Quality of integrated chronic care measured by patient survey: identification, selection and application of most appropriate instruments\ud

Objective  To identify the most appropriate generic instrument to measure experience and/or satisfaction of people receiving integrated chronic care.\ud \ud Background  Health care is becoming more user-centred and, as a result, the experience of users of care and evaluation of their experience and/or satisfaction is taken more seriously. It is unclear to what extent existing instruments are appropriate in measuring the experience and/or satisfaction of people using integrated chronic care.\ud \ud Methods  Instruments were identified by means of a systematic literature review. Appropriateness of instruments was analysed on seven criteria. The two most promising instruments were translated into Dutch, if necessary, and administered to a convenience sample of 109 people with a chronic illness. Data derived from respondents were analysed statistically. Focus-group interviews were conducted to assess the semantic and technical equivalence as well as opinions of people about the applicability and relevance of the translated instruments.\ud \ud Results  From 37 instruments identified, the Patients’ Assessment of Care for chronIc Conditions (PACIC) and the short form of the Patient Satisfaction Questionnaire III (PSQ-18) were selected as most promising instruments. Both instruments produced similar median scores across people with different chronic conditions. The overall PACIC and its subscales and the overall PSQ-18 were highly internally consistent, but not the PSQ-18 subscales. Overall, the PACIC demonstrated better psychometric characteristics. PACIC and PSQ-18 scores were found to be moderately correlated. Whereas more respondents preferred the PSQ-18, focus-group participants regarded the PACIC to be more applicable and relevant. The technical and semantic equivalence of both instruments were sufficient.\ud \ud Conclusions  Because of its psychometric characteristics, perceived applicability and relevance, the PACIC is the most appropriate instrument to measure the experience of people receiving integrated chronic care\u

Adaptive density estimation for stationary processes

We propose an algorithm to estimate the common density $s$ of a stationary process $X_1,...,X_n$. We suppose that the process is either $\beta$ or $\tau$-mixing. We provide a model selection procedure based on a generalization of Mallows' $C_p$ and we prove oracle inequalities for the selected estimator under a few prior assumptions on the collection of models and on the mixing coefficients. We prove that our estimator is adaptive over a class of Besov spaces, namely, we prove that it achieves the same rates of convergence as in the i.i.d framework

Molecular genetic analysis of Giardia intestinalis isolates at the glutamate dehydrogenase locus

Samples of DNA from a panel of Giardia isolated from humans and animals in Europe and shown previously to consist of 2 major genotypes–‘Polish’ and ‘Belgian’–have been compared with human-derived Australian isolates chosen to represent distinct genotypes (genetic groups I–IV) defined previously by allozymic analysis. Homologous 0·52 kilobase (kb) segments of 2 trophozoite surface protein genes (tsa417 and tsp11, both present in isolates belonging to genetic groups I and II) and a 1·2 kb segment of the glutamate dehydrogenase (gdh) gene were amplified by the polymerase chain reaction (PCR) and examined for restriction fragment length polymorphisms (RFLPs). Of 21 ‘Polish’ isolates that were tested, all yielded tsa417-like and tsp11-like PCR products that are characteristic of genetic groups I or II (15 and 6 isolates respectively) in a distinct assemblage of G. intestinalis from Australia (Assemblage A). Conversely, most of the 19 ‘Belgian’ isolates resembled a second assemblage of genotypes defined in Australia (Assemblage B) which contains genetic groups III and IV. RFLP analysis of gdh amplification products showed also that ‘Polish’ isolates-were equivalent to Australian Assemblage A isolates (this analysis does not distinguish between genetic groups I and II) and that ‘Belgian’ isolates were equivalent to Australian Assemblage B isolates. Comparison of nucleotide sequences determined for a 690 base-pair portion of the gdh PCR products revealed ≥ 99·0% identity between group I and group II (Assemblage A/‘Polish’) genotypes, 88·3–89·7% identity between Assemblage A and Assemblage B genotypes, and ≥ 98·4% identity between various Assemblage B/‘Belgian’ genotypes. The results confirm that the G. duodenalis isolates examined in this study (inclusive of G. intestinalis from humans) can be divided into 2 major genetic clusters: Assemblage A (= ‘Polish’ genotype) containing allozymically defined groups I and II, and Assemblage B (= ‘Belgian’ genotype) containing allozymically defined groups III and IV and other related genotypes

