Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study.

BACKGROUND: The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction. METHODS: We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006-2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 329 community-dwelling participants from Finland (baseline 1986-2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and death registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk. RESULTS: In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the type of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36-9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40-1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82-10.03] during the first month; HR, 1.41 [95% CI, 1.34-1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort. CONCLUSIONS: Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded.

Long-term outcomes of SARS-CoV-2 variants and other respiratory infections: evidence from the Virus Watch prospective cohort in England.

This study compared the likelihood of long-term sequelae following infection with SARS-CoV-2 variants, other acute respiratory infections (ARIs) and non-infected individuals. Participants (n=5,630) were drawn from Virus Watch, a prospective community cohort investigating SARS-CoV-2 epidemiology in England. Using logistic regression, we compared predicted probabilities of developing long-term symptoms (>2 months) during different variant dominance periods according to infection status (SARS-CoV-2, other ARI, or no infection), adjusting for confounding by demographic and clinical factors and vaccination status. SARS-CoV-2 infection during early variant periods up to Omicron BA.1 was associated with greater probability of long-term sequalae (adjusted predicted probability (PP) range 0.27, 95% CI = 0.22-0.33 to 0.34, 95% CI = 0.25-0.43) compared with later Omicron sub-variants (PP range 0.11, 95% CI 0.08-0.15 to 0.14, 95% CI 0.10-0.18). While differences between SARS-CoV-2 and other ARIs (PP range 0.08, 95% CI 0.04-0.11 to 0.23, 95% CI 0.18-0.28) varied by period, all post-infection estimates substantially exceeded those for non-infected participants (PP range 0.01, 95% CI 0.00, 0.02 to 0.03, 95% CI 0.01-0.06). Variant was an important predictor of SARS-CoV-2 post-infection sequalae, with recent Omicron sub-variants demonstrating similar probabilities to other contemporaneous ARIs. Further aetiological investigation including between-pathogen comparison is recommended.

Bayesian reconstruction of household transmissions to infer the serial interval of COVID-19 by variants of concern: analysis from a prospective community cohort study (Virus Watch).

BACKGROUND: The serial interval is a key epidemiological measure that quantifies the time between an infector's and an infectee's onset of symptoms. This measure helps investigate epidemiological links between cases, and is an important parameter in transmission models used to estimate transmissibility and inform control strategies. The emergence of multiple variants of concern (VOC) during the SARS-CoV-2 pandemic has led to uncertainties about potential changes in the serial interval of COVID-19. We estimated the household serial interval of multiple VOC using data collected by the Virus Watch study. This online, prospective, community cohort study followed-up entire households in England and Wales since mid-June 2020. METHODS: This analysis included 5842 symptomatic individuals with confirmed SARS-CoV-2 infection among 2579 households from Sept 1, 2020, to Aug 10, 2022. SARS-CoV-2 variant designation was based upon national surveillance data of variant prevalence by date and geographical region. We used a Bayesian framework to infer who infected whom by exploring all transmission trees compatible with the observed dates of symptoms, given assumptions on the incubation period and generation time distributions using the R package outbreaker2. FINDINGS: We characterised the serial interval of COVID-19 by VOC. The mean serial interval was shortest for omicron BA5 (2·02 days; 95% credible interval [CrI] 1·26-2·84) and longest for alpha (3·37 days; 2·52-4·04). The mean serial interval before alpha (wild-type) was 2·29 days (95% CrI 1·39-2·94), 3·11 days (2·28-3·90) for delta, 2·72 days (2·01-3·47) for omicron BA1, and 2·67 days (1·90-3·46) for omicron BA2. We estimated that 17% (95% CrI 5-26) of serial interval values are negative across all variants. INTERPRETATION: Most methods estimating the reproduction number from incidence time series do not allow for a negative serial interval by construction. Further research is needed to extend these methods and assess biases introduced by not accounting for negative serial intervals. To our knowledge, this study is the first to use a Bayesian framework to estimate the serial interval of all major SARS-CoV-2 VOC from thousands of confirmed household cases. FUNDING: UK Medical Research Council and Wellcome Trust.

Inequalities in access to paid sick leave among workers in England and Wales.

