Publications

BACKGROUND

Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome.

METHODS

A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection.

RESULTS

One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46-2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01-4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36-3.43; P=0.001).

CONCLUSIONS

T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

INTRODUCTION

Gay and bisexual men and other men who have sex with men are among the small number of groups for whom HIV remains uncontrolled worldwide. Although there have been recent and notable decreases in HIV incidence across several countries, prevalence and incidence is consistently higher or rising among men who have sex with men when compared with other groups.

METHODS

In 2014, MSMGF (the Global Forum on MSM & HIV) conducted its third biennial Global Men's Health and Rights Study, an international, multilingual, web-based cross-sectional survey of men who have sex with men recruited through online convenience sampling. We tested hypothesized correlates (selected ) of successfully achieving each step along the HIV prevention and treatment continuum by fitting separate generalized estimating equation models adjusted for clustering by country in multivariate analyses. All models controlled for ability to meet basic financial needs, age, healthcare coverage, having a regular provider, region and country-level income.

RESULTS

Higher provider discrimination and sexual stigma were associated with lower odds of perceived access to services, service utilization and virologic suppression. Conversely, accessing services from community-based organizations focused on lesbian, gay, bisexual and transgender people; greater engagement in gay community; and comfort with healthcare providers were associated with higher odds of achieving steps along the prevention and treatment continuum.

CONCLUSIONS

To meet accelerated global HIV targets, global leaders must adopt a differentiated and bolder response, in keeping with current epidemiologic trends and community-based research. The HIV-related needs of gay and bisexual men and other men who have sex with men must be addressed openly, quickly and with sufficient resources to support evidence-based, community-led and human rights-affirming interventions at scale.

The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.

Candida albicans is a ubiquitous commensal of the mammalian microbiome and the most prevalent fungal pathogen of humans. A cell-type transition between yeast and hyphal morphologies in C. albicans was thought to underlie much of the variation in virulence observed in different host tissues. However, novel yeast-like cell morphotypes, including opaque(a/α), grey and gastrointestinally induced transition (GUT) cell types, were recently reported that exhibit marked differences in vitro and in animal models of commensalism and disease. In this Review, we explore the characteristics of the classic cell types - yeast, hyphae, pseudohyphae and chlamydospores - as well as the newly identified yeast-like morphotypes. We highlight emerging knowledge about the associations of these different morphotypes with different host niches and virulence potential, as well as the environmental cues and signalling pathways that are involved in the morphological transitions.

Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. Methods We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. Results NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining ( P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype ( P < .001), advanced-stage disease at diagnosis ( P = .02), higher rate of liver and bone metastasis ( P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. Conclusion NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.

Purpose Using the example of community access programs (CAPs), the purpose of this paper is to describe resource allocation and policy decisions related to providing health services for the uninsured in the USA and the organizational values affecting these decisions. Design/methodology/approach The study used comparative case study methodology at two geographically diverse sites. Researchers collected data from program documents, meeting observations, and interviews with program stakeholders. Findings Five resource allocation or policy decisions relevant to providing healthcare services were described at each site across three categories: designing the health plan, reacting to funding changes, and revising policies. Organizational values of access to care and stewardship most frequently affected resource allocation and policy decisions, while economic and political pressures affect the relative prioritization of values. Research limitations/implications Small sample size, the potential for social desirability or recall bias, and the exclusion of provider, member or community perspectives beyond those represented among participating board members. Practical implications Program directors or researchers can use this study to assess the extent to which resource allocation and policy decisions align with organizational values and mission statements. Social implications The description of how healthcare decisions are actually made can be matched with literature that describes how healthcare resource decisions ought to be made, in order to provide a normative grounding for future decisions. Originality/value This study addresses a gap in literature regarding how CAPs actually make resource allocation decisions that affect access to healthcare services.