bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
Authors: Mousseau Guillaume , Kessing Cari F. , Fromentin Rémi , Trautmann Lydie , Chomont Nicolas , Valente Susana T. 
Published: July 2015

ABSTRACTAntiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4+T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs.IMPORTANCEAntiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4+T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.
Injuries in women's international ice hockey: an 8-year study of the World Championship tournaments and Olympic Winter Games
Authors: Tuominen Markku , Stuart Michael J , Aubry Mark , Kannus Pekka , Tokola Kari , Parkkari Jari 
Published: July 2015

BackgroundWe report the incidence, type, mechanism and severity of ice hockey injuries in women's international ice hockey championships.MethodsAll injuries in the International Ice Hockey Federation World Women's Championship, World Women's under-18 Championship and Olympic Winter Games tournaments were analysed over an 8-year period using a strict injury definition, standardised reporting and team physician diagnosis.Results168 injuries were recorded in 637 games over an 8-year period resulting in an injury rate (IR) of 6.4 per 1000 player-games and 22.0/1000 player-game hours. The IRs were 2.7/1000 player-games for the lower body, 1.4 for the upper body, 1.3 for the head and face and 0.9 for the spine and trunk. Contusion was the most common injury followed by a sprain. The most commonly injured site was the knee (48.6% of lower body injuries; IR 1.3/1000 player-games). The Medial collateral ligament sprain occurred in 37.1% and ACL rupture in 11.4% of knee injuries. A concussion (74.3%; IR 1.0/1000 player-games) was the most common head injury.Conclusions and recommendationsThe risk of injury to female ice hockey players at World Championship and Olympic tournaments was about half of that observed in the men's Championships. Full facial protection decreases the risk of lacerations and should be continued in all future female tournaments. More effective prevention strategies for knee, ankle and shoulder injuries are needed in women's ice hockey. Improved concussion education is necessary to promote more consistent diagnosis and return to play protocols.
Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)
Authors: Dietsch Gregory N. , Randall Tressa D. , Gottardo Raphael , Northfelt Donald W. , Ramanathan Ramesh K. , Cohen Peter A. , Manjarrez Kristi L. , Newkirk Mona , Bryan James Kyle , Hershberg Robert M. 
Published: July 2015

AbstractPurpose: Immunotherapy as a treatment for cancer holds the promise of complete and durable tumor remission, yet the immunosuppressive environment created by many tumors, advanced patient age, and previous treatments with cytotoxic agents may limit the approach. The activity of motolimod (VTX-2337), a potent and selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the context of advanced, late-stage cancer patients.Experimental Design: The repertoire of mediators induced from human peripheral blood mononuclear cells in response to motolimod was characterized. Translational studies in cynomolgus monkeys elucidated the activity of motolimod on an intact immune system, identified biomarkers of TLR8 activation, and defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) response. The PK/PD relationship for motolimod in cancer patients was assessed, compared with preclinical findings, and contrasted with activity in healthy volunteers.Results: In late-stage cancer patients, plasma levels of multiple biomarkers, including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod dose. The magnitude and breadth of the biomarker response closely aligned with the response seen in preclinical studies, demonstrating that advanced cancer patients remained responsive to TLR8 activation. In addition, the PK/PD response in cancer patients closely aligned with the activity of motolimod seen in healthy volunteers.Conclusions: Late-stage cancer patients are highly sensitive to TLR8 activation by motolimod. Tumor burden, advanced age, and prior treatment history with cytotoxic agents did not moderate or modify the response predicted by nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 21(24); 5445–52. ©2015 AACR.
Physical Activity from Early Adulthood and Risk of Prostate Cancer: A 24-Year Follow-Up Study among Icelandic Men
Authors: Hrafnkelsdóttir Soffia M. , Torfadóttir Jóhanna E. , Aspelund Thor , Magnusson Kristjan T. , Tryggvadóttir Laufey , Gudnason Vilmundur , Mucci Lorelei A. , Stampfer Meir , Valdimarsdóttir Unnur A. 
Published: July 2015

