No action is without its side effects: Adverse drug reactions and missed doses of antituberculosis therapy, a scoping review.

AIMS: A key reason for the failure of antituberculosis (anti-TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are 1 cause of missed doses, but the global evidence, their relative contribution to missed doses vs. other causes, the patterns of missed doses due to ADRs and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. METHODS: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined (PROSPERO: CRD42022295209). RESULTS: Searches identified 108 eligible studies: 88/108 (81%) studies associated ADRs with an increase in missed doses; 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs; 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR-missed doses relations regarding drug susceptibility testing profile and whether the missed doses originated from the patient, healthcare professionals, or both were found. CONCLUSION: There is extensive evidence that ADRs are a key driver for missed doses of anti-TB treatment. Some papers examined specific ADRs and none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed is essential in providing targeted interventions to improve treatment outcomes.

Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening in Drug-sensitive Tuberculosis.

Rationale: "Forgiveness" charts the ability of a drug or regimen to withstand nonadherence without negative clinical consequences. Objectives: We aimed to determine the influence of regimen length, regimen drugs, and dosing, and when during treatment nonadherence occurs on the forgiveness of antituberculosis regimens. Methods: Using data from three randomized controlled trials comparing experimental 4-month regimens for drug-sensitive tuberculosis with the standard 6-month regimen, we used generalized linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and the absolute number of doses missed were calculated during the intensive and continuation phases of treatment, and overall. A mediation analysis was undertaken to determine how much the association between intensive phase dose-taking and the negative composite outcome was mediated through continuation phase dose-taking. Measurements and Main Results: Forgiveness of the 4- and 6-month regimens did not differ for any treatment period. Importantly, 4-month regimens were no less forgiving of small numbers of absolute missed doses than the 6-month regimen (e.g., for 3-7 missed doses vs. no missed doses [baseline], 6-month regimen adjusted risk ratio 1.65 [95% confidence interval, 0.80-3.41] and 4-month regimens 1.80 [1.33-2.45]). No 4-month regimen was conclusively more forgiving than another. We found evidence of mediation by continuation phase dose-taking on the intensive phase dose-taking and negative composite outcome relationship. Conclusions: With the current appetite for, and progress toward, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of nonadherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected.

Mendelian randomisation identifies priority groups for prophylactic EBV vaccination.

BACKGROUND: Epstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin's, non-Hodgkin's lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors-sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV. METHODS: We mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal. RESULTS: Our GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus. CONCLUSIONS: Given the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced.

Measuring and reporting treatment adherence: What can we learn by comparing two respiratory conditions?

Medication non-adherence, defined as any deviation from the regimen recommended by their healthcare provider, can increase morbidity, mortality and side effects, while reducing effectiveness. Through studying two respiratory conditions, asthma and tuberculosis (TB), we thoroughly review the current understanding of the measurement and reporting of medication adherence. In this paper, we identify major methodological issues in the standard ways that adherence has been conceptualised, defined and studied in asthma and TB. Between and within the two diseases there are substantial variations in adherence reporting, linked to differences in dosing intervals and treatment duration. Critically, the communicable nature of TB has resulted in dose-by-dose monitoring becoming a recommended treatment standard. Through the lens of these similarities and contrasts, we highlight contemporary shortcomings in the generalised conceptualisation of medication adherence. Furthermore, we outline elements in which knowledge could be directly transferred from one condition to the other, such as the application of large-scale cost-effective monitoring methods in TB to resource-poor settings in asthma. To develop a more robust evidence-based approach, we recommend the use of standard taxonomies detailed in the ABC taxonomy when measuring and discussing adherence. Regimen and intervention development and use should be based on sufficient evidence of the commonality and type of adherence behaviours displayed by patients with the relevant condition. A systematic approach to the measurement and reporting of adherence could improve the value and generalisability of research across all health conditions.

Trade-offs between cost and accuracy in active case finding for tuberculosis: A dynamic modelling analysis.

