bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance
Authors: Liang Jiaming , Mesplède Thibault , Oliveira Maureen , Anstett Kaitlin , Wainberg Mark A. 
Published: August 2015

ABSTRACTThe R263K substitution in integrase has been selected in tissue culture with dolutegravir (DTG) and has been reported for several treatment-experienced individuals receiving DTG as part of salvage therapy. The R263K substitution seems to be incompatible with the presence of common resistance mutations associated with raltegravir (RAL), a different integrase strand transfer inhibitor (INSTI). T66I is a substitution that is common in individuals who have developed resistance against a different INSTI termed elvitegravir (EVG), but it is not known whether these two mutations might be compatible in the context of resistance against DTG or what impact the combination of these substitutions might have on resistance against INSTIs. E138K is a common secondary substitution observed with various primary resistance substitutions in RAL- and EVG-treated individuals. Viral infectivity, replicative capacity, and resistance against INSTIs were measured in cell-based assays. Strand transfer and 3′ processing activities were measured biochemically. The combination of the R263K and T66I substitutions decreased HIV-1 infectivity, replicative capacity, and strand transfer activity. The addition of the E138K substitution partially compensated for these deficits and resulted in high levels of resistance against EVG but not against DTG or RAL. These findings suggest that the presence of the T66I substitution will not compromise the activity of DTG and may also help to prevent the additional generation of the R263K mutation. Our observations support the use of DTG in second-line therapy for individuals who experience treatment failure with EVG due to the T66I substitution.IMPORTANCEThe integrase strand transfer inhibitors (INSTIs) elvitegravir and dolutegravir are newly developed inhibitors against human immunodeficiency virus type 1 (HIV-1). HIV drug-resistant mutations in integrase that can arise in individuals treated with elvitegravir commonly include the T66I substitution, whereas R263K is a signature resistance substitution against dolutegravir. In order to determine how different combinations of integrase resistance mutations can influence the outcome of therapy, we report here the effects of the T66I, E138K, and R263K substitutions, alone and in combination, on viral replicative capacity and resistance to integrase inhibitors. Our results show that the addition of R263K to the T66I substitution diminishes viral replicative capacity and strand transfer activity while not compromising susceptibility to dolutegravir. This supports the use of dolutegravir in second-line therapy for patients failing elvitegravir therapy who harbor the T66I resistance substitution.
Remote Activation of Host Cell DNA Synthesis in Uninfected Cells Signaled by Infected Cells in Advance of Virus Transmission
Authors: Schmidt Nora , Hennig Thomas , Serwa Remigiusz A. , Marchetti Magda , O'Hare Peter 
Published: August 2015

ABSTRACT
Viruses modulate cellular processes and metabolism in diverse ways, but these are almost universally studied in the infected cell itself. Here, we study spatial organization of DNA synthesis during multiround transmission of herpes simplex virus (HSV) using pulse-labeling with ethynyl nucleotides and cycloaddition of azide fluorophores. We report a hitherto unknown and unexpected outcome of virus-host interaction. Consistent with the current understanding of the single-step growth cycle, HSV suppresses host DNA synthesis and promotes viral DNA synthesis in spatially segregated compartments within the cell. In striking contrast, during progressive rounds of infection initiated at a single cell, we observe that infection induces a clear and pronounced stimulation of cellular DNA replication in remote uninfected cells. This induced DNA synthesis was observed in hundreds of uninfected cells at the extended border, outside the perimeter of the progressing infection. Moreover, using pulse-chase analysis, we show that this activation is maintained, resulting in a propagating wave of host DNA synthesis continually in advance of infection. As the virus reaches and infects these activated cells, host DNA synthesis is then shut off and replaced with virus DNA synthesis. Using nonpropagating viruses or conditioned medium, we demonstrate a paracrine effector of uninfected cell DNA synthesis in remote cells continually in advance of infection. These findings have significant implications, likely with broad applicability, for our understanding of the ways in which virus infection manipulates cell processes not only in the infected cell itself but also now in remote uninfected cells, as well as of mechanisms governing host DNA synthesis.

