bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissection of Epitope-Specific Mechanisms of Neutralization of Influenza Virus by Intact IgG and Fab Fragments
Authors: Williams James A. , Gui Long , Hom Nancy , Mileant Alexander , Lee Kelly K.
Published: December 2017

The neutralizing antibody (nAb) response against the influenza virus hemagglutinin (HA) fusion glycoprotein is important for preventing viral infection, but we lack a comprehensive understanding of the mechanisms by which these antibodies act. Here we investigated the effect of nAb binding and the role of IgG bivalency in the inhibition of HA function for nAbs targeting distinct HA epitopes. HC19 targets the receptor binding pocket at the distal end of HA, while FI6v3 binds primarily to the HA2 fusion subunit toward the base of the stalk. Surprisingly, HC19 inhibited the ability of HA to induce lipid mixing by preventing the structural rearrangement of HA under fusion-activating conditions. These results suggest that nAbs such as HC19 not only act by blocking receptor binding but also inhibit key late-stage HA conformational changes required for fusion. Intact HC19 IgG was also shown to cross-link separate virus particles, burying large proportions of HA within aggregates where they are blocked from interacting with target membranes; Fabs yielded no such aggregation and displayed weaker neutralization than IgG, emphasizing the impact of bivalency on the ability to neutralize virus. In contrast, the stem-targeting nAb FI6v3 did not aggregate particles. The Fab fragment was significantly less effective than IgG in preventing both membrane disruption and fusion. We infer that interspike cross-linking within a given particle by FI6v3 IgG may be critical to its potent neutralization, as no significant neutralization occurred with Fabs. These results demonstrate that IgG bivalency enhances HA inhibition through functionally important modes not evident in pared-down Fab-soluble HA structures.

IMPORTANCE
The influenza virus hemagglutinin (HA) fusion glycoprotein mediates entry into target cells and is the primary antigenic target of neutralizing antibodies (nAbs). Our current structural understanding of mechanisms of antibody (Ab)-mediated neutralization largely relies on the high-resolution characterization of antigen binding (Fab) fragments in complex with soluble, isolated antigen constructs by cryo-electron microscopy (EM) single-particle reconstruction or X-ray crystallography. Interactions between full-length IgG and whole virions have not been well characterized, and a gap remains in our understanding of how intact Abs neutralize virus and prevent infection. Using structural and biophysical approaches, we observed that Ab-mediated inhibition of HA function and neutralization of virus infectivity occur by multiple coexisting mechanisms, are largely dependent on the specific epitope that is targeted, and are highly dependent on the bivalent nature of IgG molecules.
Healthcare resource availability and cardiovascular health in the USA
Authors: Pilkerton Courtney S , Singh Sarah S , Bias Thomas K , Frisbee Stephanie J
Published: December 2017

Objectives

Cardiovascular disease (CVD) remains the leading cause of death in the USA. Reducing the population-level burden of CVD disease will require a better understanding and support of cardiovascular health (CVH) in individuals and entire communities. The objectives for this study were to examine associations between community-level healthcare resources (HCrRes) and CVH in individuals and entire communities.

Setting

This study consisted of a retrospective, cross-sectional study design, using multivariable epidemiological analyses.

Participants

All participants in the 2011 Behavioral Risk Factor Surveillance System (BRFSS) survey were examined for eligibility. CVH, defined using the American Heart Association CVH Index (CVHI), was determined using self-reported responses to 2011 BRFSS questions. Data for determining HCrRes were obtained from the Area Health Resource File. Regression analysis was performed to examine associations between healthcare resources and CVHI in communities (linear regression) and individuals (Poisson regression).

Results

Mean CVHI was 3.3±0.005 and was poorer in the Southeast and Appalachian regions of the USA. Supply of primary care physicians and physician assistants were positively associated with individual and community-level CVHI, while CVD specialist supply was negatively associated with CVHI. Individuals benefiting most from increased supply of primary care providers were: middle aged; female; had non-Hispanic other race/ethnicity; those with household income <$25 000/year; and those in non-urban communities with insurance coverage.

