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TEXTS: Cantalamessa, The Mystery of God’s Word Kalas, Preaching from the Soul Lischer, The Company of Preachers Long & Plantinga, A Cloud of Witnesseshttps://place.asburyseminary.edu/syllabi/3735/thumbnail.jp

Sexual Seroadaptation: Lessons for Prevention and Sex Research from a Cohort of HIV-Positive Men Who Have Sex with Men

BACKGROUND: Surveillance data on sexually transmitted infections (STIs) and behavioral characteristics identified in studies of the risk of seroconversion are often used as to track sexual behaviors that spread HIV. However, such analyses can be confounded by "seroadaptation"--the restriction of unprotected anal intercourse (UAI), especially unprotected insertive UAI, to seroconcordant partnerships. METHODS: We utilized sexual network methodology and repeated-measures statistics to test the hypothesis that seroadaptive strategies reduce the risk of HIV transmission despite numerous partnerships and frequent UAI. PRINCIPAL FINDINGS: In a prospective cohort study of HIV superinfection including 168 HIV-positive men who have sex with men (MSM), we found extensive seroadaptation. UAI was 15.5 times more likely to occur with a positive partner than a negative one (95% confidence interval [CI], 9.1-26.4). Receptive UAI was 4.3 times more likely in seroconcordant partnerships than with negative partners (95% CI, 2.8-6.6), but insertive UAI was 13.6 times more likely with positives (95% CI, 7.2-25.6). Our estimates suggest that seroadaptation reduced HIV transmissions by 98%. CONCLUSION: Potentially effective HIV prevention strategies, such as seroadaptation, have evolved in communities of MSM before they have been recognized in research or discussed in the public health forum. Thus, to be informative, studies of HIV risk must be designed to assess seroadaptive behaviors rather than be limited to individual characteristics, unprotected intercourse, and numbers of partners. STI surveillance is not an effective indicator of trends in HIV incidence where there are strong patterns of seroadaptation

Lactate Dehydrogenase-Elevating Virus Induces Systemic Lymphocyte Activation via TLR7-Dependent IFNα Responses by Plasmacytoid Dendritic Cells

BACKGROUND:Lactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies. PRINCIPAL FINDINGS:A known inducer of early lymphocyte activation is IFNalpha, a cytokine strongly induced by LDV infection. Neutralization of IFNalpha in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFNalpha in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFNalpha response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFNalpha response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFNalpha response. CONCLUSION:Results indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by TLR7 pattern recognition receptors in pDC's that respond with a lymphocyte-inducing IFNalpha response

Sequential and Spontaneous Star Formation Around the Mid-Infrared Halo HII Region KR 140

We use 2MASS and MSX infrared observations, along with new molecular line (CO) observations, to examine the distribution of young stellar objects (YSOs) in the molecular cloud surrounding the halo HII region KR 140 in order to determine if the ongoing star-formation activity in this region is dominated by sequential star formation within the photodissociation region (PDR) surrounding the HII region. We find that KR 140 has an extensive population of YSOs that have spontaneously formed due to processes not related to the expansion of the HII region. Much of the YSO population in the molecular cloud is concentrated along a dense filamentary molecular structure, traced by C18O, that has not been erased by the formation of the exciting O star. Some of the previously observed submillimetre clumps surrounding the HII region are shown to be sites of recent intermediate and low-mass star formation while other massive starless clumps clearly associated with the PDR may be the next sites of sequential star formation.Comment: Accepted for publication in MNRAS, 8 pages, 10 figure

A sharper view of the outer Galaxy at 1420 and 408 MHz from the Canadian Galactic Plane Survey II: The catalogue of extended radio sources

A new catalogue of extended radio sources has been prepared based on arcminute-resolution 1420 MHz images from the Canadian Galactic Plane Survey (CGPS). The new catalogue provides both 1420 MHz and 408 MHz flux density measurements on sources found near the Galactic plane in the second quadrant of our Galaxy. In addition cross-identifications are made with other major radio catalogues and information is provided to facilitate the recovery of CGPS image data associated with each catalogued source. Numerous new radio sources are identified and the catalogue provides a comprehensive summary of both newly discovered and previously known HII regions and supernova remnants in the outer Galaxy. The catalogue should be of use both for synoptic studies of Galactic structure and for placing higher resolution observations, at radio and other wavelengths, in context.Comment: accepted for publication in MNRAS, 8 pages, 6 figure