IMPORTANCE
We show that during infection initiated by a single particle with progressive cell-cell virus transmission (i.e., the normal situation), HSV induces host DNA synthesis in uninfected cells, mediated by a virus-induced paracrine effector. The field has had no conception that this process occurs, and the work changes our interpretation of virus-host interaction during advancing infection and has implications for understanding controls of host DNA synthesis. Our findings demonstrate the utility of chemical biology techniques in analysis of infection processes, reveal distinct processes when infection is examined in multiround transmission versus single-step growth curves, and reveal a hitherto-unknown process in virus infection, likely relevant for other viruses (and other infectious agents) and for remote signaling of other processes, including transcription and protein synthesis.
Prevalence, repairs and complications of hypospadias: an Australian population-based study
Authors: Schneuer Francisco Javier , Holland Andrew J A , Pereira Gavin , Bower Carol , Nassar Natasha 
Published: August 2015

ObjectiveTo investigate hypospadias’ prevalence and trends, rate of surgical repairs and post-repair complications in an Australian population.MethodsHypospadias cases were identified from all live-born infants in New South Wales, Australia, during the period 2001–2010, using routinely collected birth and hospital data. Prevalence, trends, surgical procedures or repairs, hospital admissions and complications following surgery were evaluated. Risk factors for reoperation and complications were assessed using multivariate logistic regression.ResultsThere were 3186 boys with hypospadias in 2001–2010. Overall prevalence was 35.1 per 10 000 live births and remained constant during the study period. Proportions of anterior, middle, proximal and unspecified hypospadias were 41.3%, 26.2%, 5.8% and 26.6%, respectively. Surgical procedures were performed in 1945 boys (61%), with 1718 primary repairs. The overall post-surgery complication rate involving fistulas or strictures was 13%, but higher (33%) for proximal cases. Complications occurred after 1 year post-repair in 52.3% of cases and up to 5 years. Boys with proximal or middle hypospadias were at increased risk of reoperation or complications, but age at primary repair did not affect the outcome.ConclusionOne in 285 infants were affected with hypospadias, 60% required surgical repair or correction and one in eight experienced complications. The frequency of late complications would suggest that clinical review should be maintained for >1 year post-repair.
Timing of access to secondary healthcare services and lower extremity amputations in patients with diabetes: a case–control study
Authors: Buckley Claire M , Ali Fauzi , Roberts Graham A , Kearney Patricia M , Perry Ivan J , Bradley Colin P 
Published: August 2015

ObjectiveTo investigate the association between timing of patient access to secondary healthcare services for diabetes management and lower extremity amputation (LEA) among patients with diabetes.Research design and methodsA case–control study was conducted in the secondary healthcare system in Ireland. Cases were 116 patients with diabetes who underwent a first major non-traumatic LEA between 2006 and 2012. Controls were 348 patients with diabetes, over 45 years, admitted to the same hospital as an emergency or electively, frequency-matched for gender, type of diabetes, and year. Data were collected for 7 years prior to the event year. ORs for LEA in patients with diabetes comparing early versus late referral from primary to secondary healthcare were calculated.ResultsStatistically significant risk factors associated with LEA in patients with diabetes included being single, chronic kidney disease, hypertension, and hyperglycemia. Documented retinopathy was a significant protective factor. In unconditional logistic regression analysis adjusted for potential confounders, there was no evidence of a reduced risk of LEA among patients referred earlier to secondary healthcare for diabetes management.ConclusionsSpecialist referral may need to occur earlier than the 7-year cut-off used to demonstrate an effect on reducing LEA risk. Documented retinopathy was associated with reduced risk of LEA, most likely as a proxy for better self-care. Variation in the management of diabetes in primary care may also be impacting on outcomes. Efforts to develop more integrated care between primary and secondary services may be beneficial, rather than focusing on timing of referral to secondary healthcare.
Changes in cardiovascular health score and atherosclerosis progression in middle-aged and older persons in China: a cohort study
Authors: Gao Jingsheng , Bao Minghui , Liu Yan , Shi Jihong , Huang Zhe , Xing Aijun , Wang Yang , An Shasha , Cai Jun , Wu Shouling , Yang Xinchun 
Published: August 2015

