bluuebunny/crossref_metadata_2025_split huggingface dataset:
FADS1 and FADS2 polymorphism are associated with changes in fatty acid concentrations after calorie-restricted Central European and Mediterranean diets
Authors: Muzsik Agata , Bajerska Joanna , Jeleń Henryk H. , Walkowiak Jarosław , Krzyżanowska-Jankowska Patrycja , Chmurzynska Agata 
Published: September 2019

AbstractObjective:In the present study, we tested whether calorie-restricted diets differing in their percentage of energy derived from monounsaturated fatty acids and carbohydrates can affect the metabolism of fatty acids (FAs) in postmenopausal women. Moreover, we examined whether polymorphisms ofFADS1andFADS2are associated with these changes.Methods:Postmenopausal women (the mean age: 60.5 ± 5.0 y) were randomized for 16 weeks to two different calorie-restricted diets: a Central European diet (CED) or a Mediterranean diet (MED).Results:After the intervention, levels of most FAs in red blood cells decreased in both groups. The delta values for the 20:1n-9 and the 20:2n-6 levels differed between the CED and the MED (−1.55 ± 4.02 μg/mL vs 0.39 ± 4.11 μg/mL and −0.62 ± 10.93 μg/mL vs 3.06 ± 8.75 μg/mL;P< 0.05). Women in the CED group with at least one minor allele ofFADSgenes had greater decreases of α-linolenic acid, dihomo-γ-linolenic acid, total n-6, and total PUFA (by approximately 70%, 40%, 35%, and 35%, respectively) than did women with the major alleles. After the intervention, the change in the lipid accumulation product index was −28.28 ± 27.84 and −32.00 ± 78.55 in the CED and the MED group, respectively.Conclusions:The effect of the dietary intervention on FA metabolism seems to depend mostly on calorie restriction, but not on type of diet.FADS1andFADS2gene polymorphisms can modify the response to the CED.
The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects
Authors: Cavallone Laura F. , Montana Michael C. , Frey Karen , Kallogjeri Dorina , Wages James M. , Rodebaugh Thomas L. , Doshi Tina , Kharasch Evan D. , Gereau Robert W. 
Published: September 2019

Abstract
Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. Furthermore, fenobam showed no signs of analgesic tolerance with up to 2 weeks of daily dosing in mice. Analgesic effects of fenobam in humans have not been reported. The purpose of this investigation was to evaluate fenobam pharmacokinetics and analgesic effects in humans. We first evaluated single-dose oral fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization using capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of hyperalgesia and allodynia around the area applied with heat/capsaicin. Secondary outcome measures included nociception, measured as pain rating on a visual analog scale, heat pain detection threshold, and effects on cognition and mood. Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose. Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.
Medication Nonadherence or Self-care? Understanding the Medication Decision-Making Process and Experiences of Older Adults With Heart Failure
Authors: Meraz Rebecca 
Published: September 2019

Background
More than half of all patients with heart failure (HF) do not take medications as prescribed, resulting in negative health outcomes. Research has shown that medication adherence may be intentional rather than the ability to follow prescribed regimens, yet very little is known about medication-taking decisions in older patients with HF.

Objective
The purpose of this qualitative study was to gain insight into the decision-making processes and experiences of older patients with HF by exploring the different aspects in choosing to take or not take medications as prescribed in the community setting.

Methods
Using a narrative inquiry approach, the personal narratives of 11 adults 65 years or older who took at least 2 daily medications for HF were gathered using in-depth, semistructured interviews. The data in this study were organized and analyzed using Riessman's framework for narrative analysis.

Results
Participants made intentional decisions to take particular medications differently than prescribed. A worrisome symptom prompted a naturalistic decision-making process. When a medication interfered with attaining a personal goal, participants coped by individualizing their medication regimen. Participants did not consider taking a medication differently than prescribed as nonadherence but a necessary aspect of maintaining a personal level of health, which could be seen as self-care.

Conclusions
The older patient with HF should be carefully assessed for nonadherence. The development of interventions that are patient specific, target medications with the greatest potential for nonadherence, and use easy-to-access resources may promote decisions for medication adherence. More research is needed to develop interventions that promote decisions for medication adherence.
Palpable Purpura on the Legs and Buttocks
Authors: Patel Dharmik , Martin Kari L. 
Published: September 2019

ABSTRACT
This is a case of a young girl with palpable purpura on the legs and buttocks who was seen using telecommunication technology. Store-and-forward teledermatology increases overall access to dermatology care by sending protected medical information electronically to off-site medical providers (Roman & Jacob, 2014). The following case of palpable purpura is presented in the standardized teledermatological reader format.
The Relation Between Tinnitus and a Neurovascular Conflict of the Cochleovestibular Nerve on Magnetic Resonance Imaging
Authors: Peters Thomas T. A. , van den Berge Minke J. C. , Free Rolien H. , van der Vliet Anton M. , Knoppel Hanna , van Dijk Pim , Hofman Rutger 
Published: September 2019

Introduction:
Magnetic resonance (MR) imaging is often used in diagnostic evaluation of tinnitus patients. Incidental findings like a neurovascular conflict (NVC) in the cerebellopontine angle are often found; however, the diagnostic value of this finding remains unclear. The aim of this study is to investigate whether the type or degree of compression of the vestibulocochlear nerve is of diagnostic value in patients with a NVC.

Methods:
A retrospective study was performed in 111 tinnitus patients with available MR imaging between 2013 and 2015. Clinical and audiometric variables were gathered and MR imaging was reevaluated by two neuroradiologists. NVCs were analyzed using a grading system based on previous research by Sirikci et al.

Results:
In total, 220 ears were available for assessment. In patients with unilateral tinnitus a loop compression and an indentation of the cochleovestibular nerve were more frequent than in patients with bilateral tinnitus. However, there was no significant difference in distribution of the type of compression between tinnitus and nontinnitus ears. Patient with unilateral tinnitus had a significantly higher degree of hearing loss in the symptomatic ear, compared with the asymptomatic ear and with the bilateral tinnitus group. Also, it was found that the degree of hearing loss did not differ between the various types of compression.

Conclusion:
This study did not find a diagnostic value of specific types of compression in patients with a NVC. Although the distribution of NVC classification was different in patients with unilateral and bilateral tinnitus, there was no definite relation between the type of NVC and the presence of ipsilateral tinnitus. Also, the degree of hearing loss was not related to specific types of NVC.
Insulin Therapy: Future Perspectives
Authors: Cernea Simona , Raz Itamar 
Published: September 2019

Background:
Insufficient insulin secretion is a core pathogenetic mechanism of diabetes mellitus and therefore, insulin therapy remains the cornerstone of management. Over the past 100 years, much progress has been made in the development of insulin therapy, including elaboration of novel insulin formulations and delivery methods.

Areas of Uncertainty:
Despite significant advances, there are still many barriers, challenges, and uncertainties involving insulin therapy. With newer pharmacological and technological approaches, there are many potential drawbacks to be addressed, such as immunogenicity, biocompatibility, degradation/clearance of delivery materials, stability, precision of dosing, reproducibility, predictability of performance, and safety over time, etc. In addition, the new formulations/delivery systems should be cost-effective and accessible.

Data Sources:
A literature search of original and review articles, editorials, and meta-analyses in Medline/PubMed and Google Scholar has been performed. ClinicalTrials.gov website was searched for ongoing relevant clinical trials.

Therapeutic Advances:
New insulin formulations (ultralong basal and ultrarapid analogues) were designed to obtain a prolonged, flatter profile, with less hypoglycemia and improvement of postprandial glucose control, respectively. The next generation of insulin therapy is probably best represented by the “smart” (glucose-responsive) insulins, which deliver it according to an endogenous glucose-sensing feedback mechanism. Another area of continuous advances includes insulin delivery systems with new jet injectors, smart pens, patch pumps, and other needle-free devices for subcutaneous administrations. Many alternative routes of insulin delivery (pulmonary, nasal, buccal, oral, and transdermal) have also been explored, with some reaching clinical use. The digitalization of diabetes care has made considerable progress in the past several years and will most probably make even more so in the near future.