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia; Sudden cardiac death; Ventricular arrhythmiasTaquicardia ventricular polimórfica catecolaminérgica; Muerte cardíaca súbita; Arritmias ventricularesTaquicàrdia ventricular polimòrfica catecolaminèrgica; Mort cardíaca sobtada; Arítmies ventricularsBACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14–29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7–3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4–7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0–6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38–0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31–0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14–0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.A.A.W. was funded by Predict-2, EU E-rare grant (Transnational Research Projects on Rare Diseases 2015, Improving CPVT). S.S. was funded by the Heart and Stroke Foundation (grant G-19-0024239). M.J.A. was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. A.L. was funded by a grant from Programme Hospitalier de Recherche Clinique–PHRC 2014 (Ministère de la Santé N° AOR 04070). C.S. is the recipient of a National Health and Medical Research Council Practitioner Fellowship (No.1154992) and was supported by a New South Wales Health Cardiovascular Disease Clinician Scientist Grant. S.O. was funded by AMED (JP18ek0109202] and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K09689). J.T.H. was funded by the John and Birthe Meyer Family Foundation. K.H.H. was funded by the Norwegian Research Council (ProCardio No.309762, GENE POSITIVE No. 288438, and EMPATHY No. 298736). E.Z. was funded by Mécanismes Proarythmiques Dépendant du Sodium et du Calcium, Agènce Nationale de la Recherche (ANR-19-CE14-0031-001)

Evaluating blood-brain barrier permeability in delayed cerebral infarction after aneurysmal subarachnoid hemorrhage

BACKGROUND AND PURPOSE: Patients with SAH are at increased risk of delayed infarction. Early detection and treatment of delayed infarction remain challenging. We assessed blood-brain barrier permeability, measured as permeability surface area product, by using CTP in patients with SAH with delayed infarction. MATERIALS AND METHODS: We performed a retrospective study of patients with SAH with delayed infarction on follow-up NCCT. CTP was performed before the development of delayed infarction. CTP data were postprocessed into permeability surface area product, CBF, and MTT maps. Coregistration was performed to align the infarcted region on the follow-up NCCT with the corresponding location on the CTP maps obtained before infarction. Permeability surface area product, CBF, and MTT values were then obtained in the location of the subsequent infarction. The contralateral noninfarcted region was compared with the affected side in each patient. Wilcoxon signed rank tests were performed to determine statistical significance. Clinical data were collected at the time of CTP and at the time of follow-up NCCT. RESULTS: Twenty-one patients with SAH were included in the study. There was a statistically significant increase in permeability surface area product in the regions of subsequent infarction compared with the contralateral control regions (P \u3c .0001). However, CBF and MTT values were not significantly different in these 2 regions. Subsequent follow-up NCCT demonstrated new delayed infarction in all 21 patients, at which time 38% of patients had new focal neurologic deficits. CONCLUSIONS: Our study reveals a statistically significant increase in permeability surface area product preceding delayed infarction in patients with SAH. Further investigation of early permeability changes in SAH may provide new insights into the prediction of delayed infarction

Regulatory T Cell Suppression of Gag-Specific CD8+ T Cell Polyfunctional Response After Therapeutic Vaccination of HIV-1-Infected Patients on ART

We tested the hypothesis that therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T cell response. HIV-1-infected subjects on antiretroviral therapy (N = 17) enrolled in a phase I therapeutic vaccine trial received 2 doses of autologous dendritic cells (DC) loaded with HIV-1 peptides. The frequency of CD4+CD25hiFOXP3+ Treg in blood was determined prior to and after vaccination in subjects and normal controls. Polyfunctional CD8+ T cell responses were determined pre- and post-vaccine (N = 7) for 5 immune mediators after in vitro stimulation with Gag peptide, staphylococcal enterotoxin B (SEB), or medium alone. Total vaccine response (post-vaccine–pre-vaccine) was compared in the Treg(+) and Treg-depleted (Treg-) sets. After vaccination, 12/17 subjects showed a trend of increased Treg frequency (P = 0.06) from 0.74% to 1.2%. The increased frequency did not correlate with CD8+ T cell vaccine response by enzyme linked immunosorbent assay for interferon γ production. Although there was no significant change in CD8+ T cell polyfunctional response after vaccination, Treg depletion increased the polyfunctionality of the total vaccine response (P = 0.029), with a >2-fold increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T cell response to SEB, implying specificity of suppression to HIV-1 Gag. Therapeutic immunization with a DC-based vaccine against HIV-1 caused a modest increase in Treg frequency and a significant increase in HIV-1-specific, Treg suppressive function. The Treg suppressive effect masked an increase in the vaccine-induced anti-HIV-1-specific polyfunctional response. The role of Treg should be considered in immunotherapeutic trials of HIV-1 infection

Code-level model checking in the software development workflow at Amazon Web Services

This article describes a style of applying symbolic model checking developed over the course of four years at Amazon Web Services (AWS). Lessons learned are drawn from proving properties of numerous C‐based systems, for example, custom hypervisors, encryption code, boot loaders, and an IoT operating system. Using our methodology, we find that we can prove the correctness of industrial low‐level C‐based systems with reasonable effort and predictability. Furthermore, AWS developers are increasingly writing their own formal specifications. As part of this effort, we have developed a CI system that allows integration of the proofs into standard development workflows and extended the proof tools to provide better feedback to users. All proofs discussed in this article are publicly available on GitHub