Abstract
Physical activity in adult life may reduce prostate cancer risk. Data are scarce on the role of activity during early adulthood, as well as combined recreational and occupational physical activity on prostate cancer risk and mortality. We undertook a prospective study of 8,221 Icelandic men (born 1907 to 1935) in the population-based Reykjavik Study. At enrollment, between 1967 and 1987, the men provided information on regular recreational physical activity since the age of 20 years as well as current occupational activity. Through linkage to nationwide cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality through 2009. We used Cox models to calculate the relative risk of prostate cancer by level of physical activity. During a mean follow-up of 24.8 years, 1,052 men were diagnosed with prostate cancer, of whom 349 had advanced disease (stage 3+ or prostate cancer death). Neither recreational nor occupational physical activity was, independently or combined, associated with overall or localized prostate cancer. Compared with physically inactive men, we observed a nonsignificant lower risk of advanced prostate cancer [HR, 0.67; 95% confidence interval (CI), 0.42–1.07] among men reporting both recreational and occupational physical activities (P value for interaction = 0.03). Awaiting confirmation in larger studies with detailed assessment of physical activity, our data suggest that extensive physical activity beginning in early adulthood may reduce the risk of advanced prostate cancer. Cancer Prev Res; 8(10); 905–11. ©2015 AACR.
Ticagrelor Versus Clopidogrel in Black Patients With Stable Coronary Artery Disease
Authors: Waksman Ron , Maya Juan , Angiolillo Dominick J. , Carlson Glenn F. , Teng Renli , Caplan Richard J. , Ferdinand, Keith C. 
Published: July 2015

Background—
The burden of coronary artery disease (CAD) is high in blacks, highlighting the need for clinical research of antiplatelet agents in this population. We sought to evaluate platelet reactivity during loading and maintenance dosing of ticagrelor versus clopidogrel, and the pharmacokinetic profile of ticagrelor and its metabolite AR-C124910XX, in black patients with stable CAD taking low-dose aspirin (acetylsalicylic acid).

Methods and Results—

In a multicenter, randomized, open-label, crossover study, 34 blacks with stable CAD receiving acetylsalicylic acid 75 to 100 mg/d were randomized to clopidogrel (600 mg, then 75 mg QD for 7–9 days) or ticagrelor (180 mg, then 90 mg BID for 7–9 days). After washout 10 to 14 days, patients switched regimens. The primary end point was platelet reactivity 2 hours post loading dose (P2Y
12
reactivity units [PRU] measured by the VerifyNow assay). Least-squares mean PRU at 2 hours post loading dose was lower with ticagrelor (27.6) versus clopidogrel (211.2); least-squares mean difference was –183.6 (95% confidence interval, –213.9 to –153.3;
P
<0.001). At all time points, the least-squares mean PRU was significantly lower, and the percent reduction in PRU from baseline was statistically greater, with ticagrelor versus clopidogrel. At 2 hours post dose, the prevalence of high on-treatment platelet reactivity (≥208 PRU) was lower with ticagrelor (0%) than with clopidogrel (57.1%). Pharmacokinetic profiles of ticagrelor and AR-C124910XX were consistent with previous reports in stable CAD populations.

Conclusions—
In black patients with stable CAD receiving low-dose acetylsalicylic acid, ticagrelor provided a faster onset and greater degree of platelet inhibition than clopidogrel.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01523392.
Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup
Authors: Lee Joo Myung , Hwang Doyeon , Park Jonghanne , Kim Kyung-Jin , Ahn Chul , Koo Bon-Kwon 
Published: July 2015

Background—
Emergency coronary artery bypass grafting for unsuccessful percutaneous coronary intervention (PCI) is now rare. We aimed to evaluate the current safety and outcomes of primary PCI and nonprimary PCI at centers with and without on-site surgical backup.

Methods and Results—

We performed an updated systematic review and meta-analysis by using mixed-effects models. We included 23 high-quality studies that compared clinical outcomes and complication rates of 1 101 123 patients after PCI at centers with or without on-site surgery. For primary PCI for ST-segment–elevation myocardial infarction (133 574 patients), all-cause mortality (without on-site surgery versus with on-site surgery: observed rates, 4.8% versus 7.2%; pooled odds ratio [OR], 0.99; 95% confidence interval, 0.91–1.07;
P
=0.729;
I
2
=3.4%) or emergency coronary artery bypass grafting rates (observed rates, 1.5% versus 2.4%; pooled OR, 0.76; 95% confidence interval, 0.56–1.01;
P
=0.062;
I
2
=42.5%) did not differ by presence of on-site surgery. For nonprimary PCI (967 549 patients), all-cause mortality (observed rates, 1.6% versus 2.1%; pooled OR, 1.15; 95% confidence interval, 0.94–1.41;
P
=0.172;
I
2
=67.5%) and emergency coronary artery bypass grafting rates (observed rates, 0.5% versus 0.8%; pooled OR, 1.14; 95% confidence interval, 0.62–2.13;
P
=0.669;
I
2
=81.7%) were not significantly different. PCI complication rates (cardiogenic shock, stroke, aortic dissection, tamponade, recurrent infarction) also did not differ by on-site surgical capability. Cumulative meta-analysis of nonprimary PCI showed a temporal decrease of the effect size (OR) for all-cause mortality after 2007.