Conclusions

Our results support the importance of primary care provider supply for both individual and community CVHI, though not all sociodemographic groups benefited equally from additional primary care providers. Further research should investigate policies and factors that can effectively increase primary care provider supply and influence where they practice.
Study protocol forSmartphoneMonitoring forAtrial fibrillation inReal-Time in India (SMART-India): a community-based screening and referral programme
Authors: Soni Apurv , Karna Sunil , Patel Harshil , Fahey Nisha , Raithatha Shyamsundar , Handorf Anna , Bostrom John , Bashar Syed , Talati Kandarp , Shah Ravi , Goldberg Robert J , Thanvi Sunil , Phatak Ajay Gajanan , Allison Jeroan J , Chon Ki , Nimbalkar Somashekhar Marutirao , McManus David D
Published: December 2017

Introduction

Atrial fibrillation (AF), the world’s most common arrhythmia, often goes undetected and untreated in low-resource communities, including India, where AF epidemiology is undefined. AF is an important risk factor for stroke, which plagues an estimated 1.6 million Indians annually. As such, early detection of AF and management of high-risk patients is critically important to decrease stroke burden in individuals with AF. This study aims to describe the epidemiology of AF in Anand District, Gujarat, India, characterise the clinical profile of individuals who are diagnosed with AF and determine the performance of two mobile technologies for community-based AF screening.

Methods

This observational study builds on findings from a previous feasibility study and leverages two novel technologies as well as an existing community health programme to perform door-to-door AF screening for 2000 people from 60 villages of Anand District, Gujarat, India using local health workers. A single-lead ECG and a pulse-based application is used to screen each individual for AF three times over a period of 5 days. Participants with suspected arrhythmias are followed up by study cardiologist who makes final diagnoses. Participants diagnosed with AF are initiated on treatment based on current anticoagulation guidelines and clinical reasoning.

Analytical plan

Age-stratified and sex-stratified prevalence of AF in the Anand District will be calculated for sample and estimated for Anand distribution using survey design weights. Sociodemographic and clinical factors associated with AF will be evaluated using multivariable regression methods. Performance of each mobile technology in detecting AF will be evaluated using a 12-lead ECG interpretation as the gold standard.

Ethics and dissemination

This protocol was approved separately by the Institutional Review Board of University of Massachusetts Medical School and the Human Research Ethics Committee at Charutar Arogya Mandal. The findings of this study will be disseminated through peer-reviewed journals and scientific conferences.
Oral medicine modification for older adults: a qualitative study of nurses
Authors: Mc Gillicuddy Aoife , Crean Abina M , Kelly Maria , Sahm Laura
Published: December 2017

Objective

Oral medicines are frequently modified (eg, tablets crushed) for older adults. However, these modifications can have clinical, legal and/or ethical implications. Nurses bear responsibility for medicine administration and hence, perform these modifications. The aim of this study was to investigate the knowledge, attitudes and beliefs of nurses about oral medicine modification for older adults.

Design

A qualitative study was conducted using semi-structured, face-to-face interviews with nurses providing care to older adults in acute and long-term care settings. Interviews were audio-recorded, transcribed verbatim and analysed thematically.

Settings

Sixteen purposively selected care settings; 4 acute-care and 12 long-term care settings were included. Nurses were recruited by convenience sampling at these sites.

Participants

Eighteen nurses participated (83% female, 67% long-term care, 33% acute-care, median age (IQR) 38 years (32.5–52.0)).

Results

Three major themes: modifying—a necessary evil, nurses’ role as patient advocate and modifying—we are working very much as a teamand two minor themes: fractional dosing, and covert administration emerged from the data. Nurses viewed oral medicine modifications as being a routine and necessary occurrence in geriatric patient care due to limitations of available formulations and the presence of age-related challenges in drug administration. Nurses’ knowledge of residents’ requirements ensured that they advocate for those with individualised formulation needs, however, nurses rely on pharmacists for information about modifications. Nurses expressed a desire for supports including increased education and ward-specific, pharmacist-developed recommendations on common modifications.

Conclusions

This study has provided useful insights into the views of nurses regarding oral medicine modification for older adults. The unique and varied formulation requirements of older adults must be acknowledged. Increased engagement by healthcare professionals, the pharmaceutical industry, regulatory agencies and policy-makers is required to facilitate the development of age-appropriate formulations. In the interim, practical interventions, informed by the findings of this study, are required.
Dialogues between nurses, patients with heart failure and their partners during a dyadic psychoeducational intervention: a qualitative study
Authors: Liljeroos Maria , Ågren Susanna , Jaarsma Tiny , Stromberg Anna
Published: December 2017

Objectives

To describe nurses’ documentation of the content in a psychoeducational intervention inspired by Stuifbergen’s model addressing cognitive, supportive and behavioural needs of patient–partner dyads affected by heart failure.

Design

A descriptive qualitative design was used analysing nurses’ documentation in a dialogue guide based on a health promotion model.

Settings

The dialogue guide was used during three nurse-led sessions at two heart failure clinics in Sweden with patients affected with heart failure and their partners during the years 2005–2008.

Participants

The dialogue guides from 71 patient–partner dyads were analysed using direct deductive content analyses. Patients’ mean age was 69 years and 31% were female, partners’ mean age was 67 years and 69% were female.