BACKGROUND: It is poorly understood which workers lack access to sick pay in England and Wales. This evidence gap has been of particular interest in the context of the Covid-19 pandemic given the relationship between presenteeism and infectious disease transmission. METHOD: This cross-sectional analysis (n = 8874) was nested within a large community cohort study based across England and Wales (Virus Watch). An online survey in February 2021 asked participants in work if they had access to paid sick leave. We used logistic regression to examine sociodemographic factors associated with lacking access to sick pay. RESULTS: Only 66% (n = 5864) of participants reported access to sick pay. South Asian workers (adjusted odds ratio [OR] 1.40, 95% confidence interval [CI] 1.06-1.83) and those from Other minority ethnic backgrounds (OR 2.93, 95% CI 1.54-5.59) were more likely to lack access to sick pay compared to White British workers. Older workers (OR range 1.72 [1.53-1.93]-5.26 [4.42-6.26]), workers in low-income households (OR 2.53, 95% CI 2.15-2.98) and those in transport, trade, and service occupations (OR range 2.03 [1.58-2.61]-5.29 [3.67-7.72]) were also more likely to lack access to sick pay compared respectively to workers aged 25-44, those in high income households and managerial occupations. DISCUSSION: Unwarranted age and ethnic inequalities in sick pay access are suggestive of labour market discrimination. Occupational differences are also cause for concern. Policymakers should consider expanding access to sick pay to mitigate transmission of Covid-19 and other endemic respiratory infections in the community, and in the context of pandemic preparation.

Incidence, healthcare-seeking behaviours, antibiotic use and natural history of common infection syndromes in England: results from the Bug Watch community cohort study.

BACKGROUND: Better information on the typical course and management of acute common infections in the community could inform antibiotic stewardship campaigns. We aimed to investigate the incidence, management, and natural history of a range of infection syndromes (respiratory, gastrointestinal, mouth/dental, skin/soft tissue, urinary tract, and eye). METHODS: Bug Watch was an online prospective community cohort study of the general population in England (2018-2019) with weekly symptom reporting for 6 months. We combined symptom reports into infection syndromes, calculated incidence rates, described the proportion leading to healthcare-seeking behaviours and antibiotic use, and estimated duration and severity. RESULTS: The cohort comprised 873 individuals with 23,111 person-weeks follow-up. The mean age was 54 years and 528 (60%) were female. We identified 1422 infection syndromes, comprising 40,590 symptom reports. The incidence of respiratory tract infection syndromes was two per person year; for all other categories it was less than one. 194/1422 (14%) syndromes led to GP (or dentist) consultation and 136/1422 (10%) to antibiotic use. Symptoms usually resolved within a week and the third day was the most severe. CONCLUSIONS: Most people reported managing their symptoms without medical consultation. Interventions encouraging safe self-management across a range of acute infection syndromes could decrease pressure on primary healthcare services and support targets for reducing antibiotic prescribing.

Prevalence, incidence, and outcomes across cardiovascular diseases in homeless individuals using national linked electronic health records.

AIMS: The risk and burden of cardiovascular disease (CVD) are higher in homeless than in housed individuals but population-based analyses are lacking. The aim of this study was to investigate prevalence, incidence and outcomes across a range of specific CVDs among homeless individuals. METHODS AND RESULTS: Using linked UK primary care electronic health records (EHRs) and validated phenotypes, we identified homeless individuals aged ≥16 years between 1998 and 2019, and age- and sex-matched housed controls in a 1:5 ratio. For 12 CVDs (stable angina; unstable angina; myocardial infarction; sudden cardiac death or cardiac arrest; unheralded coronary death; heart failure; transient ischaemic attack; ischaemic stroke; subarachnoid haemorrhage; intracerebral haemorrhage; peripheral arterial disease; abdominal aortic aneurysm), we estimated prevalence, incidence, and 1-year mortality post-diagnosis, comparing homeless and housed groups. We identified 8492 homeless individuals (32 134 matched housed individuals). Comorbidities and risk factors were more prevalent in homeless people, e.g. smoking: 78.1% vs. 48.3% and atrial fibrillation: 9.9% vs. 8.6%, P < 0.001. CVD prevalence (11.6% vs. 6.5%), incidence (14.7 vs. 8.1 per 1000 person-years), and 1-year mortality risk [adjusted hazard ratio 1.64, 95% confidence interval (CI) 1.29-2.08, P < 0.001] were higher, and onset was earlier (difference 4.6, 95% CI 2.8-6.3 years, P < 0.001), in homeless, compared with housed people. Homeless individuals had higher CVD incidence in all three arterial territories than housed people. CONCLUSION: CVD in homeless individuals has high prevalence, incidence, and 1-year mortality risk post-diagnosis with earlier onset, and high burden of risk factors. Inclusion health and social care strategies should reflect this high preventable and treatable burden, which is increasingly important in the current COVID-19 context.

