IMPACT study on intervening with a manualised package to achieve treatment adherence in people with tuberculosis: protocol paper for a mixed-methods study, including a pilot randomised controlled trial.

INTRODUCTION: Compared with the rest of the UK and Western Europe, England has high rates of the infectious disease tuberculosis (TB). TB is curable, although treatment is for at least 6 months and longer when disease is drug resistant. If patients miss too many doses (non-adherence), they may transmit infection for longer and the infecting bacteria may develop resistance to the standard drugs used for treatment. Non-adherence may therefore risk both their health and that of others. Within England, certain population groups are thought to be at higher risk of non-adherence, but the factors contributing to this have been insufficiently determined, as have the best interventions to promote adherence. The objective of this study was to develop a manualised package of interventions for use as part of routine care within National Health Services to address the social and cultural factors that lead to poor adherence to treatment for TB disease. METHODS AND ANALYSIS: This study uses a mixed-methods approach, with six study components. These are (1) scoping reviews of the literature; (2) qualitative research with patients, carers and healthcare professionals; (3) development of the intervention; (4) a pilot randomised controlled trial of the manualised intervention; (5) a process evaluation to examine clinical utility; and (6) a cost analysis. ETHICS AND DISSEMINATION: This study received ethics approval on 24 December 2018 from Camberwell St. Giles Ethics Committee, UK (REC reference 18/LO/1818). Findings will be published and disseminated through peer-reviewed publications and conference presentations, published in an end of study report to our funder (the National Institute for Health Research, UK) and presented to key stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN95243114 SECONDARY IDENTIFYING NUMBERS: University College London/University College London Hospitals Joint Research Office 17/0726.National Institute for Health Research, UK 16/88/06.

Determinants of non-adherence to treatment for tuberculosis in high-income and middle-income settings: a systematic review protocol.

INTRODUCTION: Treatment for tuberculosis (TB) is highly effective if taken according to prescribed schedules. However, many people have difficulty adhering to treatment which can lead to poorer clinical outcomes, the development of drug resistance, increased duration of infectivity and consequent onward transmission of infection. A range of approaches are available to support adherence but in order to target these effectively a better understanding of the predictors of poor adherence is needed. This review aims to highlight the personal, sociocultural and structural factors that may lead to poor adherence in high-income and middle-income settings. METHODS AND ANALYSIS: Seven electronic databases, Medline, EMBASE, CINAHL, PsycInfo, The Cochrane Library, Scopus and Web of Science, will be searched for relevant articles using a prespecified search strategy. Observational studies will be targeted to explore factors that influence adherence to treatment in individuals diagnosed with TB. Screening title and abstract followed by full-text screening and critical appraisal will be conducted by two researchers. Data will be extracted using the Population, Exposure, Comparator, Outcomes, Study characteristics framework. For cross-study assessment of strength of evidence for particular risk factors affecting adherence we will use the Grading of Recommendations, Assessment, Development and Evaluation tool modified for prognostic studies. A narrative synthesis of the studies will be compiled. A meta-analysis will be considered if there are sufficient numbers of studies that are homogenous in study design, population and outcomes. DISSEMINATION: A draft conceptual framework will be identified that (A) identifies key barriers to adherence at each contextual level (eg, personal, sociocultural, health systems) and (B) maps the relationships, pathways and mechanisms of effect between these factors and adherence outcomes for people with TB. The draft conceptual framework will guide targeting of adherence interventions and further research. PROSPERO REGISTRATION NUMBER: CRD42017061049.

Outcomes of specialist discharge coordination and intermediate care schemes for patients who are homeless: analysis protocol for a population-based historical cohort.

INTRODUCTION: People who are homeless often experience poor hospital discharge arrangements, reflecting ongoing care and housing needs. Specialist integrated homeless health and care provision (SIHHC) schemes have been developed and implemented to facilitate the safe and timely discharge of homeless patients from hospital. Our study aims to investigate the health outcomes of patients who were homeless and seen by a selection of SIHHC services. METHODS AND ANALYSIS: Our study will employ a historical population-based cohort in England. We will examine health outcomes among three groups of adults: (1) homeless patients seen by specialist discharge schemes during their hospital admission; (2) homeless patients not seen by a specialist scheme and (3) admitted patients who live in deprived neighbourhoods and were not recorded as being homeless. Primary outcomes will be: time from discharge to next hospital inpatient admission; time from discharge to next accident and emergency attendance and 28-day emergency readmission. Outcome data will be generated through linkage to hospital admissions data (Hospital Episode Statistics) and mortality data for November 2013 to November 2016. Multivariable regression will be used to model the relationship between the study comparison groups and each of the outcomes. ETHICS AND DISSEMINATION: Approval has been obtained from the National Health Service (NHS) Confidentiality Advisory Group (reference 16/CAG/0021) to undertake this work using unconsented identifiable data. Health Research Authority Research Ethics approval (REC 16/EE/0018) has been obtained in addition to local research and development approvals for data collection at NHS sites. We will feedback the results of our study to our advisory group of people who have lived experience of homelessness and seek their suggestions on ways to improve or take this work further for their benefit. We will disseminate our findings to SIHHC schemes through a series of regional workshops.

Bioaerosol production by patients with tuberculosis during normal tidal breathing: implications for transmission risk.

BACKGROUND: The size and concentration of exhaled bioaerosols may influence TB transmission risk. This study piloted bioaerosol measurement in patients with TB and assessed variability in bioaerosol production during normal tidal breathing. Understanding this may provide a tool for assessing heterogeneity in infectivity and may inform mathematical models of TB control practices and policies. METHODS: Optical particle counter technology was used to measure aerosol size and concentration in exhaled air (range 0.3-20 µm in diameter) during 15 tidal breaths across four groups over time: healthy/uninfected, healthy/Mycobacterium tuberculosis-infected, patients with extrathoracic TB and patients with intrathoracic TB. High-particle production was defined as any 1-5 µm sized bioaerosol count above the median count among all participants (median count=2 counts/L). RESULTS: Data from 188 participants were obtained pretreatment (baseline). Bioaerosol production varied considerably between individuals. Multivariable analysis showed intrathoracic TB was associated with a 3½-fold increase in odds of high production of 1-5 µm bioaerosols (adjusted OR: 3.5; 95% CI 1.6 to 7.8; p=0.002) compared with healthy/uninfected individuals. CONCLUSIONS: We provide the first evidence that intrathoracic TB increases bioaerosol production in a particle size range that could plausibly transport M. tuberculosis. There is substantial variation in production within patients with TB that may conceivably relate to the degree of infectivity. Further data is needed to determine if high bioaerosol production during tidal breathing is associated with infectiousness.

Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: a systematic analysis across 1997-2013.

BACKGROUND: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. METHODS: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. RESULTS: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). CONCLUSIONS: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.

Funding infectious disease research: a systematic analysis of UK research investments by funders 1997-2010.

BACKGROUND: Research investments are essential to address the burden of disease, however allocation of limited resources is poorly documented. We systematically reviewed the investments awarded by funding organisations to UK institutions and their global partners for infectious disease research. METHODOLOGY/PRINCIPAL FINDINGS: Public and philanthropic investments for the period 1997 to 2010 were included. We categorised studies by infectious disease, cross-cutting theme, and by research and development value chain, reflecting the type of science. We identified 6165 funded studies, with a total research investment of UK £2.6 billion. Public organisations provided £1.4 billion (54.0%) of investments compared with £1.1 billion (42.4%) by philanthropic organisations. Global health studies represented an investment of £928 million (35.7%). The Wellcome Trust was the leading investor with £688 million (26.5%), closely followed by the UK Medical Research Council (MRC) with £673 million (25.9%). Funding over time was volatile, ranging from ∼£40 million to ∼£160 million per year for philanthropic organisations and ∼£30 million to ∼£230 million for public funders. CONCLUSIONS/SIGNIFICANCE: Infectious disease research funding requires global coordination and strategic long-term vision. Our analysis demonstrates the diversity and inconsistent patterns in investment, with volatility in annual funding amounts and limited investment for product development and clinical trials.

Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study.