Conclusions—
Clinical outcomes and complication rates of PCI at centers without on-site surgery did not differ from those with on-site surgery, for both primary and nonprimary PCI. Temporal trends indicated improving clinical outcomes in nonprimary PCI at centers without on-site surgery.
Body Mass Index, Outcomes, and Mortality Following Cardiac Surgery in Ontario, Canada
Authors: Johnson Ana P. , Parlow Joel L. , Whitehead Marlo , Xu Jianfeng , Rohland Susan , Milne Brian 
Published: July 2015

Background

The “obesity paradox” reflects an observed relationship between obesity and decreased morbidity and mortality, suggesting improved health outcomes for obese individuals. Studies examining the relationship between high body mass index (
BMI
) and adverse outcomes after cardiac surgery have reported conflicting results.

Methods and Results

The study population (N=78 762) was comprised of adult patients who had undergone first‐time coronary artery bypass (
CABG
) or combined
CABG
/aortic valve replacement (
AVR
) surgery from April 1, 1998 to October 31, 2011 in Ontario (data from the Institute for Clinical Evaluative Sciences). Perioperative outcomes and 5‐year mortality among pre‐defined
BMI
(kg/m
2
) categories (underweight <20, normal weight 20 to 24.9, overweight 25 to 29.9, obese 30 to 34.9, morbidly obese >34.9) were compared using Bivariate analyses and Cox multivariate regression analysis to investigate multiple confounders on the relationship between
BMI
and adverse outcomes. A reverse J‐shaped curve was found between
BMI
and mortality with their respective hazard ratios. Independent of confounding variables, 30‐day, 1‐year, and 5‐year survival rates were highest for the obese group of patients (99.1% [95% Confidence Interval {
CI
}, 98.9 to 99.2], 97.6% [95%
CI
, 97.3 to 97.8], and 90.0% [95%
CI
, 89.5 to 90.5], respectively), and perioperative complications lowest. Underweight and morbidly obese patients had higher mortality and incidence of adverse outcomes.

Conclusions
Overweight and obese patients had lower mortality and adverse perioperative outcomes after cardiac surgery compared with normal weight, underweight, and morbidly obese patients. The “obesity paradox” was confirmed for overweight and moderately obese patients. This may impact health resource planning, shifting the focus to morbidly obese and underweight patients prior to, during, and after cardiac surgery.
Estimating Total Cerebral Microinfarct Burden From Diffusion-Weighted Imaging
Authors: Auriel Eitan , Westover M. Brandon , Bianchi Matt T. , Reijmer Yael , Martinez-Ramirez Sergi , Ni Jun , Van Etten Ellis , Frosch Matthew P. , Fotiadis Panagiotis , Schwab Kris , Vashkevich Anastasia , Boulouis Grégoire , Younger Alayna P. , Johnson Keith A. , Sperling Reisa A. , Hedden Trey , Gurol M. Edip , Viswanathan Anand , Greenberg Steven M. 
Published: July 2015

Background and Purpose—
Cerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions.

Methods—
We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life.

Results—

Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%;
P
<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255–11 990).

Conclusions—
Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel–related vascular cognitive impairment.
Duration of Diabetes Mellitus and Risk of Thromboembolism and Bleeding in Atrial Fibrillation
Authors: Overvad Thure Filskov , Skjøth Flemming , Lip Gregory Y.H. , Lane Deirdre A. , Albertsen Ida Ehlers , Rasmussen Lars Hvilsted , Larsen Torben Bjerregaard 
Published: July 2015

Background and Purpose—
Guidelines advocate anticoagulant treatment to all patients with atrial fibrillation and concomitant diabetes mellitus. The potential refinement to thromboembolic risk stratification that may spring from subdividing diabetes mellitus is unexplored. The purpose was to investigate duration of diabetes mellitus as a predictor of thromboembolism and anticoagulant-related bleeding in patients with atrial fibrillation.

Methods—
Using nationwide Danish registries, we identified all patients discharged from hospital with an incident diagnosis of atrial fibrillation from 2000 to 2011. Hazard ratios with 95% confidence intervals for thromboembolism and bleeding according to years of diabetes mellitus duration in categories (0–4, 5–9, 10–14, and ≥15) and as a continuous variable using cubic splines were calculated by Cox regression.

Results—

The study population comprised 137 222 patients with atrial fibrillation, of which 12.4% had diabetes mellitus. Compared with patients without diabetes mellitus and after adjustment for anticoagulant treatment and CHA
2
DS
2
-VASc components (congestive heart failure, hypertension, age, previous stroke, vascular disease, and sex), the risk of thromboembolism was lowest in the 0 to 4 years duration category (hazard ratio, 1.11; 95% confidence interval, 1.03–1.20), and highest in the longest duration category of ≥15 years (hazard ratio, 1.48; 95% confidence interval, 1.29–1.70). When analyzed as a continuous variable, duration of diabetes mellitus was associated with risk of thromboembolism in a dose-response-dependent manner, but not with a higher risk of bleeding during anticoagulant treatment.

