bluuebunny/crossref_metadata_2025_split huggingface dataset:
QbD-Based UPLC Method for Quantification of Brexpiprazole in Presence of Impurities and Application to In Vitro Dissolution
Authors: Nadella Prasad Nukendra , Nadh Ratnakaram Venkata , Navuluri Srinivasu 
Published: October 2020

Abstract
Quality-by-design-based UPLC method was developed for chromatographic separation to quantify the antischizophrenic drug brexpiprazole in the presence of impurities. Research findings from pH-scouting studies were used as control variables which influence the chromatographic separation. The peak tailing and resolution are the response variables and established the design-space by DoE-study for selection of suitable chromatographic conditions. Separation was achieved with lower particle size stationary phase and buffer pH 2.0 in the mobile phase. The present method developed through C18 50 × 2.1 mm, Ethylene-Bridged-Hybrid technology column with 1.7 μm particles, mobile phase consists of pH 2.0 buffer and acetonitrile (67:33 v/v), flow rate of 0.5 mL min−1 and detection wavelength at 215 nm. The retention time of brexpiprazole is 0.6 min and all impurities were eluted within 2 min. The method linearity ranges were 20.4–61.3 μg mL−1 for assay and 0.88–6.59 μg mL−1 for dissolution with correlation-coefficients of 0.9999 and 0.9998 for assay and dissolution, respectively. The recovery values were found in between 99.3 and 100.9%. The method shows stability-indicating on the basis of noninterference of placebo, and impurities from forced-degradation studies. Method validation was carried out according to ICH guideline Q2 (R1).
Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes
Authors: Voskuil M D , Spekhorst L M , van der Sloot K W J , Jansen B H , Dijkstra G , van der Woude C J , Hoentjen F , Pierik M J , van der Meulen A E , de Boer N K H , Löwenberg M , Oldenburg B , Festen E A M , Weersma R K 
Published: October 2020

Abstract

Background and Aims
Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes.

Methods
Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS–phenotype (false-discovery rate [FDR] corrected p &lt;0.05) associations identified in cohort A were put forward for replication in cohort B.

Results
Crohn’s disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04].

Conclusions
Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
Arrhythmogenic potential of myocardial disarray in hypertrophic cardiomyopathy: genetic basis, functional consequences and relation to sudden cardiac death
Authors: Finocchiaro Gherardo , Sheikh Nabeel , Leone Ornella , Westaby Joe , Mazzarotto Francesco , Pantazis Antonis , Ferrantini Cecilia , Sacconi Leonardo , Papadakis Michael , Sharma Sanjay , Sheppard Mary N , Olivotto Iacopo 
Published: October 2020

Abstract
Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. Since the first pathological descriptions of hypertrophic cardiomyopathy (HCM), disarray appeared as a typical feature of this condition and sparked vivid debate regarding its specificity to the disease and clinical significance as a diagnostic marker and a risk factor for sudden death. Although much of the controversy surrounding its diagnostic value in HCM persists, it is increasingly recognized that myocardial disarray may be found in physiological contexts and in cardiac conditions different from HCM, raising the possibility that central focus should be placed on its quantity and distribution, rather than a mere presence. While further studies are needed to establish what amount of disarray should be considered as a hallmark of the disease, novel experimental approaches and emerging imaging techniques for the first time allow ex vivo and in vivo characterization of the myocardium to a molecular level. Such advances hold the promise of filling major gaps in our understanding of the functional consequences of myocardial disarray in HCM and specifically on arrhythmogenic propensity and as a risk factor for sudden death. Ultimately, these studies will clarify whether disarray represents a major determinant of the HCM clinical profile, and a potential therapeutic target, as opposed to an intriguing but largely innocent bystander.
A Path toward SARS-CoV-2 Attenuation: Metabolic Pressure on CTP Synthesis Rules the Virus Evolution
Authors: Ou Zhihua , Ouzounis Christos , Wang Daxi , Sun Wanying , Li Junhua , Chen Weijun , Marlière Philippe , Danchin Antoine 
Published: October 2020