BACKGROUND: Assessment of the effect of influenza on populations, including risk of infection, illness if infected, illness severity, and consultation rates, is essential to inform future control and prevention. We aimed to compare the community burden and severity of seasonal and pandemic influenza across different age groups and study years and gain insight into the extent to which traditional surveillance underestimates this burden. METHODS: Using preseason and postseason serology, weekly illness reporting, and RT-PCR identification of influenza from nasal swabs, we tracked the course of seasonal and pandemic influenza over five successive cohorts (England 2006-11; 5448 person-seasons' follow-up). We compared burden and severity of seasonal and pandemic strains. We weighted analyses to the age and regional structure of England to give nationally representative estimates. We compared symptom profiles over the first week of illness for different strains of PCR-confirmed influenza and non-influenza viruses using ordinal logistic regression with symptom severity grade as the outcome variable. FINDINGS: Based on four-fold titre rises in strain-specific serology, on average influenza infected 18% (95% CI 16-22) of unvaccinated people each winter. Of those infected there were 69 respiratory illnesses per 100 person-influenza-seasons compared with 44 per 100 in those not infected with influenza. The age-adjusted attributable rate of illness if infected was 23 illnesses per 100 person-seasons (13-34), suggesting most influenza infections are asymptomatic. 25% (18-35) of all people with serologically confirmed infections had PCR-confirmed disease. 17% (10-26) of people with PCR-confirmed influenza had medically attended illness. These figures did not differ significantly when comparing pandemic with seasonal influenza. Of PCR-confirmed cases, people infected with the 2009 pandemic strain had markedly less severe symptoms than those infected with seasonal H3N2. INTERPRETATION: Seasonal influenza and the 2009 pandemic strain were characterised by similar high rates of mainly asymptomatic infection with most symptomatic cases self-managing without medical consultation. In the community the 2009 pandemic strain caused milder symptoms than seasonal H3N2. FUNDING: Medical Research Council and the Wellcome Trust.

Investments in respiratory infectious disease research 1997-2010: a systematic analysis of UK funding.

OBJECTIVES: Respiratory infections are responsible for a large global burden of disease. We assessed the public and philanthropic investments awarded to UK institutions for respiratory infectious disease research to identify areas of underinvestment. We aimed to identify projects and categorise them by pathogen, disease and position along the research and development value chain. SETTING: The UK. PARTICIPANTS: Institutions that host and carry out infectious disease research. PRIMARY AND SECONDARY OUTCOME MEASURES: The total amount spent and number of studies with a focus on several different respiratory pathogens or diseases, and to correlate these against the global burden of disease; also the total amount spent and number of studies relating to the type of science, the predominant funder in each category and the mean and median award size. RESULTS: We identified 6165 infectious disease studies with a total investment of £2·6 billion. Respiratory research received £419 million (16.1%) across 1192 (19.3%) studies. The Wellcome Trust provided greatest investment (£135.2 million; 32.3%). Tuberculosis received £155 million (37.1%), influenza £80 million (19.1%) and pneumonia £27.8 million (6.6%). Despite high burden, there was relatively little investment in vaccine-preventable diseases including diphtheria (£0.1 million, 0.03%), measles (£5.0 million, 1.2%) and drug-resistant tuberculosis. There were 802 preclinical studies (67.3%) receiving £273 million (65.2%), while implementation research received £81 million (19.3%) across 274 studies (23%). There were comparatively few phase I-IV trials or product development studies. Global health research received £68.3 million (16.3%). Relative investment was strongly correlated with 2010 disease burden. CONCLUSIONS: The UK predominantly funds preclinical science. Tuberculosis is the most studied respiratory disease. The high global burden of pneumonia-related disease warrants greater investment than it has historically received. Other priority areas include antimicrobial resistance (particularly within tuberculosis), economics and proactive investments for emerging infectious threats.

Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997-2010.

