The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. ...WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.
Abstract
We perform the first simultaneous Bayesian parameter inference and optimal reconstruction of the gravitational lensing of the cosmic microwave background (CMB), using 100 deg
2
of ...polarization observations from the SPTpol receiver on the South Pole Telescope. These data reach noise levels as low as 5.8
μ
K arcmin in polarization, which are low enough that the typically used quadratic estimator (QE) technique for analyzing CMB lensing is significantly suboptimal. Conversely, the Bayesian procedure extracts all lensing information from the data and is optimal at any noise level. We infer the amplitude of the gravitational lensing potential to be
A
ϕ
=
0.949
±
0.122
using the Bayesian pipeline, consistent with our QE pipeline result, but with 17% smaller error bars. The Bayesian analysis also provides a simple way to account for systematic uncertainties, performing a similar job as frequentist “bias hardening” or linear bias correction, and reducing the systematic uncertainty on
A
ϕ
due to polarization calibration from almost half of the statistical error to effectively zero. Finally, we jointly constrain
A
ϕ
along with
A
L
, the amplitude of lensing-like effects on the CMB power spectra, demonstrating that the Bayesian method can be used to easily infer parameters both from an optimal lensing reconstruction and from the delensed CMB, while exactly accounting for the correlation between the two. These results demonstrate the feasibility of the Bayesian approach on real data, and pave the way for future analysis of deep CMB polarization measurements with SPT-3G, Simons Observatory, and CMB-S4, where improvements relative to the QE can reach 1.5 times tighter constraints on
A
ϕ
and seven times lower effective lensing reconstruction noise.
New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 ...keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.
Abstract Background and purpose To document and provide a micro analysis of the relationship between insomnia and health problems, health-care use, absenteeism, productivity and accidents. ...Participants and methods A population-based sample of 953 French-speaking adults from Québec, Canada. Participants were categorized as having insomnia syndrome (SYND) or insomnia symptoms (SYMPT) or as good sleepers (GS). They completed questionnaires on sleep, health, use of health-care services and products, accidents, work absences and reduced work productivity. Data were also obtained from the Québec-government-administered health insurance board on selected variables (e.g., consultations with health-care professionals, diagnoses). Results There were significantly more individuals in the SYND group relative to the GS group reporting at least one chronic health problem (83% vs. 53%; OR: 2.78) and who had consulted a health-care professional in the past year (81% vs. 60%; OR: 2.8). There were also higher proportions of individuals in the SYND group than in the GS group who had used prescription medications (57% vs. 30.7%; OR: 2.8), most notably to treat insomnia, mood and anxiety disorders, or who had used over-the-counter products (75.6% vs. 62.0%; OR: 1.8) and alcohol as a sleep aid (17.8% vs. 3.9%; OR: 4.6). In terms of daytime function, 25.0% of the SYND had been absent from work relative to 17.1% of GS (OR: 1.7), 40.6% reported having experienced reduced productivity compared to 12.3% of GS (OR: 4.8) and non-motor-vehicle accidents occurred at higher rates in the SYND group (12.5% vs. 6.4% for GS; OR: 2.4). No differences were found for hospitalisations or motor-vehicle accidents. Most of the associations remained significant even after controlling for psychiatric comorbidity. Rates for the SYMPT group were situated between SYND and GS on all major dependent variables. Furthermore, insomnia and fatigue were perceived as contributing significantly to accidents, absences and decreased work productivity, regardless of insomnia status. Conclusions This study indicates that insomnia is associated with significant morbidity in terms of health problems and health-care utilization, work absenteeism and reduced productivity, and risk of non-motor-vehicle accidents. Future studies should evaluate whether treating insomnia can reverse this morbidity.
To estimate the prevalence of insomnia symptoms and syndrome in the general population, describe the types of self-help treatments and consultations initiated for insomnia, and examine help-seeking ...determinants.
A randomly selected sample of 2001 French-speaking adults from the province of Quebec (Canada) responded to a telephone survey about sleep, insomnia, and its treatments.
