The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis-lessons from the South African experience.

Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6-9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa.

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters.

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.

Building the Next Generation of Implementation Science Careers to Advance Health Equity.

Rapid advancements in translational research have produced innovative clinical discoveries and evidence-based interventions that are ready for uptake in real-world settings, creating vast opportunities and challenges for implementation science. However, there is an inadequate research workforce to study effective strategies and delivery of implementation to advance the field. Novel career development initiatives will build scholars for the next generation of implementation science to bridge research to practice for diverse populations to advance health equity, specifically with a strategic focus on heart, lung, blood and sleep diseases and conditions. Along with traditional mentoring and curricula, research training includes state-of-the-art approaches using complex methods and multi-disciplinary collaborations between researchers, practice settings, and diverse communities. Implementation science scholars strive not only to decrease the lag time between the discovery of evidence-based interventions and successful implementation but also how to advance health equity and to reduce disparities for underserved populations that suffer disproportionally.

Tuberculosis.

Tuberculosis remains the leading cause of death from an infectious disease among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. Advances in diagnosis, including the use of rapid molecular testing and whole-genome sequencing in both sputum and non-sputum samples, could change this situation. Although little has changed in the treatment of drug-susceptible tuberculosis, data on increased efficacy with new and repurposed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the first time ever in 2018. Studies have shown that shorter latent tuberculosis prevention regimens containing rifampicin or rifapentine are as effective as longer, isoniazid-based regimens, and there is a promising vaccine candidate to prevent the progression of infection to the disease. But new tools alone are not sufficient. Advances must be made in providing high-quality, people-centred care for tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate the morbidity, mortality, and stigma long associated with tuberculosis, to the past.

Multidrug-Resistant TB: Implementing the Right to Health through the Right to Enjoy the Benefits of Scientific Progress.

The right to enjoy the benefits of scientific progress (REBSP) is a little-known but potentially valuable right that can contribute to rights-based approaches to addressing multidrug-resistant TB (MDR-TB). We argue that better understanding of the REBSP may help to advance legal and civil society action for health rights. While the REBSP does not provide an individual entitlement to have a new drug developed for MDR-TB, it sets up entitlements to expect a state to establish a legislative and policy framework aimed at developing scientific capacity to address the most important health issues and at disseminating the outcomes of scientific research. By making scientific findings available and accessible, people can be enabled to claim the use of science for social benefits. Inasmuch as the market fails to address neglected diseases such as MDR-TB, the REBSP provides a potential counterbalance to frame a positive obligation on states to both marshal their own resources and to coordinate the actions of multiple other actors towards this goal, including non-state actors. While the latter do not hold the same level of accountability as states, the REBSP can still enable the recognition of obligations at a level of "soft law" responsibilities.

The need to accelerate access to new drugs for multidrug-resistant tuberculosis.

Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.

On estime à un demi-million le nombre de personnes qui contractent chaque année la tuberculose multirésistante. De nos jours, à peine 20% d'entre elles reçoivent le traitement recommandé, et seulement 10% environ sont traitées avec succès. L'accès limité au traitement est probablement responsable de l'épidémie actuelle qui se propage par une transmission continue. L'amélioration de l'accès au traitement est freinée par les schémas thérapeutiques actuels, lesquels sont très longs, chers, mal tolérés et difficiles à gérer dans les régions où résident la plupart des patients. Bien que de nouveaux médicaments permettent d'améliorer les schémas thérapeutiques, les essais cliniques actuels et prévus ne laissent que peu d'espoir quant au développement de schémas qui favoriseraient l'amélioration rapide de l'accès au traitement. Dans cet article, nous soutenons que les essais cliniques sont certes nécessaires, mais qu'ils doivent être accompagnés d'une recherche opérationnelle de grande ampleur effectuée en temps voulu. Cette recherche permettrait d'obtenir des données programmatiques sur l'utilisation des nouveaux médicaments et schémas tout en améliorant l'accès à un traitement pouvant sauver des vies. Les risques perçus ­ tels que le développement rapide d'une résistance aux nouveaux médicaments ­ doivent être mis en balance avec les taux élevés de mortalité et de transmission qui se maintiendraient sans cela. Doubler l'accès au traitement et accroître son efficacité permettrait de sauver environ un million de vies au cours de la décennie à venir.