Results

The findings supported the conceptual health promotion model and identified barriers, recourses and self-efficacy described by the dyads within each category.

Conclusion

The dyads described that during the sessions, they had gained enhanced knowledge and greater confidence to handle their life situation and expressed that they needed psychoeducational support during the whole illness trajectory. The results may guide and help to improve content and quality when caring for patients affected with heart failure and their partners and also when designing new interventions.

Trial registration number

NCT02398799; Post-results.
Mapping Evidence of Patients’ Experiences in Integrated Care Settings: A Protocol for a Scoping Review
Authors: Youssef Alaa T , Constantino Rosa , Chaudhary Zarah K , Lee Andrew , Wiljer David , Mylopoulos Maria , Sockalingam Sanjeev
Published: December 2017

Introduction

Integrated care (IC) models have emerged to address gaps in care for individuals with complex healthcare needs. Although the clinical and cost-effectiveness of IC models are well-established, our understanding of whether IC models facilitate a patient-centred care experience from the patients’ perspective is not well understood. This scoping review aims to comprehensively map the literature to provide a broad overview of patients’ experiences in IC settings with a focus on the experiences of complex patients with comorbid mental and physical illnesses. It also aims to describe current gaps identified in the literature in our understanding of aspects of care that are often unrecognised.

Methods and analysis

Using established scoping review frameworks and guidelines, we will perform a comprehensive search in the following databases: MEDLINE, EMBASE, PsycINFO, CINAHL, AMED and the Cochrane Library to identify relevant studies on patients’ experiences in IC models. Grey literature sources and studies bibliographies will also be searched to identify relevant studies and documents. Data will be extracted and summarised using descriptive statistical and qualitative analyses. We will also consult with stakeholders from various backgrounds to enhance the comprehensiveness of this review.

Ethics and dissemination

This review requires no ethical approval. Findings from this study will be disseminated through publication in a peer-reviewed journal, clinical conferences and in knowledge translation settings, aiming to improve clinical practice and care delivery.
Therapist-guided internet-delivered cognitive–behavioural therapy supplemented with group exposure sessions for adolescents with social anxiety disorder: a feasibility trial
Authors: Nordh Martina , Vigerland Sarah , Öst Lars-Göran , Ljótsson Brjánn , Mataix-Cols David , Serlachius Eva , Högström Jens
Published: December 2017

Objectives

Social anxiety disorder (SAD) is one of the most common psychiatric disorders in youth, with a prevalence of about 3%–4% and increased risk of adverse long-term outcomes, such as depression. Cognitive–behavioural therapy (CBT) is considered the first-line treatment for youth with SAD, but many adolescents remain untreated due to limited accessibility to CBT. The aim of this study was to develop and evaluate the feasibility and preliminary efficacy of a therapist-guided internet-delivered CBT treatment, supplemented with clinic-based group exposure sessions (BIP SOFT).

Design

A proof-of-concept, open clinical trial with 6-month follow-up.

Participants

The trial was conducted at a child and adolescent psychiatric research clinic, and participants (n=30) were 13–17 years old (83% girls) with a principal diagnosis of SAD.

Intervention

12 weeks of intervention, consisting of nine remote therapist-guided internet-delivered CBT sessions and three group exposure sessions at the clinic for the adolescents and five internet-delivered sessions for the parents.

Results

Adolescents were generally satisfied with the treatment, and the completion rate of internet modules, as well as attendance at group sessions, was high. Post-treatment assessment showed a significant decrease in clinician-rated, adolescent-rated and parent-rated social anxiety (d=1.17, 0.85 and 0.79, respectively), as well as in general self-rated and parent-rated anxiety and depression (d=0.76 and 0.51), compared with pretreatment levels. Furthermore, 47% of participants no longer met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for SAD at post-treatment. At a 6-month follow-up, symptom reductions were maintained, or further improved, and 57% of participants no longer met criteria for SAD.

Conclusion

Therapist-guided and parent-guided internet-delivered CBT, supplemented with a limited number of group exposure sessions, is a feasible and promising intervention for adolescents with SAD.

Trial registration number

NCT02576171; Results.
Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial
Authors: Shinohara Kiyomi , Aoki Takuya , So Ryuhei , Tsujimoto Yasushi , Suganuma Aya M , Kise Morito , Furukawa Toshi A
Published: December 2017

Objectives

To investigate whether overstatements in abstract conclusions influence primary care physicians’ evaluations when they read reports of randomised controlled trials (RCTs)

Design

RCT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis.

Participants

Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into ‘without overstatement’ (n=307) and ‘with overstatement’ (n=315) groups.

Interventions

We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention.

Outcome measures

The primary outcome was the participants’ evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion.