Of the total sample, 25.3% were dissatisfied with their sleep, 29.9% reported insomnia symptoms, and 9.5% met criteria for an insomnia syndrome. Thirteen percent of the respondents had consulted a healthcare provider specifically for insomnia in their lifetime, with general practitioners being the most frequently consulted. Daytime fatigue (48%), psychological distress (40%), and physical discomfort (22%) were the main determinants prompting individuals with insomnia to seek treatment. Of the total sample, 15% had used at least once herbal/dietary products to facilitate sleep and 11% had used prescribed sleep medications in the year preceding the survey. Other self-help strategies employed to facilitate sleep included reading, listening to music, and relaxation.
These findings confirm the high prevalence of insomnia in the general population. While few insomnia sufferers seek professional consultations, many individuals initiate self-help treatments, particularly when daytime impairments such as fatigue become more noticeable. Improved knowledge of the determinants of help-seeking behaviors could guide the development of effective public health prevention and intervention programs to promote healthy sleep.
Objective assessment of activity via accelerometry can provide valuable insights into dog health and welfare. Common activity metrics involve using acceleration cut-points to group data into ...intensity categories and reporting the time spent in each category. Lack of consistency and transparency in cut-point derivation makes it difficult to compare findings between studies. We present an alternative metric for use in dogs: the acceleration threshold (as a fraction of standard gravity, 1 g = 9.81 m/s 2 ) above which the animal's X most active minutes are accumulated (MX ACC ) over a 24-hour period. We report M2 ACC, M30 ACC and M60 ACC data from a colony of healthy beagles ( n = 6) aged 3–13 months. To ensure that reference values are applicable across a wider dog population, we incorporated labelled data from beagles and volunteer pet dogs ( n = 16) of a variety of ages and breeds. The dogs' normal activity patterns were recorded at 200 Hz for 24 hours using collar-based Axivity-AX3 accelerometers. We calculated acceleration vector magnitude and MX ACC metrics. Using labelled data from both beagles and pet dogs, we characterize the range of acceleration outputs exhibited enabling meaningful interpretation of MX ACC . These metrics will help standardize measurement of canine activity and serve as outcome measures for veterinary and translational research.
American Indians (AI) have the highest smoking rates and lowest quit rates of any racial/ethnic group in the U.S. Researchers and community members from the American Indian Health Research and ...Education Alliance (AIHREA) created and evaluated a culturally-tailored smoking cessation program, All Nations Breath of Life (ANBL) as a recruitment tool for smoking cessation programs among AI. To increase enrollment in ANBL, AI smokers were approached at cultural events and asked to attend a 30-minute educational session (in-person, n= 179; tele-video, n=97). Tele-video (30%) and in-person (9%) session participants were recruited into ANBL. Pre- and post-tests showed participants in both sessions demonstrated increased motivation and confidence to quit smoking but significant differences were present in both sessions (p < 0.0001). Results indicate that theoretically guided and culturally tailored education sessions are viable approaches to educate and recruit underserved populations into programs that promote smoking cessation.
Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have ...been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (ie, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (ie, quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (ie, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (ie, quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.
Colorectal cancer (CRC) screening uptake among minorities and those with lower incomes is suboptimal. Behavioral interventions specifically tailored to these populations can increase screening rates ...and save lives. The Precaution Adoption Process Model (PAPM) allows assignment of a decisional stage for adoption of a behavior such as CRC screening. Here, we characterize the PAPM decisional stage distribution among 470 low income, racially and ethnically diverse study participants at intake into a behavioral intervention study designed to increase CRC screening uptake. We staged participants for stool blood test (SBT) and colonoscopy separately and used the highest stage for the two tests as the ‘overall’ stage for CRC screening. For SBT, sex, language (English versus Spanish) and doctor recommendation were significantly related to PAPM stage for CRC screening. For colonoscopy, language, education level, doctor recommendation and self-efficacy were related to stage. For overall CRC screening stage, all the variables associated with either SBT or colonoscopy, with the exception of language were significant. This study suggests attending to these key variables in designing interventions to promote CRC screening, particularly with respect to medically underserved populations.
PDF