BACKGROUND: Active case finding (ACF) may be valuable in tuberculosis (TB) control, but questions remain about its optimum implementation in different settings. For example, smear microscopy misses up to half of TB cases, yet is cheap and detects the most infectious TB cases. What, then, is the incremental value of using more sensitive and specific, yet more costly, tests such as Xpert MTB/RIF in ACF in a high-burden setting? METHODS AND FINDINGS: We constructed a dynamic transmission model of TB, calibrated to be consistent with an urban slum population in India. We applied this model to compare the potential cost and impact of 2 hypothetical approaches following initial symptom screening: (i) 'moderate accuracy' testing employing a microscopy-like test (i.e., lower cost but also lower accuracy) for bacteriological confirmation and (ii) 'high accuracy' testing employing an Xpert-like test (higher cost but also higher accuracy, while also detecting rifampicin resistance). Results suggest that ACF using a moderate-accuracy test could in fact cost more overall than using a high-accuracy test. Under an illustrative budget of US$20 million in a slum population of 2 million, high-accuracy testing would avert 1.14 (95% credible interval 0.75-1.99, with p = 0.28) cases relative to each case averted by moderate-accuracy testing. Test specificity is a key driver: High-accuracy testing would be significantly more impactful at the 5% significance level, as long as the high-accuracy test has specificity at least 3 percentage points greater than the moderate-accuracy test. Additional factors promoting the impact of high-accuracy testing are that (i) its ability to detect rifampicin resistance can lead to long-term cost savings in second-line treatment and (ii) its higher sensitivity contributes to the overall cases averted by ACF. Amongst the limitations of this study, our cost model has a narrow focus on the commodity costs of testing and treatment; our estimates should not be taken as indicative of the overall cost of ACF. There remains uncertainty about the true specificity of tests such as smear and Xpert-like tests in ACF, relating to the accuracy of the reference standard under such conditions. CONCLUSIONS: Our results suggest that cheaper diagnostics do not necessarily translate to less costly ACF, as any savings from the test cost can be strongly outweighed by factors including false-positive TB treatment, reduced sensitivity, and foregone savings in second-line treatment. In resource-limited settings, it is therefore important to take all of these factors into account when designing cost-effective strategies for ACF.

The impact of HIV infection on tuberculosis transmission in a country with low tuberculosis incidence: a national retrospective study using molecular epidemiology.

BACKGROUND: HIV is known to increase the likelihood of reactivation of latent tuberculosis to active TB disease; however, its impact on tuberculosis infectiousness and consequent transmission is unclear, particularly in low-incidence settings. METHODS: National surveillance data from England, Wales and Northern Ireland on tuberculosis cases in adults from 2010 to 2014, strain typed using 24-locus mycobacterial-interspersed-repetitive-units-variable-number-tandem-repeats was used retrospectively to identify clusters of tuberculosis cases, subdivided into 'first' and 'subsequent' cases. Firstly, we used zero-inflated Poisson regression models to examine the association between HIV status and the number of subsequent clustered cases (a surrogate for tuberculosis infectiousness) in a strain type cluster. Secondly, we used logistic regression to examine the association between HIV status and the likelihood of being a subsequent case in a cluster (a surrogate for recent acquisition of tuberculosis infection) compared to the first case or a non-clustered case (a surrogate for reactivation of latent infection). RESULTS: We included 18,864 strain-typed cases, 2238 were the first cases of clusters and 8471 were subsequent cases. Seven hundred and fifty-nine (4%) were HIV-positive. Outcome 1: HIV-positive pulmonary tuberculosis cases who were the first in a cluster had fewer subsequent cases associated with them (mean 0.6, multivariable incidence rate ratio [IRR] 0.75 [0.65-0.86]) than those HIV-negative (mean 1.1). Extra-pulmonary tuberculosis (EPTB) cases with HIV were less likely to be the first case in a cluster compared to HIV-negative EPTB cases. EPTB cases who were the first case had a higher mean number of subsequent cases (mean 2.5, IRR (3.62 [3.12-4.19]) than those HIV-negative (mean 0.6). Outcome 2: tuberculosis cases with HIV co-infection were less likely to be a subsequent case in a cluster (odds ratio 0.82 [0.69-0.98]), compared to being the first or a non-clustered case. CONCLUSIONS: Outcome 1: pulmonary tuberculosis-HIV patients were less infectious than those without HIV. EPTB patients with HIV who were the first case in a cluster had a higher number of subsequent cases and thus may be markers of other undetected cases, discoverable by contact investigations. Outcome 2: tuberculosis in HIV-positive individuals was more likely due to reactivation than recent infection, compared to those who were HIV-negative.