A new transdisciplinary research model to investigate and improve the health of the public.

Transdisciplinary research approaches are being applied to today's complex health problems, including the climate crisis and widening inequalities. Diverse forms of disciplinary and experiential knowledge are required to understand these challenges and develop workable solutions. We aimed to create an updated model reflective of the strengths and challenges of current transdisciplinary health research that can be a guide for future studies. We searched Medline using terms related to transdisciplinary, health and research. We coded data deductively and inductively using thematic analysis to develop a preliminary model of transdisciplinary research. The model was tested and improved through: (i) a workshop with 27 participants at an international conference in Xiamen, China and (ii) online questionnaire feedback from included study authors. Our revised model recommends the following approach: (i) co-learning, an ongoing phase that recognizes the distributed nature of knowledge generation and learning across partners; (ii) (pre-)development, activities that occur before and during project initiation to establish a shared mission and ways of working; (iii) reflection and refinement to evaluate and improve processes and results, responding to emergent information and priorities as an ongoing phase; (iv) conceptualization to develop goals and the study approach by combining diverse knowledge; (v) investigation to conduct the research; (vi) implementation to use new knowledge to solve societal problems. The model includes linear and cyclical processes that may cycle back to project development. Our new model will support transdisciplinary research teams and their partners by detailing the necessary ingredients to conduct such research and achieve health impact.

Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial.

BACKGROUND: Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s, but it is inconvenient for patients and service providers. Video-observed therapy (VOT) has been conditionally recommended by WHO as an alternative to DOT. We tested whether levels of treatment observation were improved with VOT. METHODS: We did a multicentre, analyst-blinded, randomised controlled superiority trial in 22 clinics in England (UK). Eligible participants were patients aged at least 16 years with active pulmonary or non-pulmonary tuberculosis who were eligible for DOT according to local guidance. Exclusion criteria included patients who did not have access to charging a smartphone. We randomly assigned participants to either VOT (daily remote observation using a smartphone app) or DOT (observations done three to five times per week in the home, community, or clinic settings). Randomisation was done by the SealedEnvelope service using minimisation. DOT involved treatment observation by a health-care or lay worker, with any remaining daily doses self-administered. VOT was provided by a centralised service in London. Patients were trained to record and send videos of every dose ingested 7 days per week using a smartphone app. Trained treatment observers viewed these videos through a password-protected website. Patients were also encouraged to report adverse drug events on the videos. Smartphones and data plans were provided free of charge by study investigators. DOT or VOT observation records were completed by observers until treatment or study end. The primary outcome was completion of 80% or more scheduled treatment observations over the first 2 months following enrolment. Intention-to-treat (ITT) and restricted (including only patients completing at least 1 week of observation on allocated arm) analyses were done. Superiority was determined by a 15% difference in the proportion of patients with the primary outcome (60% vs 75%). This trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN26184967. FINDINGS: Between Sept 1, 2014, and Oct 1, 2016, we randomly assigned 226 patients; 112 to VOT and 114 to DOT. Overall, 131 (58%) patients had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled observations successfully completed during the first 2 months compared with 35 (31%) of 114 on DOT (adjusted odds ratio [OR] 5·48, 95% CI 3·10-9·68; p<0·0001). In the restricted analysis, 78 (77%) of 101 patients on VOT achieved the primary outcome compared with 35 (63%) of 56 on DOT (adjusted OR 2·52; 95% CI 1·17-5·54; p=0·017). Stomach pain, nausea, and vomiting were the most common adverse events reported (in 16 [14%] of 112 on VOT and nine [8%] of 114 on DOT). INTERPRETATION: VOT was a more effective approach to observation of tuberculosis treatment than DOT. VOT is likely to be preferable to DOT for many patients across a broad range of settings, providing a more acceptable, effective, and cheaper option for supervision of daily and multiple daily doses than DOT. FUNDING: National Institute for Health Research.

