bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet components associated with adverse reactions: predictive value of mitochondrial DNA relative to biological response modifiers
Authors: Cognasse Fabrice , Aloui Chaker , Anh Nguyen Kim , Hamzeh‐Cognasse Hind , Fagan Jocelyne , Arthaud Charles‐Antoine , Eyraud Marie‐Ange , Sebban Marc , Fromont Elisa , Pozzetto Bruno , Laradi Sandrine , Garraud Olivier 
Published: October 2015

BACKGROUNDBiological response modifiers (BRMs), secreted by platelets (PLTs) during storage, play a role in adverse events (AEs) associated with transfusion. Moreover, mitochondrial DNA (mtDNA) levels in PLT components (PCs) are associated with AEs. In this study we explore whether there is a correlation between pathogenic BRMs and mtDNA levels and whether these markers can be considered predictors of transfusion pathology.STUDY DESIGN AND METHODSWe investigated a series of reported AEs after PC transfusion, combining clinical observations and mathematical modeling systems.RESULTSmtDNA was consistently released during the first days of PC storage; however, mtDNA release was earlier in “pathogenic” than in nonpathogenic PCs. PC supernatants with high levels of mtDNA along with soluble CD40 ligand (sCD40L) were significantly associated with occurrences of AEs. The fact that mtDNA did not associate with the 14 BRMs tested suggests the role of mtDNA in PC transfusion‐linked inflammation is independent of that of BRMs, known to be associated with AEs. We present evidence that PLTs generate distinct pathogenic secretion profiles of BRMs and mtDNA. The calculated area under the curve for mtDNA was significantly associated with AEs, although less stringently predictive than those of sCD40L or interleukin‐13, standard predictors of AE. The established model predicts that distinct subtypes of AEs can be distinguished, dependent on mtDNA levels and PC storage length.CONCLUSIONSFurther work should be considered to test the propensity of mtDNA in PLT concentrates to generate inflammation and cause an AE.
Determining the consequences of maternal obesity for offspring health
Authors: Patel Nashita , Pasupathy Dharmintra , Poston Lucilla 
Published: October 2015

New Findings

What is the topic of this review?
Observational studies have highlighted the association of increasing maternal body mass index with offspring adiposity and the subsequent risk of cardiometabolic disorders in adulthood. The in utero environment has become a target for intervention in order to reduce the burden of obesity, despite the mechanistic pathways of this association remaining unclear.

What advances does it highlight?
This short review provides a critical appraisal of the recent literature, including biological pathways and strategies to address causal relationships.

The global obesity epidemic has been causally linked to changes in diet and lifestyle. Observational data and animal studies have now highlighted associations between in utero environmental exposures and increased susceptibility to obesity and related cardiometabolic disorders in later life. Maternal body mass index has been reported to show an independent association with offspring adiposity from an early age and to play an important role in the predisposition to obesity and metabolic disease in later life. Thus, the in utero environment has been the focus of recent targeted interventions to improve public health. In this review, we summarize recent progress in this field, including the use of animal models to investigate mechanistic links between maternal obesity and offspring metabolic risk. We then assess the level of evidence and challenges in establishing causal inferences from present birth cohorts.
Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes
Authors: Lee Andrew C. Y. , Zhu Houshun , Zhang Anna J. X. , Li Can , Wang Pui , Li Chuangen , Chen Honglin , Hung Ivan F. N. , To Kelvin K. W. , Yuen Kwok-Yung 
Published: October 2015