AbstractIn the context of the COVID-19 pandemic, we describe here the singular metabolic background that constrains enveloped RNA viruses to evolve toward likely attenuation in the long term, possibly after a step of increased pathogenicity. Cytidine triphosphate (CTP) is at the crossroad of the processes allowing SARS-CoV-2 to multiply, because CTP is in demand for four essential metabolic steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope, it is a critical building block of the host transfer RNAs synthesis and it is required for synthesis of dolichol-phosphate, a precursor of viral protein glycosylation. The CCA 3′-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. This unique metabolic setup allowed us to highlight and provide a raison d’être to viperin, an enzyme of innate antiviral immunity, which synthesizes 3ʹ-deoxy-3′,4ʹ-didehydro-CTP as an extremely efficient antiviral nucleotide.
Assuring Quality in Nursing Homes: The Black Box of Administrative and Clinical Leadership—A Scoping Review
Authors: Siegel Elena O , Young Heather M 
Published: October 2020

AbstractBackground and ObjectivesLicensed nursing home administrators (NHA) and directors of nursing (DON) are responsible for nursing home quality and assuring optimal performance and job satisfaction/retention of their nursing home workforce. NHA/DON-focused studies have generated important foundational knowledge over the last three decades; yet, targeted research is needed to understand and apply the complexities of the black box of this top management team. This scoping review identifies, reviews, synthesizes, and maps the topical areas of research in NHA/DON positions in U.S. nursing homes.Research Design and MethodsWe conducted searches of 5 databases, yielding 3,479 records; screening/review yielded 88 unique records. We used thematic analysis to code the primary foci of the studies and the variables associated with the concepts of interest.ResultsMost papers (n = 40) focused on role characteristics, 23 examined approaches to management and leadership, 24 focused on perceptions about the role, and the remaining 12 examined role structure. The role-related themes linked to outcomes (n = 42), processes (n = 27), and structures (n = 30).Discussion and ImplicationsWe highlight important gaps for future research and offer a call to action for research, policy, practice, and education collaborations to accelerate the rate of research and translate the findings into best practices for NHA/DON to lead and manage the nursing home workforce and build capacity to ensure person-centered, high-quality care. Based on foundational descriptive studies, it is time to use what is known to design and implement interventions that enhance the capacity of NHA/DON to improve the structures, processes, and outcomes of nursing homes.
Focusing joint inversion of gravity and magnetic data using a clustering stabilizer in a space of weighted parameters
Authors: Xu Zhengwei , Zou Guangui , Wei Qianqian , Tian Junqi , Yuan Hemin 
Published: October 2020

SUMMARY
This paper develops a minimum-support focusing stabilizer to perform a joint inversion of the vertical components of gravity and magnetic data using fuzzy c-means clustering (FCM) with the regularized Newton method in a space of weighted parameters. Not only does this joint inversion technology arrive at the conditionally well-posed traditional potential field inversion, but it also increases the structural correlation between multiple inverted models. The FCM and the focusing stabilizer make it possible to balance the convergence of the data space (D) and the model space (M), guiding multimodal geophysical parameters toward assigned petrophysical values, which makes the results more stable and realistic. Two model studies are presented to illustrate the method, a simple synthetic model with two rectangular bodies in a homogenous background and a realistic model of the Volcanogenic Massive Sulfide (VMS) deposits in northeastern New Brunswick, Canada. These models demonstrate that the new focusing joint inversion algorithm produces better images than traditional methods because the FCM function uses the structural correlation of density contrast and magnetic susceptibility as constraints.
In patients undergoing valve-sparing aortic root replacement, is reimplantation superior to remodelling?
Authors: Maskell Perry , Brimfield Matthew , Ahmed Amna , Harky Amer 
Published: October 2020