Results

There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI −0.28 to 0.42, p=0.69). Participants in the ‘without’ group considered the study conclusion to be more valid than those in the ‘with’ group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001).

Conclusion

The overstatements in abstract conclusions did not significantly influence the primary care physicians’ evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported.

Trial registration number

UMIN000025317; Pre-results.
Comparing four service delivery models for adolescent girls and young women through the ‘Girl Power’ study: protocol for a multisite quasi-experimental cohort study
Authors: Rosenberg Nora E , Pettifor Audrey E , Myers Laura , Phanga Twambilile , Marcus Rebecca , Bhushan Nivedita Latha , Madlingozi Nomtha , Vansia Dhrutika , Masters Avril , Maseko Bertha , Mtwisha Lulu , Kachigamba Annie , Tang Jennifer , Hosseinipour Mina C , Bekker Linda-Gail
Published: December 2017

Introduction

In sub-Saharan Africa, adolescent girls and young women (AGYW) face a range of sexual and reproductive health (SRH) challenges. Clinical, behavioural and structural interventions have each reduced these risks and improved health outcomes. However, combinations of these interventions have not been compared with each other or with no intervention at all. The ‘Girl Power’ study is designed to systematically make these comparisons.

Methods and analysis

Four comparable health facilities in Malawi and South Africa (n=8) were selected and assigned to one of the following models of care: (1)Standard of care: AGYW can receive family planning, HIV testing and counselling (HTC), and sexually transmitted infection (STI) syndromic management in three separate locations with three separate queues with the general population. No youth-friendly spaces, clinical modifications or trainings are offered, (2)Youth-Friendly Health Services (YFHS): AGYW are meant to receive integrated family planning, HTC and STI services in dedicated youth spaces with youth-friendly modifications and providers trained in YFHS, (3)YFHS+behavioural intervention (BI): In addition to YFHS, AGYW can attend 12 monthly theory-driven, facilitator-led, interactive sessions on health, finance and relationships, (4)YFHS+BI+conditional cash transfer (CCT): in addition to YFHS and BI, AGYW receive up to 12 CCTs conditional on monthly BI session attendance.

At each clinic, 250 AGYW 15–24 years old (n=2000 total) will be consented, enrolled and followed for 1 year. Each participant will complete a behavioural survey at enrolment, 6 months and 12 months . All clinical, behavioural and CCT services will be captured. Outcomes of interest include uptake of each package element and reduction in HIV risk behaviours. A qualitative substudy will be conducted.

Ethics/dissemination

This study has received ethical approval from the University of North Carolina Institutional Review Board, the University of Cape Town Human Research Ethics Committee and Malawi’s National Health Sciences Research Committee. Study plans, processes and findings will be disseminated to stakeholders, in peer-reviewed journals and at conferences.
ASPiH standards for simulation-based education: process of consultation, design and implementation
Authors: Purva Makani , Nicklin Jane
Published: December 2017

There is widespread enthusiasm and emerging evidence of the efficacy of simulation-based education (SBE) but the full potential of SBE has not been explored. The Association for Simulated Practice in Healthcare (ASPiH) is a not-for-profit membership association with members from healthcare, education and patient safety background. ASPiH’s National Simulation Development Project in 2012 identified the lack of standardisation in the approach to SBE with failure to adopt best practice in design and delivery of SBE programmes. ASPiH created a standards project team in 2015 to address this need. The article describes the iterative process modelled on implementation science framework, spread over six stages and 2 years that resulted in the creation of the standards. The consultation process supported by Health Education England resulted in a unique document that was driven by front line providers while also having strong foundations in evidence base. The final ASPiH document consisting of 21 standards for SBE has been extensively mapped to regulatory and professional bodies in the UK and abroad ensuring that the document is relevant to a wide healthcare audience. Underpinning the standards is a detailed guidance document that summarises the key literature evidence to support the standard statements. It is envisaged the standards will be widely used by the simulation community for quality assurance and improving the standard of SBE delivered.
Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II)
Authors: Danese Silvio , Vermeire Séverine , Hellstern Paul , Panaccione Remo , Rogler Gerhard , Fraser Gerald , Kohn Anna , Desreumaux Pierre , Leong Rupert W , Comer Gail M , Cataldi Fabio , Banerjee Anindita , Maguire Mary K , Li Cheryl , Rath Natalie , Beebe Jean , Schreiber Stefan
Published: December 2017

Objective

Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.

Design

Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.

Results

247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.

Conclusions

PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.

