Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

The “Beijing” Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979–1989 Soviet–Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time

Healthcare resource use and costs for people with type 2 diabetes mellitus with and without severe mental illness in England : longitudinal matched cohort study using the Clinical Practice Research Datalink

BACKGROUND: Approximately 60 000 people in England have coexisting type 2 diabetes mellitus (T2DM) and severe mental illness (SMI). They are more likely to have poorer health outcomes and require more complex care pathways compared with those with T2DM alone. Despite increasing prevalence, little is known about the healthcare resource use and costs for people with both conditions. AIMS: To assess the impact of SMI on healthcare resource use and service costs for adults with T2DM, and explore the predictors of healthcare costs and lifetime costs for people with both conditions. METHOD: This was a matched-cohort study using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics for 1620 people with comorbid SMI and T2DM and 4763 people with T2DM alone. Generalised linear models and the Bang and Tsiatis method were used to explore cost predictors and mean lifetime costs respectively. RESULTS: There were higher average annual costs for people with T2DM and SMI (£1930 higher) than people with T2DM alone, driven primarily by mental health and non-mental health-related hospital admissions. Key predictors of higher total costs were older age, comorbid hypertension, use of antidepressants, use of first-generation antipsychotics, and increased duration of living with both conditions. Expected lifetime costs were approximately £35 000 per person with both SMI and T2DM. Extrapolating nationally, this would generate total annual costs to the National Health Service of around £250 m per year. CONCLUSIONS: Our estimates of resource use and costs for people with both T2DM and SMI will aid policymakers and commissioners in service planning and resource allocation

The impact of severe mental illness on healthcare use and health outcomes for people with type 2 diabetes

BACKGROUND: People with severe mental illnesses (SMI) have reduced life expectancy compared with the general population. Diabetes is a major contributor to this disparity with higher prevalence and poorer outcomes in people with SMI. AIM: To determine the impact of SMI on healthcare processes and outcomes for diabetes. DESIGN AND SETTING: Retrospective observational matched nested case-control study using patient records from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. METHODS: We compared a range of healthcare processes (primary care consultations, physical health checks, metabolic measurements) and outcomes (prevalence and hospitalisation for cardiovascular disease (CVD), and mortality risk) for 2,192 people with SMI and type 2 diabetes (cases) with 7,773 people with diabetes alone (controls). Socio-demographics, comorbidity and medication prescription were covariates in regression models. RESULTS: SMI was associated with increased risk of all-cause mortality (Hazard Ratio [HR]: 1.92; 95% CI: 1.60 to 2.30) and CVD-specific mortality (HR: 2.24; 1.55 to 3.25); higher physician consultation rates (Incidence Rate Ratio [IRR]: 1.15; 1.11 to 1.19); more frequent checks of blood pressure (IRR: 1.02; 1.00 to 1.05) and cholesterol (IRR: 1.04; 1.02 to 1.06); lower prevalence of angina (Odds Ratio [OR]: 0.67; 0.45 to 1.00); higher emergency admissions for angina (IRR: 1.53; 1.07 to 2.20) and lower elective admissions for ischaemic heart disease (IRR: 0.68; 0.51 to 0.92). CONCLUSION: Monitoring of metabolic measurements was comparable for people with diabetes with and without SMI. Increased mortality rates observed in SMI may be attributable to under-diagnosis of CVD and delays in treatment

Living with diabetes alongside a severe mental illness : a qualitative exploration with people with severe mental illness, family members and healthcare staff

Aims: diabetes is 2-3 times more prevalent in people with severe mental illness, yet little is known about the challenges of managing both conditions from the perspectives of people living with the comorbidity, their family members or healthcare staff. Our aim was to understand these challenges and to explore the circumstances that influence access to and receipt of diabetes care for people with severe mental illness.Methods: framework analysis of qualitative semi-structured interviews with people with severe mental illness and diabetes, family members, and staff from UK primary care, mental health and diabetes services, selected using a maximum variation sampling strategy between April and December 2018.Results: thirty-nine adults with severe mental illness and diabetes (three with type 1 diabetes, 36 with type 2 diabetes), nine family members, and 30 healthcare staff participated. Five themes were identified: 1) severe mental illness governs everyday life including diabetes management; 2) mood influences capacity and motivation for diabetes self-management; 3) cumulative burden of managing multiple physical conditions; 4) interacting conditions and overlapping symptoms; 5) support for everyday challenges. People living with the comorbidity and their family members emphasised the importance of receiving support for the everyday challenges that impact diabetes management, and identified barriers to accessing this from healthcare providers.Conclusions: more intensive support for diabetes management is needed when people’s severe mental illness (including symptoms of depression) or physical health deteriorates. Interventions that help people, including healthcare staff, distinguish between symptoms of diabetes and severe mental illness are also needed. <br/

Improving diabetes outcomes for people with severe mental illness : a longitudinal observational and qualitative study in England

Background: people with severe mental illness experience poorer health outcomes than the general population. Diabetes contributes significantly to this health gap.Objectives: the objectives were to identify the determinants of diabetes and to explore variation in diabetes outcomes for people with severe mental illness.Design: under a social inequalities framework, a concurrent mixed-methods design combined analysis of linked primary care records with qualitative interviews.Setting: the quantitative study was carried out in general practices in England (2000–16). The qualitative study was a community study (undertaken in the North West and in Yorkshire and the Humber).Participants: the quantitative study used the longitudinal health records of 32,781 people with severe mental illness (a subset of 3448 people had diabetes) and 9551 ‘controls’ (with diabetes but no severe mental illness), matched on age, sex and practice, from the Clinical Practice Research Datalink (GOLD version). The qualitative study participants comprised 39 adults with diabetes and severe mental illness, nine family members and 30 health-care staff.Data sources: the Clinical Practice Research Datalink (GOLD) individual patient data were linked to Hospital Episode Statistics, Office for National Statistics mortality data and the Index of Multiple Deprivation.Results: people with severe mental illness were more likely to have diabetes if they were taking atypical antipsychotics, were living in areas of social deprivation, or were of Asian or black ethnicity. A substantial minority developed diabetes prior to severe mental illness. Compared with people with diabetes alone, people with both severe mental illness and diabetes received more frequent physical checks, maintained tighter glycaemic and blood pressure control, and had fewer recorded physical comorbidities and elective admissions, on average. However, they had more emergency admissions (incidence rate ratio 1.14, 95% confidence interval 0.96 to 1.36) and a significantly higher risk of all-cause mortality than people with diabetes but no severe mental illness (hazard ratio 1.89, 95% confidence interval 1.59 to 2.26). These paradoxical results may be explained by other findings. For example, people with severe mental illness and diabetes were more likely to live in socially deprived areas, which is associated with reduced frequency of health checks, poorer health outcomes and higher mortality risk. In interviews, participants frequently described prioritising their mental illness over their diabetes (e.g. tolerating antipsychotic side effects, despite awareness of harmful impacts on diabetes control) and feeling overwhelmed by competing treatment demands from multiple morbidities. Both service users and practitioners acknowledged misattributing physical symptoms to poor mental health (‘diagnostic overshadowing’).Limitations: data may not be nationally representative for all relevant covariates, and the completeness of recording varied across practices.Conclusions: people with severe mental illness and diabetes experience poorer health outcomes than, and deficiencies in some aspects of health care compared with, people with diabetes alone.Future work: these findings can inform the development of targeted interventions aimed at addressing inequalities in this population.Study registration: National Institute for Health Research (NIHR) Central Portfolio Management System (37024); and ClinicalTrials.gov NCT03534921.Funding: this project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 10. See the NIHR Journals Library website for further project information.<br/

Retinoid-Induced Expression and Activity of an Immediate Early Tumor Suppressor Gene in Vascular Smooth Muscle Cells

Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE) located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β) in cultured smooth muscle cells (SMC) as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA) regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall

Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation

On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful

Proceedings of Patient Reported Outcome Measure’s (PROMs) Conference Oxford 2017: Advances in Patient Reported Outcomes Research

A33-Effects of Out-of-Pocket (OOP) Payments and Financial Distress on Quality of Life (QoL) of People with Parkinson’s (PwP) and their Carer

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist