Gasping in Response to Basic Resuscitation Efforts: Observation in a Swine Model of Cardiac Arrest

Objective. To analyze the effect of basic resuscitation efforts on gasping and of gasping on survival. Methods. This is secondary analysis of a previously reported study comparing continuous chest compressions (CCC CPR) versus chest compressions plus ventilation (30:2 CPR) on survival. 64 swine were randomized to 1 of these 2 basic CPR approaches after either short (3 or 4 minutes) or long (5 or 6 minutes) durations of untreated VF. At 12 minutes of VF, all received the same Guidelines 2005 Advanced Cardiac Life Support. Neurologically status was evaluated at 24 hours. A score of 1 is normal, 2 is abnormal, such as not eating or drinking normally, unsteady gait, or slight resistance to restraint, 3 severely abnormal, where the animal is recumbent and unable to stand, 4 is comatose, and 5 is dead. For this analysis a neurological outcome score of 1 or 2 was classified as “good”, and a score of 3, 4, or 5 was classified as “poor.” Results. Gasping was more likely to continue or if absent, to resume in the animals with short durations of untreated VF before basic resuscitation efforts. With long durations of untreated VF, the frequency of gasping and survival was better in swine receiving CCC CPR. In the absence of frequent gasping, intact survival was rare in the long duration of untreated VF group. Conclusions. Gasping is an important phenomenon during basic resuscitation efforts for VF arrest and in this model was more frequent with CCC-CPR

Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits

Background: The trimeric envelope glycoproteins (Env) on the surface of HIV-1 virions are the targets for neutralizing antibodies (NAbs). No candidate HIV-1 immunogen has yet induced potent, broadly active NAbs (bNAbs). Part of the explanation may be that previously tested Env proteins inadequately mimic the functional, native Env complex. Trimerization and the proteolytic processing of Env precursors into gp120 and gp41 profoundly alter antigenicity, but soluble cleaved trimers are too unstable to serve as immunogens. By introducing stabilizing mutations (SOSIP), we constructed soluble, cleaved Env trimers derived from the HIV-1 subtype A isolate BG505 that resemble native Env spikes on virions both structurally and antigenically. Results: We used surface plasmon resonance (SPR) to quantify antibody binding to different forms of BG505 Env: the proteolytically cleaved SOSIP.664 trimers, cleaved gp120-gp41ECTO protomers, and gp120 monomers. Non-NAbs to the CD4-binding site bound only marginally to the trimers but equally well to gp120-gp41ECTO protomers and gp120 monomers, whereas the bNAb VRC01, directed to the CD4bs, bound to all three forms. In contrast, bNAbs to V1V2 glycan-dependent epitopes bound preferentially (PG9 and PG16) or exclusively (PGT145) to trimers. We also explored the antigenic consequences of three different features of SOSIP.664 gp140 trimers: the engineered inter-subunit disulfide bond, the trimer-stabilizing I559P change in gp41ECTO, and proteolytic cleavage at the gp120-gp41ECTO junction. Each of these three features incrementally promoted native-like trimer antigenicity. We compared Fab and IgG versions of bNAbs and validated a bivalent model of IgG binding. The NAbs showed widely divergent binding kinetics and degrees of binding to native-like BG505 SOSIP.664. High off-rate constants and low stoichiometric estimates of NAb binding were associated with large amounts of residual infectivity after NAb neutralization of the corresponding BG505.T332N pseudovirus. Conclusions: The antigenicity and structural integrity of cleaved BG505 SOSIP.664 trimers render these proteins good mimics of functional Env spikes on virions. In contrast, uncleaved gp140s antigenically resemble individual gp120-gp41ECTO protomers and gp120 monomers, but not native trimers. Although NAb binding to functional trimers may thus be both necessary and sufficient for neutralization, the kinetics and stoichiometry of the interaction influence the neutralizing efficacy of individual NAbs

Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine

Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes

Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN 3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen

The Empirical Foundations of Telemedicine Interventions for Chronic Disease Management

The telemedicine intervention in chronic disease management promises to involve patients in their own care, provides continuous monitoring by their healthcare providers, identifies early symptoms, and responds promptly to exacerbations in their illnesses. This review set out to establish the evidence from the available literature on the impact of telemedicine for the management of three chronic diseases: congestive heart failure, stroke, and chronic obstructive pulmonary disease. By design, the review focuses on a limited set of representative chronic diseases because of their current and increasing importance relative to their prevalence, associated morbidity, mortality, and cost. Furthermore, these three diseases are amenable to timely interventions and secondary prevention through telemonitoring. The preponderance of evidence from studies using rigorous research methods points to beneficial results from telemonitoring in its various manifestations, albeit with a few exceptions. Generally, the benefits include reductions in use of service: hospital admissions/re-admissions, length of hospital stay, and emergency department visits typically declined. It is important that there often were reductions in mortality. Few studies reported neutral or mixed findings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140284/1/tmj.2014.9981.pd