Trial registration number

NCT01287897 and NCT01345318.
Viruses causing lower respiratory symptoms in young children: findings from the ORChID birth cohort
Authors: Sarna Mohinder , Lambert Stephen B , Sloots Theo P , Whiley David M , Alsaleh Asma , Mhango Lebogang , Bialasiewicz Seweryn , Wang David , Nissen Michael D , Grimwood Keith , Ware Robert S
Published: December 2017

Introduction

Viral acute respiratory infections (ARIs) cause substantial child morbidity. Sensitive molecular-based assays aid virus detection, but the clinical significance of positive tests remains uncertain as some viruses may be found in both acutely ill and healthy children. We describe disease-pathogen associations of respiratory viruses and quantify virus-specific attributable risk of ARIs in healthy children during the first 2 years of life.

Methods

One hundred fifty-eight term newborn babies in Brisbane, Australia, were recruited progressively into a longitudinal, community-based, birth cohort study conducted between September 2010 and October 2014. A daily tick-box diary captured predefined respiratory symptoms from birth until their second birthday. Weekly parent-collected nasal swabs were batch-tested for 17 respiratory viruses by PCR assays, allowing calculation of virus-specific attributable fractions in the exposed (AFE) to determine the proportion of virus-positive children whose ARI symptoms could be attributed to that particular virus.

Results

Of 8100 nasal swabs analysed, 2646 (32.7%) were virus-positive (275 virus codetections, 3.4%), with human rhinoviruses accounting for 2058/2646 (77.8%) positive swabs. Viruses were detected in 1154/1530 (75.4%) ARI episodes and in 984/4308 (22.8%) swabs from asymptomatic periods. Respiratory syncytial virus (AFE: 68% (95% CI 45% to 82%)) and human metapneumovirus (AFE: 69% (95% CI 43% to 83%)) were strongly associated with higher risk of lower respiratory symptoms.

Discussion

The strong association of respiratory syncytial virus and human metapneumovirus with ARIs and lower respiratory symptoms in young children managed within the community indicates successful development of vaccines against these two viruses should provide substantial health benefits.
Effects of carbohydrate and branched-chain amino acid beverage ingestion during acute upper body resistance exercise on performance and postexercise hormone response
Authors: Smith JohnEric W. , Krings Ben M. , Shepherd Brandon D. , Waldman Hunter S. , Basham Steven A. , McAllister Matthew J.
Published: December 2017

The purpose of this investigation was to examine the individual and combined effects of ingesting carbohydrates (CHO) and branched-chain amino acids (BCAA) during high-volume upper body resistance exercise (RE) on markers of catabolism and performance. Thirteen resistance-trained males completed 4 experimental trials with supplementation, ingesting beverages containing CHO, BCAA, CHO+BCAA, or placebo (PLA) in a randomized, double-blind design. The beverages were ingested in 118-mL servings 6 times during an ∼60-min RE session consisting of bench press, bent-over row, incline press, and close-grip row. Each RE was performed with 5 sets of repetitions at 65% 1-repetition maximum until volitional fatigue. Blood samples were collected at baseline, immediately postexercise, and 60 min postexercise to assess glucose and insulin. Cortisol was assessed immediately and at 60 min postexercise. No significant performance benefits were observed for any RE. CHO+BCAA (152.4 ± 71.4 ng/mL) resulted in the lowest cortisol levels, which was lower than BCAA and PLA (193.7 ± 88.5, 182.8 ± 67.5 ng/mL, p < 0.05), but not different from CHO (165 ± 76.5 ng/mL, p = 0.342). Postexercise insulin concentrations were significantly higher with CHO (4.79 ± 3.4 mU/L) compared with BCAA and PLA (3.7 ± 2.0, 3.5 ± 1.8 mU/L, p < 0.05), but not different from CHO+BCAA (4.3 ± 2.5 mU/L, p = 0.339). There was no treatment effect for glucose, but glucose significantly increased from baseline to immediately postexercise and significantly decreased at 60 min postexercise. Ingesting beverages containing CHO with or without BCAA during upper body resistance exercise may promote a more favorable postexercise less catabolic environment.
Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves
Authors: Siddique Ateeque , Yu Bin , Khan Kashif , Buyting Ryan , Al-Kindi Hamood , Alaws Hossny , Rhéaume Eric , Tardif Jean-Claude , Cecere Renzo , Schwertani Adel
Published: December 2017

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.
A Logical Characterization of Small 2NFAs
Authors: Kapoutsis Christos A. , Mulaffer Lamana
Published: December 2017

Let 2N be the class of families of problems solvable by families of two-way nondeterministic finite automata of polynomial size. We characterize 2N in terms of families of formulas of transitive-closure logic. These formulas apply the transitive-closure operator on a quantifier-free disjunctive normal form of first-order logic with successor and constants, where (i) apart from two special variables, all others are equated to constants in every clause, and (ii) no clause simultaneously relates these two special variables and refers to fixed input cells. We prove that automata with polynomially many states are as powerful as formulas with polynomially many clauses and polynomially large constants. This can be seen as a refinement of Immerman’s theorem that nondeterministic logarithmic space matches positive transitive-closure logic ([Formula: see text]).
Regular Approximation of Weighted Linear Context-Free Tree Languages
Authors: Teichmann Markus
Published: December 2017

