Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study.

BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001). INTERPRETATION: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants. FUNDING: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study

BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001). INTERPRETATION: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants. FUNDING: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre

Million Migrants study of healthcare and mortality outcomes in non-EU migrants and refugees to England: Analysis protocol for a linked population-based cohort study of 1.5 million migrants.

Background: In 2017, 15.6% of the people living in England were born abroad, yet we have a limited understanding of their use of health services and subsequent health conditions. This linked population-based cohort study aims to describe the hospital-based healthcare and mortality outcomes of 1.5 million non-European Union (EU) migrants and refugees in England. Methods and analysis: We will link four data sources: first, non-EU migrant tuberculosis pre-entry screening data; second, refugee pre-entry health assessment data; third, national hospital episode statistics; and fourth, Office of National Statistics death records. Using this linked dataset, we will then generate a population-based cohort to examine hospital-based events and mortality outcomes in England between Jan 1, 2006, and Dec 31, 2017. We will compare outcomes across three groups in our analyses: 1) non-EU international migrants, 2) refugees, and 3) general population of England. Ethics and dissemination: We will obtain approval to use unconsented patient identifiable data from the Secretary of State for Health through the Confidentiality Advisory Group and the National Health Service Research Ethics Committee. After data linkage, we will destroy identifying data and undertake all analyses using the pseudonymised dataset. The results will provide policy makers and civil society with detailed information about the health needs of non-EU international migrants and refugees in England

The role of WNK in modulation of KCl cotransport activity in red cells from normal individuals and patients with sickle cell anaemia

Abstract: Abnormal activity of red cell KCl cotransport (KCC) is involved in pathogenesis of sickle cell anaemia (SCA). KCC-mediated solute loss causes shrinkage, concentrates HbS, and promotes HbS polymerisation. Red cell KCC also responds to various stimuli including pH, volume, urea, and oxygen tension, and regulation involves protein phosphorylation. The main aim of this study was to investigate the role of the WNK/SPAK/OSR1 pathway in sickle cells. The pan WNK inhibitor WNK463 stimulated KCC with an EC50 of 10.9 ± 1.1 nM and 7.9 ± 1.2 nM in sickle and normal red cells, respectively. SPAK/OSR1 inhibitors had little effect. The action of WNK463 was not additive with other kinase inhibitors (staurosporine and N-ethylmaleimide). Its effects were largely abrogated by pre-treatment with the phosphatase inhibitor calyculin A. WNK463 also reduced the effects of physiological KCC stimuli (pH, volume, urea) and abolished any response of KCC to changes in oxygen tension. Finally, although protein kinases have been implicated in regulation of phosphatidylserine exposure, WNK463 had no effect. Findings indicate a predominant role for WNKs in control of KCC in sickle cells but an apparent absence of downstream involvement of SPAK/OSR1. A more complete understanding of the mechanisms will inform pathogenesis whilst manipulation of WNK activity represents a potential therapeutic approach

Reduction in tuberculosis incidence in the UK from 2011 to 2015: a population-based study

Background: Following nearly two decades of increasing tuberculosis in the UK, TB incidence decreased by 32% from 2011 to 2015. Explaining this reduction is crucial to informing ongoing TB control efforts. Methods: We stratified TB cases notified in the UK and TB cases averted in the UK through pre-entry screening (PES) between 2011 and 2015 by country of birth and time since arrival. We used population estimates and migration data to establish denominators, and calculated incidence rate ratios (IRRs) between 2011 and 2015. We calculated the contribution of changing migrant population sizes, PES and changes in TB rates to the reduction in TB notifications. Results: TB IRRs fell in all non-EU migrant and UK-born populations between 2011 and 2015 (0.61; 95%  CI 0.59 to 0.64 and 0.78; 0.73 to 0.83 respectively), with the greatest decrease in recent non-EU migrants (0.54; 0.48 to 0.61). 61.9% of the reduction in TB notifications was attributable to decreases in TB rates, 33.4% to a fall in the number of recent/mid-term non-EU migrants and 11.4% to PES. A small increase in notifications in EU-born migrants offset the reduction by 6.6%. Conclusions: Large decreases in TB rates in almost all populations accounted for the majority of the reduction in TB notifications, providing evidence of the impact of recent interventions to improve UK TB control. The particularly large decrease in TB rates in recent non-EU migrants provides evidence of the effectiveness of screening interventions that target this population. These findings will inform ongoing improvements to TB control

Effectiveness of interventions for reducing TB incidence in countries with low TB incidence: a systematic review of reviews

AIMS: What is the evidence base for the effectiveness of interventions to reduce tuberculosis (TB) incidence in countries which have low TB incidence? METHODS: We conducted a systematic review of interventions for TB control and prevention relevant to low TB incidence settings (<10 cases per 100 000 population). Our analysis was stratified according to "direct" or "indirect" effects on TB incidence. Review quality was assessed using AMSTAR2 criteria. We summarised the strength of review level evidence for interventions as "sufficient", "tentative", "insufficient" or "no" using a framework based on the consistency of evidence within and between reviews. RESULTS: We found sufficient review level evidence for direct effects on TB incidence/case prevention of vaccination and treatment of latent TB infection. We also found sufficient evidence of beneficial indirect effects attributable to drug susceptibility testing and adverse indirect effects (measured as sub-optimal treatment outcomes) in relation to use of standardised first-line drug regimens for isoniazid-resistant TB and intermittent dosing regimens. We found insufficient review level evidence for direct or indirect effects of interventions in other areas, including screening, adherence, multidrug-resistant TB, and healthcare-associated infection. DISCUSSION: Our review has shown a need for stronger evidence to support expert opinion and country experience when formulating TB control policy

Effectiveness of nationwide programmatic testing and treatment for latent tuberculosis infection in migrants in England: a retrospective, population-based cohort study.

BACKGROUND: In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme. METHODS: We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16-35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system. FINDINGS: Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases [95% CI 176-238] per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases [77-86] per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio [HR] 0·76 [95% CI 0·63-0·91]) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 [7·63-12·9) and a lower risk after 6 months (0·57 [0·41-0·79]). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 [20·4-49·8]). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases [95% CI 0·89-3·93] per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases [9·16-12·9] per 1000 person-years; HR 0·14 [95% CI 0·06-0·32]). INTERPRETATION: A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence. FUNDING: National Institute for Health Research Health Protection Research Unit in Respiratory Infections