Summary
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: in patients undergoing valve-sparing aortic root replacement, is reimplantation superior to remodelling? The purpose of this best evidence topic was to re-review the updated evidence that has become available in the near decade since the previous review published in 2011. Altogether more than 300 papers were found using the reported search, of which 8 papers represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The included studies have significant limitations relating to low-level evidence study design, variable outcome collection and limited significance testing with direct comparison. Long-term outcomes such as survival, recurrence of aortic regurgitation and valve reintervention were largely equal between the two procedures across the studies. This review, updated from the previous best evidence topic, continues to suggest that there are no clear recommendations or even consensus to guide clinical decision-making when choosing between remodelling or reimplantation approaches to valve-sparing aortic root replacement. To date, no study provides strong clinical benefit to favour either procedure in terms of perioperative outcomes, medium–long term survival or reintervention of the aortic valve. As such, procedure selection should be based upon patient factors and valve evaluation, combined with surgeon preference and experience.
Intrusive tech-enabled surveillance and ‘National Security’ secrecy: mounting concerns of mass snooping amid informational asymmetry
Authors: Babele Aryan 
Published: October 2020

Abstract
The onset of technological innovations such as Big Data and Analytics is changing the ways in which law enforcement agencies police and investigate crimes in India. Pervasive technologies like smartphones, closed-circuit cameras, etc, coupled with such innovations have augmented abilities of law enforcement to identify, monitor and predict suspicious individuals and activities. However, the expansive adoption of intrusive technologies for law enforcement challenge the statutory and the constitutional limits on mass surveillance. Also, the government has not been forthcoming in disclosing details about the extent and the ambition of such surveillance technologies. The secrecy has resulted in an informational asymmetry between the people and the government which raises profound concerns of mistrust, transparency and public-accountability. This article examines the feasibility of the ‘national security’ argument that law enforcement agencies normatively use to justify such secrecy of their surveillance powers. They argue that such disclosures may negatively affect their investigational strategies and render them susceptible to circumvention, such that it may be a risk to ‘national security’. The article analyses such ‘national security’ secrecy claims that currently exist without any proper surveillance law and external oversight. The article seeks to recommend meaningful approaches to limit the over-broad ‘national security’ secrecy claims and initiate an informed public conversation on expansive tech-enabled surveillance practices of the Indian government.
Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention
Authors: Podany A T , Leon-Cruz J , Hakim J , Supparatpinyo K , Omoz-Oarhe A , Langat D , Mwelase N , Kanyama C , Gupta A , Benson C A , Chaisson R E , Swindells S , Fletcher C V ,   the AIDS Clinical Trials Group A5279 Team, Kim Peter , Johnson Daniel , Moran Laura , Andersen Janet , Bao Yajing , Wu Shirley , Blanchard-Horan Christina , Walawander Ann , Shin Katherine , Ebiasah Ruth , Holland David , JeanJuste Marc Antoine , Nuermberger Eric , Pillay Sandy , Sanne Ian , Nicotera Janet , Shugarts David , Shali Amina , Tutko Jimi , Demers Brigitte , Maroni Marilyn , Sanchez Jorge L , Iglesias David , Lama Javier , Matoga Mitch , do Amaral Calvet Guilherme , Tonui Ronald Kibet , Modise Taolo , Kasaro Margaret , Naidoo Kogieleum , Kadam Deelip , Burman William 
Published: October 2020

Abstract

Background
The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug–drug interactions with concomitantly used ART.

Objectives
To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV.

Methods
Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated.

Results
Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13–66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266–9302) ng/mL; week 2, 5537 (3552–8462) ng/mL; and week 4, 5388 (3516–8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58–2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81–3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26–1.33).