We show how to train a weighted regular tree grammar such that it best approximates a weighted linear context-free tree grammar concerning the Kullback–Leibler divergence between both grammars. Furthermore, we construct a regular tree grammar that approximates the tree language induced by a context-free tree grammar.
Cube-Connected Circulants as Efficient Models for Interconnection Networks
Authors: MOKHTAR HAMID
Published: December 2017

We introduce cube-connected circulants as efficient models for communication networks. We give an algorithm for computing a shortest path between any pair of vertices in a cube-connected circulant. We give formulas for the diameter of a cube-connected circulant and the distance between any pair of vertices in such a graph. Then we give an embedding of cube-connected circulants into hypercubes, and an embedding of hypercubes into cube-connected circulants. We show cube-connected circulants outperform a few well-known network structures in several invariants.
Revisiting Constructions of Large Cayley Graphs of Given Degree and Diameter from Regular Orbits
Authors: BACHRATÝ MARTIN , ŠIAGIOVÁ JANA , ŠIRÁŇ JOZEF
Published: December 2017

The largest order [Formula: see text] of a Cayley graph of degree [Formula: see text] and diameter [Formula: see text] cannot exceed the Moore bound [Formula: see text] the asymptotic form of which is [Formula: see text] for [Formula: see text] and a fixed k. The second and the third author and the three authors proved by direct constructions that the Moore bound for diameter [Formula: see text] and [Formula: see text], respectively, can be approached asymptotically by Cayley graphs in the sense that [Formula: see text] for some sequences of degrees [Formula: see text]. In this note we present a unifying principle underlying the two results, based on the existence of certain regular orbits of automorphism groups of suitable graphs.
Numerical Simulation of the Grains Growth on Titanium Alloy Electron Beam Welding Process
Authors: Liu Xiaogang , Guo Haiding , Yu M. M.
Published: December 2017

In the paper, the grain growth of TC4-DT (Damage Tolerance) alloy joint during electron beam welding (EBW) process was simulated by using Cellular Automaton method. In order to consider the effects of the growth of neighborhood cellular on the center cells in the model, the solid fraction and solute distribution algorithms of classical CA model were improved. The growth of equiaxed grains and columnar crystals under uniform and nonuniform temperature fields was simulated successfully by applying the modified model, respectively. The temperature distribution near the fusion line of TC4-DT EBW joint was also calculated by using double ellipsoid heat source model. Then, coupling the CA model with the temperature field, the grain growth process of the cross-section of the welded zone was simulated. The simulation result fits well with experimental ones on the morphology and the size of the columnar crystals.
Numerical groundwater modelling in karst
Authors: Kresic Neven , Panday Sorab
Published: December 2017

The success of translating a conceptual site model for a karst site into a numerical groundwater model will depend on both the experience of the user and the capabilities and limitations of the selected computer program. Despite its numerous advantages, even MODFLOW – probably the most widely used, tested and verified modelling program currently available – has conceptual limitations that many karst hydrogeologists have to deal with on a routine basis while searching for an equivalent porous medium approach that may work. This includes assigning very high values of hydraulic conductivity to those model cells known, or suspected, to contain highly transmissive conduits, or assigning an unreasonable, very low effective porosity to the model cells with virtual ‘conduits’ to simulate high groundwater velocities. A new version of MODFLOW called MODFLOW-USG (UnStructured Grid) has been developed and released to the public domain. This new version retains full compatibility with previous versions of MODFLOW while taking advantage of unstructured grids and finite volume numerical solutions. It enables hydrogeologists to accurately translate even the most complex conceptual site models in karst into a numerical environment, thus eliminating the need for various surrogate modelling solutions based on an equivalent porous medium approach.
Carbon and hydrogen isotopic compositions of
n
-alkanes as a tool in petroleum exploration
Authors: Pedentchouk Nikolai , Turich Courtney
Published: December 2017

Compound-specific isotope analysis (CSIA) of individual organic compounds is a powerful but underutilized tool in petroleum exploration. When integrated with other organic geochemical methodologies it can provide evidence of fluid histories including source, maturity, charge history and reservoir processes that can support field development planning and exploration efforts. The purpose of this chapter is to provide a review of the methodologies used for generating carbon and hydrogen isotope data for mid- and high-molecular-weight
n
-alkanes.