Conclusions:
The improved insulin formulations, newer delivery methods/routes, and digital technologies are rapidly becoming effective and have great potential to improve metabolic control as well as other outcomes, including quality of life of persons living with diabetes mellitus.
Performance of an Automated Screening Algorithm for Early Detection of Pediatric Severe Sepsis*
Authors: Eisenberg Matthew , Madden Kate , Christianson Jeffrey R. , Melendez Elliot , Harper Marvin B. 
Published: September 2019

Objectives:
To create and evaluate a continuous automated alert system embedded in the electronic health record for the detection of severe sepsis among pediatric inpatient and emergency department patients.

Design:
Retrospective cohort study. The main outcome was the algorithm’s appropriate detection of severe sepsis. Episodes of severe sepsis were identified by chart review of encounters with clinical interventions consistent with sepsis treatment, use of a diagnosis code for sepsis, or deaths. The algorithm was initially tested based upon criteria of the International Pediatric Sepsis Consensus Conference; we present iterative changes which were made to increase the positive predictive value and generate an improved algorithm for clinical use.

Setting:
A quaternary care, freestanding children’s hospital with 404 inpatient beds, 70 ICU beds, and approximately 60,000 emergency department visits per year

Patients:
All patients less than 18 years presenting to the emergency department or admitted to an inpatient floor or ICU (excluding neonatal intensive care) between August 1, 2016, and December 28, 2016.

Intervention:
Creation of a pediatric sepsis screening algorithm.

Measurements and Main Results:
There were 288 (1.0%) episodes of severe sepsis among 29,010 encounters. The final version of the algorithm alerted in 9.0% (CI, 8.7–9.3%) of the encounters with sensitivity 72% (CI, 67–77%) for an episode of severe sepsis; specificity 91.8% (CI, 91.5–92.1%); positive predictive value 8.1% (CI, 7.0–9.2%); negative predictive value 99.7% (CI, 99.6–99.8%). Positive predictive value was highest in the ICUs (10.4%) and emergency department (9.6%).

Conclusions:
A continuous, automated electronic health record-based sepsis screening algorithm identified severe sepsis among children in the inpatient and emergency department settings and can be deployed to support early detection, although performance varied significantly by hospital location.
Rituximab Versus Cyclophosphamide for Central Nervous System Involvement of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Krishna Rachana , De Giacomi Federica , Kumar Neeraj , Kalina Peter , Specks Ulrich , Baqir Misbah 
Published: September 2019

Objective
To compare the effectiveness of rituximab (RTX) with cyclophosphamide (CYC) in patients who have central nervous system (CNS) involvement in antineutrophil cytoplasmic antibody–associated vasculitis (AAV).

Methods
A computer-assisted search was conducted to identify all adults who received a diagnosis of AAV with CNS involvement from January 1, 1997, through July 1, 2017, at our institution.

Results
Of the 17 patients identified, 11 had received RTX, and 6 had received CYC. Age at diagnosis of CNS involvement was similar in both groups. In the RTX group, 91% of the patients were women; in the CYC group, 33% were women (p = 0.03). At the time of CNS presentation, orbital involvement had occurred in 6 patients in the RTX group and in none of the patients in the CYC group. Initial remission of induction was achieved in all patients (100%) in the CYC group and in 10 patients (91%) in the RTX group. Two patients had no response to RTX: 1 patient when RTX was used for remission induction at the time of diagnosis and the second patient when RTX was used for remission induction after relapse. The median follow-up was 38 months (range, 9–127 months). Central nervous system relapse occurred in 4 patients in the RTX group and in 1 patient in the CYC group. Of the 4 patients in the RTX group with relapse, 3 had marked ocular involvement. Both nonresponder patients in the RTX group had ocular involvement.

