bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance of the Abbott RealTi
m
e MTB and MTB RIF/INH Assays in a Setting of High Tuberculosis and HIV Coinfection in South Africa
Authors: Scott Lesley , David Anura , Noble Lara , Nduna Matilda , Da Silva Pedro , Black Andrew , Venter Francois , Stevens Wendy 
Published: June 2017

ABSTRACT

South Africa is a country with a high incidence of tuberculosis (TB), complicated by coinfection with human immunodeficiency virus (HIV). The Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is used in South Africa as the test for the initial diagnosis of TB, and other molecular platforms such as the
m
2000 (Abbott Molecular, Des Plaines, IL, USA) are widely used for molecular monitoring of HIV load. The latter platform is now also equipped with the RealTi
m
e (RT) MTB and RealTi
m
e MTB RIF/INH assays for TB and first-line drug resistance screening but has not been evaluated in settings of HIV and TB coinfection. A prospective clinical validation study was conducted at a community health center in Johannesburg, South Africa, and consenting individuals with presumptive pulmonary TB were enrolled. The performance of the Abbott assays was compared with those of the Xpert MTB/RIF, liquid culture, drug susceptibility testing, and clinical case definitions. A statistical analysis was performed on 206 individuals (73% were HIV positive). The sensitivity and specificity of the RT MTB were 82.5% (confidence interval [CI], 67.2 to 92.7) and 93.1% (CI, 86.2 to 97.2) on raw sputum and 77.5% (CI, 61.5 to 89.2) and 95.1% (CI, 88.9 to 98.4) on concentrated sputum, respectively, compared with those from liquid culture. The RT MTB correctly identified 17/35 more smear-negative culture-positive specimens than the Xpert MTB/RIF. Both the RT MTB and the Xpert MTB/RIF displayed sensitivities >70% and specificities >90% in HIV-positive individuals. The available drug resistance results concurred with MTBDR
plus
and drug susceptibility profiles. The RT MTB assay has similar diagnostic performance to the Xpert MTB/RIF and is suited to testing presumptive TB patients coinfected with HIV. The existing laboratory information system connectivity, training, and technical support make this a viable polyvalent option to scale up TB alongside HIV laboratory testing services in South Africa.
Rapid and Robust Identification of the Agents of Black-Grain Mycetoma by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry
Authors: Fraser Mark , Borman Andrew M. , Johnson Elizabeth M. 
Published: June 2017

ABSTRACT

Eumycetoma, a chronic fungal infection endemic in India, Indonesia, and parts of Africa and South and Central America, follows traumatic implantation of saprophytic fungi and frequently requires radical surgery or amputation in the absence of appropriate treatment. Fungal species that can cause black-grain mycetomas include
Madurella
spp.,
Falciformispora
spp.,
Trematosphaeria grisea
,
Nigrograna mackinnonii
,
Pseudochaetosphaeronema larense
,
Medicopsis romeroi
, and
Emarellia
spp.
Rhytidhysteron rufulum
and
Parathyridaria percutanea
cause similar subcutaneous infections, but these infections lack the draining sinuses and fungal grains characteristic of eumycetoma. Accurate identification of the agents of subcutaneous fungal infection is essential to guide appropriate antifungal therapy. Since phenotypic identification of the causative fungi is often difficult, time-consuming molecular approaches are currently required. In the study described here we evaluated whether matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry might allow the accurate identification of eumycetoma agents and related fungi. A panel of 57 organisms corresponding to 10 different species from confirmed cases of eumycetoma and subcutaneous pedal masses, previously formally identified by PCR amplification and sequencing of internal transcribed spacer 1 (ITS1), was employed. Representative isolates of each species were used to create reference MALDI-TOF spectra, which were then used for the identification of the remaining isolates in a user-blinded manner. Here, we demonstrate that MALDI-TOF mass spectrometry accurately identified all of the test isolates, with 100%, 90.4%, and 67.3% of isolates achieving log scores greater than 1.8, 1.9, and 2.0, respectively.
Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response
Authors: Hou Shangmei , Kumar Anil , Xu Zaikun , Airo Adriana M. , Stryapunina Iryna , Wong Cheung Pang , Branton William , Tchesnokov Egor , Götte Matthias , Power Christopher , Hobman Tom C. 
Published: June 2017

ABSTRACT

Zika virus (ZIKV), a member of the
Flaviviridae
family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2α and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication.