ABSTRACTInfluenza A(H7N9) virus pneumonia is associated with a high case fatality rate in humans. Multiple viral factors have been postulated to account for the high virulence of the virus. It has been reported that patients with influenza A(H7N9) virus infection have relatively low titers of neutralizing antibodies compared to those with seasonal influenza virus infections. In this study, we compared serum hemagglutination inhibition (HI) and microneutralization (MN) antibody titers of mice challenged with wild-type A(H7N9) viruses [H7N9(Anhui) and H7N9(Zhejiang)], an A(H1N1)pdm09 virus [pH1N1(2009)], and a recombinant A(H7N9) virus with PR8/H1N1 internal genes (rg-PR8-H7-N9). All mice infected by H7N9(Anhui) and H7N9(Zhejiang) developed serum HI antibodies at 14 days postinfection (dpi) but no detectable MN antibodies, even at 28 dpi. A low level of neutralizing activity was detected in H7N9(Anhui)- and H7N9(Zhejiang)-infected mice using fluorescent focus MN assay, but convalescent-phase serum samples obtained from H7N9(Anhui)-infected mice did not reduce the mortality of naive mice after homologous virus challenge. Reinfection with homologous A(H7N9) virus induced higher HI and MN titers than first infection. In contrast, pH1N1(2009) virus infection induced robust HI and MN antibody responses, even during the first infection. Moreover, rg-PR8-H7-N9 induced significantly higher HI and MN antibody titers than H7N9(Zhejiang). In conclusion, the internal genes of A(H7N9) virus can affect the humoral immune response against homologous viral surface proteins, which may also contribute to the virulence of A(H7N9) virus.
Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague
Authors: Tiner Bethany L. , Sha Jian , Ponnusamy Duraisamy , Baze Wallace B. , Fitts Eric C. , Popov Vsevolod L. , van Lier Christina J. , Erova Tatiana E. , Chopra Ashok K. 
Published: October 2015

ABSTRACTEarlier, we showed that the ΔlppΔmsbBΔailtriple mutant ofYersinia pestisCO92 with deleted genes encoding Braun lipoprotein (Lpp), an acyltransferase (MsbB), and the attachment invasion locus (Ail), respectively, was avirulent in a mouse model of pneumonic plague. In this study, we further evaluated the immunogenic potential of the ΔlppΔmsbBΔailtriple mutant and its derivative by different routes of vaccination. Mice were immunized via the subcutaneous (s.c.) or the intramuscular (i.m.) route with two doses (2 × 106CFU/dose) of the above-mentioned triple mutant with 100% survivability of the animals. Upon subsequent pneumonic challenge with 70 to 92 50% lethal doses (LD50) of wild-type (WT) strain CO92, all of the mice survived when immunization occurred by the i.m. route. Since Ail has virulence and immunogenic potential, a mutated version of Ail devoid of its virulence properties was created, and the genetically modifiedailreplaced the nativeailgene on the chromosome of the ΔlppΔmsbBdouble mutant, creating a ΔlppΔmsbB::ailL2vaccine strain. This newly generated mutant was attenuated similarly to the ΔlppΔmsbBΔailtriple mutant when administered by the i.m. route and provided 100% protection to animals against subsequent pneumonic challenge. Not only were the two above-mentioned mutants cleared rapidly from the initial i.m. site of injection in animals with no histopathological lesions, the immunized mice did not exhibit any disease symptoms during immunization or after subsequent exposure to WT CO92. These two mutants triggered balanced Th1- and Th2-based antibody responses and cell-mediated immunity. A substantial increase in interleukin-17 (IL-17) from the T cells of vaccinated mice, a cytokine of the Th17 cells, further augmented their vaccine potential. Thus, the ΔlppΔmsbBΔailand ΔlppΔmsbB::ailL2mutants represent excellent vaccine candidates for plague, with the latter mutant still retaining Ail immunogenicity but with a much diminished virulence potential.
Commentary: Individualized Quality Control Plan (IQCP): Is It Value-Added for Clinical Microbiology?
Authors: Sharp Susan E. , Miller Melissa B. , Hindler Janet 
Published: October 2015

ABSTRACT

The Center for Medicaid and Medicare Services (CMS) recently published their Individualized Quality Control Plan (IQCP [
https://www.cms.gov/regulations-and-guidance/legislation/CLIA/Individualized_Quality_Control_Plan_IQCP.html
]), which will be the only option for quality control (QC) starting in January 2016 if laboratories choose not to perform Clinical Laboratory Improvement Act (CLIA) [U.S. Statutes at Large 81(1967):533] default QC. Laboratories will no longer be able to use “equivalent QC” (EQC) or the Clinical and Laboratory Standards Institute (CLSI) standards alone for quality control of their microbiology systems. The implementation of IQCP in clinical microbiology laboratories will most certainly be an added burden, the benefits of which are currently unknown.
Genetic Pathway of HIV-1 Resistance to Novel Fusion Inhibitors Targeting the Gp41 Pocket
Authors: Su Yang , Chong Huihiui , Xiong Shengwen , Qiao Yuanyuan , Qiu Zonglin , He Yuxian 
Published: October 2015