Antibiotic prescribing in UK care homes 2016-2017: retrospective cohort study of linked data.

BACKGROUND: Older people living in care homes are particularly susceptible to infections and antibiotics are therefore used frequently for this population. However, there is limited information on antibiotic prescribing in this setting. This study aimed to investigate the frequency, patterns and risk factors for antibiotic prescribing in a large chain of UK care homes. METHODS: Retrospective cohort study of administrative data from a large chain of UK care homes (resident and care home-level) linked to individual-level pharmacy data. Residents aged 65 years or older between 1 January 2016 and 31 December 2017 were included. Antibiotics were classified by type and as new or repeated prescriptions. Rates of antibiotic prescribing were calculated and modelled using multilevel negative binomial regression. RESULTS: 13,487 residents of 135 homes were included. The median age was 85; 63% residents were female. 28,689 antibiotic prescriptions were dispensed, the majority were penicillins (11,327, 39%), sulfonamides and trimethoprim (5818, 20%), or other antibacterials (4665, 16%). 8433 (30%) were repeat prescriptions. The crude rate of antibiotic prescriptions was 2.68 per resident year (95% confidence interval (CI) 2.64-2.71). Increased antibiotic prescribing was associated with residents requiring more medical assistance (adjusted incidence rate ratio for nursing opposed to residential care 1.21, 95% CI 1.13-1.30). Prescribing rates varied widely by care home but there were no significant associations with the care home-level characteristics available in routine data. CONCLUSIONS: Rates of antibiotic prescribing in care homes are high and there is substantial variation between homes. Further research is needed to understand the drivers of this variation to enable development of effective stewardship approaches that target the influences of prescribing.

Morbidity and mortality in homeless individuals, prisoners, sex workers, and individuals with substance use disorders in high-income countries: a systematic review and meta-analysis.

BACKGROUND: Inclusion health focuses on people in extremely poor health due to poverty, marginalisation, and multimorbidity. We aimed to review morbidity and mortality data on four overlapping populations who experience considerable social exclusion: homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library for studies published between Jan 1, 2005, and Oct 1, 2015. We included only systematic reviews, meta-analyses, interventional studies, and observational studies that had morbidity and mortality outcomes, were published in English, from high-income countries, and were done in populations with a history of homelessness, imprisonment, sex work, or substance use disorder (excluding cannabis and alcohol use). Studies with only perinatal outcomes and studies of individuals with a specific health condition or those recruited from intensive care or high dependency hospital units were excluded. We screened studies using systematic review software and extracted data from published reports. Primary outcomes were measures of morbidity (prevalence or incidence) and mortality (standardised mortality ratios [SMRs] and mortality rates). Summary estimates were calculated using a random effects model. FINDINGS: Our search identified 7946 articles, of which 337 studies were included for analysis. All-cause standardised mortality ratios were significantly increased in 91 (99%) of 92 extracted datapoints and were 11·86 (95% CI 10·42-13·30; I2=94·1%) in female individuals and 7·88 (7·03-8·74; I2=99·1%) in men. Summary SMR estimates for the International Classification of Diseases disease categories with two or more included datapoints were highest for deaths due to injury, poisoning, and other external causes, in both men (7·89; 95% CI 6·40-9·37; I2=98·1%) and women (18·72; 13·73-23·71; I2=91·5%). Disease prevalence was consistently raised across the following categories: infections (eg, highest reported was 90% for hepatitis C, 67 [65%] of 103 individuals for hepatitis B, and 133 [51%] of 263 individuals for latent tuberculosis infection), mental health (eg, highest reported was 9 [4%] of 227 individuals for schizophrenia), cardiovascular conditions (eg, highest reported was 32 [13%] of 247 individuals for coronary heart disease), and respiratory conditions (eg, highest reported was 9 [26%] of 35 individuals for asthma). INTERPRETATION: Our study shows that homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals experience extreme health inequities across a wide range of health conditions, with the relative effect of exclusion being greater in female individuals than male individuals. The high heterogeneity between studies should be explored further using improved data collection in population subgroups. The extreme health inequity identified demands intensive cross-sectoral policy and service action to prevent exclusion and improve health outcomes in individuals who are already marginalised. FUNDING: Wellcome Trust, National Institute for Health Research, NHS England, NHS Research Scotland Scottish Senior Clinical Fellowship, Medical Research Council, Chief Scientist Office, and the Central and North West London NHS Trust.