Se estima que alrededor de 500.000 personas al año desarrollan tuberculosis multirresistente. Apenas el 20% de estas personas recibe un tratamiento recomendado y solo el 10% se somete a un tratamiento eficaz. Probablemente la epidemia actual, a través de la transmisión continua, se deba al escaso acceso al tratamiento. La ampliación del tratamiento se ve obstaculizada por los regímenes terapéuticos actuales, que son prolongados, caros, producen intolerancia y son complicados de administrar en los lugares donde residen los pacientes. A pesar de que los nuevos fármacos son una oportunidad de mejorar los regímenes terapéuticos, los ensayos clínicos actuales y planificados no ofrecen demasiadas esperanzas para desarrollar regímenes que faciliten una ampliación del tratamiento a corto plazo. En este artículo sostenemos que los ensayos clínicos, mientras sea necesario, deberían ir acompañados de una investigación operativa oportuna a gran escala que proporcione información programática sobre el uso de los nuevos fármacos y regímenes, mientras mejora el acceso a un tratamiento que salvará vidas. Los riesgos, como el rápido desarrollo de la resistencia a nuevos fármacos, deberían equilibrarse frente a los altos niveles de mortalidad y transmisión que, de otro modo, continuarán existiendo. Duplicar el acceso al tratamiento y aumentar su éxito podría salvar alrededor de un millón de vidas en la próxima década.

Cost per patient of treatment for rifampicin-resistant tuberculosis in a community-based programme in Khayelitsha, South Africa.

OBJECTIVES: The high cost of rifampicin-resistant tuberculosis (RR-TB) treatment hinders treatment access. South Africa has a high RR-TB burden, and national policy outlines decentralisation to improve access and reduce costs. We analysed health system costs associated with RR-TB treatment by drug resistance profile and treatment outcome in a decentralised programme. METHODS: Retrospective, routinely collected patient-level data were combined with unit cost data to determine costs for each patient in a cohort treated between January 2009 and December 2011. Drug costs were based on recommended regimens according to drug resistance and treatment duration. Hospitalisation costs were estimated based on admission/discharge dates, while clinic visit and diagnostic/monitoring costs were estimated according to recommendations and treatment duration. Missing data were imputed. RESULTS: Among 467 patients (72% HIV infected), 49% were successfully treated. Treatment was initiated in primary care for 62%, with the remainder as inpatients. The mean cost per patient treated was $7916 (range 260-87,140), ranging from $5369 among patients who did not complete treatment to $23,006 for treatment failure. Mean cost for successful treatment was $8359 (2585-32,506). Second-line drug resistance was associated with a mean cost of $15,567 vs. $6852 for only first-line resistance, with the major cost difference due to hospitalisation. Costs are reported in 2013 USD. CONCLUSIONS: RR-TB treatment cost was high and varied according to treatment outcome. Despite decentralisation, hospitalisation remained a significant cost, particularly among those with more extensive resistance and those with treatment failure. These cost estimates can be used to model the impact of new interventions to improve patient outcomes.

Access to new medications for the treatment of drug-resistant tuberculosis: patient, provider and community perspectives.

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.

Patients' perspectives on the educational preparation of cardiac nurses.

