Modeled Health and Economic Impact of Team-Based Care for Hypertension

IntroductionTeam-based interventions for hypertension care have been widely studied and shown effective in improving hypertension outcomes. Few studies have evaluated long-term effects of these interventions; none have assessed broad-scale implementation. This study estimates the prospective health, economic, and budgetary impact of universal adoption of a team-based care intervention model that targets people with treated but uncontrolled hypertension in the U.S.MethodsAnalysis was conducted in 2014−2015 using a microsimulation model, constructed with various data sources from 1948 to 2014, designed to evaluate prospective cardiovascular disease (CVD)−related interventions in the U.S. population. Ten-year primary outcomes included prevalence of uncontrolled hypertension; incident myocardial infarction, stroke, CVD events, and CVD-related mortality; intervention and net medical costs by payer; productivity; and quality-adjusted life years.ResultsAbout 4.7 million (13%) fewer people with uncontrolled hypertension and 638,000 prevented cardiovascular events would be expected over 10 years. Assuming $525 per enrollee, implementation would cost payers$22.9 billion, but $25.3 billion would be saved in averted medical costs. Estimated net cost savings for Medicare approached$5.8 billion. Net costs were especially sensitive to intervention costs, with break-even thresholds of $300 (private),$450 (Medicaid), and $750 (Medicare).ConclusionsNationwide adoption of team-based care for uncontrolled hypertension could have sizable effects in reducing CVD burden. Based on the study’s assumptions, the policy would be cost saving from the perspective of Medicare and may prove to be cost effective from other payers’ perspectives. Expected net cost savings for Medicare would more than offset expected net costs for all other insurers

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A

Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration.

The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair.: This work was supported by the British Heart Foundation (BHF; Grants NH/11/1/28922, G1000847, FS/13/29/30024 and FS/18/46/33663), Oxford-Cambridge Centre for Regenerative Medicine (RM/13/3/30159), the UK Medical Research Council (MRC) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (SS), as well as National Institutes of Health Grants P01HL094374, P01GM081619, R01HL12836 and a grant from the Fondation Leducq Transatlantic Network of Excellence (CEM). J.B. was supported by a Cambridge National Institute for Health Research Biomedical Research Centre Cardiovascular Clinical Research Fellowship and subsequently, by a BHF Studentship (Grant FS/13/65/30441). DI received a University of Cambridge Commonwealth Scholarship. LG is supported by BHF Award RM/l3/3/30159 and LPO is funded by a Wellcome Trust Fellowship (203568/Z/16/Z). NF was supported by BHF grants RG/13/14/30314. NL was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). SS and MB were supported by the British Heart Foundation Centre for Cardiovascular Research Excellence. Core support was provided by the Wellcome-MRC Cambridge Stem Cell Institute (203151/Z/16/Z), The authors thank Osiris for provision of the primary mesenchymal stem cells (59

At the brink of eusociality: transcriptomic correlates of worker behaviour in a small carpenter bee

Background: There is great interest in understanding the genomic underpinnings of social evolution, in particular, the evolution of eusociality (caste-containing societies with non-reproductives that care for siblings). Subsociality is a key precursor for the evolution of eusociality and characterized by prolonged parental care and parent-offspring interaction. Here, we provide the first transcriptomic data for the small carpenter bee, Ceratina calcarata. This species is of special interest because it is subsocial and in the same family as the highly eusocial honey bee, Apis mellifera. In addition, some C. calcarata females demonstrate alloparental care without reproduction, which provides a unique opportunity to study worker behaviour in a non-eusocial species. Results: We uncovered similar gene expression patterns related to maternal care and sibling care in different groups of females. This agrees with the maternal heterochrony hypothesis, specifically, that changes in timing of offspring care gene expression are related to worker behaviour in incipient insect societies. In addition, we also detected some similarity to caste-related gene expression patterns in highly eusocial honey bees, and uncovered large lifetime changes in gene expression that accompany shifts in reproductive and maternal care behaviour. Conclusions: For Ceratina calcarata, we found that transcript expression profiles were most similar between sibling care and maternal care females. The maternal care behaviour exhibited post-reproductively by Ceratina mothers is concordant in terms of transcript expression with the alloparental care exhibited by workers. In line with theoretical predictions, our data are consistent with the maternal heterochrony hypothesis for the evolutionary development of worker behaviour in subsocial bees

Benefits and risks of antiretroviral therapy for perinatal HIV prevention.

CAPRISA, 2016.Abstract available in pdf

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer