Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Intra- and interpersonal effects of coping style and self-efficacy on anxiety, depression and life satisfaction in patient-partner couples after stroke.

Many stroke patients and partners suffer from anxiety, depression, and low life satisfaction. Psychological factors such as coping style and self-efficacy can be protective factors within individuals. The close relationship between stroke patients and partners suggests that there may be interdependence in psychological functioning. The aim of this study was to examine intra- and interpersonal effects of coping style and self-efficacy on anxiety, depression, and life satisfaction in patient-partners couples. In this prospective cohort study, pro-active coping (UPCC), general self-efficacy (GSES), anxiety (HADS-A), depression (HADS-D), and life satisfaction (1-6 scale) were assessed in 215 couples at 2 and 12 months post-stroke. Effects within couples were assessed using structural equation modelling. Several intra- and interpersonal effects of coping style and self-efficacy at 2 months post-stroke were related to emotional health at 12 months post-stroke. Most effects were intrapersonal effects. The interpersonal effects were small but showed that pro-active coping by the patient was associated with lower anxiety of the partner. Higher self-efficacy of the partner was associated with lower depression scores and higher life satisfaction of the patient. This study underscores the importance of a dyadic approach to post-stroke functioning. It supports a family-based approach for treating post-stroke emotional problems.

Development and operation of the defence COVID-19 lab as a SARS-CoV-2 diagnostic screening capability for UK military personnel.

BACKGROUND: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel. LABORATORY STRUCTURE AND RESOURCE: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists. LABORATORY RESULTS: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started. CONCLUSIONS: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses.

Early mortality during rifampicin-resistant TB treatment.

BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.RESULTS: By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Estimating the global burden of scabies: what else do we need?

Scabies is one of the most common disorders identified in any estimate of global skin disease prevalence. Furthermore, quantifying its impact on individuals and societies has been problematic. There has been a lack of clear case definitions and laboratory tests. There have been few epidemiological studies, particularly those focusing on low-income countries, variation in prevalence within high-income countries, or estimates of the effect of scabies on health beyond the skin, such as renal disease or mental wellbeing. Economic studies are also lacking. However, the new strategy of integrating surveillance for skin Neglected Tropical Diseases may well produce advancements on these issues, in addition to providing an overarching structure for health improvement and disease control.

Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.

Overcoming barriers to the access and uptake of newer drugs for multidrug-resistant TB.

To improve the unsatisfactory treatment outcomes of multidrug-resistant TB (MDR-TB), it is essential we use new regimens based on newer drugs. To address challenges in the introduction of BDQ and the shorter treatment regimen (STR), the USAID has committed to support countries receiving BDQ (through the USAID/Janssen Bedaquiline Donation Program), with targeted short-term technical assistance (TA). Six MDR-TB clinical consultants were recruited and provided TA to 17 countries between 2017 and 2019. Building on other in-country support, this short-term TA proved instrumental in overcoming barriers, such as misconceptions about BDQ safety, inadequate clinical skills to manage patients and limited expansion plans to increase access to BDQ and the STR.

Ischiorectal fossa: benign and malignant neoplasms of this "ignored" radiological anatomical space.

PURPOSE: To review the pertinent anatomy and the imaging features of common and uncommon benign and malignant neoplasms and masses of the ischiorectal fossa. RESULTS: The ischiorectal or ischioanal fossa is the largest space in the anorectal region. The benign neoplasms that develop in the ischiorectal originate from the different components that forms the fossa including vascular tumors such as aggressive angiomyxoma or hemangioma; neural tumors as plexiform neurofibroma or schwannoma; fat tumors as lipoma; skin/skin appendages tumors as hidradenoma papilliferum; smooth or skeletal muscle tumors as solitary fibrous tumor. The malignant neoplasms that develop in the ischiorectal fossa also originate from different components that forms the fossa including vascular tumors such as angiosarcoma, neural tumors as malignant granular cell tumor and malignant peripheral nerve sheath tumor; fat tumors as liposarcoma; smooth or skeletal muscle tumors as leiomyosarcoma, rhabdomyosarcoma, malignant PEComa, or undifferentiated pleomorphic sarcoma. Additionally, the ischiorectal fossa can also harbor secondary hematogenous metastases and be affected by direct invasion from neoplasms of adjacent pelvic organs and structures. Furthermore, other miscellaneous masses can occur in the ischiorectal fossa including congenital and developmental lesions, and inflammatory and infectious processes. CONCLUSION: Knowledge of the anatomy, and the spectrum of imaging findings of common and uncommon benign and malignant neoplasms of the ischiorectal fossa is crucial for the radiologists during interpretation of images allowing them to make contributions to the diagnosis and better patient management.

Health care gaps in the global burden of drug-resistant tuberculosis.

The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

Tumor markers: myths and facts unfolded.

OBJECTIVE: The purpose of this article is to review the most commonly used tumor markers in abdominal and pelvic tumors, describe their limitations and explain how to use them in the context of known cancer in order to optimize multidisciplinary care of oncologic patients. CONCLUSION: Tumor markers are important for the diagnosis, staging, monitoring of treatment and detection of recurrence in many cancers. This knowledge is crucial in the daily interpretation of images of oncologic and non-oncologic patients. However, radiologists should also be aware of the limitations of the most commonly used tumor markers and they should not be used solely, but interpreted in conjunction with diagnostic imaging, clinical history and physical examination that will help optimize the multidisciplinary care and management of oncologic patients.

