A phase type survival tree model for clustering patients’ hospital length of stay

Clinical investigators, health professionals and managers are often interested in developing criteria for clustering patients into clinically meaningful groups according to their expected length of stay. In this paper, we propose phase-type survival trees which extend previous work on exponential survival trees. The trees are used to cluster the patients with respect to length of stay where partitioning is based on covariates such as gender, age at the time of admission and primary diagnosis code. Likelihood ratio tests are used to determine optimal partitions. The approach is illustrated using nationwide data available from the English Hospital Episode Statistics (HES) database on stroke-related patients, aged 65 years and over, who were discharged from English hospitals over a 1-year period.peer-reviewe

Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer’s Disease

Certain endogenous bile acids have been proposed as potential therapies for ameliorating Alzheimer’s disease (AD) but their role, if any, in the pathophysiology of this disease is not currently known. Given recent evidence of bile acids having protective and anti-inflammatory effects on the brain, it is important to establish how AD affects levels of endogenous bile acids. Using LC-MS/MS, this study profiled 22 bile acids in brain extracts and blood plasma from AD patients (n = 10) and age-matched control subjects (n = 10). In addition, we also profiled brain/plasma samples from APP/PS1 and WT mice (aged 6 and 12 months). In human plasma, we detected significantly lower cholic acid (CA, p = 0.03) in AD patients than age-matched control subjects. In APP/PS1 mouse plasma we detected higher CA (p = 0.05, 6 months) and lower hyodeoxycholic acid (p = 0.04, 12 months) than WT. In human brain with AD pathology (Braak stages V-VI) taurocholic acid (TCA) were significantly lower (p = 0.01) than age-matched control subjects. In APP/PS1 mice we detected higher brain lithocholic acid (p = 0.05) and lower tauromuricholic acid (TMCA; p = 0.05, 6 months). TMCA was also decreased (p = 0.002) in 12-month-old APP/PS1 mice along with 5 other acids: CA (p = 0.02), β-muricholic acid (p = 0.02), Ω-muricholic acid (p = 0.05), TCA (p = 0.04), and tauroursodeoxycholic acid (p = 0.02). The levels of bile acids are clearly disturbed during the development of AD pathology and, since some bile acids are being proposed as potential AD therapeutics, we demonstrate a method that can be used to support work to advance bile acid therapeutics

Exploiting Locality in Quantum Computation for Quantum Chemistry

Accurate prediction of chemical and material properties from first principles quantum chemistry is a challenging task on traditional computers. Recent developments in quantum computation offer a route towards highly accurate solutions with polynomial cost, however this solution still carries a large overhead. In this perspective, we aim to bring together known results about the locality of physical interactions from quantum chemistry with ideas from quantum computation. We show that the utilization of spatial locality combined with the Bravyi-Kitaev transformation offers an improvement in the scaling of known quantum algorithms for quantum chemistry and provide numerical examples to help illustrate this point. We combine these developments to improve the outlook for the future of quantum chemistry on quantum computers.Chemistry and Chemical Biolog

Physical Fatigue, Fitness and Muscle Function in Patients with Anti-neutrophil Cytoplasm Antibody-Associated Vasculitis.

Objective. This study investigated differences in cardiorespiratory fitness, muscular function, perceived exertion, and anxiety/depression between patients and healthy controls (HCs) and assessed which of these variables may account for the fatigue experienced by patients. Methods. Fatigue was measured in 48 antineutrophil cytoplasmic antibody–associated vasculitis patients and 41 healthy controls using the Multidimensional Fatigue Inventory (MFI-20), focusing on the physical component. Quality of life, anxiety/depression, and sleep quality were assessed by validated questionnaires. Muscle mass was measured by dual-energy x-ray absorptiometry scan, strength as the maximal voluntary contraction (MVC) force, and endurance as sustained isometric contraction at 50% MVC of the quadriceps. Voluntary activation was assessed by superimposed electrical stimulation. Cardiorespiratory fitness (_Vo2 max and oxygen pulse [O2 pulse]) and perceived exertion (Borg scale) were measured during progressive submaximal exercise. Results. Patients reported elevated physical fatigue scores compared to HCs (patients MFI-20 physical 13 [interquar-tile range (IQR) 8–16], HCs MFI-20 physical 5.5 [IQR 4–8]; P<0.001). Muscle mass was the same in both groups, but MVC and time to failure in the endurance test were lower due to reduced voluntary activation in patients. Estimated _Vo2max and O2 pulse were the same in both groups. For the same relative workload, patients reported higher ratings of perceived exertion, which correlated with reports of MFI-20 physical fatigue (R 25 0.2). Depression (R 25 0.6), anxiety (R250.3), and sleep disturbance (R 25 0.3) were all correlated with MFI-20 physical fatigue. Conclusion. These observations suggest that fatigue in patients is of a central rather than peripheral origin, supported by associations of fatigue with heightened perception of exertion, depression, anxiety, and sleep disturbance but normal muscle and cardiorespiratory function

Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation.

Vaccines are the most effective medical intervention due to their continual success in preventing infections and improving mortality worldwide. Early vaccines were developed empirically however, rational design of vaccines can allow us to optimise their efficacy, by tailoring the immune response. Establishing the immune correlates of protection greatly informs the rational design of vaccines. This facilitates the selection of the best vaccine antigens and the most appropriate vaccine adjuvant to generate optimal memory immune T cell and B cell responses. This review outlines the range of vaccine types that are currently authorised and those under development. We outline the optimal immunological correlates of protection that can be targeted. Finally we review approaches to rational antigen selection and rational vaccine adjuvant design. Harnessing current knowledge on protective immune responses in combination with critical vaccine components is imperative to the prevention of future life-threatening diseases

Inferring the distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii

Spontaneous mutations are the source of new genetic variation and are thus central to the evolutionary process. In molecular evolution and quantitative genetics, the nature of genetic variation depends critically on the distribution of effects of mutations on fitness and other quantitative traits. Spontaneous mutation accumulation (MA) experiments have been the principal approach for investigating the overall rate of occurrence and cumulative effect of mutations but have not allowed the phenotypic effects of individual mutations to be studied directly. Here, we crossed MA lines of the green alga Chlamydomonas reinhardtii with its unmutated ancestral strain to create haploid recombinant lines, each carrying an average of 50% of the accumulated mutations in a large number of combinations. With the aid of the genome sequences of the MA lines, we inferred the genotypes of the mutations, assayed their growth rate as a measure of fitness, and inferred the distribution of fitness effects (DFE) using a Bayesian mixture model. We infer that the DFE is highly leptokurtic (L-shaped). Of mutations with absolute fitness effects exceeding 1%, about one-sixth increase fitness in the laboratory environment. The inferred distribution of effects for deleterious mutations is consistent with a strong role for nearly neutral evolution. Specifically, such a distribution predicts that nucleotide variation and genetic variation for quantitative traits will be insensitive to change in the effective population size