Effectiveness of sitagliptin compared to sulfonylureas for type 2 diabetes mellitus inadequately controlled on metformin: a systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of sitagliptin compared to sulfonylureas as add-on to metformin in adults with type 2 diabetes mellitus from both randomised controlled trials (RCTs) and 'real-world' non-randomised studies. METHODS AND ANALYSES: We conducted a systematic review of EMBASE, MEDLINE, CENTRAL and grey literature for RCTs and non-randomised studies. We reported outcomes relating to change in HbA1c, fasting glucose, weight, blood pressure and lipids from baseline and need for treatment change. No study investigating macrovascular and microvascular diabetes complications was found. Meta-analysis was used where studies were sufficiently homogenous. RESULTS: Seven RCTs and five non-randomised studies were eligible for inclusion from 1335 articles retrieved. Meta-analysis of three homogenous RCTs revealed a statistically significant decrease in weight with sitagliptin when compared to sulfonylureas (weighted mean difference (WMD) -2.05 kg; 95% CI -2.38 to -1.71); however, a similar change from baseline in HbA1c (WMD 0.05; 95% CI -0.03 to 0.12), fasting glucose (WMD 0.11; 95% CI -0.08 to -0.29), blood pressure, lipids and the proportion achieving HbA1c <7% by study end (OR 0.98; 95% CI 0.85 to 1.13) was observed.Non-randomised studies identified consisted of four prospective and one retrospective cohort study. Three of these five studies were of moderate/high quality, and results though less precise suggested similar real-world comparative glycaemic and weight effectiveness for both treatments. Data from two cohort studies suggested that treatment change (HR 0.65; 95% CI 0.57 to 0.73) and insulin initiation (HR 0.76; 95% CI 0.65 to 0.90) were less likely among those prescribed sitagliptin; however, inadequate reporting of HbA1c at time of treatment change made interpreting results challenging. CONCLUSION: Sitagliptin users experienced modest weight loss compared to gain with sulfonylureas; however, this difference was around 2 kg, which may not be of major clinical significance for most individuals. Similar change was observed across most other effectiveness outcomes reported. Further studies are needed to address longer-term effectiveness outcomes for sitagliptin compared to sulfonylureas as add-on to metformin. PROSPERO REGISTRATION NUMBER: CRD42016033983

Antibiotic prescribing frequency amongst patients in primary care: a cohort study using electronic health records

BACKGROUND: Reducing inappropriate antibiotic prescribing in primary care is a public health priority. Objectives: We hypothesized that a subset of patients account for the majority of antibiotic prescriptions in primary care. We investigated the relationship between the total amount of antibiotics prescribed, individual-level antibiotic use and comorbidity. METHODS: This was a cohort study using electronic health records from 1 948 390 adults registered with 385 primary care practices in the UK in 2011-13. We estimated the average number of antibiotic prescriptions per patient and the association between prescribing and comorbidity. We modelled the impact on total prescribing of reducing antibiotic use in those prescribed antibiotics most frequently. RESULTS: On average 30.1% (586 194/1 948 390) of patients were prescribed at least one antibiotic per year. Nine percent (174 602/1 948 390) of patients were prescribed 53% (2 091 496/3 922 732) of the total amount of antibiotics, each of whom received at least five antibiotic prescriptions over 3 years. The presence of any comorbidity increased the prescribing rate by 44% [adjusted incidence rate ratio (IRR) 1.44, 95% CI 1.43-1.45]; rates of prescribing to women exceeded those in men by 62% (adjusted IRR 1.62, 95% CI 1.62-1.63). CONCLUSIONS: Half of antibiotics prescribed to adults in primary care were for <10% of patients. Efforts to tackle antimicrobial resistance should consider the impact of this on total prescribing

Peptide nanofiber hydrogel adjuvanted live virus vaccine enhances cross-protective immunity to porcine reproductive and respiratory syndrome virus