QTc and anti-tuberculosis drugs: a perfect storm or a tempest in a teacup? Review of evidence and a risk assessment.

Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens. DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use. RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them. CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?

For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Missed opportunities for earlier diagnosis of rifampicin-resistant tuberculosis despite access to Xpert® MTB/RIF.

OBJECTIVE: To assess the proportion of rifampicin-resistant tuberculosis (RR-TB) patients with potential earlier RR-TB diagnoses in Khayelitsha, South Africa. DESIGN: We conducted a retrospective analysis among RR-TB patients diagnosed from 2012 to 2014. Patients were considered to have missed opportunities for earlier diagnosis if 1) they were incorrectly screened according to the Western Cape diagnostic algorithm; 2) the first specimen was not tested using Xpert® MTB/RIF; 3) no specimen was ever tested; or 4) the initial Xpert test showed a negative result, but no subsequent specimen was sent for follow-up testing in human immunodeficiency virus-positive patients. RESULTS: Among 543 patients, 386 (71%) were diagnosed with Xpert and 112 (21%) had had at least one presentation at a health care facility within the 6 months before the presentation at which RR-TB was diagnosed. Overall, 95/543 (18%) patients were screened incorrectly at some point: 48 at diagnostic presentation only, 38 at previous presentation only, and 9 at both previous and diagnostic presentations. CONCLUSIONS: These data show that a significant proportion of RR-TB patients might have been diagnosed earlier, and suggest that case detection could be improved if diagnostic algorithms were followed more closely. Further training and monitoring is required to ensure the greatest benefit from universal Xpert implementation.

Is the Ergogenicity of Caffeine Affected by Increasing Age? The Direct Effect of a Physiological Concentration of Caffeine on the Power Output of Maximally Stimulated EDL and Diaphragm Muscle Isolated from the Mouse.

INTRODUCTION: Caffeine is a well-established performance enhancing nutritional supplement in a young healthy population, however far less is known about how its ergogenicity is affected by increasing age. A recent review has highlighted the value of studies examining the direct effect of caffeine on isolated skeletal muscle contractility, but the present work is the first to assess the direct effect of 70µM caffeine (physiological maximum) on the maximal power output of isolated mammalian muscle from an age range representing developmental to early ageing. METHOD: Female CD1 mice were aged to 3, 10, 30 and 50 weeks (n = 20 in each case) and either whole EDL or a section of the diaphragm was isolated and maximal power output determined using the work loop technique. Once contractile performance was maximised, each muscle preparation was treated with 70µM caffeine and its contractile performance was measured for a further 60 minutes. RESULTS: In both mouse EDL and diaphragm 70µM caffeine treatment resulted in a significant increase in maximal muscle power output that was greatest at 10 or 30 weeks (up to 5% and 6% improvement respectively). This potentiation of maximal muscle power output was significantly lower at the early ageing time point, 50 weeks (up to 3% and 2% improvement respectively), and in mice in the developmental stage, at 3 weeks of age (up to 1% and 2% improvement respectively). CONCLUSION: Uniquely, the present findings indicate a reduced age specific sensitivity to the performance enhancing effect of caffeine in developmental and aged mice which is likely to be attributed to age related muscle growth and degradation, respectively. Importantly, the findings indicate that caffeine may still provide a substantial ergogenic aid in older populations which could prove important for improving functional capacity in tasks of daily living.

Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis.

OBJECTIVE: To determine the duration of clinical benefit among patients with psoriatic arthritis (PsA) discontinuing tumour necrosis factor inhibitor (TNFi) therapy while in low disease activity (LDA), and to identify patient characteristics associated with prolonged clinical benefit. METHODS: We performed an observational cohort study assessing patients with PsA from the Consortium of Rheumatology Researchers of North America (CORRONA) registry who had discontinued TNFi after achieving LDA, defined as clinical disease activity index (CDAI) score ≤10 and physician's global assessment (PGA) of skin psoriasis ≤20/100. Kaplan-Meier method was used to estimate the duration of clinical benefit. RESULTS: Of the 5945 patients with PsA in CORRONA, 302 patients had discontinued TNFi (n=325) while in LDA and had follow-up data available. At time of discontinuation, mean PsA duration was 9.8 years, mean CDAI was 3.9, and mean duration of TNFi use was 1.5 years; 52.6% of patients had discontinued their first TNFi. Median time to loss of benefit was 29.2 months. 179 (55.1%) patients had persistent benefit at their previous clinic visit. An increased risk of losing clinical benefit was seen among patients with higher disease activity at discontinuation (CDAI≥3.2 vs <3.2; HR 1.43 (p=0.32)) and among smokers (HR 1.78 (p=0.027)). CONCLUSIONS: Patients with PsA who achieve LDA may maintain clinical benefit after discontinuation of TNFi therapy.

World Health Organization recommendations for multidrug-resistant tuberculosis: should different standards be applied?

The World Health Organization uses a Grading of Recommendations Assessment, Development, and Evaluation process to make recommendations for treating multidrug-resistant tuberculosis. Even with this standardized approach, there have been discrepancies between recommendations for newer drugs such as bedaquiline and delamanid and the shorter regimen. This may be because newer drugs are novel chemical entities and may merit closer scrutiny. Here, we explore the problematic nature of this supposition, arguing that although the newer drugs have been used in fewer individuals, they may have more robust efficacy and safety data than many of the second-line drugs used in the shorter regimen.