ABSTRACT
The peptide drug enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but it easily induces drug resistance, calling for new strategies for developing effective drugs. On the basis of the M-T hook structure, we recently developed highly potent short-peptide HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the conserved gp41 pocket and possess high genetic barriers to resistance. Here, we focused on the selection and characterization of HIV-1 escape mutants of MTSC22, which revealed new resistance pathways and mechanisms. Two mutations (E49K and L57R) located at the inhibitor-binding site and two mutations (N126K and E136G) located at the C-terminal heptad repeat region of gp41 were identified as conferring high resistance either singly or in combination. While E49K reduced the C-terminal binding of inhibitors via an electrostatic repulsion, L57R dramatically disrupted the N-terminal binding of M-T hook structure and pocket-binding domain. Unlike E49K and N126K, which enhanced the stability of the endogenous viral six-helical bundle core (6-HB), L57R and E136G conversely destabilized the 6-HB structure. We also demonstrated that both primary and secondary mutations caused the structural changes in 6-HB and severely impaired the capability for HIV-1 entry. Collectively, our data provide novel insights into the mechanisms of short-peptide fusion inhibitors targeting the gp41 pocket site and help increase our understanding of the structure and function of gp41 and HIV-1 evolution.

IMPORTANCE
The deep pocket on the N-trimer of HIV-1 gp41 has been considered an ideal drug target because of its high degree of conservation and essential role in viral entry. Short-peptide fusion inhibitors, which contain an M-T hook structure and mainly target the pocket site, show extremely high binding and inhibitory activities as well as high genetic barriers to resistance. In this study, the HIV-1 mutants resistant to MTSC22 were selected and characterized, which revealed that the E49K and L57R substitutions at the inhibitor-binding site and the N126K and E136G substitutions at the C-terminal heptad repeat region of gp41 critically determine the resistance phenotype. The data provide novel insights into the mechanisms of action of the M-T hook structure-based fusion inhibitors which will help further our understanding of the structure-function relationship of gp41 and molecular pathways of HIV-1 evolution and eventually facilitate the development of new anti-HIV drugs.
Infections Acquired in the Garden
Authors: Cunha Cheston B. , Cunha Burke A. 
Published: October 2015

ABSTRACT
Gardening is a wonderful pastime, and the garden is a very peaceful place to enjoy one’s vacation. However, the garden may be a treacherous place for very young or compromised hosts when one takes into account the infectious potential residing in the soil, as well as the insect vectors on plants and animals. Even normal hosts may acquire a variety of infections from the soil, animals, or animal-related insect bites. The location of the garden, its natural animal and insect inhabitants, and the characteristics of the soil play a part in determining its infectious potential. The most important factor making the garden an infectious and dangerous place is the number and interaction of animals, whether they are pets or wild, that temporarily use the garden for part of their daily activities. The clinician should always ask about garden exposure, which will help in eliminating the diagnostic possibilities for the patient. The diagnostic approach is to use epidemiological principles in concert with clinical clues, which together should suggest a reasonable list of diagnostic possibilities. Organ involvement and specific laboratory tests help further narrow the differential diagnosis and determine the specific tests necessary to make a definitive diagnosis.
Prevalence and outcomes of multimorbidity in South Asia: a systematic review
Authors: Pati Sanghamitra , Swain Subhashisa , Hussain Mohammad Akhtar , van den Akker Marjan , Metsemakers Job , Knottnerus J André , Salisbury Chris 
Published: October 2015