We discuss the factors that control stable carbon and hydrogen isotope compositions of
n
-alkanes and related compounds in sedimentary and petroleum systems and review current and future applications of this methodology for petroleum exploration. We discuss basin-specific case studies that demonstrate the usefulness of CSIA either when addressing particular aspects of petroleum exploration (e.g. charge evaluation, source rock–oil correlation, and investigation of maturity and in-reservoir processes) or when this technique is used to corroborate interpretations from integrated petroleum systems analysis, providing unique insights which may not be revealed when using other methods. CSIA of
n
-alkanes and related
n
-alkyl structures can provide independent data to strengthen petroleum systems concepts from generation and expulsion of fluids from source rock, to charge history, connectivity, and in-reservoir processes.
The isotopic structures of geological organic compounds
Authors: Eiler John M. , Clog Matthieu , Lawson Michael , Lloyd Max , Piasecki Alison , Ponton Camilo , Xie Hao
Published: December 2017

Organic compounds are ubiquitous in the Earth's surface, sediments and many rocks, and preserve records of geological, geochemical and biological history; they are also critical natural resources and major environmental pollutants. The naturally occurring stable isotopes of volatile elements (D,
13
C,
15
N,
17,18
O,
33,34,36
S) provide one way of studying the origin, evolution and migration of geological organic compounds. The study of bulk stable isotope compositions (i.e. averaged across all possible molecular isotopic forms) is well established and widely practised, but frequently results in non-unique interpretations. Increasingly, researchers are reading the organic isotopic record with greater depth and specificity by characterizing stable isotope ‘structures’ – the proportions of site-specific and multiply substituted isotopologues that contribute to the total rare-isotope inventory of each compound. Most of the technologies for measuring stable isotope structures of organic molecules have been only recently developed and to date have been applied only in an exploratory way. Nevertheless, recent advances have demonstrated that molecular isotopic structures provide distinctive records of biosynthetic origins, conditions and mechanisms of chemical transformation during burial, and forensic fingerprints of exceptional specificity. This paper provides a review of this young field, which is organized to follow the evolution of molecular isotopic structure from biosynthesis, through diagenesis, catagenesis and metamorphism.
Testing clumped isotopes as a reservoir characterization tool: a comparison with fluid inclusions in a dolomitized sedimentary carbonate reservoir buried to 2–4 km
Authors: MacDonald John M. , John Cédric M. , Girard Jean-Pierre
Published: December 2017

Constraining basin thermal history is a key part of reservoir characterization in carbonate rocks. Conventional palaeothermometric approaches cannot always be used: fluid inclusions may be reset or not present, while δ
18
O palaeothermometry requires an assumption on the parent fluid composition. The clumped isotope palaeothermometer, however, is a promising technique for constraining the thermal history of basins. In this study, we test if clumped isotopes record temperatures of recrystallization in deeply-buried dolomitic reservoirs, through comparison with fluid-inclusion data. The studied reservoir is the Cretaceous Pinda Formation, offshore Angola, a deeply-buried dolomitized sedimentary carbonate hydrocarbon reservoir. It provides an ideal test case as samples from industry wells are available over a relatively wide burial depth range of
c.
2000–4000 m below seafloor (mbsf) and the constituent dolomites are relatively homogeneous.

Across this depth range, fluid-inclusion homogenization temperatures for the Pinda Formation record a range of temperatures from
c.
110 to 170°C, increasing with depth. These closely match present-day ambient well temperatures, indicating recent resetting of the fluid inclusions. Clumped isotopes, however, record temperatures significantly (
c.
20–60°C) below fluid-inclusion and well temperatures for the seven samples analysed. The deepest five samples (
c.
2800–3700 mbsf) record clumped isotope temperatures of around 100–120°C, interpreted to represent a deep burial recrystallization event responsible for a massive (re)dolomitization of the reservoir. The lower clumped isotope temperatures (65 and 82°C) of the shallower (2055 and 2740 mbsf) samples are interpreted to represent physical mixing of two dolomite generations due to incomplete burial recrystallization of an early shallow dolomite. Determination of temperature through clumped isotopes allows calculation of the parent fluid δ
18
O values. In the five deepest samples, the fluid δ
18
O values of 3.7–6.5‰ cluster around the modern-day porewater composition (5‰), suggesting that burial dolomitization occurred in the presence of evolved brine. Mineral δ
18
O values of
c
. −7 to −4.5‰ are lower than pristine Cretaceous marine dolomite and are in accordance with burial recrystallization. Clumped isotopes are therefore interpreted to record temperatures corresponding to open-system burial recrystallization events. This study shows that clumped isotopes are a valuable tool in characterizing the thermal history of deeply-buried (>2000 m) carbonate hydrocarbon reservoirs.
Nested Weighted Automata
Authors: Chatterjee Krishnendu , Henzinger Thomas A. , Otop Jan
Published: December 2017