Factors associated with cytomegalovirus serostatus in young people in England: a cross-sectional study.

BACKGROUND: Human cytomegalovirus (CMV) is a common herpesvirus which is estimated to infect 83% of the global population. Whilst many infections are asymptomatic, it is an important cause of morbidity and mortality, particularly for immunocompromised people and for infants who are congenitally infected. A vaccine against CMV has been stated as a public health priority, but there are gaps in our understanding of CMV epidemiology. To guide potential future vaccination strategies, our aim was to examine risk factors for CMV seropositivity in young people in England. METHODS: The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected through questionnaires, and blood samples are taken. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for CMV antibodies. We undertook descriptive and regression analyses of CMV seroprevalence and risk factors for infection. RESULTS: Demographic data and serostatus were available for 732 individuals, of whom 175 (23.7%) were CMV-seropositive. CMV seroprevalence was associated with age, with 18.3% seropositive at 11-14 years compared to 28.3% at 22-24 years. CMV serostatus was also higher in people of non-white ethnicity (adjusted odds ratio [aOR] 6.22, 95% confidence interval [CI] 3.47-11.14), and in adults who were seropositive for EBV (aOR 2.08 [1.06-4.09]). There was no evidence that smoking status, occupation, body mass index and region of England were associated with CMV serostatus. CONCLUSIONS: CMV seroprevalence is strongly associated with ethnicity, and modestly increases with age in 11-24-year-olds. A greater understanding of the transmission dynamics of CMV, and the impact of this on CMV-associated morbidity and mortality, is necessary to inform effective vaccination strategies when a vaccine for CMV becomes available.

Improving engagement with healthcare in hepatitis C: a randomised controlled trial of a peer support intervention.

BACKGROUND: Peer support can enable patient engagement with healthcare services, particularly for marginalised populations. In this randomised controlled trial, the efficacy of a peer support intervention at promoting successful engagement with clinical services for chronic hepatitis C was assessed. METHODS: In London, UK, potential participants were approached through outreach services for problematic drug use and homelessness. Individuals positive for hepatitis C virus (HCV) after confirmatory testing were randomised using an online service to the intervention (peer support) or standard of care. The primary outcome of interest was successful engagement with clinical hepatitis services. The study was non-blinded. Absolute differences were calculated using a generalised linear model and the results compared to logistic regression. RESULTS: Three hundred sixty-four individuals consented to participate. One hundred one had chronic hepatitis C and were randomised, 63 to receive the intervention (peer support). A successful outcome was achieved by 23 individuals in this arm (36.5%) and seven (18.4%) receiving the standard of care, giving an absolute increase of 18.1% (95% confidence interval 1.0-35.2%, p value = 0.04). This was mirrored in the logistic regression (odds ratio 2.55 (0.97-6.70), p = 0.06). No serious adverse events were reported. CONCLUSIONS: Peer support can improve the engagement of patients with chronic HCV with healthcare services. TRIAL REGISTRATION: ISRCTN24707359 . Registered 19th October 2012.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Hepatitis B vaccination uptake in hard-to-reach populations in London: a cross-sectional study.