High prevalence of latent tuberculosis and bloodborne virus infection in a homeless population.

INTRODUCTION: Urban homeless populations in the UK have been shown to have high rates of active tuberculosis, but less is known about the prevalence of latent tuberculosis infection (LTBI). This study aimed to estimate the prevalence of LTBI among individuals using homeless hostels in London. METHODS: We performed a cross-sectional survey with outcome follow-up in homeless hostels in London. Our primary outcome was prevalence of LTBI. Recruitment for the study took place between May 2011 and June 2013. To estimate an LTBI prevalence of 10% with 95% CIs between 8% and 13%, we required 500 participants. RESULTS: 491/804 (61.1%) individuals agreed to be screened. The prevalence of LTBI was 16.5% (81/491; 95% CI 13.2 to 19.8). In UK-born individuals, a history of incarceration was associated with increased risk of LTBI (OR 3.49; 95% CI 1.10 to 11.04; P=0.018) after adjusting for age, length of time spent homeless and illicit drug use. Of the three subjects who met English treatment guidelines for LTBI at the time of the study, none engaged with services after referral for treatment. Prevalence of past hepatitis B infection was 10.4% (51/489; 95% CI 7.7 to 13.1), and 59.5% (291/489; 95% CI 55.1 to 63.9) of individuals were non-immune. Prevalence of current hepatitis C infection was 10.4% (51/489; 95% CI 7.8 to 13.1). CONCLUSIONS: This study demonstrates the high prevalence of LTBI in homeless people in London and the associated poor engagement with care. There is a large unmet need for LTBI and hepatitis C infection treatment, and hepatitis B vaccination, in this group.

Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland.

While acute respiratory tract infections can trigger cardiovascular events, the differential effect of specific organisms is unknown. This is important to guide vaccine policy.Using national infection surveillance data linked to the Scottish Morbidity Record, we identified adults with a first myocardial infarction or stroke from January 1, 2004 to December 31, 2014 and a record of laboratory-confirmed respiratory infection during this period. Using self-controlled case series analysis, we generated age- and season-adjusted incidence ratios (IRs) for myocardial infarction (n=1227) or stroke (n=762) after infections compared with baseline time.We found substantially increased myocardial infarction rates in the week after Streptococcus pneumoniae and influenza virus infection: adjusted IRs for days 1-3 were 5.98 (95% CI 2.47-14.4) and 9.80 (95% CI 2.37-40.5), respectively. Rates of stroke after infection were similarly high and remained elevated to 28 days: day 1-3 adjusted IRs 12.3 (95% CI 5.48-27.7) and 7.82 (95% CI 1.07-56.9) for S. pneumoniae and influenza virus, respectively. Although other respiratory viruses were associated with raised point estimates for both outcomes, only the day 4-7 estimate for stroke reached statistical significance.We showed a marked cardiovascular triggering effect of S. pneumoniae and influenza virus, which highlights the need for adequate pneumococcal and influenza vaccine uptake. Further research is needed into vascular effects of noninfluenza respiratory viruses.

A standardized methodology for the surveillance of antimicrobial prescribing linked to clinical indications in primary care.

