Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial

Background: The STREAM trial demonstrated that a 9–11-month “short” regimen had non-inferior efficacy and comparable safety to a 20+ month “long” regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. / Methods: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. / Results: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3–4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. / Conclusion: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included

Experimental Analysis of Nonlinear Impairments in Fibre Optic Transmission Systems up to 7.3 THz

An effective way of increasing the overall optical fibre capacity is by expanding the bandwidth used to transmit signals. In this paper, the impact of expanding the transmission bandwidth on the optical communication system is experimentally studied using the achievable rates as a performance metric. The trade-offs between the use of larger bandwidths and higher nonlinear interference (NLI) noise is experimentally and theoretically analysed. The growth of NLI noise is investigated for spectral bandwidths from 40 GHz up to 7.3 THz using 64-QAM and Nyquist pulse-shaping. Experimental results are shown to be in line with the predictions from the Gaussian-Noise model showing a logarithmic growth in NLI noise as the signal bandwidth is extended. A reduction of the information rate of only 10 % was found between linear and non-linear transmission across several transmission bandwidths, increasing up to 7.3 THz. Finally, the power transfer between channels due to stimulated Raman scattering effect is analysed showing up to 2 dB power tilt at optimum power for the largest transmitted bandwidth of 7.3 THz

Contribution of anadromous fish to the diet of European catfish in a large river system

Many anadromous fish species, when migrating from the sea to spawn in fresh waters, can potentially be a valuable prey for larger predatory fish, thereby efficiently linking these two ecosystems. Here, we assess the contribution of anadromous fish to the diet of European catfish (Silurus glanis) in a large river system (Garonne, southwestern France) using stable isotope analysis and allis shad (Alosa alosa) as an example of anadromous fish. Allis shad caught in the Garonne had a very distinct marine delta(13)C value, over 8 per thousand higher after lipid extraction compared to the mean delta(13)C value of all other potential freshwater prey fish. The delta(13)C values of European catfish varied considerably between these two extremes and some individuals were clearly specializing on freshwater prey, whereas others specialized on anadromous fish. The mean contribution of anadromous fish to the entire European catfish population was estimated to be between 53% and 65%, depending on the fractionation factor used for delta(13)C

Neurovascular coupling and cerebral autoregulation in atrial fibrillation

© The Author(s) 2019. The risk of cognitive decline and stroke is increased by atrial fibrillation (AF). We sought to determine whether neurovascular coupling and cerebral autoregulation are blunted in people with AF in comparison with age-matched, patients with hypertension and healthy controls. Neurovascular coupling was assessed using five cycles of visual stimulation for 30 s followed by 30 s with both eyes-closed. Cerebral autoregulation was examined using a sit–stand test, and a repeated squat-to-stand (0.1 Hz) manoeuvre with transfer function analysis of mean arterial pressure (MAP; input) and middle cerebral artery mean blood flow velocity (MCA Vm; output) relationships at 0.1 Hz. Visual stimulation increased posterior cerebral artery conductance, but the magnitude of the response was blunted in patients with AF (18 [8] %; mean [SD]) and hypertension (17 [8] %), in comparison with healthy controls (26 [9] %) (P < 0.05). In contrast, transmission of MAP to MCA Vm was greater in AF patients compared to hypertension and healthy controls, indicating diminished cerebral autoregulation. We have shown for the first time that AF patients have impaired neurovascular coupling responses to visual stimulation and diminished cerebral autoregulation. Such deficits in cerebrovascular regulation may contribute to the increased risk of cerebral dysfunction in people with AF

The Evaluation of a Standardised Treatment Regimen of anti-Tuberculosis Drugs for Patients with MDR-TB (STREAM): study protocol for a randomised controlled trial

Background: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection. Methods/Design: STREAM is a multi-centre randomized trial of n on-inferiority design comparing a nine-month regimen to the treatment currently recommended by th e World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites. Discussion: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM t rial together with data fr om ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB. Trial registration: This trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010

Identifying factors likely to influence compliance with diagnostic imaging guideline recommendations for spine disorders among chiropractors in North America: a focus group study using the Theoretical Domains Framework

Background: The Theoretical Domains Framework (TDF) was developed to investigate determinants of specific clinical behaviors and inform the design of interventions to change professional behavior. This framework was used to explore the beliefs of chiropractors in an American Provider Network and two Canadian provinces about their adherence to evidence-based recommendations for spine radiography for uncomplicated back pain. The primary objective of the study was to identify chiropractors’ beliefs about managing uncomplicated back pain without xrays and to explore barriers and facilitators to implementing evidence-based recommendations on lumbar spine xrays. A secondary objective was to compare chiropractors in the United States and Canada on their beliefs regarding the use of spine x-rays. Methods: Six focus groups exploring beliefs about managing back pain without x-rays were conducted with a purposive sample. The interview guide was based upon the TDF. Focus groups were digitally recorded, transcribed verbatim, and analyzed by two independent assessors using thematic content analysis based on the TDF. Results: Five domains were identified as likely relevant. Key beliefs within these domains included the following: conflicting comments about the potential consequences of not ordering x-rays (risk of missing a pathology, avoiding adverse treatment effects, risks of litigation, determining the treatment plan, and using x-ray-driven techniques contrasted with perceived benefits of minimizing patient radiation exposure and reducing costs; beliefs about consequences); beliefs regarding professional autonomy, professional credibility, lack of standardization, and agreement with guidelines widely varied (social/professional role & identity); the influence of formal training, colleagues, and patients also appeared to be important factors (social influences); conflicting comments regarding levels of confidence and comfort in managing patients without x-rays (belief about capabilities); and guideline awareness and agreements (knowledge). Conclusions: Chiropractors’ use of diagnostic imaging appears to be influenced by a number of factors. Five key domains may be important considering the presence of conflicting beliefs, evidence of strong beliefs likely to impact the behavior of interest, and high frequency of beliefs. The results will inform the development of a theorybased survey to help identify potential targets for behavioral-change strategies

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

The systematic guideline review: method, rationale, and test on chronic heart failure

Background: Evidence-based guidelines have the potential to improve healthcare. However, their de-novo-development requires substantial resources-especially for complex conditions, and adaptation may be biased by contextually influenced recommendations in source guidelines. In this paper we describe a new approach to guideline development-the systematic guideline review method (SGR), and its application in the development of an evidence-based guideline for family physicians on chronic heart failure (CHF). Methods: A systematic search for guidelines was carried out. Evidence-based guidelines on CHF management in adults in ambulatory care published in English or German between the years 2000 and 2004 were included. Guidelines on acute or right heart failure were excluded. Eligibility was assessed by two reviewers, methodological quality of selected guidelines was appraised using the AGREE instrument, and a framework of relevant clinical questions for diagnostics and treatment was derived. Data were extracted into evidence tables, systematically compared by means of a consistency analysis and synthesized in a preliminary draft. Most relevant primary sources were re-assessed to verify the cited evidence. Evidence and recommendations were summarized in a draft guideline. Results: Of 16 included guidelines five were of good quality. A total of 35 recommendations were systematically compared: 25/35 were consistent, 9/35 inconsistent, and 1/35 un-rateable (derived from a single guideline). Of the 25 consistencies, 14 were based on consensus, seven on evidence and four differed in grading. Major inconsistencies were found in 3/9 of the inconsistent recommendations. We re-evaluated the evidence for 17 recommendations (evidence-based, differing evidence levels and minor inconsistencies) - the majority was congruent. Incongruity was found where the stated evidence could not be verified in the cited primary sources, or where the evaluation in the source guidelines focused on treatment benefits and underestimated the risks. The draft guideline was completed in 8.5 man-months. The main limitation to this study was the lack of a second reviewer. Conclusion: The systematic guideline review including framework development, consistency analysis and validation is an effective, valid, and resource saving-approach to the development of evidence-based guidelines

A demographic and epidemiological study of a Mexican chiropractic college public clinic

<p>Abstract</p> <p>Background</p> <p>Descriptive studies of chiropractic patients are not new, several have been performed in the U.S., Australia, Canada, and Europe. None have been performed in a Latin American country. The purpose of this study is to describe the patients who visited a Mexican chiropractic college public clinic with respect to demographics and clinical characteristics.</p> <p>Methods</p> <p>This study was reviewed and approved by the IRB of Parker College of Chiropractic and the Universidad Estatal del Valle de Ecatepec (UNEVE). Five hundred patient files from the UNEVE public clinic from May 2005 to May 2007 were selected from an approximate total number of 3,700. Information was collected for demographics, chief complaints, associated complaints, and previous care sought.</p> <p>Results</p> <p>The sample comprised 306 (61.2%) female. Most files (44.2%) were in the age range of 40–59 years (mean of 43.4 years). The most frequent complaints were lumbar pain (29.2%) and extremity pain (28.0%), most commonly the knee. Most (62.0%) described their complaints as greater than one year. Trauma (46.6%) was indicated as the initial cause. Mean VAS score was 6.26/10 with 20% rated at 8/10.</p> <p>Conclusion</p> <p>Demographic results compared closer to studies conducted with private clinicians (females within the ages of 40–59). The primary complaint and duration was similar to previous studies (low back pain and chronic), except in this population the cause was usually initiated by trauma. The most striking features were the higher number of extremity complaints and the marked increased level of VAS score (20% rated as 8/10).</p