BACKGROUND: In the UK, hepatitis B virus (HBV) incidence is associated with migrants from particular high-burden countries and population groups deemed 'hard-to-reach' by standard healthcare services: the homeless, people who inject drugs and ex-prisoners. Currently, there is a national targeted HBV vaccine policy for such at-risk groups, but there is limited recent evidence about 1) the levels of vaccine uptake, 2) the factors associated with incomplete vaccination, and 3) reasons for incomplete vaccination. METHODS: A questionnaire capturing social and medical history, demographic factors and information about HBV vaccination status was completed by individuals deemed hard-to-reach due to socio-structural factors that criminalise, isolate and stigmatise who consented to participate in a randomised controlled trial of a peer intervention to promote engagement with hepatitis C services. The questionnaire also captured the reasons for incomplete vaccination. Descriptive, univariable and multivariable regression analyses were undertaken. RESULTS: Three hundred fourty six participants completed the questionnaire. 1) 52.3% (n = 181) reported full HBV vaccination. 2) Within a multivariable model adjusting for sociodemographic variables, the presence of one or two or more socio-structural factors that are included in the national targeted vaccination policy was associated with protection against incomplete HBV vaccination (51.7% vaccine coverage in those with one factor, odds ratio 0.43 [95% confidence interval 0.20-0.92]); 70.1% coverage with two or more factors, 0.19 [0.09-0.39]; overall p-value < 0.001). Being female was also associated with lower vaccine uptake (2.37 [1.24-4.57], 0.01). Examining the socio-structural factors individually, intravenous drug use was associated with protection against incomplete HBV vaccination. 3) The most common reasons declared for incomplete vaccination were never being offered the vaccine or not returning for further doses. CONCLUSION: Within this study of HBV vaccination uptake among hard-to-reach population groups in London, UK, we document 52.3% coverage of the full vaccine course. Critically, although participants recommended for immunisation within national guidelines had an increased likelihood of receiving a complete vaccine course, we note surprisingly low coverage in the presence of the risk factors that are national indicators for vaccination. Public health bodies should make additional efforts to improve coverage in the hard-to-reach through improved vaccine delivery systems. TRIAL REGISTRATION: ISRCTN24707359 , Registered 19th October 2012.

Predictors of Epstein-Barr virus serostatus in young people in England.

BACKGROUND: Epstein-Barr virus (EBV) is an important human pathogen which causes lifelong infection of > 90% people globally and is linked to infectious mononucleosis (arising from infection in the later teenage years) and several types of cancer. Vaccines against EBV are in development. In order to determine the most cost-effective public health strategy for vaccine deployment, setting-specific data on the age at EBV acquisition and risk factors for early infection are required. Such data are also important to inform mathematical models of EBV transmission that can determine the required target product profile of vaccine characteristics. We thus aimed to examine risk factors for EBV infection in young people in England, in order to improve our understanding of EBV epidemiology and guide future vaccination strategies. METHODS: The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected via questionnaires and blood samples. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for EBV and cytomegalovirus (CMV) antibodies. We undertook descriptive and regression analyses of EBV seroprevalence and risk factors for infection. RESULTS: Demographic data and serostatus were available for 732 individuals. EBV seroprevalence was strongly associated with age, increasing from 60.4% in 11-14 year olds throughout adolescence (68.6% in 15-18 year olds) and stabilising by early adulthood (93.0% in those aged 22-24 years). In univariable and multivariable logistic regression models, ethnicity was associated with serostatus (adjusted odds ratio for seropositivity among individuals of other ethnicity versus white individuals 2.33 [95% confidence interval 1.13-4.78]). Smoking was less strongly associated with EBV seropositivity. CONCLUSIONS: By the age of 11 years, EBV infection is present in over half the population, although age is not the only factor associated with serostatus. Knowledge of the distribution of infection in the UK population is critical for determining future vaccination policies, e.g. comparing general versus selectively targeted vaccination strategies.

Trends in, and factors associated with, HIV infection amongst tuberculosis patients in the era of anti-retroviral therapy: a retrospective study in England, Wales and Northern Ireland.