Conclusions—
In patients with atrial fibrillation, longer duration of diabetes mellitus was associated with a higher risk of thromboembolism, but not with a higher risk of anticoagulant-related bleeding. Considering the critical balance between preventing thromboembolism and avoiding bleeding, longer duration of diabetes mellitus may favor initiation of anticoagulant therapy.
Zonal Extension and Retraction of the Subtropical Westerly Jet Stream and Evolution of Precipitation over East Asia and the Western Pacific
Authors: Xie Zhiqing , Du Yin , Yang Song 
Published: July 2015

Abstract
The relationship between the zonal extension and retraction of the East Asian subtropical westerly jet stream (EASWJ) and the seasonal evolution of precipitation is investigated. The EASWJ exhibits significant zonal variations associated with its seasonal evolution, which affects both large-scale atmospheric circulation and precipitation over East Asia and the North Pacific. The midlatitude rain belts and the intertropical convergence zone are located more eastward and southward during jet extensions compared to jet retractions. The seasonal cycle of the zonal variations of EASWJ can be divided into four periods: December–February, March–May, June–July, and September–November. Particularly in the mei-yu period of June–July, jet retraction events are associated with a northward shift of rain belts over eastern China, which may play an important role in the northward movement of the mei-yu rain belt to the Huaihe River valley of eastern China after 1999. The zonal extension and retraction of the jet stream are more likely to occur in the ENSO decaying phase. A composite analysis of diabatic heating and outgoing longwave radiation shows a tripolar anomaly pattern that is strongest in El Niño winter and is important for the zonal extension of the jet stream over the Pacific. This spatial structure is conducive to a strengthening local Hadley cell over the Pacific and can also appear in weak El Niño periods. On the other hand, there is no tripolar anomaly pattern for zonally retracted jet streams.
Spreading of Denmark Strait Overflow Water in the Western Subpolar North Atlantic: Insights from Eddy-Resolving Simulations with a Passive Tracer
Authors: Xu Xiaobiao , Rhines Peter B. , Chassignet Eric P. , Schmitz William J. 
Published: July 2015

AbstractThe oceanic deep circulation is shared between concentrated deep western boundary currents (DWBCs) and broader interior pathways, a process that is sensitive to seafloor topography. This study investigates the spreading and deepening of Denmark Strait overflow water (DSOW) in the western subpolar North Atlantic using two ° eddy-resolving Atlantic simulations, including a passive tracer injected into the DSOW. The deepest layers of DSOW transit from a narrow DWBC in the southern Irminger Sea into widespread westward flow across the central Labrador Sea, which remerges along the Labrador coast. This abyssal circulation, in contrast to the upper levels of overflow water that remain as a boundary current, blankets the deep Labrador Sea with DSOW. Farther downstream after being steered around the abrupt topography of Orphan Knoll, DSOW again leaves the boundary, forming cyclonic recirculation cells in the deep Newfoundland basin. The deep recirculation, mostly driven by the meandering pathway of the upper North Atlantic Current, leads to accumulation of tracer offshore of Orphan Knoll, precisely where a local maximum of chlorofluorocarbon (CFC) inventory is observed. At Flemish Cap, eddy fluxes carry ~20% of the tracer transport from the boundary current into the interior. Potential vorticity is conserved as the flow of DSOW broadens at the transition from steep to less steep continental rise into the Labrador Sea, while around the abrupt topography of Orphan Knoll, potential vorticity is not conserved and the DSOW deepens significantly.
Interannual Variation of Annual Subduction Rate in the North Pacific Estimated from a Gridded Argo Product
Authors: Toyama Katsuya , Iwasaki Aiko , Suga Toshio 
Published: July 2015

AbstractSpatiotemporal variability of the subduction rate in the North Pacific from 2005 to 2012 is examined based on the Argo observational data. The subduction rate in the subtropical North Pacific varies significantly from year to year between 25 and 50 Sverdrups (Sv; 1 Sv ≡ 106 m3 s−1), and it is well correlated with the Pacific decadal oscillation. The temporal change of the subduction rate is largely determined by that of the late winter mixed layer depth through the lateral induction term. The increase (decrease) in the subduction rate in the subtropical mode water areas accompanies densification (lightening) of the mode density class of the subducted water. The subduction rate variability in the central mode water and eastern subtropical mode water regions is anticorrelated as found in the previous study using the output from an ocean GCM. The subduction rate in the central mode water density range changes dramatically, which is very large in 2005 and 2010 but almost disappears in 2009. The subduction rate variability in the western subtropical mode water regions seems to be correlated with the Pacific decadal oscillation with a lag of a few years.