IMPORTANCE
There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication.
Mapping of Transcription Termination within the S Segment of SFTS Phlebovirus Facilitated Generation of NSs Deletant Viruses
Authors: Brennan Benjamin , Rezelj Veronica V. , Elliott Richard M. 
Published: June 2017

ABSTRACT
SFTS phlebovirus (SFTSV) is an emerging tick-borne bunyavirus that was first reported in China in 2009. Here we report the generation of a recombinant SFTSV (rHB29NSsKO) that cannot express the viral nonstructural protein (NSs) upon infection of cells in culture. We show that rHB29NSsKO replication kinetics are greater in interferon (IFN)-incompetent cells and that the virus is unable to suppress IFN induced in response to viral replication. The data confirm for the first time in the context of virus infection that NSs acts as a virally encoded IFN antagonist and that NSs is dispensable for virus replication. Using 3′ rapid amplification of cDNA ends (RACE), we mapped the 3′ end of the N and NSs mRNAs, showing that the mRNAs terminate within the coding region of the opposite open reading frame. We show that the 3′ end of the N mRNA terminates upstream of a 5′-GCCAGCC-3′ motif present in the viral genomic RNA. With this knowledge, and using virus-like particles, we could demonstrate that the last 36 nucleotides of the NSs open reading frame (ORF) were needed to ensure the efficient termination of the N mRNA and were required for recombinant virus rescue. We demonstrate that it is possible to recover viruses lacking NSs (expressing just a 12-amino-acid NSs peptide or encoding enhanced green fluorescent protein [eGFP]) or an NSs-eGFP fusion protein in the NSs locus. This opens the possibility for further studies of NSs and potentially the design of attenuated viruses for vaccination studies.

IMPORTANCE
SFTS phlebovirus (SFTSV) and related tick-borne viruses have emerged globally since 2009. SFTSV has been shown to cause severe disease in humans. For bunyaviruses, it has been well documented that the nonstructural protein (NSs) enables the virus to counteract the human innate antiviral defenses and that NSs is one of the major determinants of virulence in infection. Therefore, the use of reverse genetics systems to engineer viruses lacking NSs is an attractive strategy to rationally attenuate bunyaviruses. Here we report the generation of several recombinant SFTS viruses that cannot express the NSs protein or have the NSs open reading frame replaced with a reporter gene. These viruses cannot antagonize the mammalian interferon (IFN) response mounted to virus infection. The generation of NSs-lacking viruses was achieved by mapping the transcriptional termination of two S-segment-derived subgenomic mRNAs, which revealed that transcription termination occurs upstream of a 5′-GCCAGCC-3′ motif present in the virus genomic S RNA.
Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review
Authors: Kenneally Susan , Sier Joanna H , Moore J Bernadette 
Published: June 2017

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with prevalence above 30% in many adult populations. Strongly associated with obesity, weight loss through diet and physical activity is the mainstay of its management. Weight loss can be difficult to achieve and maintain however, and uncertainty exists as to which lifestyle changes are most effective.ObjectiveThe aim of this work was to systematically evaluate randomised controlled trials assessing diet, exercise or combination interventions aimed at reducing steatosis or markers of NAFLD activity.DesignMedline, Scopus and Cochrane databases were searched from 1 January 1980 through to 31 July 2016, for intervention trials assessing the effects of diet, weight loss, exercise or any combination thereof, on NAFLD disease markers in human adults. Risk of publication bias and study quality was assessed using the American Dietetic Association Quality Criteria Checklist.ResultsFrom a total of 1710 identified records, 24 articles met the inclusion and exclusion criteria; 6 assessed weight loss using dietary restriction, 10 assessed exercise and 8 were combination interventions. While all of the trials demonstrated significant reduction in steatosis and/or markers of NAFLD activity, combination interventions appear to be the most effective at improving NAFLD. Results suggest that 5–10% weight loss using a modestly hypocaloric diet of 500 kcal less per day than calculated energy requirement, in combination with 30–60 min exercise on 3–5 days per week should be recommended.ConclusionsWe conclude this amount of weight loss is achievable in the trial setting but is challenging in the clinical environment. High-intensity, multidisciplinary intervention in specialist clinics is likely to be required in order to manage NAFLD by lifestyle modification alone. This systematic review protocol was registered prospectively at PROSPERO as CRD42016032764.
CD14+ CD15− HLA-DR− myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
Authors: Bernsmeier Christine , Triantafyllou Evangelos , Brenig Robert , Lebosse Fanny J , Singanayagam Arjuna , Patel Vishal C , Pop Oltin T , Khamri Wafa , Nathwani Rooshi , Tidswell Robert , Weston Christopher J , Adams David H , Thursz Mark R , Wendon Julia A , Antoniades Charalambos Gustav 
Published: June 2017

ObjectiveImmune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.DesignPatients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.ResultsCirculating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.ConclusionImmunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
Patterns of cannabis use during adolescence and their association with harmful substance use behaviour: findings from a UK birth cohort
Authors: Taylor Michelle , Collin Simon M , Munafò Marcus R , MacLeod John , Hickman Matthew , Heron Jon 
Published: June 2017

BackgroundEvidence on the role of cannabis as a gateway drug is inconsistent. We characterise patterns of cannabis use among UK teenagers aged 13–18 years, and assess their influence on problematic substance use at age 21 years.MethodsWe used longitudinal latent class analysis to derive trajectories of cannabis use from self-report measures in a UK birth cohort. We investigated (1) factors associated with latent class membership and (2) whether latent class membership predicted subsequent nicotine dependence, harmful alcohol use and recent use of other illicit drugs at age 21 years.Results5315 adolescents had three or more measures of cannabis use from age 13 to 18 years. Cannabis use patterns were captured as four latent classes corresponding to ‘non-users’ (80.1%), ‘late-onset occasional’ (14.2%), ‘early-onset occasional’ (2.3%) and ‘regular’ users (3.4%). Sex, mother's substance use, and child's tobacco use, alcohol consumption and conduct problems were strongly associated with cannabis use. At age 21 years, compared with the non-user class, late-onset occasional, early-onset occasional and regular cannabis user classes had higher odds of nicotine dependence (OR=3.5, 95% CI 0.7 to 17.9; OR=12.1, 95% CI 1.0 to 150.3; and OR=37.2, 95% CI 9.5 to 144.8, respectively); harmful alcohol consumption (OR=2.6, 95% CI 1.5 to 4.3; OR=5.0, 95% CI 2.1 to 12.1; and OR=2.6, 95% CI 1.0 to 7.1, respectively); and other illicit drug use (OR=22.7, 95% CI 11.3 to 45.7; OR=15.9, 95% CI 3.9 to 64.4; and OR=47.9, 95% CI 47.9 to 337.0, respectively).ConclusionsOne-fifth of the adolescents in our sample followed a pattern of occasional or regular cannabis use, and these young people were more likely to progress to harmful substance use behaviours in early adulthood.
Skeletal muscle morphology, protein synthesis, and gene expression in Ehlers-Danlos syndrome
Authors: Nygaard Rie H. , Jensen Jakob K. , Voermans Nicol C. , Heinemeier Katja M. , Schjerling Peter , Holm Lars , Agergaard Jakob , Mackey Abigail L. , Andersen Jesper L. , Remvig Lars , Kjaer Michael 
Published: June 2017