BACKGROUND: HIV increases the progression of latent tuberculosis (TB) infection to active disease and contributed to increased TB in the UK until 2004. We describe temporal trends in HIV infection amongst patients with TB and identify factors associated with HIV infection. METHODS: We used national surveillance data of all TB cases reported in England, Wales and Northern Ireland from 2000 to 2014 and determined HIV status through record linkage to national HIV surveillance. We used logistic regression to identify associations between HIV and demographic, clinical and social factors. RESULTS: There were 106,829 cases of TB in adults (≥ 15 years) reported from 2000 to 2014. The number and proportion of TB patients infected with HIV decreased from 543/6782 (8.0%) in 2004 to 205/6461 (3.2%) in 2014. The proportion of patients diagnosed with HIV > 91 days prior to their TB diagnosis increased from 33.5% in 2000 to 60.2% in 2013. HIV infection was highest in people of black African ethnicity from countries with high HIV prevalence (32.3%), patients who misused drugs (8.1%) and patients with miliary or meningeal TB (17.2%). CONCLUSIONS: There has been an overall decrease in TB-HIV co-infection and a decline in the proportion of patients diagnosed simultaneously with both infections. However, high rates of HIV remain in some sub-populations of patients with TB, particularly black Africans born in countries with high HIV prevalence and people with a history of drug misuse. Whilst the current policy of testing all patients diagnosed with TB for HIV infection is important in ensuring appropriate management of TB patients, many of these TB cases would be preventable if HIV could be diagnosed before TB develops. Improving screening for both latent TB and HIV and ensuring early treatment of HIV in these populations could help prevent these TB cases. British HIV Association guidelines on latent TB testing for people with HIV from sub-Saharan Africa remain relevant, and latent TB screening for people with HIV with a history of drug misuse, homelessness or imprisonment should also be considered.

Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis.

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI. PURPOSE: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children. DATA SOURCES: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied. STUDY SELECTION: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB). DATA EXTRACTION: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol. DATA SYNTHESIS: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy. LIMITATION: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies. CONCLUSION: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin. PRIMARY FUNDING SOURCE: U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).

TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I.

The US11 gene product of human cytomegalovirus promotes viral immune evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US11 initiates dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation. Despite the critical role for ubiquitin in this degradation pathway, the responsible E3 ligase is unknown. In a forward genetic screen for host ERAD components hijacked by US11 in near-haploid KBM7 cells, we identified TMEM129, an uncharacterized polytopic membrane protein. TMEM129 is essential and rate-limiting for US11-mediated MHC-I degradation and acts as a novel ER resident E3 ubiquitin ligase. TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. Together with its E2 conjugase Ube2J2, TMEM129 is responsible for the ubiquitination, dislocation, and subsequent degradation of US11-associated MHC-I. US11 engages two degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for "free" US11 degradation. Our data show that TMEM129 is a novel ERAD E3 ligase and the central component of a novel mammalian ERAD complex.

Using peer advocates to improve access to services among hard-to-reach populations with hepatitis C: a qualitative study of client and provider relationships.

BACKGROUND: Peer support programmes use individuals with specific experiences to improve engagement and outcomes among new clients. However, the skills and techniques used to achieve this engagement have not been mapped. This potentially restricts the development and replication of successful peer advocate models of care. This study explored how a group of peer advocates with experience of homelessness, alcohol and drug misuse made and sustained relationships with their client group. For the purposes of this project, the client group were located among a hepatitis C-positive cohort of people who have a history of injecting drug use and homelessness. METHODS: Five self-selecting advocates gave a narrative interview lasting 40-90 min. These interviews were double transcribed using both thematic analysis and narrative analysis in order to triangulate the data and provide a robust set of findings about the unique skills of peer advocates in creating and sustaining relationships with clients from hard-to-reach populations. RESULTS: Peer advocates build rapport with clients through disclosing personal details about their lives. While this runs counter to assumptions about the need to maintain distance in client-patient relationships, the therapeutic benefits appear to outweigh the potential costs of this engagement. CONCLUSION: We conclude the therapeutic benefits of self-disclosure between peer advocates and their clients offer a moral grounding for self-disclosure as a means of building relationships with key hard-to-reach populations.