BACKGROUND: Over the last two decades the UK health service has endeavoured to place patient and public involvement at the heart of its modernisation agenda. Despite these aspirations the role of patients in the development of nursing curricula remains limited. AIM: A descriptive qualitative design was used to explore the views of cardiac patients about the educational preparation of cardiac nurses. METHOD: Eight participants attending an annual conference of a patient and carer support group were recruited to the study. A focus group was conducted to explore their views on how the educational preparation of cardiac nurses in the UK should develop. Tape-recorded data were transcribed and a thematic analysis was undertaken. FINDINGS: Four themes were identified: contradictions around practice and education; demonstrating compassion; delivering rehabilitation expertise; leadership in practice. Participants perceived that they had a valuable role in the educational development of nurses, enhancing nurses' understanding of how individuals live and adjust to living with cardiovascular disease. CONCLUSION: Cardiac patients believe that the education of cardiac nurses should be driven by experiences in practice, nevertheless they want nurses to be equipped to deliver care that is underpinned by a strong knowledge base and skills combined with an ability to engage, educate and deliver high quality care that is both compassionate and individualised.

A pragmatic multicentered randomized controlled trial of yoga for chronic low back pain: economic evaluation.

STUDY DESIGN: Multicentered randomized controlled trial with quality of life and resource use data collected. OBJECTIVE: The objective of this study was to evaluate the cost-effectiveness of yoga intervention plus usual care compared with usual care alone for chronic or recurrent low back pain. SUMMARY OF BACKGROUND DATA: Yoga has been shown as an effective intervention for treating chronic or recurrent low back pain. However, there is little evidence on its cost-effectiveness. The data are extracted from a pragmatic, multicentered, randomized controlled trial that has been conducted to evaluate the effectiveness and cost-effectiveness of a 12-week progressive program of yoga plus usual care in patients with chronic or recurrent low back pain. METHODS: With this trial data, a cost-effectiveness analysis during the time period of 12 months from both perspectives of the UK National Health Service and the societal is presented. Main outcome measure is an incremental cost per quality-adjusted life-year (QALY). RESULTS: From the perspective of the U.K. National Health Service, yoga intervention yields an incremental cost-effectiveness ratio of £13,606 per QALY. Given a willingness to pay for an additional QALY of £20,000, the probability of yoga intervention being cost-effective is 72%. From the perspective of the society, yoga intervention is a dominant treatment compared with usual care alone. This result is surrounded by fewer uncertainties-the probability of yoga being cost-effective reaches 95% at a willingness to pay for an additional QALY of £20,000. Sensitive analyses suggest the same results that yoga intervention is likely to be cost-effective in both perspectives. CONCLUSION: On the basis of this trial, 12 weekly group classes of specialized yoga are likely to be a cost-effective intervention for treating patients with chronic or recurrent low back pain.

Randomized controlled trial of a lay-facilitated angina management programme.

AIMS: This article reports a randomized controlled trial of lay-facilitated angina management (registered trial acronym: LAMP). BACKGROUND: Previously, a nurse-facilitated angina programme was shown to reduce angina while increasing physical activity, however most people with angina do not receive a cardiac rehabilitation or self-management programme. Lay people are increasingly being trained to facilitate self-management programmes. DESIGN: A randomized controlled trial comparing a lay-facilitated angina management programme with routine care from an angina nurse specialist. METHODS: Participants with new stable angina were randomized to the angina management programme (intervention: 70 participants) or advice from an angina nurse specialist (control: 72 participants). Primary outcome was angina frequency at 6 months; secondary outcomes at 3 and 6 months included: risk factors, physical functioning, anxiety, depression, angina misconceptions and cost utility. Follow-up was complete in March 2009. Analysis was by intention-to-treat; blind to group allocation. RESULTS: There was no important difference in angina frequency at 6 months. Secondary outcomes, assessed by either linear or logistic regression models, demonstrated important differences favouring the intervention group, at 3 months for: Anxiety, angina misconceptions and for exercise report; and at 6 months for: anxiety; depression; and angina misconceptions. The intervention was considered cost-effective. CONCLUSION: The angina management programme produced some superior benefits when compared to advice from a specialist nurse.

The hidden contribution of the health care assistant: a survey-based exploration of support to their role in caring for the acutely ill patient in the general ward setting.

AIM: To examine the feelings, support and feedback available to health care assistants (HCA) when caring for acutely ill ward patients. BACKGROUND: The role of the HCA continues to evolve with increased responsibility for patient care. Contextual issues that affect their contribution to acute care management of the ward patient have been given limited attention. METHODS: A survey of HCAs (n = 131) was conducted within two district general hospitals. RESULTS: There were a number of emotions and stressors associated with the care of acutely ill patients. While normal hierarchical systems were in place in order to obtain help HCAs additionally bypassed these normal channels. Support mechanisms included registered nurses, ward doctors, peers and family. Feedback regarding performance was limited. CONCLUSION: HCAs play a significant role in the care of the acutely ill patient. Feedback mechanisms need to be developed and associated emotions recognized. IMPLICATIONS FOR NURSING MANAGEMENT: HCAs support needs to be more evident and clinical feedback mechanisms need to be reviewed in order to improve care delivery.

Acupuncture for irritable bowel syndrome: a protocol for a pragmatic randomised controlled trial.

BACKGROUND: There is insufficient evidence on the effectiveness of acupuncture for irritable bowel syndrome (IBS) for conclusions to be drawn. Given the current interest in acupuncture by patients, it is in the public interest to establish more rigorous evidence. Building on the positive findings from a pilot study, in this paper we present the protocol for a fully-powered trial designed to establish whether or not acupuncture is effective and cost-effective. METHODS/DESIGN: In this pragmatic randomised controlled trial we will randomise patients recruited directly from GP databases to either 10 sessions of acupuncture plus usual GP care or to usual GP care alone. The primary clinical outcome will be the IBS Symptom Severity Score (SSS) (maximum score 500) at three months, and at 12 month assessing whether there is an overall benefit. We estimate the sample size required to detect a minimum clinical difference at 90% power and 5% significance to be 188 patients. To allow for loss to follow up we will recruit 220 patients drawn from an estimated primary care population of 140 000. Analysis will be by intention-to-treat, and multiple imputation is to be used for missing data.In a nested qualitative study using in-depth interviews, we will explore how patients, acupuncturists, and GPs explain and subsequently understand acupuncture to work. We will use purposive sampling to identify patients and flexible topic guides for the interviews. The data analysis will lead to a thematic description of how patients and practitioners explain how acupuncture works, and whether or not the explanations influence treatment outcome and/or referrals.We will undertake a cost-effectiveness analysis at 12 months by comparing resource use in the two groups with any treatment benefit. We will use the EQ-5D to measure health-related quality of life and convert into quality adjusted life years (QALYs). We will generate cost effectiveness acceptability curves (CEACs) exploring the probability that acupuncture will produce an acceptable cost per QALY at different cost-effectiveness thresholds. DISCUSSION: The trial has received NHS ethics approval and recruited 233 patients between November 2008 and June 2009. Results are expected in 2011. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

Issues in the provision of nursing care to people undergoing cardiac surgery who also have type 2 diabetes.

There has been little investigation of the issues associated with caring for patients presenting for cardiac surgery with a comorbid diagnosis of diabetes although there is some evidence that the diabetes management is suboptimal. This study aimed to identify issues that patients and cardiac specialist nurses experience with the provision of inpatient services for people undergoing cardiac surgery who also have type 2 diabetes. A qualitative interpretive design, using individual interviews with patients and nurses, provided data about some of these issues. The study found that nurses had high levels of confidence in their cardiac care but little confidence in diabetes management. Patients described concerns about their diabetes care and treatment regimens. A 'typical journey' for a person with diabetes undergoing cardiac surgery was identified. The findings support the need to build increased capacity in specialist nurses to support diabetes care as a secondary diagnosis.

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study.

BACKGROUND: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pounds for the completion of postal questionnaires. METHODS: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pounds to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pounds incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. RESULTS: The response rate following reminders for the historical controls was 78.1% (82 of 105) compared with 88.0% (389 of 442) for those patients who received the 5 pounds payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response (adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial--the extra cost per additional respondent was almost 50 pounds. CONCLUSION: The direct payment of 5 pounds significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study.