Beneficial effects of brown fat activation on top of PCSK9 inhibition with alirocumab on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by lowering circulating very low density lipoprotein (VLDL)-cholesterol. We hypothesized that the therapeutic effectiveness of PCSK9 inhibition can be increased by accelerating the generation of VLDL remnants, which typically have a high affinity for the LDLR. Therefore, we aimed to investigate whether accelerating lipolytic processing of VLDL by brown fat activation can further lower (V)LDL and reduce atherosclerosis on top of PCSK9 inhibition. APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the anti-PCSK9 antibody alirocumab or saline. After 2 weeks, both groups of mice were randomized to receive either the selective beta 3-adrenergic receptor (AR) agonist CL316,243 to activate brown fat or saline for 3 additional weeks to evaluate VLDL clearance or 12 additional weeks to analyze atherosclerosis development. beta 3-AR agonism and alirocumab combined decreased (V)LDL-cholesterol compared to alirocumab alone, which was explained by an accelerated plasma clearance of VLDL-cholesteryl esters that were mainly taken up by the liver. In addition, the combination promoted the transfer of VLDL-phospholipids to HDL to a higher extent than alirocumab alone, accompanied by higher plasma HDL-cholesterol levels and increased cholesterol efflux capacity. Consequently, combination treatment largely reduced atherosclerotic lesion area compared to vehicle. Together, beta 3-AR agonism enhances the lipoprotein-modulating effects of alirocumab to further improve dyslipidemia and non-significantly further attenuate atherosclerosis development. Our findings demonstrate that brown fat activation may enhance the therapeutic effects of PCSK9 inhibition in dyslipidemia.Diabetes mellitus: pathophysiological changes and therap

Plasma Apolipoprotein CI and CIII Levels Are Associated With Increased Plasma Triglyceride Levels and Decreased Fat Mass in Men With the Metabolic Syndrome

OBJECTIVE—To determine whether, in accordance with observations in mouse models, high concentrations of the lipoprotein lipase inhibitors apolipoprotein (Apo) CI and ApoCIII are associated with increased triglyceride concentrations and decreased fat mass in men with the metabolic syndrome

Plasma Apolipoprotein CI and CIII Levels Are Associated With Increased Plasma Triglyceride Levels and Decreased Fat Mass in Men With the Metabolic Syndrome

OBJECTIVE—To determine whether, in accordance with observations in mouse models, high concentrations of the lipoprotein lipase inhibitors apolipoprotein (Apo) CI and ApoCIII are associated with increased triglyceride concentrations and decreased fat mass in men with the metabolic syndrome

The effect of a lifestyle intervention on type 2 diabetes pathophysiology and remission: the Stevenshof pilot study

Although lifestyle interventions can lead to diabetes remission, it is unclear to what extent type 2 diabetes (T2D) remission alters or improves the underlying pathophysiology of the disease. Here, we assess the effects of a lifestyle intervention on T2D reversal or remission and the effects on the underlying pathology. In a Dutch primary care setting, 15 adults with an average T2D duration of 13.4 years who were (pharmacologically) treated for T2D received a diabetes subtyping ("diabetyping") lifestyle intervention (DLI) for six months, aiming for T2D remission. T2D subtype was determined based on an OGTT. Insulin and sulphonylurea (SU) derivative treatment could be terminated for all participants. Body weight, waist/hip ratio, triglyceride levels, HbA1c, fasting, and 2h glucose were significantly improved after three and six months of intervention. Remission and reversal were achieved in two and three participants, respectively. Indices of insulin resistance and beta cell capacity improved, but never reached healthy values, resulting in unchanged T2D subtypes. Our study implies that achieving diabetes remission in individuals with a longer T2D duration is possible, but underlying pathology is only minimally affected, possibly due to an impaired beta cell function. Thus, even when T2D remission is achieved, patients need to continue adhering to lifestyle therapy.Diabetes mellitus: pathophysiological changes and therap

Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation

The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p < 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p < 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p < 0.05) and 2.1-fold (p < 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality

Hepatic scavenger receptor class B type 1 knockdown reduces atherosclerosis and enhances the antiatherosclerotic effect of brown fat activation in APOE*3-Leiden.CETP mice

Objective:Brown fat activation attenuates atherosclerosis development by accelerating triglyceride-rich lipoprotein turnover and/or stimulation of reverse cholesterol transport via the SRB1 (scavenger receptor class B type 1). The aim of this study was to investigate the specific role of hepatic SRB1 in the atheroprotective properties of brown fat activation.Approach and Results:APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism and atherosclerosis, were treated with vehicle or adenoassociated virus serotype 8-short hairpin RNA, which decreased hepatic SRB1 protein levels by 40% to 55%. After 2 weeks, mice without or with hepatic SRB1 knockdown were treated with vehicle or the beta 3-adrenergic receptor agonist CL316 243 to activate brown fat for 4 weeks to determine HDL (high-density lipoprotein) catabolism and for 9 weeks to evaluate atherosclerosis. Surprisingly, hepatic SRB1 knockdown additively improved the beneficial effects of beta 3-adrenergic receptor agonism on atherosclerosis development. In fact, hepatic SRB1 knockdown per se not only increased HDL-cholesterol levels but also reduced plasma triglyceride and non-HDL-cholesterol levels, thus explaining the reduction in atherosclerosis development. Mechanistic studies indicated that this is due to increased lipolytic processing and hepatic uptake of VLDL (very low density lipoprotein) by facilitating VLDL-surface transfer to HDL.Conclusions:Hepatic SRB1 knockdown in a mouse model with an intact ApoE (apolipoprotein E)-LDLR (low density lipoprotein receptor) clearance pathway, relevant to human lipoprotein metabolism, reduced atherosclerosis and improved the beneficial effect of brown fat activation on atherosclerosis development, explained by pleiotropic effects of hepatic SRB1 knockdown on lipolytic processing and hepatic uptake of VLDL. Brown fat activation could thus be an effective strategy to treat cardiovascular disease also in subjects with impaired SRB1 function.Functional Genomics of Systemic Disorder

FPGA acceleration of the phylogenetic likelihood function for Bayesian MCMC inference methods

Background Likelihood (ML)-based phylogenetic inference has become a popular method for estimating the evolutionary relationships among species based on genomic sequence data. This method is used in applications such as RAxML, GARLI, MrBayes, PAML, and PAUP. The Phylogenetic Likelihood Function (PLF) is an important kernel computation for this method. The PLF consists of a loop with no conditional behavior or dependencies between iterations. As such it contains a high potential for exploiting parallelism using micro-architectural techniques. In this paper, we describe a technique for mapping the PLF and supporting logic onto a Field Programmable Gate Array (FPGA)-based co-processor. By leveraging the FPGA\u27s on-chip DSP modules and the high-bandwidth local memory attached to the FPGA, the resultant co-processor can accelerate ML-based methods and outperform state-of-the-art multi-core processors. Results We use the MrBayes 3 tool as a framework for designing our co-processor. For large datasets, we estimate that our accelerated MrBayes, if run on a current-generation FPGA, achieves a 10× speedup relative to software running on a state-of-the-art server-class microprocessor. The FPGA-based implementation achieves its performance by deeply pipelining the likelihood computations, performing multiple floating-point operations in parallel, and through a natural log approximation that is chosen specifically to leverage a deeply pipelined custom architecture. Conclusions Heterogeneous computing, which combines general-purpose processors with special-purpose co-processors such as FPGAs and GPUs, is a promising approach for high-performance phylogeny inference as shown by the growing body of literature in this field. FPGAs in particular are well-suited for this task because of their low power consumption as compared to many-core processors and Graphics Processor Units (GPUs)