Decreased Time to Treatment Initiation for Multidrug-Resistant Tuberculosis Patients after Use of Xpert MTB/RIF Test, Latvia.

Few studies have examined whether the Xpert MTB/RIF test improves time to treatment initiation for persons with multidrug-resistant tuberculosis (MDR TB). We determined the impact of this test in Latvia, where it was introduced in 2010. After descriptive analyses of pulmonary MDR TB patients in Latvia during 2009-2012, time to treatment initiation was calculated, and univariate and multivariable accelerated failure time models were constructed. Univariate results showed strong evidence of an association between having rifampin-resistant TB detected by Xpert MTB/RIF and reduced time to treatment initiation versus the test not being used. A multivariable model stratifying by previous TB showed similar results. Our finding that in Latvia, time to treatment initiation was decreased for MDR TB cases that were rifampin-resistant TB by XpertMTB/RIF has implications for the use of this test in other settings with a high burden of MDR TB in which rifampin resistance is highly predictive of MDR TB.

Mind the gap: TB trends in the USA and the UK, 2000-2011.

BACKGROUND: TB remains a major public health concern, even in low-incidence countries like the USA and the UK. Over the last two decades, cases of TB reported in the USA have declined, while they have increased substantially in the UK. We examined factors associated with this divergence in TB trends between the two countries. METHODS: We analysed all cases of TB reported to the US and UK national TB surveillance systems from 1 January 2000 through 31 December 2011. Negative binominal regression was used to assess potential demographic, clinical and risk factor variables associated with differences in observed trends. FINDINGS: A total of 259,609 cases were reported. From 2000 to 2011, annual TB incidence rates declined from 5.8 to 3.4 cases per 100,000 in the USA, whereas in the UK, TB incidence increased from 11.4 to 14.4 cases per 100,000. The majority of cases in both the USA (56%) and the UK (64%) were among foreign-born persons. The number of foreign-born cases reported in the USA declined by 15% (7731 in 2000 to 6564 in 2011) while native-born cases fell by 54% (8442 in 2000 to 3883 in 2011). In contrast, the number of foreign-born cases reported in the UK increased by 80% (3380 in 2000 to 6088 in 2011), while the number of native-born cases remained largely unchanged (2158 in 2000 to 2137 in 2011). In an adjusted negative binomial regression model, significant differences in trend were associated with sex, age, race/ethnicity, site of disease, HIV status and previous history of TB (p<0.01). Among the foreign-born, significant differences in trend were also associated with time since UK or US entry (p<0.01). INTERPRETATION: To achieve TB elimination in the UK, a re-evaluation of current TB control policies and practices with a focus on foreign-born are needed. In the USA, maintaining and strengthening control practices are necessary to sustain the progress made over the last 20 years.

Interpreting whole genome sequencing for investigating tuberculosis transmission: a systematic review.

BACKGROUND: Whole genome sequencing (WGS) is becoming an important part of epidemiological investigations of infectious diseases due to greater resolution and cost reductions compared to traditional typing approaches. Many public health and clinical teams will increasingly use WGS to investigate clusters of potential pathogen transmission, making it crucial to understand the benefits and assumptions of the analytical methods for investigating the data. We aimed to understand how different approaches affect inferences of transmission dynamics and outline limitations of the methods. METHODS: We comprehensively searched electronic databases for studies that presented methods used to interpret WGS data for investigating tuberculosis (TB) transmission. Two authors independently selected studies for inclusion and extracted data. Due to considerable methodological heterogeneity between studies, we present summary data with accompanying narrative synthesis rather than pooled analyses. RESULTS: Twenty-five studies met our inclusion criteria. Despite the range of interpretation tools, the usefulness of WGS data in understanding TB transmission often depends on the amount of genetic diversity in the setting. Where diversity is small, distinguishing re-infections from relapses may be impossible; interpretation may be aided by the use of epidemiological data, examining minor variants and deep sequencing. Conversely, when within-host diversity is large, due to genetic hitchhiking or co-infection of two dissimilar strains, it is critical to understand how it arose. Greater understanding of microevolution and mixed infection will enhance interpretation of WGS data. CONCLUSIONS: As sequencing studies have sampled more intensely and integrated multiple sources of information, the understanding of TB transmission and diversity has grown, but there is still much to be learnt about the origins of diversity that will affect inferences from these data. Public health teams and researchers should combine epidemiological, clinical and WGS data to strengthen investigations of transmission.