ObjectiveTo systematically review the studies of prevalence, patterns and consequences of multimorbidity reported from South Asia.DesignSystematic review.SettingSouth Asia.Data sourcesArticles were retrieved from two electronic databases (PubMed and Embase) and from the relevant references lists. Methodical data extraction according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines was followed. English-language studies published between 2000 and March 2015 were included.Eligibility criteriaStudies addressing prevalence, consequences and patterns of multimorbidity in South Asia. Articles documenting presence of two or more chronic conditions were included in the review. The quality and risk of bias were assessed using STROBE criteria.Data selectionTwo reviewers independently assessed studies for eligibility, extracted data and assessed study quality. Due to heterogeneity in methodologies among reported studies, only narrative synthesis of the results was carried out.ResultsOf 11 132, 61 abstracts were selected and 13 were included for final data synthesis. The number of health conditions analysed per study varied from 7 to 22, with prevalence of multimorbidity from 4.5% to 83%. The leading chronic conditions were hypertension, arthritis, diabetes, cardiac problems and skin diseases. The most frequently reported outcomes were increased healthcare utilisation, lowered physical functioning and quality of life, and psychological distress.ConclusionsOur study, a comprehensive mapping of multimorbidity research in South Asia, reveals the insufficient volume of work carried out in this domain. The published studies are inadequate to provide an indication of the magnitude of multimorbidity in these countries. Research into clinical and epidemiological aspects of multimorbidity is warranted to build up scientific evidence in this geographic region. The wide heterogeneity observed in the present review calls for greater methodological rigour while conducting these epidemiological studies.Trial registration numberCRD42013005456.
A protocol for engaging unlicensed private drug shops in Rural Eastern Uganda for Integrated Community Case Management (ICCM) of malaria, pneumonia and diarrhoea in children under 5 years of age
Authors: Buchner Denise L , Awor Phyllis 
Published: October 2015

IntroductionMalaria, pneumonia and diarrhoea are leading causes of death in young children in Uganda. In 2010, Integrated Community Case Management (ICCM) was adopted in Uganda for community level diagnosis and treatment of these diseases through community health workers. However, 50–60% of sick children will receive treatment from the private sector, especially drug shops. Only about half of drug shops are licensed and the quality of care is poor. There is an urgent need to improve quality of care and regulation of drug shops in Uganda.MethodsThis is a pre–post cross-sectional study with before and after measurement in an intervention area in Kamujli district. A snowball mapping exercise, exit interviews, focus group discussions and interviews will be used. 25 randomly selected drug shops will be selected for an intervention that will assist drug shops to become licensed, and provide five days of ICCM training, subsidised prepackaged medicines (artemisinin-based combination therapies for malaria, amoxicillin for pneumonia, Oral Rehydration Salts/zinc for diarrhoea) and free diagnostic tools (rapid diagnostic tests, respiratory timers, thermometers, algorithms). We anticipate a sample size of 1200 (600 at baseline and 600 at the end of the study).AnalysisQuantitative data will be analysed using SPSS for proportions and CIs. Bivariate and multiple logistic regression analysis with adjustment for clustering of data will be performed to adjust for confounding and determine intervention effect. Qualitative data will be entered into NVivo 10 and analysed using content analysis.Ethics and DisseminationResearch ethics approval is received from the University of Calgary (REB 14–0269), and Makerere University (IRB00011353). Findings from this study will be disseminated through journal articles and conference presentations, and will illustrate the feasibility of introducing ICCM for drug shops.
Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors
Authors: Patnaik Amita , Weiss Glen J. , Leonard John E. , Rasco Drew Warren , Sachdev Jasgit C. , Fisher Terrence L. , Winter Laurie A. , Reilly Christine , Parker Robert B. , Mutz Danielle , Blaydorn Lisa , Tolcher Anthony W. , Zauderer Maurice , Ramanathan Ramesh K. 
Published: October 2015

Abstract
Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients.
Experimental Design: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane–associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated.
Results: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥8 weeks, and 8 (19%) had SD for ≥16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival.
Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents. Clin Cancer Res; 22(4); 827–36. ©2015 AACR.
Prior chronic clopidogrel therapy is associated with increased adverse events and early stent thrombosis
Authors: Fefer Paul , Sabbag Avi , Herscovici Romana , Regev Ehud , Mazin Israel , Shlomo Nir , Zahger Doron , Atar Shaul , Hammerman Haim , Polak Arthur , Beigel Roy , Matetzky Shlomi , Asher Elad ,   for The PLATIS (Platelets and Thrombosis in Sheba) Study Group
Published: October 2015