Recently there has been a significant effort to handle quantitative properties in formal verification and synthesis. While weighted automata over finite and infinite words provide a natural and flexible framework to express quantitative properties, perhaps surprisingly, some basic system properties such as average response time cannot be expressed using weighted automata or in any other known decidable formalism. In this work, we introduce nested weighted automata as a natural extension of weighted automata, which makes it possible to express important quantitative properties such as average response time. In nested weighted automata, a master automaton spins off and collects results from weighted slave automata, each of which computes a quantity along a finite portion of an infinite word. Nested weighted automata can be viewed as the quantitative analogue of monitor automata, which are used in runtime verification. We establish an almost-complete decidability picture for the basic decision problems about nested weighted automata and illustrate their applicability in several domains. In particular, nested weighted automata can be used to decide average response time properties.
Metric 1-Median Selection
Authors: Chang Ching-Lueh
Published: December 2017

Consider the problem of finding a point in a metric space ({ 1,2,…,
n
},
d
) with the minimum average distance to other points. We show that this problem has no deterministic
o
(
n

1+1/(
h
-1)

/
h
)-query 2
h
· (1-ϵ))-approximation algorithms for any constant ϵ >0 and any
h
=
h
(
n
)∈ Z
+
\ {1} satisfying
h
=
o
(
n

1/(
h
-1)

). Combining our result with existing ones, we determine the best approximation ratio achievable by deterministic
O
(
n
1+ϵ
)-query (respectively,
O
(
n
1+ϵ
)-time) algorithms to be 2⌈ 1/ϵ ⌉, for
all
constants ϵ ∈ (0,1).
Parameterized Property Testing of Functions
Authors: Pallavoor Ramesh Krishnan S. , Raskhodnikova Sofya , Varma Nithin
Published: December 2017

We investigate the parameters in terms of which the complexity of sublinear-time algorithms should be expressed. Our goal is to find input parameters that are tailored to the combinatorics of the specific problem being studied and design algorithms that run faster when these parameters are small. This direction enables us to surpass the (worst-case) lower bounds, expressed in terms of the input size, for several problems. Our aim is to develop a similar level of understanding of the complexity of sublinear-time algorithms to the one that was enabled by research in parameterized complexity for classical algorithms.

Specifically, we focus on testing properties of functions. By parameterizing the query complexity in terms of the size
r
of the image of the input function, we obtain testers for monotonicity and convexity of functions of the form
f
:[
n
]→ R with query complexity
O
(log
r
), with no dependence on
n
. The result for monotonicity circumvents the Ω (log
n
) lower bound by Fischer (Inf. Comput. 2004) for this problem. We present several other parameterized testers, providing compelling evidence that expressing the query complexity of property testers in terms of the input size is not always the best choice.
Replicated Computational Results (RCR) Report for “ProPPA: Probabilistic Programming for Stochastic Dynamical Systems”
Authors: Parker David
Published: December 2017

“ProPPA: Probabilistic Programming for Stochastic Dynamical Systems,” by Georgoulas, Hillston, and Sanguinetti, introduces the ProPPA formalism, which brings together ideas from stochastic process algebras with those from the paradigm of probabilistic programming. The article formally defines the ProPPA language and its semantics and presents a tool-set, along with results from illustrative examples. This replicated computational results report installs and runs the tool-set and repeats the simulation-based results from the article, finding that the published results are repeatable.
Guest Column
Authors: Baumeister D.
Published: December 2017

Abstract argumentation frameworks introduced by Dung [Dun95] are a formal way of representing discussions de ned through arguments and a binary attack relation between them. In dynamic settings there is a need to allow for uncertainty in such argumentation frameworks, hence attack-incomplete and argument-incomplete argumentation frameworks are considered as well. Different semantics are de ned in order to identify a set of acceptable arguments, and the verification problem asks whether some given set is an extension for a given semantics. This survey gives an overview of the complexity of the verification problem for different semantics in complete and incomplete argumentation frameworks.
Computational Geometry Column 66
Authors: Elbassioni Khaled , Dumitrescu Adrian
Published: December 2017

The list update problem is a well studied online problem in the area of self-adjusting data structures. Understanding the o?ine version of this problem is crucial because of the role it plays in the competitive analysis of online list update algorithms. In this paper we settle a long-standing open problem by showing that the o?ine list update problem is NP-hard.
Discovery of IDO1 Inhibitors: From Bench to Bedside
Authors: Prendergast George C. , Malachowski William P. , DuHadaway James B. , Muller Alexander J.
Published: December 2017

Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic. Cancer Res; 77(24); 6795–811. ©2017 AACR.