National Telemedicine Initiatives: Essential to Healthcare Reform

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78116/1/tmj.2009.9960.pd

Characterisation of the muon beams for the Muon Ionisation Cooling Experiment

A novel single-particle technique to measure emittance has been developed and used to characterise seventeen different muon beams for the Muon Ionisation Cooling Experiment (MICE). The muon beams, whose mean momenta vary from 171 to 281 MeV/c, have emittances of approximately 1.2–2.3 π mm-rad horizontally and 0.6–1.0 π mm-rad vertically, a horizontal dispersion of 90–190 mm and momentum spreads of about 25 MeV/c. There is reasonable agreement between the measured parameters of the beams and the results of simulations. The beams are found to meet the requirements of MICE

Effect of Peer Health Workers on AIDS Care in Rakai, Uganda: A Cluster-Randomized Trial

Human resource limitations are a challenge to the delivery of antiretroviral therapy (ART) in low-resource settings. We conducted a cluster randomized trial to assess the effect of community-based peer health workers (PHW) on AIDS care of adults in Rakai, Uganda.15 AIDS clinics were randomized 2:1 to receive the PHW intervention (n = 10) or control (n = 5). PHW tasks included clinic and home-based provision of counseling, clinical, adherence to ART, and social support. Primary outcomes were adherence and cumulative risk of virologic failure (>400 copies/mL). Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART. Analysis was by intention to treat. From May 2006 to July 2008, 1336 patients were followed. 444 (33%) of these patients were already on ART at the start of the study. No significant differences were found in lack of adherence (<95% pill count adherence risk ratio [RR] 0.55, 95% confidence interval [CI] 0.23-1.35; <100% adherence RR 1.10, 95% CI 0.94-1.30), cumulative risk of virologic failure (RR 0.81, 95% CI 0.61-1.08) or in shorter-term virologic outcomes (24 week virologic failure RR 0.93, 95% CI 0.65-1.32; 48 week, RR 0.83, 95% CI 0.47-1.48; 72 week, RR 0.81, 95% CI 0.44-1.49). However, virologic failure rates >or=96 weeks into ART were significantly decreased in the intervention arm compared to the control arm (96 week failure RR 0.50, 95% CI 0.31-0.81; 120 week, RR 0.59, 95% CI 0.22-1.60; 144 week, RR 0.39, 95% CI 0.16-0.95; 168 week, RR 0.30, 95% CI 0.097-0.92; 192 week, RR 0.067, 95% CI 0.0065-0.71).A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART, but did not affect cumulative risk of virologic failure, adherence measures, or shorter-term virologic outcomes. PHWs may be an effective intervention to sustain long-term ART in low-resource settings.ClinicalTrials.gov NCT00675389

A broad iron line in LMC X‐1

We present results from a deep Suzaku observation of the black hole in LMC X‐1, supplemented by coincident monitoring with the Rossi X‐ray Timing Explorer ( RXTE ). We identify broad relativistic reflection features in a soft disc‐dominated spectrum. A strong and variable power‐law component of emission is present which we use to demonstrate that enhanced Comptonization strengthens disc reflection. We constrain the spin parameter of the black hole by modelling LMC X‐1's broad reflection features. For our primary and most comprehensive spectral model, we obtain a high value for the spin: a * = 0 . 97 − 0.13 + 0.01 (68 per cent confidence). However, by additionally considering two alternate models as a measure of our systematic uncertainty, we obtain a broader constraint: a * = 0 . 97 − 0.25 + 0.02 . Both of these spin values are entirely consistent with a previous estimate of spin obtained using the continuum‐fitting method. At 99 per cent confidence, the reflection features require a * > 0.2. In addition to modelling the relativistically broadened reflection, we also model a sharp and prominent reflection component that provides strong evidence for substantial reprocessing in the wind of the massive companion. We infer that this wind sustains the ionization cone surrounding the binary system; this hypothesis naturally produces appropriate and consistent mass, time and length scales for the cone structure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94516/1/mnr22128.pd