World TB Day 2016: an interview with leading experts in tuberculosis research.

In this interview, we talk to leading tuberculosis (TB) experts from University College London and the London School of Hygiene and Tropical Medicine about the current challenges in TB research. The video of this interview is available here: https://www.youtube.com/watch?v=75Die7MQBec&feature=youtu.be . The video can also be downloaded via Additional file 1

Impact of prophylactic and 'rescue pack' antibiotics on the airway microbiome in chronic lung disease

The management of many chronic lung diseases involves multiple antibiotic prescriptions either to treat acute exacerbations or as prophylactic therapy to reduce the frequency of exacerbations and improve patients’ quality of life. AIM: To investigate the effects of antibiotics on the homeostasis of bacterial communities in the airways, and how this may contribute to antimicrobial resistance (AMR) among respiratory pathogens and microbiota. METHODS: Within an observational cohort study, sputum was collected from 84 patients with chronic obstructive pulmonary disease and/or bronchiectasis at stable state: 47 were receiving antibiotic prophylaxis therapy. V3-V4 16S-rRNA sequencing on Illumina MiSeq, quantitative PCR for typical respiratory pathogens, bacteriology cultures and antimicrobial susceptibility testing of sputum isolates, resistome analysis on a subset of 17 sputum samples using MinION metagenomics sequencing were performed. FINDINGS: The phylogenetic α-diversity and the total bacterial density in sputum were significantly lower in patients receiving prophylactic antibiotics (p=0.014 and 0.029, respectively). Antibiotic prophylaxis was associated with significantly lower relative abundance of respiratory pathogens such as Pseudomonas aeruginosa, Moraxella catarrhalis and members of family Enterobacteriaceae in the airway microbiome, but not Haemophilus influenzae and Streptococcus pneumoniae. No major definite directional shifts in the microbiota composition were identified with prophylactic antibiotic use at the cohort level. Surveillance of AMR and resistome analysis revealed a high frequency of resistance to macrolide and tetracycline in the cohort. AMR expressed by pathogenic bacterial isolates was associated with antibiotics prescribed as ‘rescue packs’ for prompt initiation of self-treatment of exacerbations (Spearman’s rho=0.408, p=0.02). CONCLUSIONS: Antibiotic prophylactic therapy suppresses recognised pathogenic bacteria in the sputum of patients with chronic lung disease. The use of antibiotic rescue packs may be driving AMR in this cohort rather than prophylactic antibiotics

Forgiveness Is the Attribute of the Strong:Nonadherence and Regimen-Shortening in Drug-Sensitive TB

RATIONALE: 'Forgiveness' charts the ability of a drug or regimen to withstand non-adherence without negative clinical consequences. OBJECTIVES: We aimed to determine the influence of regimen length, regimen drugs and dosing, and when during treatment non-adherence occurs on the forgiveness of anti-tuberculosis regimens. METHODS: Using data from three randomised controlled trials comparing experimental four-month regimens for drug-sensitive tuberculosis with the standard six-month regimen, we used generalised linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and 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 of 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 four-month and six-month regimens did not differ for any treatment period. Importantly, four-month regimens were no less forgiving of small numbers of absolute missed doses than the six-month regimen (e.g. for 3-7 missed doses versus no missed doses (baseline), six-month regimen adjusted risk ratio 1.65 (95% confidence interval 0.80-3.41) and four-month regimens 1.80 (1.33-2.45)). No four-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 towards, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of non-adherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected

Cross-sectional study evaluating the impact of SARS-CoV-2 variants on Long COVID outcomes in UK hospital survivors

OBJECTIVES: COVID-19 studies report on hospital admission outcomes across SARS-CoV-2 waves of infection but knowledge of the impact of SARS-CoV-2 variants on the development of Long COVID in hospital survivors is limited. We sought to investigate Long COVID outcomes, aiming to compare outcomes in adult hospitalised survivors with known variants of concern during our first and second UK COVID-19 waves, prior to widespread vaccination. DESIGN: Prospective observational cross-sectional study. SETTING: Secondary care tertiary hospital in the UK. PARTICIPANTS: This study investigated Long COVID in 673 adults with laboratory-positive SARS-CoV-2 infection or clinically suspected COVID-19, 6 weeks after hospital discharge. We compared adults with wave 1 (wildtype variant, admitted from February to April 2020) and wave 2 patients (confirmed Alpha variant on viral sequencing (B.1.1.7), admitted from December 2020 to February 2021). OUTCOME MEASURES: Associations of Long COVID presence (one or more of 14 symptoms) and total number of Long COVID symptoms with SARS-CoV-2 variant were analysed using multiple logistic and Poisson regression, respectively. RESULTS: 322/400 (wave 1) and 248/273 (wave 2) patients completed follow-up. Predictors of increased total number of Long COVID symptoms included: pre-existing lung disease (adjusted count ratio (aCR)=1.26, 95% CI 1.07, 1.48) and more COVID-19 admission symptoms (aCR=1.07, 95% CI 1.02, 1.12). Weaker associations included increased length of inpatient stay (aCR=1.02, 95% CI 1.00, 1.03) and later review after discharge (aCR=1.00, 95% CI 1.00, 1.01). SARS-CoV-2 variant was not associated with Long COVID presence (OR=0.99, 95% CI 0.24, 4.20) or total number of symptoms (aCR=1.09, 95% CI 0.82, 1.44). CONCLUSIONS: Patients with chronic lung disease or greater COVID-19 admission symptoms have higher Long COVID risk. SARS-CoV-2 variant was not predictive of Long COVID though in wave 2 we identified fewer admission symptoms, improved clinical trajectory and outcomes. Addressing modifiable factors such as length of stay and timepoint of clinical review following discharge may enable clinicians to move from Long COVID risk stratification towards improving its outcome

