Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses

CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study

<p>Abstract</p> <p>Background</p> <p>It is unknown whether defining chronic kidney disease (CKD) based on one versus two estimated glomerular filtration rate (eGFR) assessments changes the prognostic importance of reduced eGFR in a community-based population.</p> <p>Methods</p> <p>Participants in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study were classified into 4 groups based on two eGFR assessments separated by 35.3 ± 2.5 months: sustained eGFR < 60 mL/min per 1.73 m²(1 mL/sec per 1.73 m²); eGFR increase (change from below to above 60); eGFR decline (change from above to below 60); and eGFR persistently ≥60. Outcomes assessed in stratified multivariable Cox models included cardiac events and a composite of cardiac events, stroke, and mortality.</p> <p>Results</p> <p>There were 891 (4.9%) participants with sustained eGFR < 60, 278 (1.5%) with eGFR increase, 972 (5.4%) with eGFR decline, and 15,925 (88.2%) with sustained eGFR > 60. Participants with eGFR sustained < 60 were at highest risk of cardiac and composite events [HR = 1.38 (1.15, 1.65) and 1.58 (1.41, 1.77)], respectively, followed by eGFR decline [HR = 1.20 (1.00, 1.45) and 1.32 (1.17, 1.49)]. Individuals with eGFR increase trended toward increased cardiac risk [HR = 1.25 (0.88, 1.77)] and did not significantly differ from eGFR decline for any outcome. Results were similar when estimating GFR with the CKD-EPI equation.</p> <p>Conclusion</p> <p>Individuals with persistently reduced eGFR are at highest risk of cardiovascular outcomes and mortality, while individuals with an eGFR < 60 mL/min per 1.73 m²at any time are at intermediate risk. Use of even a single measurement of eGFR to classify CKD in a community population appears to have prognostic value.</p

Reference Data for the Ruff Figural Fluency Test Stratified by Age and Educational Level

The Ruff Figural Fluency Test (RFFT) was developed to avoid the difficulties that were encountered in earlier tests of figural fluency. Although the test characteristics of the RFFT seem to be good and it is a valuable addition to neuropsychological assessments, reference data are still scarce. To this aim, we required 2,404 community dwelling persons in Groningen, the Netherlands to perform the RFFT. All 1,651 persons with a complete RFFT and known educational level formed the reference sample. Their age ranged from 35 to 82 years and their educational level from primary school to university grade. Ninety-six percent of the persons were of Western European descent. All tests were analyzed by two independent examiners and subsequently three measures were calculated: number of unique designs, number of perseverative errors and error ratio. The main finding was that performance on the RFFT was dependent on age and educational level. This was not only observed in older persons but also in young and middle-aged persons. Reference data for the three RFFT measures are presented in groups of five years of age ranging from 35–39 years to 75 years or older

The stigma of obesity in the general public and its implications for public health - a systematic review

<p>Abstract</p> <p>Background</p> <p>Up to this date, prevalence rates of obesity are still rising. Aside from co-morbid diseases, perceived discrimination and stigmatization leads to worsen outcomes in obese individuals. Higher stigmatizing attitudes towards obese individuals may also result in less support of preventive and interventive measures. In light of the immense burden of obesity on health care systems and also on the individuals' quality of life, accepted and subsidized preventive measures are needed. Policy support might be determined by views of the lay public on causes of obesity and resulting weight stigma. This study seeks to answer how representative samples of the lay public perceive people with obesity or overweight status (stigmatizing attitudes); what these samples attribute obesity to (causal attribution) and what types of interventions are supported by the lay public and which factors determine that support (prevention support).</p> <p>Methods</p> <p>A systematic literature search was conducted. All studies of representative samples reporting results on (a) stigmatizing attitudes towards overweight and obese individuals, (b) causal beliefs and (c) prevention support were included.</p> <p>Results</p> <p>Only 7 articles were found. One study reported prevalence rates of stigmatizing attitudes. About a quarter of the population in Germany displayed definite stigmatizing attitudes. Other studies reported causal attributions. While external influences on weight are considered as well, it seems that internal factors are rated to be of higher importance. Across the studies found, regulative prevention is supported by about half of the population, while childhood prevention has highest approval rates. Results on sociodemographic determinants differ substantially.</p> <p>Conclusions</p> <p>Further research on public attitudes toward and perception of overweight and obesity is urgently needed to depict the prevailing degree of stigmatization. Introducing a multidimensional concept of the etiology of obesity to the lay public might be a starting point in stigma reduction.</p

Information Discovery on Electronic Health Records Using Authority Flow Techniques

<p>Abstract</p> <p>Background</p> <p>As the use of electronic health records (EHRs) becomes more widespread, so does the need to search and provide effective information discovery within them. Querying by keyword has emerged as one of the most effective paradigms for searching. Most work in this area is based on traditional Information Retrieval (IR) techniques, where each document is compared individually against the query. We compare the effectiveness of two fundamentally different techniques for keyword search of EHRs.</p> <p>Methods</p> <p>We built two ranking systems. The traditional BM25 system exploits the EHRs' content without regard to association among entities within. The Clinical ObjectRank (CO) system exploits the entities' associations in EHRs using an authority-flow algorithm to discover the most relevant entities. BM25 and CO were deployed on an EHR dataset of the cardiovascular division of Miami Children's Hospital. Using sequences of keywords as queries, sensitivity and specificity were measured by two physicians for a set of 11 queries related to congenital cardiac disease.</p> <p>Results</p> <p>Our pilot evaluation showed that CO outperforms BM25 in terms of sensitivity (65% vs. 38%) by 71% on average, while maintaining the specificity (64% vs. 61%). The evaluation was done by two physicians.</p> <p>Conclusions</p> <p>Authority-flow techniques can greatly improve the detection of relevant information in EHRs and hence deserve further study.</p

Prevalence and factors associated with poor performance in the 5‐chair stand test: findings from the Cognitive Function and Ageing Study II and proposed Newcastle protocol for use in the assessment of sarcopenia

Background Poor performance in the 5‐chair stand test (5‐CST) indicates reduced lower limb muscle strength. The 5‐CST has been recommended for use in the initial assessment of sarcopenia, the accelerated loss of muscle strength and mass. In order to facilitate the use of the 5‐CST in sarcopenia assessment, our aims were to (i) describe the prevalence and factors associated with poor performance in the 5‐CST, (ii) examine the relationship between the 5‐CST and gait speed, and (iii) propose a protocol for using the 5‐CST. Methods The population‐based study Cognitive Function and Ageing Study II recruited people aged 65 years and over from defined geographical localities in Cambridgeshire, Newcastle, and Nottingham. The study collected data for assessment of functional ability during home visits, including the 5‐CST and gait speed. We used multinomial logistic regression to assess the associations between factors including the SARC‐F questionnaire and the category of 5‐CST performance: fast (15 s), or unable, with slow/unable classed as poor performance. We reviewed previous studies on the protocol used to carry out the 5‐CST. Results A total of 7190 participants aged 65+ from the three diverse localities of Cognitive Function and Ageing Study II were included (54.1% female). The proportion of those with poor performance in the 5‐CST increased with age, from 34.3% at age 65–69 to 89.7% at age 90+. Factors independently associated with poor performance included positive responses to the SARC‐F questionnaire, physical inactivity, depression, impaired cognition, and multimorbidity (all P < 0.005). Most people with poor performance also had slow gait speed (57.8%) or were unable to complete the gait speed test (18.4%). We found variation in the 5‐CST protocol used, for example, timing until a participant stood up for the fifth time or until they sat down afterwards. Conclusions Poor performance in the 5‐CST is increasingly common with age and is associated with a cluster of other factors that characterize risk for poor ageing such as physical inactivity, impaired cognition, and multimorbidity. We recommend a low threshold for performing the 5‐CST in clinical settings and provide a protocol for its use

A Model for the Ultrastructure of Bone Based on Electron Microscopy of Ion-Milled Sections

The relationship between the mineral component of bone and associated collagen has been a matter of continued dispute. We use transmission electron microscopy (TEM) of cryogenically ion milled sections of fully-mineralized cortical bone to study the spatial and topological relationship between mineral and collagen. We observe that hydroxyapatite (HA) occurs largely as elongated plate-like structures which are external to and oriented parallel to the collagen fibrils. Dark field images suggest that the structures (“mineral structures”) are polycrystalline. They are approximately 5 nm thick, 70 nm wide and several hundred nm long. Using energy-dispersive X-ray analysis we show that approximately 70% of the HA occurs as mineral structures external to the fibrils. The remainder is found constrained to the gap zones. Comparative studies of other species suggest that this structural motif is ubiquitous in all vertebrates

An evaluation of access to health care services along the rural-urban continuum in Canada