ObjectivesThe American Heart Association (AHA) proposed a definition of 4 cardiovascular health behaviours and 3 health factors. On the basis of the 7 metrics, the cardiovascular health score (CHS) was used to estimate individual-level changes in cardiovascular health status. The aim of this study was to investigate whether changes in CHS (⊿CHS) at different time-points are associated with atherosclerosis progression in middle-aged and older persons.DesignProspective cohort study in China.SettingsWe defined 8 groups (≤−4, −3, −2, −1, 0, 1, 2 and ≥3) according to ⊿CHS. The impact of ⊿CHS on the change of brachial–ankle pulse wave velocity (⊿baPWV) and atherosclerosis progression was analysed.ParticipantsA total of 3951 individuals met the inclusion criteria (≥40 years old; no history of stroke, transient ischaemic attack or myocardial infarction) and had complete information.Results⊿baPWV decreased gradually (126.46±355.91, 78.4±343.81, 69.6±316.27, 49.59±287.57, 57.07±261.17, 40.45±264.27, 37.45±283.26 and 21.66±264.17 cm/s, respectively) with increasing ⊿CHS (p for trend<0.05). Multivariate linear regression analysis suggested a negative relationship between these 2 variables, which persisted after adjustment for other risk factors. Each increase in CHS was associated with a reduced baPWV for 15.22 cm/s (B value −15.22, p<0.001).Conclusions⊿CHS were negatively related to ⊿baPWV, which proved to be an independent predictor of the progression of atherosclerosis in middle-aged and older persons.Trial registration numberKailuan study (ChiCTR-TNC-11001489).
Environmental tobacco smoke and the risk of eczema symptoms among school children in South Africa: a cross-sectional study
Authors: Shirinde Joyce , Wichmann Janine , Voyi Kuku 
Published: August 2015

ObjectiveThe aim of this study was to investigate the association between eczema ever (EE) and current eczema symptoms (ES) in relation to exposure to environmental tobacco smoke (ETS).DesignA cross-sectional study using the International Study of Asthma and Allergies in Childhood questionnaire.Setting16 schools were randomly selected from two neighbourhoods situated in Ekurhuleni Metropolitan Municipality, Gauteng Province, South Africa.ParticipantsFrom a total population of 3764 school children aged 12–14 years, 3468 completed the questionnaire (92% response rate). A total of 3424 questionnaires were included in the final data analysis.Primary outcomeThe prevalence of EE and current ES was the primary outcome in this study.ResultsData were analysed using Multilevel Logistic Regression Analysis (MLRA). The likelihood of EE was increased by exposure to ETS at home (OR 1.30 95% CI 1.01 to 1.67) and at school (OR 1.26 95% CI 1.00 to 1.60). The likelihood of EE was lower for males (OR 0.66 95% CI 0.51 to 0.84). The likelihood of ES was increased by ETS at home (OR 1.93 95% CI 1.43 to 2.59) and school (1.44 95% CI 1.09 to 1.90). The likelihood of ES was again lower for males (OR 0.56 95% CI 0.42 to 0.76). Smoking by mother/female guardian increased the likelihood of EE and ES, however, this was not significant in the multivariate analysis.ConclusionsSymptoms of eczema were positively associated with exposure to ETS at home and school. The results support the hypothesis that ETS is an important factor in understanding the occurrence of eczema.
Laser capture microdissection as a tool to evaluate human papillomavirus genotyping and methylation as biomarkers of persistence and progression of anal lesions
Authors: Cornall Alyssa M , Roberts Jennifer M , Molano Monica , Machalek Dorothy A , Phillips Samuel , Hillman Richard J , Grulich Andrew E , Jin Fengyi , Poynten I Mary , Templeton David J , Garland Suzanne M , Tabrizi Sepehr N 
Published: August 2015