Conclusions
The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug–drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.
Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection
Authors: Bekerman Elena , Cox Stephanie , Babusis Darius , Campigotto Federico , Das Moupali , Barouch Dan H , Cihlar Tomas , Callebaut Christian 
Published: October 2020

AbstractObjectivesCurrent prophylaxis options for people at risk for HIV infection include two US FDA-approved daily pre-exposure prophylaxis (PrEP) regimens and guidelines for a 2-1-1 event-driven course specifically for men who have sex with men. Despite this, PrEP use rates remain suboptimal, and additional PrEP options may help to improve uptake among diverse populations. Here, we evaluated protective efficacy of two-dose PrEP and two-dose postexposure prophylaxis (PEP) schedules with emtricitabine (FTC)/tenofovir alafenamide (TAF) with or without bictegravir (BIC) in an SHIV macaque model.MethodsMacaques received one oral dose of 200 mg emtricitabine, 25 mg tenofovir alafenamide and 25-100 mg of bictegravir to establish pharmacokinetic profiles of each drug either in the plasma or the peripheral blood mononuclear cells. Protective efficacy of multiple two-dose PrEP and PEP schedules with FTC/TAF with or without bictegravir was then assessed in two repeat low-dose rectal SHIV challenge studies.ResultsThe data revealed over 95% per-exposure risk reduction with FTC/TAF PrEP initiated 2 h before the exposure, but a loss of significant protection with treatment initiation postexposure. In contrast, FTC/TAF plus BIC offered complete protection as PrEP and greater than 80% per-exposure risk reduction with treatment initiation up to 24 h postexposure.ConclusionsTogether, these results demonstrate that two-dose schedules can protect macaques against SHIV acquisition and highlight the protective advantage of adding the integrase inhibitor bictegravir to the reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide as part of event-driven prophylaxis.
African Junta and Defence Spending: A Capture Effect or Self-preservation?
Authors: Kodila-Tedika Oasis , Khalifa Sherif 
Published: October 2020

Abstract
This paper examines the effect of the presence of a military ruler on military expenditure using a panel of sub-Saharan Africa countries. The paper also explores whether the relationship reflects a capture effect, is an outcome of the confrontational climate of the cold war or is a self-preservation effort by military rulers. The panel data estimations show that the presence of a military ruler has a statistically significant negative effect on military spending as a percentage of GDP. The coefficients are also not significantly different before or after the end of the cold war era. This implies that the negative relationship is driven by an effort by military rulers to preempt the ability of their peers to overthrow them from power. We also attempt to deal with potential endogeneity and consider the possibility of persistence in military spending. The paper uses the Arellano and Bond (1991) estimation technique that shows a negative but insignificant effect of the presence of a military ruler on military expenditure, while military spending shows a high degree of persistence.
Method Matters: Comparing Cancer-Related Adjustment of Siblings to Norms and Well-matched Peers
Authors: Tomatsu Saori C , Stanley Caroline , Conroy Rowena , Alderfer Melissa A 
Published: October 2020

Abstract

Objective
The purpose of this study was to better understand conflicting findings in the literature regarding the adjustment of siblings of children with cancer by examining, in a single sample, differences in patterns of results as a function of reporter and comparator used (i.e., population norms, demographically matched classmates).

Method
Self- and parent-report standardized measures of depression, anxiety, and behavioral problems were collected for 67 siblings and 67 demographically matched classmates. Comparisons were made to norms and controls.

Results
Siblings consistently demonstrated poorer psychosocial functioning than their demographically matched peers across all measures but their scores did not differ from norms. A significantly greater percentage of siblings fell outside the normal range than that expected in the general population for parent-reported total and internalizing problems, but not for externalizing problems or the self-report measures.

Conclusions
Findings regarding the psychological adjustment of siblings of children with cancer differ according to the research methods used. It is important to use rigorous methods such as demographically matched peer comparisons when investigating the impact of childhood cancer on siblings.
COVID-19 Pandemic Preparedness in a UK Tertiary and Quaternary Children’s Hospital: Tales of the Unexpected
Authors: Alders Nele , Penner Justin , Grant Karlie , Patterson Charlotte , Hassell Jane , MacDermott Nathalie , Pincott Sian , Bamford Alasdair , du Pré Pascale , Johnson Mae , Moshal Karyn 
Published: October 2020

Abstract
We describe the adaptive coping strategies required in the management of a heterogeneous group of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pediatric patients. The diverse range of presentations, presenting in distinct phenotypic waves, exemplified the importance of preparedness for the unknown. Lessons learned will be essential in planning for a likely second wave of SARS-CoV-2.