“You have to change your whole life”: a qualitative study of the dynamics of treatment adherence among adults with tuberculosis in the United Kingdom

Karina Kielmann - ORCID: 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Aaron S. Karat - ORCID: 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XVoR deposited 2021-04-13.Maintaining adherence to treatment for tuberculosis (TB) is essential if the disease is to be eliminated. As part of formative research to develop an intervention to improve adherence, we documented the lived experiences of adults receiving anti-TB treatment (ATT) in three UK cities and examined how personal, social, and structural circumstances interacted to impact on individuals’ adherence to treatment. Using a topic guide that explored social circumstances and experiences of TB care, we conducted in-depth interviews with 18 adults (six women) who were being or had been treated for TB (patients) and four adults (all women) who were caring for a friend, relative, or partner being treated for TB (caregivers). We analysed transcripts using an adapted framework method that classified factors affecting adherence as personal, social, structural, health systems, or treatment-related. Eleven of 18 patients were born outside the UK (in South, Central, and East Asia, and Eastern and Southern Africa); among the seven who were UK-born, four were Black, Asian, or Minority Ethnic and three were White British. TB and its treatment were often disruptive: in addition to debilitating symptoms and side effects of ATT, participants faced job insecurity, unstable housing, stigma, social isolation, worsening mental health, and damaged relationships. Those who had a strong support network, stable employment, a routine that could easily be adapted, a trusting relationship with their TB team, and clear understanding of the need for treatment reported finding it easier to adhere to ATT. Changes in circumstances sometimes had dramatic effects on an individual’s ability to take ATT; participants described how the impact of certain acute events (e.g., the onset of side effects or fatigue, episodes of stigmatisation, loss of income) were amplified by their timing or through their interaction with other elements of the individual’s life. We suggest that the dynamic and fluctuating nature of these factors necessitates comprehensive and regular review of needs and potential problems, conducted before and during ATT; this, coupled with supportive measures that consider (and seek to mitigate) the influence of social and structural factors, may help improve adherence.This work was supported by the National Institute for Health Research (NIHR) Health Technology Assessment Programme, UK grant number 16/88/06.https://doi.org/10.1016/j.jctube.2021.10023323pubpu

Predicting Peptide Binding Affinities to MHC Molecules Using a Modified Semi-Empirical Scoring Function

The Major Histocompatibility Complex (MHC) plays an important role in the human immune system. The MHC is involved in the antigen presentation system assisting T cells to identify foreign or pathogenic proteins. However, an MHC molecule binding a self-peptide may incorrectly trigger an immune response and cause an autoimmune disease, such as multiple sclerosis. Understanding the molecular mechanism of this process will greatly assist in determining the aetiology of various diseases and in the design of effective drugs. In the present study, we have used the Fresno semi-empirical scoring function and modify the approach to the prediction of peptide-MHC binding by using open-source and public domain software. We apply the method to HLA class II alleles DR15, DR1, and DR4, and the HLA class I allele HLA A2. Our analysis shows that using a large set of binding data and multiple crystal structures improves the predictive capability of the method. The performance of the method is also shown to be correlated to the structural similarity of the crystal structures used. We have exposed some of the obstacles faced by structure-based prediction methods and proposed possible solutions to those obstacles. It is envisaged that these obstacles need to be addressed before the performance of structure-based methods can be on par with the sequence-based methods

Impact of voluntary exercise and housing conditions on hippocampal glucocorticoid receptor, miR-124 and anxiety

Background: Lack of physical activity and increased levels of stress contribute to the development of multiple physical and mental disorders. An increasing number of studies relate voluntary exercise with greater resilience to psychological stress, a process that is highly regulated by the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanisms underlying the beneficial effects of exercise on stress resilience are still poorly understood. Here we have studied the impact of long term exercise and housing conditions on: a) hippocampal expression of glucocorticoid receptor (Nr3c1), b) epigenetic regulation of Nr3c1 (DNA methylation at the Nr3c1-1F promoter and miR-124 expression), c) anxiety (elevated plus maze, EPM), and d) adrenal gland weight and adrenocorticotropic hormone receptor (Mc2r) expression. Results: Exercise increased Nr3c1 and Nr3c1-1F expression and decreased miR-124 levels in the hippocampus in single-housed mice, suggesting enhanced resilience to stress. The opposite was found for pair-housed animals. Bisulfite sequencing showed virtually no DNA methylation in the Nr3c1-1F promoter region. Single-housing increased the time spent on stretch attend postures. Exercise decreased the time spent at the open arms of the EPM, however, the mobility of the exercise groups was significantly lower. Exercise had opposite effects on the adrenal gland weight of single and pair-housed mice, while it had no effect on adrenal Mc2r expression. Conclusions: These results suggest that exercise exerts a positive impact on stress resilience in single-housed mice that could be mediated by decreasing miR-124 and increasing Nr3c1 expression in the hippocampus. However, pair-housing reverses these effects possibly due to stress from dominance disputes between pairs