SummaryDespite the growing use of clopidogrel, limited data exist regarding the prognostic significance of chronic clopidogrel therapy in patients sustaining acute coronary syndrome (ACS). Our aim was to determine whether patients sustaining ACS while on chronic clopidogrel therapy have a worse prognosis than clopidogrel-naïve patients. A total of 5,386 consecutive ACS patients were prospectively characterised and followed-up for 30 days. Of them, 680 (13 %) were treated with clopidogrel prior to the index ACS. Major adverse cardiovascular events (MACE) were defined as death, recurrent ACS, stroke and/or stent thrombosis. Compared with clopidogrel-naïve, chronic clopidogrel-treated patients were older (66 ± 12 vs 63 ± 13, respectively; p< 0.01), suffered more from diabetes mellitus, hypertension, dyslipidaemia, prior cardiovascular history, including prior myocardial infarction, revascularisation, coronary artery bypass graft and stroke (p< 0.01 for all), and were less likely to present with ST-elevation myocardial infarction (21 % vs 45 %; respectively; p < 0.001). Prior clopidogrel therapy was associated with a two-fold increase in in-hospital (1.6 °% vs 0.6, respectively; p =0.006) as well as 30-day stent thrombosis (2.2 % vs 1.0 %, respectively; p=0.007). MACE at 30 days was also higher among chronic clopidogrel-treated compared with clopidogrel-naïve patients [12.3 % vs 9.4 %, respectively; p< 0.01]. In multivariate log regression analysis chronic clopidogrel treatment was an independent predictor of stent thrombosis [OR=2.6 (95 %CI 1.2–5.6), p=0.001]. Patients sustaining ACS while on chronic clopidogrel treatment are at higher risk for in-hospital and 30-day adverse outcomes, including stent thrombosis.
A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system
Authors: Schnee Janet , Fraeman Kathy , Siu Kimberly , Reynolds Matthew W. , Collins Jenna , Schwartzman Eric , Villines Todd C. 
Published: October 2015

SummaryDabigatran is approved for stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data from diverse clinical practice settings will help establish whether the risk:benefit ratio seen in clinical trials is comparable with routine clinical care. This study aimed to compare the safety and effectiveness of dabigatran and warfarin in clinical practice. We undertook a propensity score-matched (PSM) cohort study (N=12,793 per group; mean age 74) comparing treatment with dabigatran or warfarin in the US Department of Defense claims database, October 2009 to July 2013. Treatment-naïve patients with first prescription claim for dabigatran (either FDA-approved dose) or warfarin between October 2010 and July 2012 (index) and a diagnosis of NVAF during the 12 months before index date were included. Primary outcomes were stroke and major bleeding. Secondary outcomes included ischaemic and haemorrhagic stroke, major gastrointestinal (GI), urogenital or other bleeding, myocardial infarction (MI) and death. Time-to-event was investigated using Kaplan-Meier survival analyses. Outcomes comparisons were made utilising Cox-proportional hazards models of PSM groups. Dabigatran users experienced fewer strokes (adjusted hazard ratio [95 % confidence intervals] 0.73 [0.55–0.97]), major intracranial (0.49 [0.30–0.79]), urogenital (0.36 [0.18–0.74]) and other (0.38 [0.22–0.66]) bleeding, MI (0.65 [0.45–0.95]) and deaths (0.64 [0.55–0.74]) than the warfarin group. Major bleeding (0.87 [0.74–1.03]) and major GI bleeding (1.13 [0.94–1.37]) was similar between groups and major lower GI bleeding events were more frequent (1.30 [1.04–1.62]) with dabigatran. In conclusion, compared with warfarin, dabigatran treatment was associated with a lower risk of stroke and most outcomes measured, but increased incidence of major lower GI bleeding.