OBJECTIVES: To assess the level of research funding awarded to UK institutions specifically for antimicrobial resistance-related research and how closely the topics funded relate to the clinical and public health burden of resistance. METHODS: Databases and web sites were systematically searched for information on how infectious disease research studies were funded for the period 1997-2010. Studies specifically related to antimicrobial resistance, including bacteriology, virology, mycology and parasitology research, were identified and categorized in terms of funding by pathogen and disease and by a research and development value chain describing the type of science. RESULTS: The overall dataset included 6165 studies receiving a total investment of £2.6 billion, of which £102 million was directed towards antimicrobial resistance research (5.5% of total studies, 3.9% of total spend). Of 337 resistance-related projects, 175 studies focused on bacteriology (40.2% of total resistance-related spending), 42 focused on antiviral resistance (17.2% of funding) and 51 focused on parasitology (27.4% of funding). Mean annual funding ranged from £1.9 million in 1997 to £22.1 million in 2009. CONCLUSIONS: Despite the fact that the emergence of antimicrobial resistance threatens our future ability to treat many infections, the proportion of the UK infection-research spend targeting this important area is small. There are encouraging signs of increased investment in this area, but it is important that this is sustained and targeted at areas of projected greatest burden. Two areas of particular concern requiring more investment are tuberculosis and multidrug-resistant Gram-negative bacteria.

Differences in research funding for women scientists: a systematic comparison of UK investments in global infectious disease research during 1997-2010.

OBJECTIVES: There has not previously been a systematic comparison of awards for research funding in infectious diseases by sex. We investigated funding awards to UK institutions for all infectious disease research from 1997 to 2010, across disease categories and along the research and development continuum. DESIGN: Systematic comparison. METHODS: Data were obtained from several sources for awards from the period 1997 to 2010 and each study assigned to-disease categories; type of science (preclinical, phases I-III trials, product development, implementation research); categories of funding organisation. Fold differences and statistical analysis were used to compare total investment, study numbers, mean grant and median grant between men and women. RESULTS: 6052 studies were included in the final analysis, comprising 4357 grants (72%) awarded to men and 1695 grants (28%) awarded to women, totalling £2.274 billion. Of this, men received £1.786 billion (78.5%) and women £488 million (21.5%). The median value of award was greater for men (£179 389; IQR £59 146-£371 977) than women (£125 556; IQR £30 982-£261 834). Awards were greater for male principal investigators (PIs) across all infectious disease systems, excepting neurological infections and sexually transmitted infections. The proportion of total funding awarded to women ranged from 14.3% in 1998 to 26.8% in 2009 (mean 21.4%), and was lowest for preclinical research at 18.2% (£285.5 million of £1.573 billion) and highest for operational research at 30.9% (£151.4 million of £489.7 million). CONCLUSIONS: There are consistent differences in funding received by men and women PIs: women have fewer funded studies and receive less funding in absolute and in relative terms; the median funding awarded to women is lower across most infectious disease areas, by funder, and type of science. These differences remain broadly unchanged over the 14-year study period.

UK investments in global infectious disease research 1997-2010: a case study.

BACKGROUND: Infectious diseases account for 15 million deaths per year worldwide, and disproportionately affect young people, elderly people, and the poorest sections of society. We aimed to describe the investments awarded to UK institutions for infectious disease research. METHODS: We systematically searched databases and websites for information on research studies from funding institutions and created a comprehensive database of infectious disease research projects for the period 1997-2010. We categorised studies and funding by disease, cross-cutting theme, and by a research and development value chain describing the type of science. Regression analyses were reported with Spearman's rank correlation coefficient to establish the relation between research investment, mortality, and disease burden as measured by disability-adjusted life years (DALYs). FINDINGS: We identified 6170 funded studies, with a total research investment of UK£2·6 billion. Studies with a clear global health component represented 35·6% of all funding (£927 million). By disease, HIV received £461 million (17·7%), malaria £346 million (13·3%), tuberculosis £149 million (5·7%), influenza £80 million (3·1%), and hepatitis C £60 million (2·3%). We compared funding with disease burden (DALYs and mortality) to show low levels of investment relative to burden for gastrointestinal infections (£254 million, 9·7%), some neglected tropical diseases (£184 million, 7·1%), and antimicrobial resistance (£96 million, 3·7%). Virology was the highest funded category (£1 billion, 38·4%). Leading funding sources were the Wellcome Trust (£688 million, 26·4%) and the Medical Research Council (£673 million, 25·8%). INTERPRETATION: Research funding has to be aligned with prevailing and projected global infectious disease burden. Funding agencies and industry need to openly document their research investments to redress any inequities in resource allocation. FUNDING: None.