Patients with Ehlers-Danlos syndrome (EDS) are known to have genetically impaired connective tissue and skeletal muscle symptoms in form of pain, fatigue, and cramps; however earlier studies have not been able to link these symptoms to morphological muscle changes. We obtained skeletal muscle biopsies in patients with classic EDS [cEDS; n = 5 (Denmark)+ 8 (The Netherlands)] and vascular EDS (vEDS; n = 3) and analyzed muscle fiber morphology and content (Western blotting and muscle fiber type/area distributions) and muscle mRNA expression and protein synthesis rate (RT-PCR and stable isotope technique). The cEDS patients did not differ from healthy controls ( n = 7–11) with regard to muscle fiber type/area, myosin/α-actin ratio, muscle protein synthesis rate, or mRNA expression. In contrast, the vEDS patients demonstrated higher expression of matrix proteins compared with cEDS patients (fibronectin and MMP-2). The cEDS patients had surprisingly normal muscle morphology and protein synthesis, whereas vEDS patients demonstrated higher mRNA expression for extracellular matrix remodeling in skeletal musculature compared with cEDS patients. NEW & NOTEWORTHY This study is the first of its kind to systematically investigate muscle biopsies from Ehlers-Danlos patients, focusing on muscle structure and function. These patients suffer from severe muscle symptoms, but in our study they show surprisingly normal muscle findings, which points toward indirect muscle symptoms originating from the surrounding connective tissue. These findings have basal physiological importance and implications for future physiotherapeutic treatment options for these patients.
Extracellular nucleic acids in immunity and cardiovascular responses: between alert and disease
Authors: Preissner Klaus T. , Herwald Heiko 
Published: June 2017

SummarySevere inflammatory complications are a potential consequence in patients with predetermined conditions of infections, pulmonary diseases, or cardiovascular disorders. Notably, the amplitude of the inflammatory response towards these complications can dictate the disease progression and outcome. During the recent years, evidence from basic research as well as from clinical studies has identified self-extracellular nucleic acids as important players in the crosstalk between immunity and cardiovascular diseases. These stress- or injury-induced endogenous polymeric macromolecules not only serve as “alarmins” or “Danger-associated molecular patterns” (DAMPs), but their functional repertoire goes far beyond such activities in innate immunity. In fact, (patho-) physiological functions of self-extracellular DNA and RNA are associated and in many cases causally related to arterial and venous thrombosis, atherosclerosis, ischemia-reperfusion injury or tumour progression. Yet, the underlying molecular mechanisms are far from being completely understood. Interestingly enough, however, novel antagonistic approaches in vitro and in vivo, particularly using natural endonucleases or synthetic nucleic acid binding polymers, appear to be promising and safe therapeutic options for future studies. The aim of this review article is to provide an overview of the current state of (patho-) physiological functions of self-extracellular nucleic acids with special emphasis on their role as beneficial / alerting or adverse / damaging factors in connection with immune responses, inflammation, thrombosis, and cardiovascular diseases.
Angiogenesis in metabolic-vascular disease
Authors: Breier Georg , Chavakis Triantafyllos , Hirsch Emilio 
Published: June 2017

SummaryAngiogenesis, literally formation of new blood vessels, is the main process through which the vascular system expands during embryonic and postnatal development. Endothelial cells, which constitute the inner lining of all blood vessels, are typically in a quiescent state in the healthy adult organism. However, in vascular and metabolic diseases, the endothelium becomes unstable and dysfunctional. The resulting tissue hypoxia may thereby induce pathological angiogenesis, which is a hallmark of disease conditions like cancer or diabetic retinopathy. However, recent evidence suggests that angiogenesis is also a major player in the context of further metabolic diseases, especially in obesity. In particular, deregulated angiogenesis is linked with adipose tissue dysfunction and insulin resistance. On the other hand, signalling pathways, such as the PI3K pathway, may regulate metabolic activities in the endothelium. Endothelial cell metabolism emerges as an important regulator of angiogenesis. This review summarises the role of angiogenesis in metabolic-vascular disease, with specific focus on the role of angiogenesis in obesity-related metabolic dysfunction and on signaling pathways, especially PI3K, linking cell metabolism to endothelial function.
Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension
Authors: Amsallem Myriam , Sweatt Andrew J. , Aymami Marie C. , Kuznetsova Tatiana , Selej Mona , Lu HongQuan , Mercier Olaf , Fadel Elie , Schnittger Ingela , McConnell Michael V. , Rabinovitch Marlene , Zamanian Roham T. , Haddad Francois 
Published: June 2017

Background—
Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension.

Methods and Results—

From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ
2
, 62.2;
P
<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test–retest characteristics.

Conclusions—
RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.