World TB Day 2016: an interview with leading experts in tuberculosis research

In this interview, we talk to leading tuberculosis (TB) experts from University College London and the London School of Hygiene and Tropical Medicine about the current challenges in TB research. The video of this interview is available here: https://www.youtube.com/watch?v=75Die7MQBec&feature=youtu.be . The video can also be downloaded via Additional file 1

Changes in short-term (in-ICU and in-hospital) mortality following Intensive Care Unit admission in adults Living with HIV: 2000-2019

OBJECTIVE: Limited data suggest intensive care unit (ICU) outcomes have improved in people with HIV (PWH). We describe trends in in-ICU/in-hospital mortality among PWH following admission to ICU in a single UK-based HIV referral centre, from 1 January 2000 to 31 December 2019. METHODS: Modelling of associations between ICU admission and calendar year of admission was done using logistic regression with adjustment for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, CD4+ T-cell count and diagnosis of HIV at/within the past 3 months. RESULTS: Among 221 PWH (71% male, median [interquartile range (IQR)] age 45 years [38-53]) admitted to ICU, median [IQR] APACHE II score and CD4+ T-cell count were 19 [14-25] and 122 cells/mm3 [30-297], respectively; HIV-1 viral load was ≤50 copies/ml in 46%. The most common ICU admission diagnosis was lower respiratory tract infection (30%).In-ICU and in-hospital, mortality were 29% and 38.5%, respectively. The odds of in-ICU mortality decreased over the 20-year period by 11% per year [odds ratio (OR): 0.89 (95% confidence interval (CI): 0.84-0.94)] with in-hospital mortality decreasing by 14% per year [0.86 (0.82-0.91)]. After adjusting for patient demographics and clinical factors, both estimates were attenuated, however, the odds of in-hospital mortality continued to decline over time [in-ICU mortality: adjusted OR: 0.97 (0.90-1.05); in-hospital mortality: 0.90 (0.84-0.97)]. CONCLUSION: Short-term mortality of critically ill PWH admitted to ICU has continued to decline in the ART era. This may result from changing indications for ICU admission, advances in critical care and improvements in HIV-related immune status

Determinants of non-adherence to anti-TB treatment in high income, low TB incidence settings: a scoping review.

BACKGROUND: Improving adherence to anti-TB treatment is a public health priority in high-income, low incidence (HILI) regions. We conducted a scoping review to identify reported determinants of non-adherence in HILI settings.METHODS: Key terms related to TB, treatment and adherence were used to search MEDLINE, EMBASE, Web of Science, PsycINFO and CINAHL in June 2019. Quantitative studies examining determinants (demographic, clinical, health systems or psychosocial) of non-adherence to anti-TB treatment in HILI settings were included.RESULTS: From 10,801 results, we identified 24 relevant studies from 10 countries. Definitions and methods of assessing adherence were highly variable, as were documented levels of non-adherence (0.9-89%). Demographic factors were assessed in all studies and clinical factors were frequently assessed (23/24). Determinants commonly associated with non-adherence were homelessness, incarceration, and alcohol or drug misuse. Health system (8/24) and psychosocial factors (6/24) were less commonly evaluated.CONCLUSION: Our review identified some key factors associated with non-adherence to anti-TB treatment in HILI settings. Modifiable determinants such as psychosocial factors are under-evidenced and should be further explored, as these may be better targeted by adherence support. There is an urgent need to standardise definitions and measurement of adherence to more accurately identify the strongest determinants

Comparative assessment of viral dynamic models for SARS-CoV-2 for pharmacodynamic assessment in early treatment trials

Pharmacometric analyses of time series viral load data may detect drug effects with greater power than approaches using single time points. Because SARS-CoV-2 viral load rapidly rises and then falls, viral dynamic models have been used. We compared different modelling approaches when analysing Phase II-type viral dynamic data. Using two SARS-CoV-2 datasets of viral load starting within 7 days of symptoms, we fitted the slope-intercept exponential decay (SI), reduced target cell limited (rTCL), target cell limited (TCL) and TCL with eclipse phase (TCLE) models using nlmixr. Model performance was assessed via Bayesian information criterion (BIC), visual predictive checks (VPCs), goodness-of-fit plots, and parameter precision. The most complex (TCLE) model had the highest BIC for both datasets. The estimated viral decline rate was similar for all models except the TCL model for dataset A with a higher rate [median (range) day-1 : dataset A; 0.63 (0.56 - 1.84); dataset B: 0.81 (0.74-0.85)]. Our findings suggest simple models should be considered during pharmacodynamic model development