Porcine reproductive and respiratory syndrome virus (PRRSV) is prevalent in swine farms worldwide and is a major source of economic loss and animal suffering. Rapid genetic variation of PRRSV makes it difficult for current vaccines to confer protection against newly emerging strains. We recently demonstrated that a novel peptide nanofiber hydrogel (H9e) could act as a potent adjuvant for killed H1N1 vaccines. Therefore, the objective of this study was to evaluate H9e as an adjuvant for PRRSV modified live virus (MLV) vaccines. Pigs were vaccinated with Ingelvac PRRSV MLV with or without H9e adjuvant before being challenged with the VR-2332 (parental vaccine strain) or MN184A (genetically diverse strain) PRRSV. Pigs vaccinated with MLV+H9e had higher levels of circulating vaccine virus. More importantly, pigs vaccinated with MLV+H9e had improved protection against challenge by both PRRSV strains, as demonstrated by reduced challenge-induced viremia compared with pigs vaccinated with MLV alone. Pigs vaccinated with MLV+H9e had lower frequency of T-regulatory cells and IL-10 production but higher frequency of Th/memory cells and IFN-γ secretion than that in pigs vaccinated with MLV alone. Taken together, our studies suggest that the peptide nanofiber hydrogel H9e, when combined with the PRRSV MLV vaccine, can enhance vaccine efficacy against two different PRRSV strains by modulating both host humoral and cellular immune responses

13 Years of TOPEX/POSEIDON Precision Orbit Determination and the 10-fold Improvement in Expected Orbit Accuracy

Launched in the summer of 1992, TOPEX/POSEIDON (T/P) was a joint mission between NASA and the Centre National d Etudes Spatiales (CNES), the French Space Agency, to make precise radar altimeter measurements of the ocean surface. After the remarkably successful 13-years of mapping the ocean surface T/P lost its ability to maneuver and was de-commissioned January 2006. T/P revolutionized the study of the Earth s oceans by vastly exceeding pre-launch estimates of surface height accuracy recoverable from radar altimeter measurements. The precision orbit lies at the heart of the altimeter measurement providing the reference frame from which the radar altimeter measurements are made. The expected quality of orbit knowledge had limited the measurement accuracy expectations of past altimeter missions, and still remains a major component in the error budget of all altimeter missions. This paper describes critical improvements made to the T/P orbit time series over the 13-years of precise orbit determination (POD) provided by the GSFC Space Geodesy Laboratory. The POD improvements from the pre-launch T/P expectation of radial orbit accuracy and Mission requirement of 13-cm to an expected accuracy of about 1.5-cm with today s latest orbits will be discussed. The latest orbits with 1.5 cm RMS radial accuracy represent a significant improvement to the 2.0-cm accuracy orbits currently available on the T/P Geophysical Data Record (GDR) altimeter product

Relief of the Dma1-mediated checkpoint requires Dma1 autoubiquitination and dynamic localization

© 2018 Jones, Chen, et al. Chromosome segregation and cell division are coupled to prevent aneuploidy and cell death. In the fission yeast Schizosaccharomyces pombe, the septation initiation network (SIN) promotes cytokinesis, but upon mitotic checkpoint activation, the SIN is actively inhibited to prevent cytokinesis from occurring before chromosomes have safely segregated. SIN inhibition during the mitotic checkpoint is mediated by the E3 ubiquitin ligase Dma1. Dma1 binds to the CK1-phosphorylated SIN scaffold protein Sid4 at the spindle pole body (SPB), and ubiquitinates it. Sid4 ubiquitination antagonizes the SPB localization of the Polo-like kinase Plo1, the major SIN activator, so that SIN signaling is delayed. How this checkpoint is silenced once spindle defects are resolved has not been clear. Here we establish that Dma1 transiently leaves SPBs during anaphase B due to extensive autoubiquitination. The SIN is required for Dma1 to return to SPBs later in anaphase. Blocking Dma1 removal from SPBs by permanently tethering it to Sid4 prevents SIN activation and cytokinesis. Therefore, controlling Dma1’s SPB dynamics in anaphase is an essential step in S. pombe cell division and the silencing of the Dma1-dependent mitotic checkpoint

GSFC OSTM, Jason-l and TOPEX POD Update

The OSTM (Jason-2) has been in orbit for three years (since June 2008), and the full suite of altimeter data from TOPEX/Poseidon, Jason-I and Jason-2 now span nearly twenty years since the launch of TOPEX in 1992. Issues that affect the stability of the orbits through time and the orbit accuracy include the reference frame, the radiation pressure models for the altimeter satellites and the fidelity of the dynamic force model, including time-variable gravity, as well as the performance of the individual tracking systems. We have conducted detailed analyses of the new ITRF2008 reference frame and find only a small effect on global mean sea level compared to ITRF2005, although we note an improvement in POD quality over the most recent time periods for Jason-2. In the past year we have developed a new time series of orbits for TOPEX/Poseidon, Jason-I, and Jason-2 based on the ITRF2008 reference frame using SLR and DORIS data and for Jason-2 using GPS data. In addition, we have continued to experiment with improvements to the radiation pressure model for the altimeter satellites in particular the Jason satellites since these nonconservative force model errors now rank as the most outstanding source of error on altimeter satellite POD. In the previous (ITRF2005-based) and current (ITRF2008-based) orbits we have relied on a simplified time-variable gravity (TVG) model, derived from GRACE solutions. We have recently experimented with improvements using higher fidelity TVG models (both temporally and spatially) and report on the results. We have computed a time series of GPS-only reduced-dynamic orbits at GSFC, and used these in conjunction with the SLR-DORIS dynamic and reduced-dynamic orbits to assess reference fiame stability with respect to the different tracking systems for both ITRF2005 and ITRF2008. We show through internal (GSFConly) and external comparisons (with other analysis centers) that the radial orbit accuracy for Jason-2 remains at I cm

Capturing Old-Growth Values for Use in Forest Decision-Making

Abstract Old-growth forests have declined significantly across the world. Decisions related to old growth are often mired in challenges of value diversity, conflict, data gaps, and resource pressures. This article describes old-growth values of citizens and groups in Nova Scotia, Canada, for integration in sustainable forest management (SFM) decision-making. The study is based on data from 76 research subjects who participated in nine field trips to forest stands. Research subjects were drawn from Aboriginal groups, environmental organizations, forestry professionals, and rural and urban publics. Diaries, group discussions, and rating sheets were used to elicit information during the field trips. Findings show that different elicitation techniques can influence the articulation of intensity with which some values are held. In addition, certain values are more often associated with old-growth than with other forest-age classes. Some values associated with old-growth are considered more important than others, and some silvicultural treatments are perceived to compromise old-growth values more than others. Demographic characteristics, such as constituency group, gender, and age, are shown to influence value priorities. Ideas on how to incorporate old-growth values into SFM decision-making are highlighted

Assessment of Current Global and Regional Mean Sea Level Estimates Based on the TOPEX/Poseidon Jason-1 and 2 Climate Data Record

Recent developments in Precise Orbit Determinations (POD) due to in particular to revisions to the terrestrial reference frame realization and the time variable gravity (TVG) continues to provide improvements to the accuracy and stability of the PO directly affecting mean sea level (MSL) estimates. Long-term credible MSL estimates require the development and continued maintenance of a stable reference frame, along with vigilant monitoring of the performance of the independent tracking systems used to calculate the orbits for altimeter spacecrafts. The stringent MSL accuracy requirements of a few tenths of an mm/yr are particularly essential for mass budget closure analysis over the relative short time period of Jason-l &2, GRACE, and Argo coincident measurements. In an effort to adhere to cross mission consistency, we have generated a full time series of experimental orbits (GSFC stdlllO) for TOPEX/Poseidon (TP), Jason-I, and OSTM based on an improved terrestrial reference frame (TRF) realization (ITRF2008), revised static (GGM03s), and time variable gravity field (Eigen6s). In this presentation we assess the impact of the revised precision orbits on inter-mission bias estimates, and resultant global and regional MSL trends. Tide gauge verification results are shown to assess the current stability of the Jason-2 sea surface height time series that suggests a possible discontinuity initiated in early 2010. Although the Jason-2 time series is relatively short (approximately 3 years), a thorough review of the entire suite of geophysical and environmental range corrections is warranted and is underway to maintain the fidelity of the record

Weight change over two years in people prescribed olanzapine, quetiapine and risperidone in UK primary care: Cohort study in THIN, a UK primary care database

BACKGROUND: Follow-up studies of weight gain related to antipsychotic treatment beyond a year are limited in number. We compared weight change in the three most commonly prescribed antipsychotics in a representative UK General Practice database. METHOD: We conducted a cohort study in United Kingdom primary care records of people newly prescribed olanzapine, quetiapine or risperidone. The primary outcome was weight in each six month period for two years after treatment initiation. Weight changes were compared using linear regression, adjusted for age, baseline weight and diagnosis. RESULTS: N = 6338 people received olanzapine, 12,984 quetiapine and 6556 risperidone. Baseline weight was lowest for men treated with olanzapine (80.8 kg versus 83.5 kg quetiapine, 82.0 kg risperidone) and women treated with olanzapine (67.7 kg versus 71.5 kg quetiapine 68.4 kg risperidone. Weight gain occurred during treatment with all three drugs. Compared with risperidone mean weight gain was higher with olanzapine (adjusted co-efficient +1.24 kg (95% confidence interval: 0.69–1.79 kg per six months) for men and +0.77 kg (95% confidence interval: 0.29–1.24 kg) for women). Weight gain with quetiapine was lower in unadjusted models compared with risperidone, but this difference was not significant after adjustment. CONCLUSION: Olanzapine is more commonly prescribed to people with lower weight. However, after accounting for baseline weight, age, sex and diagnosis, olanzapine is still associated with greater weight gain over two years than risperidone or quetiapine. Baseline weight does not ameliorate the risks of weight gain associated with antipsychotic medication. Weight gain should be assertively discussed and managed for people prescribed antipsychotics, especially olanzapine

Structural and functional analysis of the pro-domain of human cathelicidin, LL-37

Cathelicidins form a family of small host defense peptides distinct from another class of cationic antimicrobial peptides, the defensins. They are expressed as large precursor molecules with a highly conserved pro-domain known as the cathelin-like domain (CLD). CLDs have high degrees of sequence homology to cathelin, a protein isolated from pig leukocytes and belonging to the cystatin family of cysteine protease inhibitors. In this report, we describe for the first time the X-ray crystal structure of the human CLD (hCLD) of the sole human cathelicidin, LL-37. The structure of hCLD, determined at 1.93 Å resolution, shows the cystatin-like fold and is highly similar to the structure of the CLD of the pig cathelicidin, protegrin-3. We assayed the in vitro antibacterial activities of hCLD, LL-37 and the precursor form, pro-cathelicidin (also known as hCAP18), and we found that the unprocessed protein inhibited the growth of Gramnegative bacteria with efficiencies comparable to the mature peptide, LL-37. In addition, the antibacterial activity of LL-37 was not inhibited by hCLD intermolecularly, since exogenously added hCLD had no effect on the bactericidal activity of the mature peptide. hCLD itself lacked antimicrobial function and did not inhibit the cysteine protease, cathepsin L. Our results contrast with previous reports of hCLD activity. A comparative structural analysis between hCLD and the cysteine protease inhibitor stefin A showed why hCLD is unable to function as an inhibitor of cysteine proteases. In this respect, the cystatin scaffold represents an ancestral structural platform from which proteins evolved divergently, with some losing inhibitory functions