Trends in HbA1c thresholds for initiation of hypoglycemic agents:Impact of changed recommendations for older and frail patients

Aims: Less strict glycated hemoglobin (HbA1c) thresholds have been recommended in older and/or frail type 2 diabetes (T2D) patients than in younger and less frail patients for initiating hypoglycemic agents since 2011. We aimed to assess trends in HbA1c thresholds at initiation of a first hypoglycemic agent(s) in T2D patients and the influence of age and frailty on these trends. Materials and methods: The groningen initiative to analyze type 2 diabetes treatment (GIANTT) database was used, which includes primary care T2D patients from the north of the Netherlands. Patients initiating a first non-insulin hypoglycemic agent(s) between 2008 and 2014 with an HbA1c measurement within 120 days before initiation were included. The influence of calendar year, age, or frailty and the interaction between calendar year and age or frailty were assessed using multilevel regression analyses adjusted for confounders. Results: We included 4588 patients. The mean HbA1c threshold at treatment initiation was 7.4% up to 2010, decreasing to 7.1% in 2011 and increasing to 7.4% in 2014. This quadratic change over the years was significant (P 0.05). Conclusions: HbA1c thresholds at initiation of a first hypoglycemic agent(s) changed significantly over time, showing a decrease after 2010 and an increase after 2012. The HbA1c threshold at initiation was not influenced by age or frailty, which is in contrast with recommendations for more personalized treatment

Spontaneous upper limb monoplegia secondary to probable cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a clinicopathological disorder characterised by vascular amyloid deposition initially in leptomeningeal and neocortical vessels, and later affecting cortical and subcortical regions. The presence of amyloid within the walls of these vessels leads to a propensity for primary intracerebral haemorrhage. We report the unusual case of a 77-year-old female who presented to our emergency department with sudden onset isolated hypoaesthesia and right upper limb monoplegia. A CT scan demonstrated a peripheral acute haematoma involving the left perirolandic cortices. Subsequent magnetic resonance imaging demonstrated previous superficial haemorrhagic events. One week following discharge the patient re-attended with multiple short-lived episodes of aphasia and jerking of the right upper limb. Further imaging demonstrated oedematous changes around the previous haemorrhagic insult. Cerebral amyloid angiopathy is an overlooked cause of intracerebral haemorrhage; the isolated nature of the neurological deficit in this case illustrates the many guises in which it can present

The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation

The ataxia telangiectasia mutated (ATM) and the ATM- related (ATR) kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933) or ATM and ATR (CGK733) have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB). Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles

Extensor tendon release in tennis elbow: results and prognostic factors in 80 elbows

Purpose The objectives of this study were to evaluate the results in the outpatient treatment of recalcitrant lateral epicondylitis with release of the common extensor origin according to Hohmann and to determine any prognostic factors. Methods Eighty tennis elbows in 77 patients with a characteristic history of activity-related pain at the lateral epicondyle interfering with the activities of daily living refractory to conservative care for at least 6 months and a confirmatory physical examination were included. Clinical outcome was evaluated using the QuickDASH score system. Data were collected before the operation and at the medians of 18 months (range 6–36 months; short term) and 4 years (range 3–6 years; medium term) postoperatively. Results The mean QuickDASH was improved both at the short- and the medium-term follow-ups and did not change significantly between the follow-ups. At the final followup, the QuickDASH was improved in 78 out of 80 elbows and 81% was rated as excellent or good (QuickDASH\40 points). We found a weak correlation between residual symptoms (a high QuickDASH score) at the final follow-up and high level of baseline symptoms (r = 0.388), acute occurrence of symptoms (r = 0.362), long duration of symptoms (r = 0.276), female gender (r = 0.269) and young age (r = 0.203), whereas occurrence in dominant arm, a work-related cause or strenuous work did not correlate significantly with the outcome. Conclusion Open lateral extensor release performed as outpatient surgery results in improved clinical outcome at both short- and medium-term follow-ups with few complications. High baseline disability, sudden occurrence of symptoms, long duration of symptoms, female gender and young age were found to be weak predictors of poor outcome

Conservation of resources theory and research use in health systems

<p>Abstract</p> <p>Background</p> <p>Health systems face challenges in using research evidence to improve policy and practice. These challenges are particularly evident in small and poorly resourced health systems, which are often in locations (in Canada and globally) with poorer health status. Although organizational resources have been acknowledged as important in understanding research use resource theories have not been a focus of knowledge translation (KT) research. What resources, broadly defined, are required for KT and how does their presence or absence influence research use?</p> <p>In this paper, we consider conservation of resources (COR) theory as a theoretical basis for understanding the capacity to use research evidence in health systems. Three components of COR theory are examined in the context of KT. First, resources are required for research uptake. Second, threat of resource loss fosters resistance to research use. Third, resources can be optimized, even in resource-challenged environments, to build capacity for KT.</p> <p>Methods</p> <p>A scan of the KT literature examined organizational resources needed for research use. A multiple case study approach examined the three components of COR theory outlined above. The multiple case study consisted of a document review and key informant interviews with research team members, including government decision-makers and health practitioners through a retrospective analysis of four previously conducted applied health research studies in a resource-challenged region.</p> <p>Results</p> <p>The literature scan identified organizational resources that influence research use. The multiple case study supported these findings, contributed to the development of a taxonomy of organizational resources, and revealed how fears concerning resource loss can affect research use. Some resources were found to compensate for other resource deficits. Resource needs differed at various stages in the research use process.</p> <p>Conclusions</p> <p>COR theory contributes to understanding the role of resources in research use, resistance to research use, and potential strategies to enhance research use. Resources (and a lack of them) may account for the observed disparities in research uptake across health systems. This paper offers a theoretical foundation to guide further examination of the COR-KT ideas and necessary supports for research use in resource-challenged environments.</p

Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002

BACKGROUND: Although diet and activity are key factors in the obesity epidemic, laboratory studies suggest that endocrine disrupting chemicals may also affect obesity. METHODS: We analyzed associations between six phthalate metabolites measured in urine and body mass index (BMI) and waist circumference (WC) in National Health and Nutrition Examination Survey (NHANES) participants aged 6–80. We included 4369 participants from NHANES 1999–2002, with data on mono-ethyl (MEP), mono-2-ethylhexyl (MEHP), mono-n-butyl (MBP), and mono-benzyl (MBzP) phthalate; 2286 also had data on mono-2-ethyl-5-hydroxyhexyl (MEHHP) and mono-2-ethyl-5-oxohexyl (MEOHP) phthalate (2001–2002). Using multiple regression, we computed mean BMI and WC within phthalate quartiles in eight age/gender specific models. RESULTS: The most consistent associations were in males aged 20–59; BMI and WC increased across quartiles of MBzP (adjusted mean BMI = 26.7, 27.2, 28.4, 29.0, p-trend = 0.0002), and positive associations were also found for MEOHP, MEHHP, MEP, and MBP. In females, BMI and WC increased with MEP quartile in adolescent girls (adjusted mean BMI = 22.9, 23.8, 24.1, 24.7, p-trend = 0.03), and a similar but less strong pattern was seen in 20–59 year olds. In contrast, MEHP was inversely related to BMI in adolescent girls (adjusted mean BMI = 25.4, 23.8, 23.4, 22.9, p-trend = 0.02) and females aged 20–59 (adjusted mean BMI = 29.9, 29.9, 27.9, 27.6, p-trend = 0.02). There were no important associations among children, but several inverse associations among 60–80 year olds. CONCLUSION: This exploratory, cross-sectional analysis revealed a number of interesting associations with different phthalate metabolites and obesity outcomes, including notable differences by gender and age subgroups. Effects of endocrine disruptors, such as phthalates, may depend upon endogenous hormone levels, which vary dramatically by age and gender. Individual phthalates also have different biologic and hormonal effects. Although our study has limitations, both of these factors could explain some of the variation in the observed associations. These preliminary data support the need for prospective studies in populations at risk for obesity.National Institutes of Environmental Health Sciences (R21ES013724

Sympatric and Allopatric Divergence of MHC Genes in Threespine Stickleback

Parasites can strongly affect the evolution of their hosts, but their effects on host diversification are less clear. In theory, contrasting parasite communities in different foraging habitats could generate divergent selection on hosts and promote ecological speciation. Immune systems are costly to maintain, adaptable, and an important component of individual fitness. As a result, immune system genes, such as those of the Major Histocompatability Complex (MHC), can change rapidly in response to parasite-mediated selection. In threespine stickleback (Gasterosteus aculeatus), as well as in other vertebrates, MHC genes have been linked with female mating preference, suggesting that divergent selection acting on MHC genes might influence speciation. Here, we examined genetic variation at MHC Class II loci of sticklebacks from two lakes with a limnetic and benthic species pair, and two lakes with a single species. In both lakes with species pairs, limnetics and benthics differed in their composition of MHC alleles, and limnetics had fewer MHC alleles per individual than benthics. Similar to the limnetics, the allopatric population with a pelagic phenotype had few MHC alleles per individual, suggesting a correlation between MHC genotype and foraging habitat. Using a simulation model we show that the diversity and composition of MHC alleles in a sympatric species pair depends on the amount of assortative mating and on the strength of parasite-mediated selection in adjacent foraging habitats. Our results indicate parallel divergence in the number of MHC alleles between sympatric stickleback species, possibly resulting from the contrasting parasite communities in littoral and pelagic habitats of lakes

Characterizing blood metabolomics profiles associated with self-reported food intakes in female twins

Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations

ViennaRNA Package 2.0

<p>Abstract</p> <p>Background</p> <p>Secondary structure forms an important intermediate level of description of nucleic acids that encapsulates the dominating part of the folding energy, is often well conserved in evolution, and is routinely used as a basis to explain experimental findings. Based on carefully measured thermodynamic parameters, exact dynamic programming algorithms can be used to compute ground states, base pairing probabilities, as well as thermodynamic properties.</p> <p>Results</p> <p>The <monospace>ViennaRNA</monospace> Package has been a widely used compilation of RNA secondary structure related computer programs for nearly two decades. Major changes in the structure of the standard energy model, the <it>Turner 2004 </it>parameters, the pervasive use of multi-core CPUs, and an increasing number of algorithmic variants prompted a major technical overhaul of both the underlying <monospace>RNAlib</monospace> and the interactive user programs. New features include an expanded repertoire of tools to assess RNA-RNA interactions and restricted ensembles of structures, additional output information such as <it>centroid </it>structures and <it>maximum expected accuracy </it>structures derived from base pairing probabilities, or <it>z</it>-<it>scores </it>for locally stable secondary structures, and support for input in <monospace>fasta</monospace> format. Updates were implemented without compromising the computational efficiency of the core algorithms and ensuring compatibility with earlier versions.</p> <p>Conclusions</p> <p>The <monospace>ViennaRNA Package 2.0</monospace>, supporting concurrent computations <monospace>via OpenMP</monospace>, can be downloaded from <url>http://www.tbi.univie.ac.at/RNA</url>.</p