Background: A key component of strategies to reduce antimicrobial resistance is better antimicrobial prescribing. The majority of antibiotics are prescribed in primary care. While many existing surveillance systems can monitor trends in the quantities of antibiotics prescribed in this setting, it can be difficult to monitor the quality of prescribing as data on the condition for which prescriptions are issued are often not available. We devised a standardized methodology to facilitate the monitoring of condition-specific antibiotic prescribing in primary care. Methods: We used a large computerized general practitioner database to develop a standardized methodology for routine monitoring of antimicrobial prescribing linked to clinical indications in primary care in the UK. Outputs included prescribing rate by syndrome and percentages of consultations with antibiotic prescription, for recommended antibiotic, and of recommended treatment length. Results: The standardized methodology can monitor trends in proportions of common infections for which antibiotics were prescribed, the specific drugs prescribed and duration of treatment. These data can be used to help assess the appropriateness of antibiotic prescribing and to assess the impact of prescribing guidelines. Conclusions: We present a standardized methodology that could be applied to any suitable national or local database and adapted for use in other countries.

Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland.

BACKGROUND: Tuberculosis elimination in countries with a low incidence of the disease necessitates multiple interventions, including innovations in migrant screening. We examined a cohort of migrants screened for tuberculosis before entry to England, Wales, and Northern Ireland and tracked the development of disease in this group after arrival. METHODS: As part of a pilot pre-entry screening programme for tuberculosis in 15 countries with a high incidence of the disease, the International Organization for Migration screened all applicants for UK visas aged 11 years or older who intended to stay for more than 6 months. Applicants underwent a chest radiograph, and any with results suggestive of tuberculosis underwent sputum testing and culture testing (when available). We tracked the development of tuberculosis in those who tested negative for the disease and subsequently migrated to England, Wales, and Northern Ireland with the Enhanced Tuberculosis Surveillance system. Primary outcomes were cases of all forms of tuberculosis (including clinically diagnosed cases), and bacteriologically confirmed pulmonary tuberculosis. FINDINGS: Our study cohort was 519 955 migrants who were screened for tuberculosis before entry to the UK between Jan 1, 2006, and Dec 31, 2012. Cases notified on the Enhanced Tuberculosis Surveillance system between Jan 1, 2006, and Dec 31, 2013, were included. 1873 incident cases of all forms of tuberculosis were identified, and, on the basis of data for England, Wales, and Northern Ireland, the estimated incidence of all forms of tuberculosis in migrants screened before entry was 147 per 100 000 person-years (95% CI 140-154). The estimated incidence of bacteriologically confirmed pulmonary tuberculosis in migrants screened before entry was 49 per 100 000 person-years (95% CI 45-53). Migrants whose chest radiographs were compatible with active tuberculosis but with negative pre-entry microbiological results were at increased risk of tuberculosis compared with those with no radiographic abnormalities (incidence rate ratio 3·2, 95% CI 2·8-3·7; p<0·0001). Incidence of tuberculosis after migration increased significantly with increasing WHO-estimated prevalence of tuberculosis in migrants' countries of origin. 35 of 318 983 pre-entry screened migrants included in a secondary analysis with typing data were assumed index cases. Estimates of the rate of assumed reactivation tuberculosis ranged from 46 (95% CI 42-52) to 91 (82-102) per 100 000 population. INTERPRETATION: Migrants from countries with a high incidence of tuberculosis screened before being granted entry to low-incidence countries pose a negligible risk of onward transmission but are at increased risk of tuberculosis, which could potentially be prevented through identification and treatment of latent infection in close collaboration with a pre-entry screening programme. FUNDING: Wellcome Trust, UK National Institute for Health Research, UK Medical Research Council, Public Health England, and Department of Health Policy Research Programme.

Impact of long-term care facility residence on the antibiotic resistance of urinary tract Escherichia coli and Klebsiella.