Conclusion
Rituximab is as effective as CYC in remission induction in patients with CNS involvement in AAV.
Healthy ageing men have normal reproductive function but display germline-specific molecular changes
Authors: Laurentino S. , Cremers J.-F. , Horsthemke B. , Tüttelmann F. , Czeloth K. , Zitzmann M. , Pohl E. , Rahmann S. , Schröder C. , Berres S. , Redmann K. , Krallmann C. , Schlatt S. , Kliesch S. , Gromoll J. 
Published: September 2019

AbstractChildren of older fathers have higher risk for certain diseases. Nevertheless, how ageing specifically affects male germ cells is so far not completely understood. In a cohort of 197 healthy men (18-84 years), we found that semen and reproductive parameters remained normal over six decades. Along with an age-dependent increase in telomere length in sperm (r=0.41, p>0.001), we found accelerated DNA fragmentation, more prominent after the sixth decate of life, and with around 60% of men older than 66 showing abnormal levels of DNA breaks. At the epigenetic level, by whole genome bisulfite sequencing we identified 236 sperm-specific differentially methylated regions between the youngest and oldest group, affecting mostly regions associated with homeobox genes and nervous system development. Therefore, we propose that during ageing, male germ cells are affected by an intrinsic and specific ageing process, distinguishable from the soma. These age-dependent changes might have consequences for fertility and offspring of older men.
From rare Copy Number Variations to biological processes in ADHD
Authors: Harich Benjamin , van der Voet Monique , Klein Marieke , Čížek Pavel , Fenckova Michaela , Schenck Annette , Franke Barbara 
Published: September 2019

AbstractAimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.MethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.ResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26,POLR3CandRBFOX1were also supported by common genetic variants.ConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.
Cytosine methylation affects the mutability of neighbouring nucleotides in human, Arabidopsis, and rice
Authors: Kusmartsev Vassili , Warnecke Tobias 
Published: September 2019

ABSTRACTMethylated cytosines deaminate at higher rates than unmethylated cytosines and the lesions they produce are repaired less efficiently. As a result, methylated cytosines are mutational hotspots. Here, combining rare polymorphism and base-resolution methylation data in humans,Arabidopsis thaliana, and rice (Oryza sativa), we present evidence that methylation state affects mutation dynamics not only at the focal cytosine but also at neighbouring nucleotides. In humans, contrary to prior suggestions, we find that nucleotides in the close vicinity (±3nt) of methylated cytosines mutate less frequently. In contrast, methylation is associated with increased neighbourhood mutation risk inA. thalianaand rice. The difference in mutation risk associated with methylation is less pronounced further away from the focal CpG, is modulated by regional GC content, and enhanced in heterochromatic regions. Our results are consistent with a model where elevated risk at neighbouring bases is linked to lesion formation at the focal cytosine and subsequent long-patch repair. Our results provide evidence that cytosine methylation has a broader mutational footprints than commonly assumed. They also illustrate that methylation is not intrinsically associated with higher mutation risk for surrounding bases, but that mutagenic effects reflect evolved species-specific and lesion-specific predispositions to elicit error-prone long-patch DNA repair.
Transmission Chains or Independent Solvers? A Comparative Study of Two Collective Problem-Solving Methods
Authors: Yahosseini Kyanoush Seyed , Moussaïd Mehdi 
Published: September 2019

AbstractGroups can be very successful problem-solvers. This collective achievement crucially depends on how the group is structured, that is, how information flows between members and how individual contributions are merged. Numerous methods have been proposed, which can be divided into two major categories: those that involve an exchange of information between the group members, and those that do not. Here we compare two instances of such methods for solving complex problems: (1) transmission chains, where individuals tackle the problem one after the other, each one building on the solution of the predecessor and (2) groups of independent solvers, where individuals tackle the problem independently, and the best solution found in the group is selected afterwards.By means of numerical simulations and experimental observations, we show that the best performing method is determined by the interplay between two key factors: the skills of the individuals and the difficulty of the problem. We find that transmission chains are superior either when the problem is rather easy, or when the group is composed of rather unskilled individuals. On the contrary, groups of independent solvers are preferable for harder problems or for groups of rather skillful individuals. Finally, we deepen the comparison by studying the impact of the group size and diversity. Our research stresses that efficient collective problem-solving requires a good matching between the nature of the problem and the structure of the group.
Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach
Authors: de Macedo Abdo Luiza , Barros Luciana Rodrigues Carvalho , Viegas Mariana Saldanha , Marques Luisa Vieira Codeço , de Sousa Ferreira Priscila , Chicaybam Leonardo , Bonamino Martín Hernán 
Published: September 2019

AbstractRecently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 hours of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggests that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries.