support from caregivers. The impact of caring for people dependent on dialysis on the quality of life of the caregivers has been incompletely characterized. Study Design: Systematic review of quantitative studies of quality of life and burden to caregivers. Setting & Study Population: Caregivers of adults receiving maintenance dialysis. Selection Criteria for Studies: The Cochrane Library, Embase, PsycINFO, CINAHL, PubMed, and MEDLINE were systematically searched from inception until December 2016 for quantitative studies of caregivers. Pediatric and non–English language studies were excluded. Study quality was assessed using a modified Newcastle-Ottawa scale. Data Extraction: 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. Analytical Approach: Descriptive reports of demographics, measurement scales, and outcomes. Quantitative meta-analysis using random effects when possible. Results: 61 studies were identified that included 5,367 caregivers from 21 countries and assessed the impact on caregivers using 70 different scales. Most (85%) studies were cross-sectional. The largest identified group of caregivers was female spouses who cared for recipients of facility-based hemodialysis (72.3%) or peritoneal dialysis (20.6%). Caregiver quality of life was poorer than in the general population, mostly comparable with caregivers of people with other chronic diseases, and often better than experienced by the dialysis patients cared for. Caregiver quality of life was comparable across dialysis modalities. Limitations: Heterogeneity in study design and outcome measures made comparisons between studies difficult and precluded quantitative meta-analysis. Study quality was generally poor. Conclusions: Quality of life of caregivers of dialysis recipients is poorer than in the general population and comparable to that of caregivers of individuals with other chronic diseases. The impact of caring for recipients of home hemodialysis or changes in the impact of caring over time have not been well studied. Further research is needed to optimally inform dialysis programs how to educate and support caregivers

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

BackgroundSeveral clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes.MethodsWe systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events.FindingsWe identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0&ndash;18) for major cardiovascular events (p=0&middot;048) and a 13% RR reduction (7&ndash;19) for coronary events (p&lt;0&middot;0001), but had no benefit on stroke (&minus;3%, &minus;16 to 9; p=0&middot;69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, &minus;8 to 7; p=0&middot;92), cardiovascular mortality (3%, &minus;7 to 12; p=0&middot;59), sudden death (11%, &minus;6 to 26; p=0&middot;19), or non-vascular mortality (&minus;10%, &minus;21 to 0&middot;5; p=0&middot;063). Fibrates reduced the risk of albuminuria progression by 14% (2&ndash;25; p=0&middot;028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1&middot;21, 0&middot;91&ndash;1&middot;61; p=0&middot;19), although increases in serum creatinine concentrations were common (1&middot;99, 1&middot;46&ndash;2&middot;70; p&lt;0&middot;0001).InterpretationFibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia

Duration and effectiveness of glucose-lowering regimens in the real world management of diabetes: Data from the Australian EXTEND45 Linked Cohort Study

Background: Diabetes is a common condition that often requires increasing intensity of glucose lowering regimens. We describe the population trends in the intensity of regimens, and associations of achieved HbA1c and treatment persistence. Methods: We performed an episode-based analysis of the EXTEND-45 dataset, assessing trends in glucose lowering therapy and the associated outcomes of HbA1c and treatment persistence. Trends from 2009 to 2014 were assessed for each intensity level of a glucose lowering therapy regimen, according to the year prescribed. Episodes were defined as the length of time that an individual adhered to a regimen through ongoing prescription, and this was used as to define persistence. Mean HbA1c were calculated for each episode. Persistence and HbA1c were compared across the different regimens of treatment intensity. Results: The intensity of glucose lowering therapy remained stable over time with around one third of episodes utilising a single glucose lowering agent. Mean HbA1c was higher for insulin-based treatment (mean 7.9 % SD = 1.3 %), and lowest for episodes of no glucose lowering treatment (mean 6.3 % (SD = 0.8 %). Around half of participants achieved glycemic targets of 7 %. While there was considerable variation in persistence, the median persistence was around 3 months (94 days, IQR 51–201 days). Conclusions: Therapeutic intensity for diabetes has remained stable over 9 years. Whilst there was considerable variability in persistence with glucose lowering regimens, the mean duration of all regimens was less than a year. Requirement for higher intensity treatment with insulin was related to poorer glycemic control