Towards better guidance on caseload thresholds to promote positive tuberculosis treatment outcomes: a cohort study.

BACKGROUND: In low-incidence countries, clinical experience of tuberculosis is becoming more limited, with potential consequences for patient outcomes. In 2007, the Department of Health released a guidance 'toolkit' recommending that tuberculosis patients in England should not be solely managed by clinicians who see fewer than 10 cases per year. This caseload threshold was established to try to improve treatment outcomes and reduce transmission, but was not evidence based. We aimed to assess the association between clinician or hospital caseload and treatment outcomes, as well as the relative suitability of making recommendations using each caseload parameter. METHODS: Demographic and clinical data for tuberculosis cases in England notified to Public Health England's Enhanced Tuberculosis Surveillance system between 2003 and 2012 were extracted. Mean clinician and hospital caseload over the past 3 years were calculated and treatment outcomes grouped into good/neutral and unfavourable. Caseloads over time and their relationship with outcomes were described and analysed using random effects logistic regression, adjusted for clustering. RESULTS: In a fully adjusted multivariable model (34,707 cases)there was very strong evidence that management of tuberculosis by clinicians with fewer than 10 cases per year was associated with greater odds of an unfavourable outcome compared to clinicians who managed greater numbers of cases (cluster-specific odds ratio, 1.14; 95 % confidence interval, 1.05-1.25; P = 0.002). The relationship between hospital caseload and treatment outcomes was more complex and modified by a patient's place of birth and ethnicity. The clinician caseload association held after adjustment for hospital caseload and when the clinician caseload threshold was reduced down to one. CONCLUSIONS: Despite the relative ease of making recommendations at the hospital level and the greater reliability of recorded hospital versus named clinician, our results suggest that clinician caseload thresholds are more suitable for clinical guidance. The current recommended clinician caseload threshold is functional. Sensitivity analyses reducing the threshold indicated that clinical experience is pertinent even at very low average caseloads, which is encouraging for low burden settings.

Working conditions and tuberculosis mortality in England and Wales, 1890-1912: a retrospective analysis of routinely collected data.

BACKGROUND: Modelling studies suggest that workplaces may be important sites of Mycobacterium tuberculosis transmission in high burden countries today. Contemporary data on tuberculosis by occupation from these settings are scarce. However, historical data on tuberculosis risk in different occupations are available and may provide insight into workplace transmission. We aimed to ascertain whether, in a high burden setting, individuals working in crowded indoor environments (exposed) had greater tuberculosis mortality than individuals employed elsewhere (unexposed). METHODS: The Registrar General's Decennial Supplements from 1890-2, 1900-2 and 1910-2 contain data on mortality from tuberculosis by occupation for men in England and Wales. In these data, the association between occupational exposure to crowded indoor environments and tuberculosis mortality was assessed using an overdispersed Poisson regression model adjusting for socioeconomic position, age and decade. RESULTS: There were 23,962 deaths from tuberculosis during 14.8 million person-years of follow-up among men working in exposed occupations and 28,483 during 19.9 million person-years of follow-up among men working in unexposed occupations. We were unable to categorise a large number of occupations as exposed or unexposed. The adjusted rate ratio for death from tuberculosis was 1.34 (95 % confidence interval 1.26-1.43) comparing men working in exposed occupations to those in unexposed occupations. CONCLUSIONS: Tuberculosis mortality in England and Wales at the turn of the 20th century was associated with occupational exposure to crowded indoor environments. The association between working conditions and TB in contemporary high burden settings requires further study.