<p>Abstract</p> <p>Background</p> <p>Studies comparing the access to health care of rural and urban populations have been contradictory and inconclusive. These studies are complicated by the influence of other factor which have been shown to be related to access and utilization. This study assesses the equity of access to health care services across the rural-urban continuum in Canada before and after taking other determinants of access into account.</p> <p>Methods</p> <p>This is a cross-sectional study of the population of the 10 provinces of Canada using data from the Canadian Community Health Survey (CCHS 2.1). Five different measures of access and utilization are compared across the continuum of rural-urban. Known determinants of utilization are taken into account according to Andersen's Health Behaviour Model (HBM); location of residence at the levels of province, health region, and community is also controlled for.</p> <p>Results</p> <p>This study found that residents of small cities not adjacent to major centres, had the highest reported utilisation rates of influenza vaccines and family physician services, were most likely to have a regular medical doctor, and were most likely to report unmet need. Among the rural categories there was a gradient with the most rural being least likely to have had a flu shot, use specialist physicians services, or have a regular medical doctor. Residents of the most urban centres were more likely to report using specialist physician services. Many of these differences are diminished or eliminated once other factors are accounted for. After adjusting for other factors those living in the most urban areas were more likely to have seen a specialist physician. Those in rural communities had a lower odds of receiving a flu shot and having a regular medical doctor. People residing in the most urban and most rural communities were less likely to have a regular medical doctor. Those in any of the rural categories were less likely to report unmet need.</p> <p>Conclusion</p> <p>Inequities in access to care along the rural-urban continuum exist and can be masked when evaluation is done at a very large scale with gross indicators of rural-urban. Understanding the relationship between rural-urban and other determinants will help policy makers to target interventions appropriately: to specific demographic, provincial, community, or rural categories.</p

Smoking cessation in severe mental ill health : what works? an updated systematic review and meta-analysis

BACKGROUND: People with severe mental ill health are more likely to smoke than those in the general population. It is therefore important that effective smoking cessation strategies are used to help people with severe mental ill health to stop smoking. This study aims to assess the effectiveness and cost -effectiveness of smoking cessation and reduction strategies in adults with severe mental ill health in both inpatient and outpatient settings. METHODS: This is an update of a previous systematic review. Electronic databases were searched during September 2016 for randomised controlled trials comparing smoking cessation interventions to each other, usual care, or placebo. Data was extracted on biochemically-verified, self-reported smoking cessation (primary outcome), as well as on smoking reduction, body weight, psychiatric symptom, and adverse events (secondary outcomes). RESULTS: We included 26 trials of pharmacological and/or behavioural interventions. Eight trials comparing bupropion to placebo were pooled showing that bupropion improved quit rates significantly in the medium and long term but not the short term (short term RR = 6.42 95% CI 0.82-50.07; medium term RR = 2.93 95% CI 1.61-5.34; long term RR = 3.04 95% CI 1.10-8.42). Five trials comparing varenicline to placebo showed that that the addition of varenicline improved quit rates significantly in the medium term (RR = 4.13 95% CI 1.36-12.53). The results from five trials of specialised smoking cessation programmes were pooled and showed no evidence of benefit in the medium (RR = 1.32 95% CI 0.85-2.06) or long term (RR = 1.33 95% CI 0.85-2.08). There was insufficient data to allowing pooling for all time points for varenicline and trials of specialist smoking cessation programmes. Trials suggest few adverse events although safety data were not always reported. Only one pilot study reported cost effectiveness data. CONCLUSIONS: Bupropion and varenicline, which have been shown to be effective in the general population, also work for people with severe mental ill health and their use in patients with stable psychiatric conditions. Despite good evidence for the effectiveness of smoking cessation interventions for people with severe mental ill health, the percentage of people with severe mental ill health who smoke remains higher than that for the general population

Left ventricular twist mechanics during incremental cycling and knee extension exercise in healthy men

Purpose: The objective of the present study was to investigate left ventricular (LV) twist mechanics in response to incremental cycling and isometric knee extension exercises. Methods: Twenty-six healthy male participants (age = 30.42 ± 6.17 years) were used to study peak twist mechanics at rest and during incremental semi-supine cycling at 30 and 60% work rate maximum (W) and during short duration (15 s contractions) isometric knee extension at 40 and 75% maximum voluntary contraction (MVC), using two-dimensional speckle tracking echocardiography. Results: Data presented as mean ± standard deviation or median (interquartile range). LV twist increased from rest to 30% W (13.21° ± 4.63° to 20.04° ± 4.76°, p  0.05), whilst twisting velocity increased (rest 89.15° ± 21.77° s to 75% MVC 124.32° ± 34.89° s, p  0.05) then increased from 40 to 75% MVC [−98.44 (43.54)° s to −138.42 (73.29)° s, p < 0.01]. Apical rotations and rotational velocities were greater than basal during all conditions and intensities (all p < 0.01). Conclusion: Cycling increased LV twist to 30% W which then remained unchanged thereafter, whereas twisting velocities showed further increases to greater intensities. A novel finding is that LV twist was unaffected by incremental knee extension, yet systolic and diastolic twisting velocities augmented with isometric exercise