IntroductionAnal squamous cell carcinoma is preceded by persistent infection with high-risk human papillomavirus (HPV) and the cancer precursor, high-grade squamous intraepithelial lesion (HSIL). Detection of specific HPV genotypes and HPV-related biomarkers may be an option for primary anal screening. However, more data on the natural history of HPV-related anal lesions are required. The outcomes from this study will enhance our understanding of the clinical and biological behaviour of HPV-related anal lesions and inform the development of future HPV genotype and/or biomarker screening tests.Methods and analysisHIV-negative and HIV-positive men who have sex with men, aged 35 years and over, recruited from community-based settings in Sydney, Australia, attend 6 clinic visits over 3 years. At the first 5 visits, participants undergo a digital anorectal examination, an anal swab for HPV genotyping and anal cytology, and high-resolution anoscopy with directed biopsy of any visible abnormalities that are suggestive of any abnormality suspicious of SIL. Tissue sections from participants diagnosed with histologically confirmed HSIL at the baseline clinic visit will undergo laser capture microdissection, HPV detection and genotyping, and quantitation of CpG methylation in baseline and follow-up biopsies. Histological and cytological findings in combination with HPV genotyping data will be used to identify persistent HSIL. HSIL will be stratified as non-persistent and persistent based on their status at 12 months. The performance of HPV genotype and methylation status in predicting disease persistence at 12 months will be assessed, along with associations with HIV status and other covariates such as age.Ethics and disseminationThe St Vincent's Hospital Ethics Committee granted ethics approval for the study. Written informed consent is obtained from all individuals before any study-specific procedures are performed. Findings from this study will be disseminated to participants and the community through study newsletters, and through peer-reviewed publications and international conferences.
Exploring the concept of need in people with very severe chronic obstructive pulmonary disease: a qualitative study
Authors: Kendall Marilyn , Buckingham Susan , Ferguson Susie , MacNee William , Sheikh Aziz , White Patrick , Worth Allison , Boyd Kirsty , Murray Scott A , Pinnock Hilary 
Published: August 2015

BackgroundDespite apparent unmet needs, people with chronic obstructive pulmonary disease (COPD) rarely ask for help. We explored the concept of need from the perspective of patients, their family carers and professionals.MethodsWe recruited inpatients at two National Health Service (NHS) Lothian hospitals to a structured, holistic review of care needs delivered at home by a respiratory nurse 4 weeks postdischarge. Using semistructured interviews and group discussions, review notes and field-notes we explored the views of patients, carers and professionals on perceptions of need and the actions requested. Data were analysed thematically using Bradshaw's classification of need.Results14 patients, 3 carers, 28 professionals provided 36 interviews and 2 discussion groups. Few needs were identified by our intervention and few actions planned. Professionals identified ‘normative’ needs some of which had been addressed during routine discharge planning. Other needs (physical/psychological limitations, social/financial concerns, existential issues) were ‘felt’ by patients and carers but articulated in response to the researcher's questions rather than actively ‘expressed’. Patients often did not wish any action to address the problems, preferring care from family members rather than formal agencies. Many spoke of the over-arching importance of retaining a sense of independence and autonomy, considering themselves as ageing rather than ill.ConclusionsIn contrast to professionally-defined ‘normative’ needs, patients rarely perceived themselves as needy, accepting their ‘felt’ needs as the result of a disability to which they had now adapted. Sensitive approaches that foster independence may enable patients to ‘express’ needs that are amenable to help without disturbing the adaptive equilibrium they have achieved.Trial registration numberNCT01650480.
Associations between fruit and vegetable consumption and depressive symptoms: evidence from a national Canadian longitudinal survey
Authors: Kingsbury Mila , Dupuis Gabrielle , Jacka Felice , Roy-Gagnon Marie-Hélène , McMartin Seanna E , Colman Ian 
Published: August 2015

BackgroundSeveral cross-sectional studies have demonstrated associations between diet quality, including fruit and vegetable consumption, and mental health. However, research examining these associations longitudinally, while accounting for related lifestyle factors (eg, smoking, physical activity) is scarce.MethodsThis study used data from the National Population Health Survey (NPHS), a large, national longitudinal survey of Canadians. The sample included 8353 participants aged 18 and older. Every 2 years from 2002/2003 to 2010/2011, participants completed self-reports of daily fruit and vegetable consumption, physical activity, smoking and symptoms of depression and psychological distress. Using generalised estimating equations, we modelled the associations between fruit and vegetable consumption at each timepoint and depression at the next timepoint, adjusting for relevant covariates.ResultsFruit and vegetable consumption at each cycle was inversely associated with next-cycle depression (β=−0.03, 95% CI −0.05 to −0.01, p<0.01) and psychological distress (β=−0.03, 95% CI −0.05 to −0.02, p<0.0001). However, once models were adjusted for other health-related factors, these associations were attenuated (β=−0.01, 95% CI −0.04 to 0.02, p=0.55; β=−0.00, 95% CI −0.03 to 0.02, p=0.78 for models predicting depression and distress, respectively).ConclusionsThese findings suggest that relations between fruit and vegetable intake, other health-related behaviours and depression are complex. Behaviours such as smoking and physical activity may have a more important impact on depression than fruit and vegetable intake. Randomised control trials of diet are necessary to disentangle the effects of multiple health behaviours on mental health.
Views of general practitioners on providing contraceptive advice and long-acting reversible contraception at the 6-week postnatal visit: a qualitative study
Authors: Lunniss Hannah , Cameron Sharon , Chen Zhong E 
Published: August 2015

BackgroundIncreased uptake of long-acting reversible contraception (LARC) postpartum could prevent more unintended pregnancies and short inter-birth intervals. General practitioners (GPs) play a pivotal role in providing postpartum contraception at the 6-week postnatal visit.AimTo explore how GPs view their role in delivering postpartum contraception at the 6-week visit and on providing LARC at this time.MethodsIn-depth, semi-structured interviews with a purposive sample of 13 GPs in Edinburgh and the surrounding region in Scotland. The interviews were audio recorded, transcribed and thematically analysed.ResultsAll GPs confirmed that contraception was routinely discussed at the postpartum visit, although this was usually the last item covered. Most felt that while 6-weeks postpartum was adequate for most women to commence contraception, it was often too late for young mothers (aged under 20 years) or women from deprived areas. GPs provided prescriptions for oral contraception at this visit, but insertion of a contraceptive implant required a further appointment. For intrauterine contraception, women typically required two additional visits to the GP (for counselling and then insertion) or were referred to a local sexual health service. Some GPs saw their role as the main provider of postpartum contraception, whereas others felt they complemented the actions of midwives and health visitors.ConclusionsThis study demonstrated that although contraception is discussed at a routine 6-week postpartum visit with a GP, there are delays for women wishing to commence LARC that create scope for unintended pregnancy. Strategies to facilitate access to LARC postpartum should be explored.
Water window attosecond sources generation by using the multi-cycle time-delay two circularly polarized pulses
Authors: Feng Li-Qiang , Liu Hang 
Published: August 2015

In this paper, a promising scheme is proposed to generate the water window isolated attosecond pulses from the high-order harmonics by using the multi-cycle time-delay two circularly polarized pulses. The results show that with the introduction of delay time of the two pulses, not only the harmonic cutoff is extended, but also the modulation on the harmonic spectrum is suppressed. Especially for the [Formula: see text] nm, [Formula: see text] nm and the [Formula: see text] nm two cases, a 341 eV and a 502 eV supercontinua including the whole water window region are obtained. Finally, by properly superposing the harmonics in the supercontinua regions, a series of sub-34as wavelength-tunable attosecond pulses in the water window region can be obtained.