Computational vaccinology: quantitative approaches.

The immune system is hierarchical and has many levels, exhibiting much emergent behaviour. However, at its heart are molecular recognition events that are indistinguishable from other types of biomacromolecular interaction. These can be addressed well by quantitative experimental and theoretical biophysical techniques, and particularly by methods from drug design. We review here our approach to computational immunovaccinology. In particular, we describe the JenPep database and two new techniques for T cell epitope prediction. One is based on quantitative structure-activity relationships (a 3D-QSAR method based on CoMSIA and another 2D method based on the Free-Wilson approach) and the other on atomistic molecular dynamic simulations using high performance computing. JenPep (http://www.jenner.ar.uk/ JenPep) is a relational database system supporting quantitative data on peptide binding to major histocompatibility complexes, TAP transporters, TCR-pMHC complexes, and an annotated list of B cell and T cell epitopes. Our 2D-QSAR method factors the contribution to peptide binding from individual amino acids as well as 1-2 and 1-3 residue interactions. In the 3D-QSAR approach, the influence of five physicochemical properties (volume, electrostatic potential, hydrophobicity, hydrogen-bond donor and acceptor abilities) on peptide affinity were considered. Both methods are exemplified through their application to the well-studied problem of peptide binding to the human class I MHC molecule HLA-A*0201

Transthoracic echocardiography and mortality in sepsis: analysis of the MIMIC-III database

Abstract Purpose While the use of transthoracic echocardiography (TTE) in the ICU is rapidly expanding, the contribution of TTE to altering patient outcomes among ICU patients with sepsis has not been examined. This study was designed to examine the association of TTE with 28-day mortality specifically in that population. Methods and results The MIMIC-III database was employed to identify patients with sepsis who had and had not received TTE. The statistical approaches utilized included multivariate regression, propensity score analysis, doubly robust estimation, the gradient boosted model, and an inverse probability-weighting model to ensure the robustness of our findings. Significant benefit in terms of 28-day mortality was observed among the TTE patients compared to the control (no TTE) group (odds ratio = 0.78, 95% CI 0.68–0.90, p < 0.001). The amount of fluid administered (2.5 vs. 2.1 L on day 1, p < 0.001), use of dobutamine (2% vs. 1%, p = 0.007), and the maximum dose of norepinephrine (1.4 vs. 1 mg/min, p = 0.001) were significantly higher for the TTE patients. Importantly, the TTE patients were weaned off vasopressors more quickly than those in the no TTE group (vasopressor-free days on day 28 of 21 vs. 19, p = 0.004). Conclusion In a general population of critically ill patients with sepsis, use of TTE is associated with an improvement in 28-day mortality

Causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study

Abstract Background Acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are associated with high in-hospital mortality. However, in cohorts of ARDS patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. Given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. These differences may provide clinicians with insight into targets for future therapeutic interventions. Methods We identified adult patients hospitalized at a single tertiary care center (2016–2017) with AHRF, defined as PaO2/FiO2 ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ARDS was adjudicated by multiple physicians using the Berlin definition. Separate abstractors blinded to ARDS status collected data on organ dysfunction and withdrawal of life support using a standardized tool. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. Results We identified 385 decedents with AHRF, of whom 127 (33%) had ARDS. The most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). Multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. Only 2% of patients had insupportable oxygenation or ventilation. Eighty-five percent died following withdrawal of life support. Patients with ARDS more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p <  0.01). Conclusions In this contemporary cohort of patients with AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. The vast majority of deaths occurred after withdrawal of life support. ARDS patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ARDS.http://deepblue.lib.umich.edu/bitstream/2027.42/173918/1/13054_2020_Article_3108.pd