bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized clinical trial of a human acellular dermal matrix demonstrated superior healing rates for chronic diabetic foot ulcers over conventional care and an active acellular dermal matrix comparator
Authors: Cazzell Shawn , Vayser Dean , Pham Hau , Walters Jodi , Reyzelman Alexander , Samsell Brian , Dorsch Kimberly , Moore Mark 
Published: May 2017

AbstractThis study compared the efficacy and safety of a human acellular dermal matrix (ADM), D‐ADM, with a conventional care arm and an active comparator human ADM arm, GJ‐ADM, for the treatment of chronic diabetic foot ulcers. The study design was a prospective, randomized controlled trial that enrolled 168 diabetic foot ulcer subjects in 13 centers across 9 states. Subjects in the ADM arms received one application but could receive one additional application of ADM if deemed necessary. Screen failures and early withdrawals left 53 subjects in the D‐ADM arm, 56 in the conventional care arm, and 23 in the GJ‐ADM arm (2:2:1 ratio). Subjects were followed through 24 weeks with major endpoints at Weeks 12, 16, and 24. Single application D‐ADM subjects showed significantly greater wound closure rates than conventional care at all three endpoints while all applications D‐ADM displayed a significantly higher healing rate than conventional care at Week 16 and Week 24. GJ‐ADM did not show a significantly greater healing rate over conventional care at any of these time points. A blinded, third party adjudicator analyzed healing at Week 12 and expressed “strong” agreement (κ = 0.837). Closed ulcers in the single application D‐ADM arm remained healed at a significantly greater rate than the conventional care arm at 4 weeks posttermination (100% vs. 86.7%; p = 0.0435). There was no significant difference between GJ‐ADM and conventional care for healed wounds remaining closed. Single application D‐ADM demonstrated significantly greater average percent wound area reduction than conventional care for Weeks 2–24 while single application GJ‐ADM showed significantly greater wound area reduction over conventional care for Weeks 4–6, 9, and 11–12. D‐ADM demonstrated significantly greater wound healing, larger wound area reduction, and a better capability of keeping healed wounds closed than conventional care in the treatment of chronic DFUs.
Mycoplasma pneumoniae from the Respiratory Tract and Beyond
Authors: Waites Ken B. , Xiao Li , Liu Yang , Balish Mitchell F. , Atkinson T. Prescott 
Published: May 2017

SUMMARYMycoplasma pneumoniaeis an important cause of respiratory tract infections in children as well as adults that can range in severity from mild to life-threatening. Over the past several years there has been much new information published concerning infections caused by this organism. New molecular-based tests forM. pneumoniaedetection are now commercially available in the United States, and advances in molecular typing systems have enhanced understanding of the epidemiology of infections. More strains have had their entire genome sequences published, providing additional insights into pathogenic mechanisms. Clinically significant acquired macrolide resistance has emerged worldwide and is now complicating treatment.In vitrosusceptibility testing methods have been standardized, and several new drugs that may be effective against this organism are undergoing development. This review focuses on the many new developments that have occurred over the past several years that enhance our understanding of this microbe, which is among the smallest bacterial pathogens but one of great clinical importance.
Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers
Authors: Ringe Rajesh P. , Ozorowski Gabriel , Rantalainen Kimmo , Struwe Weston B. , Matthews Katie , Torres Jonathan L. , Yasmeen Anila , Cottrell Christopher A. , Ketas Thomas J. , LaBranche Celia C. , Montefiori David C. , Cupo Albert , Crispin Max , Wilson Ian A. , Ward Andrew B. , Sanders Rogier W. , Klasse P. J. , Moore John P. 
Published: May 2017

ABSTRACTNative-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducingN-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged.IMPORTANCETrimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes.
A Map of the Arenavirus Nucleoprotein-Host Protein Interactome Reveals that Junín Virus Selectively Impairs the Antiviral Activity of Double-Stranded RNA-Activated Protein Kinase (PKR)
Authors: King Benjamin R. , Hershkowitz Dylan , Eisenhauer Philip L. , Weir Marion E. , Ziegler Christopher M. , Russo Joanne , Bruce Emily A. , Ballif Bryan A. , Botten Jason 
Published: May 2017

ABSTRACT
Arenaviruses are enveloped negative-strand RNA viruses that cause significant human disease. These viruses encode only four proteins to accomplish the viral life cycle, so each arenavirus protein likely plays unappreciated accessory roles during infection. Here we used immunoprecipitation and mass spectrometry to identify human proteins that interact with the nucleoproteins (NPs) of the Old World arenavirus lymphocytic choriomeningitis virus (LCMV) and the New World arenavirus Junín virus (JUNV) strain Candid #1. Bioinformatic analysis of the identified protein partners of NP revealed that host translation appears to be a key biological process engaged during infection. In particular, NP associates with the double-stranded RNA (dsRNA)-activated protein kinase (PKR), a well-characterized antiviral protein that inhibits cap-dependent protein translation initiation via phosphorylation of eIF2α. JUNV infection leads to increased expression of PKR as well as its redistribution to viral replication and transcription factories. Further, phosphorylation of PKR, which is a prerequisite for its ability to phosphorylate eIF2α, is readily induced by JUNV. However, JUNV prevents this pool of activated PKR from phosphorylating eIF2α, even following exposure to the synthetic dsRNA poly(I·C), a potent PKR agonist. This blockade of PKR function is highly specific, as LCMV is unable to similarly inhibit eIF2α phosphorylation. JUNV's ability to antagonize the antiviral activity of PKR appears to be complete, as silencing of PKR expression has no impact on viral propagation. In summary, we provide a detailed map of the host machinery engaged by arenavirus NPs and identify an antiviral pathway that is subverted by JUNV.

IMPORTANCE
Arenaviruses are important human pathogens for which FDA-approved vaccines do not exist and effective antiviral therapeutics are needed. Design of antiviral treatment options and elucidation of the mechanistic basis of disease pathogenesis will depend on an increased basic understanding of these viruses and, in particular, their interactions with the host cell machinery. Identifying host proteins critical for the viral life cycle and/or pathogenesis represents a useful strategy to uncover new drug targets. This study reveals, for the first time, the extensive human protein interactome of arenavirus nucleoproteins and uncovers a potent antiviral host protein that is neutralized during Junín virus infection. In so doing, it shows further insight into the interplay between the virus and the host innate immune response and provides an important data set for the field.
Proof of concept: short-term non-invasive cervical vagus nerve stimulation in patients with drug-refractory gastroparesis
Authors: Paulon Emma , Nastou Despoina , Jaboli Francesca , Marin Juana , Liebler Eric , Epstein Owen 
Published: May 2017

BackgroundGastric electric stimulation (GES) is a treatment approach to refractory gastroparesis, possibly acting centrally via afferent vagus nerve stimulation (VNS). Non-invasive VNS (nVNS) is a potential alternative to GES that could eliminate the safety risks of or identify likely responders to implantable neurostimulators.ObjectiveThis open-label proof-of-concept study assessed the effects of nVNS in patients with severe drug-refractory gastroparesis.MethodsPatients used the Gastroparesis Cardinal Symptom Index (GCSI) to grade symptoms in diaries daily for 2 weeks before treatment (baseline) and during ≥3 weeks of nVNS therapy. Adverse events (AEs) were also diarised. Treatment was self-administered using an nVNS device (gammaCore, electroCore) and consisted of 120 s stimulations to the vagus nerve in the neck (two stimulations to each side three times daily during weeks 1 and 2; three stimulations to each side three times daily during week 3 and beyond).Responsewas defined as a ≥1 point decrease from baseline in GCSI score.ResultsThirty-five patients enrolled; 23 were compliant with study procedures and were included in the analysis; 7 continued treatment beyond 3 weeks. Response rates were 35% (8/23) at 3 weeks and 43% (10/23) for the duration of therapy (3–6 weeks). For the entire cohort and the 10 responders, improvements from baseline were noted for mean total GCSI and GCSI subscale scores (nausea/vomiting, postprandial fullness/early satiety, bloating). No serious AEs were reported.ConclusionsThese preliminary results provide a signal that nVNS may be useful for treating refractory gastroparesis. Larger controlled studies are warranted.
Structural transect through Ellesmere Island (Canadian Arctic): superimposed Palaeozoic Ellesmerian and Cenozoic Eurekan deformation
Authors: Piepjohn Karsten , von Gosen Werner 
Published: May 2017

Abstract
The 400 km long transect through Ellesmere Island is located perpendicular to the North American continental margin between the Arctic Ocean in the NNW and the Greenland–Canadian Shield in the SSE. It provides an insight into the structural architecture and tectonic history of the upper parts of the continental crust. The northernmost segment of the transect is dominated by the composite Pearya Terrane, which amalgamated with the Laurentian margin during the Late Devonian–Early Carboniferous Ellesmerian Orogeny. The Neoproterozoic to Devonian Franklinian Basin is exposed south of the terrane boundary and most probably overlies the crystalline basement of the Greenland–Canadian Shield. The structures along the transect in this area are dominated by kilometre-scale Ellesmerian folding of the Franklinian Basin deposits above a deep-seated detachment, which is suggested to be located at the boundary between the basement of the Canadian Shield and the overlying >8 km thick Franklinian Basin. Following the development of the Late Mississippian–Palaeogene Sverdrup Basin, the complex Eurekan deformation reactivated Ellesmerian thrust faults and probably parts of the associated deep-seated detachment. In addition, large Eurekan strike-slip faults affected and displaced pre-Eocene deposits and tectonic structures, particularly in the northern part of the transect.
Chemical characteristics of the ice cores obtained after the first unsealing of subglacial Lake Vostok
Authors: Alekhina Irina , Ekaykin Alexey , Moskvin Alexey , Lipenkov Vladimir 
Published: May 2017

Abstract

Drilling fluid (DF) is one of the main sources of chemical and biological contamination of deep ice cores and lake water samples in the exploration of Subgalcial Antarctic Lake Environments (SALE). In this study, we investigated the contamination of an ice core that represented the first samples of refrozen lake water obtained 1 year after the unsealing of Lake Vostok in 2012. We show that these samples contain inclusions of the DF with a concentration of at least 16.7 mg l
−1
(0.0019% or 19 ppmv). This makes it extremely difficult to obtain reliable data on the real chemical composition of the lake water. The focus of our study is the organic components of the DF, which built up in the secondary ice while the water was freezing in the borehole. Of all the possible organic compounds of the DF, only phenol congeners (up to 32.4 mg l
−1
) and dichlorofluoroethane HCFC-141b (14.4 mg l
−1
), a DF densifier, were found in the central channel, which is the last part of the core to freeze in the borehole. We conclude that the phenol compounds emerge due to physical processes, namely fractionation, during freezing, rather than any chemical reaction between the DF and the lake water.
High-resolution mapping of gastric slow-wave recovery profiles: biophysical model, methodology, and demonstration of applications
Authors: Paskaranandavadivel N. , Cheng L. K. , Du P. , Rogers J. M. , O’Grady G. 
Published: May 2017

Slow waves play a central role in coordinating gastric motor activity. High-resolution mapping of extracellular potentials from the stomach provides spatiotemporal detail on normal and dysrhythmic slow-wave patterns. All mapping studies to date have focused exclusively on tissue activation; however, the recovery phase contains vital information on repolarization heterogeneity, the excitable gap, and refractory tail interactions but has not been investigated. Here, we report a method to identify the recovery phase in slow-wave mapping data. We first developed a mathematical model of unipolar extracellular potentials that result from slow-wave propagation. These simulations showed that tissue repolarization in such a signal is defined by the steepest upstroke beyond the activation phase (activation was defined by accepted convention as the steepest downstroke). Next, we mapped slow-wave propagation in anesthetized pigs by recording unipolar extracellular potentials from a high-resolution array of electrodes on the serosal surface. Following the simulation result, a wavelet transform technique was applied to detect repolarization in each signal by finding the maximum positive slope beyond activation. Activation-recovery (ARi) and recovery-activation (RAi) intervals were then computed. We hypothesized that these measurements of recovery profile would differ for slow waves recorded during normal and spatially dysrhythmic propagation. We found that the ARi of normal activity was greater than dysrhythmic activity (5.1 ± 0.8 vs. 3.8 ± 0.7 s; P < 0.05), whereas RAi was lower (9.7 ± 1.3 vs. 12.2 ± 2.5 s; P < 0.05). During normal propagation, RAi and ARi were linearly related with negative unit slope indicating entrainment of the entire mapped region. This relationship was weakened during dysrhythmia (slope: −0.96 ± 0.2 vs −0.71 ± 0.3; P < 0.05). NEW & NOTEWORTHY The theoretical basis of the extracellular gastric slow-wave recovery phase was defined using mathematical modeling. A novel technique utilizing the wavelet transform was developed and validated to detect the extracellular slow-wave recovery phase. In dysrhythmic wavefronts, the activation-to-recovery interval (ARi) was shorter and recovery-to-activation interval (RAi) was longer compared with normal wavefronts. During normal activation, RAi vs. ARi had a slope of −1, whereas the weakening of the slope indicated a dysrhythmic propagation.
Changes in brachial artery endothelial function and resting diameter with moderate-intensity continuous but not sprint interval training in sedentary men
Authors: Shenouda Ninette , Gillen Jenna B. , Gibala Martin J. , MacDonald Maureen J. 
Published: May 2017

Moderate-intensity continuous training (MICT) improves peripheral artery function in healthy adults, a phenomenon that reverses as continued training induces structural remodeling. Sprint interval training (SIT) elicits physiological adaptations similar to MICT, despite a lower exercise volume and time commitment; however, its effect on peripheral artery function and structure is largely unexplored. We compared peripheral artery responses to 12 wk of MICT and SIT in sedentary, healthy men (age = 27 ± 8 yr). Participants performed MICT (45 min of cycling at 70% peak heart rate; n = 10) or SIT (3 × 20-s “all out” cycling sprints with 2 min of recovery; n = 9), and responses were compared with a nontraining control group (CTL, n = 6). Allometrically scaled brachial flow-mediated dilation (FMD) increased 2.2% after 6 wk of MICT and returned to baseline levels by 12 wk, but did not change in SIT or CTL (group × time interaction, P = 0.04). Brachial artery diameter increased after 6 and 12 wk (main effect, P = 0.03), with the largest increases observed in MICT. Neither training protocol affected popliteal relative FMD and diameter, or central and lower limb arterial stiffness (carotid distensibility, central and leg pulse wave velocity) ( P > 0.05 for all). Whereas earlier and more frequent measurements are needed to establish the potential presence and time course of arterial responses to low-volume SIT, our findings suggest that MICT was superior to the intense, but brief and intermittent SIT stimulus at inducing brachial artery responses in healthy men. NEW & NOTEWORTHY We compared the effects of 12 wk of moderate-intensity continuous training (MICT) and sprint interval training (SIT) on peripheral artery endothelial function and diameter, and central and lower limb stiffness in sedentary, healthy men. Whereas neither training program affected the popliteal artery or stiffness indexes, we observed changes in brachial artery function and diameter with MICT but not SIT. Brachial artery responses to SIT may follow a different time course or may not occur at all.
Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2–Negative Metastatic Breast Cancer
Authors: Schott Anne F. , Goldstein Lori J. , Cristofanilli Massimo , Ruffini Pier Adelchi , McCanna Susan , Reuben James M. , Perez Raymond P. , Kato Giraldo , Wicha Max 
Published: May 2017

Abstract
Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).
Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m2/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.
Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses &gt;12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.
Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.
Impact of Chamber Dilatation on the Prognostic Value of Left Ventricular Geometry in Hypertension
Authors: Verdecchia Paolo , Angeli Fabio , Mazzotta Giovanni , Bartolini Claudia , Garofoli Marta , Aita Adolfo , Poltronieri Cristina , Pinzagli Maria Gabriella , Valecchi Francesca , Martone Stefania , Ramundo Elisa , Turturiello Dario , Reboldi Gianpaolo 
Published: May 2017

Background
The different geometric patterns of the left ventricle may or may not coexist with chamber dilatation. The prognostic impact of such a combination is unclear.

Methods and Results

We studied a cohort of 2635 initially untreated patients with hypertension, mean age 50 years. At entry, 24‐hour ambulatory blood pressure progressively increased across the patterns of normal geometry, concentric left ventricular (LV) remodeling, eccentric nondilated
LV
hypertrophy (
LVH
), eccentric dilated
LVH
, concentric nondilated
LVH
, and concentric dilated
LVH
. During a mean follow‐up of 9.7 years, 360 patients developed a first major cardiovascular event at a rate (×100 patient‐years) of 1.41. The event rate was 0.93 in the group with normal
LV
geometry, 1.10 in the group with
LV
concentric remodeling, 1.40 in the group with nondilated eccentric
LVH
, 2.10 in the group with eccentric dilated
LVH
, 2.34 in the group with nondilated concentric
LVH
, and 4.67 in the group with dilated concentric
LVH
(log‐rank test:
P
<0.001). In a Cox model, after adjustment for several independent covariables (age, sex, diabetes mellitus, current smoking, total cholesterol, estimated glomerular filtration rate, and average 24‐hour systolic blood pressure), concentric dilated
LVH
was associated with a 98% excess risk of cardiovascular events (
P
=0.0037). However,
LV
geometric pattern lost statistical significance when
LV
mass was entered into the model.

Conclusions

In initially untreated patients with hypertension,
LV
dilatation adds an adverse prognostic burden to the patterns of eccentric and concentric
LVH
. This phenomenon is explained by the greater
LV
mass associated with
LV
chamber dilatation.