Background: Long-term care facilities (LTCFs) are thought to be important reservoirs of antimicrobial-resistant (AMR) bacteria; however, there is no routine surveillance of resistance in LTCF residents, or large population-based studies comparing AMR in LTCFs with the community, so the relative burden of AMR in LTCFs remains unknown. Objectives: To compare the frequency of antibiotic resistance of urinary tract bacteria from residents of LTCFs for the elderly and adults aged 70 years or older living in the community. Methods: Positive urine specimens reported to any diagnostic microbiology laboratory in the West Midlands region (England) from 1 April 2010 to 31 March 2014 collected from individuals aged 70 years or older were analysed. The resistance of Escherichia coli and Klebsiella to trimethoprim, nitrofurantoin, third-generation cephalosporins and ciprofloxacin and the rate of laboratory-confirmed E. coli and Klebsiella urinary tract infection (UTI) were assessed in LTCF residents and in the community. Results: LTCF residents had a laboratory-confirmed E. coli and Klebsiella UTI rate of 21 per 100 person years compared with 8 per 100 person years in the elderly living in the community [rate ratio (RR)=2.66, 95% CI = 2.58-2.73] and a higher rate of developing E. coli and Klebsiella UTIs caused by bacteria resistant to trimethoprim (RR = 4.41, 95% CI = 4.25-4.57), nitrofurantoin (RR = 4.38, 95% CI = 3.98-4.83), ciprofloxacin (RR = 5.18, 95% CI = 4.82-5.57) and third-generation cephalosporins (RR = 4.49, 95% CI = 4.08-4.94). Conclusions: Residents of LTCFs for the elderly had more than double the rate of E. coli and Klebsiella UTI and more than four times the rate of E. coli and Klebsiella UTI caused by antibiotic-resistant bacteria compared with those living in the community.

Optimising spatial accessibility to inform rationalisation of specialist health services.

BACKGROUND: In an era of budget constraints for healthcare services, strategies for provision of services that improve quality whilst saving costs are highly valued. A proposed means to achieve this is consolidation of services into fewer specialist centres, but this may lead to reduced spatial accessibility. We describe a methodology which includes implementing a combinatorial optimisation algorithm to derive combinations of services which optimise spatial accessibility in the context of service rationalisation, and demonstrate its use through the exemplar of tuberculosis clinics in London. METHODS: Our methodology involves (1) identifying the spatial distribution of the patient population using the service; (2) calculating patient travel times to each service location, and (3) using a combinatorial optimisation algorithm to identify subsets of locations that minimise overall travel time. We estimated travel times for tuberculosis patients notified in London between 2010 and 2013 to each of 29 clinics in the city. Travel time estimates were derived from the Transport for London Journey Planner service. We identified the subset of clinics that would provide the shortest overall travel time for each possible number of clinic subsets (1-28). RESULTS: Based on the 29 existing clinic locations, mean estimated travel time to clinics used by 12,061 tuberculosis patients in London was 33 min; and mean time to their nearest clinics was 28 min. Using optimum combinations of clinic locations, and assuming that patients attended their nearest clinics, a mean travel time of less than 45 min could be achieved with three clinics; of 34 min with ten clinics, and of less than 30 min with 18 clinics. CONCLUSIONS: We have developed a methodological approach to optimise spatial accessibility which can be used to inform rationalisation of health services. In urban conurbations, this may enable service reorganisation which increases quality and efficiency without substantially affecting spatial accessibility. This approach could be used to inform planning of service reorganisations, but may not be generalisable to rural areas or smaller urban centres.

Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014.

An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management.

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.

DotMapper: an open source tool for creating interactive disease point maps.

BACKGROUND: Molecular strain typing of tuberculosis isolates has led to increased understanding of the epidemiological characteristics of the disease and improvements in its control, diagnosis and treatment. However, molecular cluster investigations, which aim to detect previously unidentified cases, remain challenging. Interactive dot mapping is a simple approach which could aid investigations by highlighting cases likely to share epidemiological links. Current tools generally require technical expertise or lack interactivity. RESULTS: We designed a flexible application for producing disease dot maps using Shiny, a web application framework for the statistical software, R. The application displays locations of cases on an interactive map colour coded according to levels of categorical variables such as demographics and risk factors. Cases can be filtered by selecting combinations of these characteristics and by notification date. It can be used to rapidly identify geographic patterns amongst cases in molecular clusters of tuberculosis in space and time; generate hypotheses about disease transmission; identify outliers, and guide targeted control measures. CONCLUSIONS: DotMapper is a user-friendly application which enables rapid production of maps displaying locations of cases and their epidemiological characteristics without the need for specialist training in geographic information systems. Enhanced understanding of tuberculosis transmission using this application could facilitate improved detection of cases with epidemiological links and therefore lessen the public health impacts of the disease. It is a flexible system and also has broad international potential application to other investigations using geo-coded health information.