Prediction of HIV transmission cluster growth with statewide surveillance data

Background:Prediction of HIV transmission cluster growth may help guide public health action. We developed a predictive model for cluster growth in North Carolina (NC) using routine HIV surveillance data.Methods:We identified putative transmission clusters with ≥2 members through pairwise genetic distances ≤1.5% from HIV-1 pol sequences sampled November 2010-December 2017 in NC. Clusters established by a baseline of January 2015 with any sequences sampled within 2 years before baseline were assessed for growth (new diagnoses) over 18 months. We developed a predictive model for cluster growth incorporating demographic, clinical, temporal, and contact tracing characteristics of baseline cluster members. We internally and temporally externally validated the final model in the periods January 2015-June 2016 and July 2016-December 2017.Results:Cluster growth was predicted by larger baseline cluster size, shorter time between diagnosis and HIV care entry, younger age, shorter time since the most recent HIV diagnosis, higher proportion with no named contacts, and higher proportion with HIV viremia. The model showed areas under the receiver-operating characteristic curves of 0.82 and 0.83 in the internal and temporal external validation samples.Conclusions:The predictive model developed and validated here is a novel means of identifying HIV transmission clusters that may benefit from targeted HIV control resources. © 2018 Wolters Kluwer Health, Inc. All rights reserved

The International Workshop on Meibomian Gland Dysfunction: Report of the Clinical Trials Subcommittee

Diagnostic tests of meibomian gland dysfunction (MGD) and of MGD-related disorders are based on the demonstration of abnormal anatomy and physiology of the glands and the detection of specific pathologic events. For this reason, this subcommittee report is divided into two sections. In part I, those aspects of meibomian anatomy and physiology that are relevant to currently available tests are described; a fuller account of the anatomy and physiology is provided in the report of the Anatomy Subcommittee of this workshop. In part II, each test and its performance is described in detail. In part III, the practical application of selected tests is summarized and recommendations for future approaches are made. Additional recommendations and a summary of pertinent literature and concepts are presented in Appendices 1 to 17

Sustained Sexual Behavior Change after Acute HIV Diagnosis in Malawi

Background Identification of acute HIV infection (AHI) allows for important opportunities for HIV prevention through behavior change and biomedical intervention. Here, we evaluate changes in sexual risk behaviors among persons with AHI enrolled in a combined behavioral and biomedical intervention designed to reduce onward transmission of HIV. Methods Participants were randomized to standard HIV counseling, a multisession behavioral intervention, or a multisession behavioral intervention plus antiretrovirals. Sexual behaviors were assessed periodically over 1 year. Results Four weeks after diagnosis, the predicted probability of reporting multiple sexual partners decreased from 24% to 9%, and the probability of reporting unprotected sex decreased from 71% to 27%. These declines in sexual risk behaviors were sustained over follow-up irrespective of study arm. Conclusions Diagnosis of AHI alone may be sufficient to achieve immediate and sustained behavior change during this highly infectious period

Human Immunodeficiency Virus (HIV)-1 Transmission among Persons with Acute HIV-1 Infection in Malawi: Demographic, Behavioral, and Phylogenetic Relationships

Background: Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods: Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results: Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions: Passive-partner referral successfully identified partners with genetically-similar HIV infections - the likely source of infection - but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration: NCT01450189

Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons with Acute HIV Infection: Opportunity for Interrupting Transmission

Background. Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Methods. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Results. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Conclusions. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission

Prognostic Significance of Myocardial Fibrosis in Hypertrophic Cardiomyopathy

ObjectivesWe investigated the significance of fibrosis detected by late gadolinium enhancement cardiovascular magnetic resonance for the prediction of major clinical events in hypertrophic cardiomyopathy (HCM).BackgroundThe role of myocardial fibrosis in the prediction of sudden death and heart failure in HCM is unclear with a lack of prospective data.MethodsWe assessed the presence and amount of myocardial fibrosis in HCM patients and prospectively followed them for the development of morbidity and mortality in patients over 3.1 ± 1.7 years.ResultsOf 217 consecutive HCM patients, 136 (63%) showed fibrosis. Thirty-four of the 136 patients (25%) in the fibrosis group but only 6 of 81 (7.4%) patients without fibrosis reached the combined primary end point of cardiovascular death, unplanned cardiovascular admission, sustained ventricular tachycardia or ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge (hazard ratio [HR]: 3.4, p = 0.006). In the fibrosis group, overall risk increased with the extent of fibrosis (HR: 1.18/5% increase, p = 0.008). The risk of unplanned heart failure admissions, deterioration to New York Heart Association functional class III or IV, or heart failure-related death was greater in the fibrosis group (HR: 2.5, p = 0.021), and this risk increased as the extent of fibrosis increased (HR: 1.16/5% increase, p = 0.017). All relationships remained significant after multivariate analysis. The extent of fibrosis and nonsustained ventricular tachycardia were univariate predictors for arrhythmic end points (sustained ventricular tachycardia or ventricular fibrillation, appropriate implantable cardioverter-defibrillator discharge, sudden cardiac death) (HR: 1.30, p = 0.014). Nonsustained ventricular tachycardia remained an independent predictor of arrhythmic end points after multivariate analysis, but the extent of fibrosis did not.ConclusionsIn patients with HCM, myocardial fibrosis as measured by late gadolinium enhancement cardiovascular magnetic resonance is an independent predictor of adverse outcome. (The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735

Eph receptors in breast cancer: roles in tumor promotion and tumor suppression

Eph receptor tyrosine kinase signaling regulates cancer initiation and metastatic progression through multiple mechanisms. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. In addition, Eph molecules function in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of these molecules to promote carcinoma progression and metastasis. The complex nature of Eph receptor signaling and crosstalk with other receptor tyrosine kinases presents a unique challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer

De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Correction to The American Journal of Human Genetics, Volume 95, Issue 4, 2 October 2014, Pages 360-370. Volume 100, Issue 1, 5 January 2017, Page 179.Peer reviewe

Eph/Ephrin Profiling in Human Breast Cancer Reveals Significant Associations between Expression Level and Clinical Outcome

Pre-clinical studies provide compelling evidence that Eph family receptor tyrosine kinases (RTKs) and ligands promote cancer growth, neovascularization, invasion, and metastasis. Tumor suppressive roles have also been reported for the receptors, however, creating a potential barrier for clinical application. Determining how these observations relate to clinical outcome is a crucial step for translating the biological and mechanistic data into new molecularly targeted therapies. We investigated eph and ephrin expression in human breast cancer relative to endpoints of overall and/or recurrence-free survival in large microarray datasets. We also investigated protein expression in commercial human breast tissue microarrays (TMA) and Stage I prognostic TMAs linked to recurrence outcome data. We found significant correlations between ephA2, ephA4, ephA7, ephB4, and ephB6 and overall and/or recurrence-free survival in large microarray datasets. Protein expression in TMAs supported these trends. While observed no correlation between ephrin ligand expression and clinical outcome in microarray datasets, ephrin-A1 and EphA2 protein co-expression was significantly associated with recurrence in Stage I prognostic breast cancer TMAs. Our data suggest that several Eph family members are clinically relevant and tractable targets for intervention in human breast cancer. Moreover, profiling Eph receptor expression patterns in the context of relevant ligands and in the context of stage may be valuable in terms of diagnostics and treatment