bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol for a prospective cohort study to investigate Hemodynamic Adaptation to Pregnancy and Placenta-related Outcome: the HAPPO study
Authors: Bijl Rianne C , Cornette Jérôme M J , van den Bosch Annemien E , Duvekot Johannes J , Molinger Jeroen , Willemsen Sten P , Koning Anton H J , Roos-Hesselink Jolien W , Franx Arie , Steegers-Theunissen Régine P M , Koster Maria P H 
Published: November 2019

IntroductionThe importance of cardiovascular health in relation to pregnancy outcome is increasingly acknowledged. Women who develop certain pregnancy complications, in particular preeclampsia, are at higher risk for future cardiovascular disease. Independent of its outcome, pregnancy requires a substantial adaptive response of the maternal cardiovascular system. In the Hemodynamic Adaptation to Pregnancy and Placenta-related Outcome (HAPPO) study, we aim to examine longitudinal maternal haemodynamic adaptation to pregnancy from the preconception period onwards. We hypothesise that women who will develop adverse pregnancy outcomes have impaired cardiovascular health before conception, leading to haemodynamic maladaptation to pregnancy and diminished uteroplacental vascular development.Methods and analysisIn this prospective cohort study embedded in the Rotterdam periconception cohort, 200 women with a history of placenta-related pregnancy complications (high-risk group) and 100 women with an uncomplicated obstetric history (low-risk group) will be included. At five moments (preconception, first, second and third trimester and postdelivery), women will undergo an extensive examination of the macrocirculatory and microcirculatory system and uteroplacental vascular development. The main outcome measures are differences in maternal haemodynamic adaptation to pregnancy between women with and without placenta-related pregnancy complications. In a multivariate linear mixed model, the relationship between maternal haemodynamic adaptive parameters, (utero)placental vascularisation indices and clinical outcomes (occurrence of pregnancy complications, embryonic and fetal growth trajectories, miscarriage rate, gestational age at delivery, birth weight) will be studied. Subgroup analysis will be performed to study baseline and trajectory differences between high-risk and low-risk women, independent of subsequent pregnancy outcome.Ethics and disseminationThis study protocol was approved by the Medical Ethics Committee of the Erasmus MC, Rotterdam, the Netherlands (MEC 2018–150). Results will be disseminated to the medical community by publications in peer-reviewed journals and presentations at scientific congresses. Also, patient associations will be informed and the public will be informed by dissemination through (social) media.Trial registration numberNL7394 (www.trialregister.nl)
Psychosocial effects of whole-body MRI screening in adult high-risk pathogenicTP53mutation carriers: a case-controlled study (SIGNIFY)
Authors: Bancroft Elizabeth K , Saya Sibel , Brown Emma , Thomas Sarah , Taylor Natalie , Rothwell Jeanette , Pope Jennifer , Chamberlain Anthony , Page Elizabeth , Benafif Sarah , Hanson Helen , Dias Alexander , Mikropoulos Christos , Izatt Louise , Side Lucy , Walker Lisa , Donaldson Alan , Cook Jackie A , Barwell Julian , Wiles Vicki , Limb Lauren , Eccles Diana M , Leach Martin O , Shanley Susan , Gilbert Fiona J , Gallagher David , Rajashanker Balashanmugam , Whitehouse Richard W , Koh Dow-Mu , Sohaib S Aslam , Evans D Gareth , Eeles Rosalind A , Walker Leslie G 
Published: November 2019

BackgroundGermlineTP53gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for femaleTP53pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44TP53pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adultTP53pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.MethodsPsychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks’ follow-up.ResultsWB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.ConclusionWB-MRI screening can be implemented inTP53pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
Patients’ and public views and attitudes towards the sharing of health data for research: a narrative review of the empirical evidence
Authors: Kalkman Shona , van Delden Johannes , Banerjee Amitava , Tyl Benoît , Mostert Menno , van Thiel Ghislaine 
Published: November 2019

IntroductionInternational sharing of health data opens the door to the study of the so-called ‘Big Data’, which holds great promise for improving patient-centred care. Failure of recent data sharing initiatives indicates an urgent need to invest in societal trust in researchers and institutions. Key to an informed understanding of such a ‘social license’ is identifying the views patients and the public may hold with regard to data sharing for health research.MethodsWe performed a narrative review of the empirical evidence addressing patients’ and public views and attitudes towards the use of health data for research purposes. The literature databases PubMed (MEDLINE), Embase, Scopus and Google Scholar were searched in April 2019 to identify relevant publications. Patients’ and public attitudes were extracted from selected references and thematically categorised.ResultsTwenty-seven papers were included for review, including both qualitative and quantitative studies and systematic reviews. Results suggest widespread—though conditional—support among patients and the public for data sharing for health research. Despite the fact that participants recognise actual or potential benefits of data research, they expressed concerns about breaches of confidentiality and potential abuses of the data. Studies showed agreement on the following conditions: value, privacy, risk minimisation, data security, transparency, control, information, trust, responsibility and accountability.ConclusionsOur results indicate that a social license for data-intensive health research cannot simply be presumed. To strengthen the social license, identified conditions ought to be operationalised in a governance framework that incorporates the diverse patient and public values, needs and interests.
Minimal dirac neutrino mass models from $$\hbox {U}(1)_{\mathrm{R}}$$ gauge symmetry and left–right asymmetry at colliders
Authors: Jana Sudip , Vishnu P. K. , Saad Shaikh 
Published: November 2019

Abstract
In this work, we propose minimal realizations for generating Dirac neutrino masses in the context of a right-handed abelian gauge extension of the Standard Model. Utilizing only $$U(1)_R$$U(1)R symmetry, we address and analyze the possibilities of Dirac neutrino mass generation via (a) tree-level seesaw and (b) radiative correction at the one-loop level. One of the presented radiative models implements the attractive scotogenic model that links neutrino mass with Dark Matter (DM), where the stability of the DM is guaranteed from a residual discrete symmetry emerging from $$U(1)_R$$U(1)R. Since only the right-handed fermions carry non-zero charges under the $$U(1)_R$$U(1)R, this framework leads to sizable and distinctive Left–Right asymmetry as well as Forward–Backward asymmetry discriminating from $$U(1)_{B-L}$$U(1)B-L models and can be tested at the colliders. We analyze the current experimental bounds and present the discovery reach limits for the new heavy gauge boson $$Z^{\prime }$$Z′ at the LHC and ILC. Furthermore, we also study the associated charged lepton flavor violating processes, dark matter phenomenology and cosmological constraints of these models.
Calcium-sensing receptor deletion in the mouse esophagus alters barrier function
Authors: Nakhoul Nazih L. , Tu Chia-Ling , Brown Karen L. , Islam M. Toriqul , Hodges Anna G. , Abdulnour-Nakhoul Solange M. 
Published: November 2019

Calcium-sensing receptor (CaSR) is the molecular sensor by which cells respond to small changes in extracellular Ca2+concentrations. CaSR has been reported to play a role in glandular and fluid secretion in the gastrointestinal tract and to regulate differentiation and proliferation of skin keratinocytes. CaSR is present in the esophageal epithelium, but its role in this tissue has not been defined. We deleted CaSR in the mouse esophagus by generating keratin 5 CreER;CaSRFlox+/+compound mutants, in which loxP sites flank exon 7 of CaSR gene. Recombination was initiated with multiple tamoxifen injections, and we demonstrated exon 7 deletion by PCR analysis of genomic DNA. Quantitative real-time PCR and Western blot analyses showed a significant reduction in CaSR mRNA and protein expression in the knockout mice (EsoCaSR−/−) as compared with control mice. Microscopic examination ofEsoCaSR−/−esophageal tissues showed morphological changes including elongation of the rete pegs, abnormal keratinization and stratification, and bacterial buildup on the luminal epithelial surface. Western analysis revealed a significant reduction in levels of adherens junction proteins E-cadherin and β catenin and tight junction protein claudin-1, 4, and 5. Levels of small GTPase proteins Rac/Cdc42, involved in actin remodeling, were also reduced. Ussing chamber experiments showed a significantly lower transepithelial resistance in knockout (KO) tissues. In addition, luminal-to-serosal-fluorescein dextran (4 kDa) flux was higher in KO tissues. Our data indicate that CaSR plays a role in regulating keratinization and cell-cell junctional complexes and is therefore important for the maintenance of the barrier function of the esophagus.NEW & NOTEWORTHY The esophageal stratified squamous epithelium maintains its integrity by continuous proliferation and differentiation of the basal cells. Here, we demonstrate that deletion of the calcium-sensing receptor, a G protein-coupled receptor, from the basal cells disrupts the structure and barrier properties of the epithelium.
Neural motor complexes propagate continuously along the full length of mouse small intestine and colon
Authors: Costa Marcello , Hibberd Timothy James , Keightley Lauren J. , Wiklendt Lukasz , Arkwright John W. , Dinning Philip G. , Brookes Simon J. H. , Spencer Nick J. 
Published: November 2019

Cyclical propagating waves of muscle contraction have been recorded in isolated small intestine or colon, referred to here as motor complexes (MCs). Small intestinal and colonic MCs are neurogenic, occur at similar frequencies, and propagate orally or aborally. Whether they can be coordinated between the different gut regions is unclear. Motor behavior of whole length mouse intestines, from duodenum to terminal rectum, was recorded by intraluminal multisensor catheter. Small intestinal MCs were recorded in 27/30 preparations, and colonic MCs were recorded in all preparations ( n = 30) with similar frequencies (0.54 ± 0.03 and 0.58 ± 0.02 counts/min, respectively). MCs propagated across the ileo-colonic junction in 10/30 preparations, forming “full intestine” MCs. The cholinesterase inhibitor physostigmine increased the probability of a full intestine MC but had no significant effect on frequency, speed, or direction. Nitric oxide synthesis blockade by Nω-nitro-l-arginine, after physostigmine, increased MC frequency in small intestine only. Hyoscine-resistant MCs were recorded in the colon but not small intestine ( n = 5). All MCs were abolished by hexamethonium ( n = 18) or tetrodotoxin ( n = 2). The enteric neural mechanism required for motor complexes is present along the full length of both the small and large intestine. In some cases, colonic MCs can be initiated in the distal colon and propagate through the ileo-colonic junction, all the way to duodenum. In conclusion, the ileo-colonic junction provides functional neural continuity for propagating motor activity that originates in the small or large intestine.NEW & NOTEWORTHY Intraluminal manometric recordings revealed motor complexes can propagate antegradely or retrogradely across the ileo-colonic junction, spanning the entire small and large intestines. The fundamental enteric neural mechanism(s) underlying cyclic motor complexes exists throughout the length of the small and large intestine.
Acute regulation of intestinal ion transport and permeability in response to luminal nutrients: the role of the enteric nervous system
Authors: Cavin Jean-Baptiste , Cuddihey Hailey , MacNaughton Wallace K. , Sharkey Keith A. 
Published: November 2019

The small intestine regulates barrier function to absorb nutrients while avoiding the entry of potentially harmful substances or bacteria. Barrier function is dynamically regulated in part by the enteric nervous system (ENS). The role of the ENS in regulating barrier function in response to luminal nutrients is not well understood. We hypothesize that the ENS regulates intestinal permeability and ion flux in the small intestine in response to luminal nutrients. Segments of jejunum and ileum from mice were mounted in Ussing chambers. Transepithelial electrical resistance (TER), short-circuit current ( Isc), and permeability to 4-kDa FITC-dextran (FD4) were recorded after mucosal stimulation with either glucose, fructose, glutamine (10 mM), or 5% Intralipid. Mucosal lipopolysaccharide (1 mg/mL) was also studied. Enteric neurons were inhibited with tetrodotoxin (TTX; 0.5 μM) or activated with veratridine (10 μM). Enteric glia were inhibited with the connexin‐43 blocker Gap26 (20 μM). Glucose, glutamine, Intralipid, and veratridine acutely modified Isc in the jejunum and ileum, but the effect of nutrients on Isc was insensitive to TTX. TTX, Gap26, and veratridine treatment did not affect baseline TER or permeability. Intralipid acutely decreased permeability to FD4, while LPS increased it. TTX pretreatment abolished the effect of Intralipid and exacerbated the LPS‐induced increase in permeability. Luminal nutrients and enteric nerve activity both affect ion flux in the mouse small intestine acutely but independently of each other. Neither neuronal nor glial activity is required for the maintenance of baseline intestinal permeability; however, neuronal activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide. NEW & NOTEWORTHY Luminal nutrients and enteric nerve activity both affect ion transport in the mouse small intestine acutely, but independently of each other. Activation or inhibition of the enteric neurons does not affect intestinal permeability, but enteric neural activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide. The enteric nervous system regulates epithelial homeostasis in the small intestine in a time-dependent, region- and stimulus-specific manner.
Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials
Authors: Kates Max , Matoso Andres , Choi Woonyoung , Baras Alexander S. , Daniels Marcus J. , Lombardo Kara , Brant Aaron , Mikkilineni Nina , McConkey David J. , Kamat Ashish M. , Svatek Robert S. , Porten Sima P. , Meeks Joshua J. , Lerner Seth P. , Dinney Colin P. , Black Peter C. , McKiernan James M. , Anderson Chris , Drake Charles G. , Bivalacqua Trinity J. 
Published: November 2019

Abstract

Purpose:
To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG).

Experimental Design:
Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort.

Results:
The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P &lt; 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1− nonresponders (50%, P &lt; 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%).

Conclusions:
One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.
СОЦІАЛЬНО-ДЕМОГРАФІЧНІ ОСОБЛИВОСТІ ХВОРИХ З ПЕРВИННИМ ЕПІЗОДОМ БІПОЛЯРНОГО АФЕКТИВНОГО РОЗЛАДУ З УРАХУВАННЯМ ГЕНДЕРНОГО ФАКТОРА
Authors: Mysula Y. I. 
Published: November 2019

Проблема біполярного афективного розладу (БАР) є однією з найактуальніших проблем сучасної психіатрії.
Мета – вивчити соціально-демографічні особливості хворих на БАР на момент первинного епізоду і впродовж життя з урахуванням гендерного фактора.
Матеріал і методи. Проаналізовано особливості перебігу первинного епізоду БАР на підставі медичної документації 180 чоловіків і 222 жінок із встановленим діагнозом БАР.
Результати. Встановлено переважання осіб з неповною середньою (загалом 24,7 %, чоловіків 28,4 %, жінок 21,6 %, р>0,05), середньою (відповідно 21,6 %, 27,9 % і 13,9 %, р<0,01), та середньою спеціальною освітою (20,4 %, 22,2 % і 18,9 %, р>0,05), меншою є питома вага осіб з незакінченою вищою (20,4 %, 18,3 % і 22,1 %, р>0,05), професійно-технічною (7,2 %; 11,1 % і 4,1 %, р<0,01) і вищою освітою (5,7 %, 6,1 % і 5,4 %, р>0,05). Більшість хворих були безробітними (40,0 %, 37,8 %, 41,9 %, р>0,05), менше – школярів (24,7 %, 28,3 % та 21,6 %, р>0,05), студентів (11,7 %, 12,8 % і 10,8 %, р>0,05), робітників (8,7 %, 10,6 % і 7,2 %, р>0,05), службовців (8,2 %, 6,1 % і 9,9 %, р>0,05), підприємців (4,0 %, 3,3 % і 4,5 %, р>0,05) та пенсіонерів (2,7 %, 1,1 % і 4,1 %, р>0,05). Більшість хворих не були одруженими (60,7 %, 66,7 % і 55,9 %, р>0,05), менше було одружених (35,9 %, 28,3 % і 41,9 %, р>0,05), розлучених (2,7 %, 3,9 % і 1,8 %, р>0,05) та вдових (0,7 %, 1,1 % і 0,4 %, р>0,05); а також бездітних (78,9 %, 79,4 % і 78,4 %, р>0,05) і тих, що проживали з батьками (59,5 %, 65,6 % і 54,5 %, р<0,05). Чоловіки частіше були курцями (58,3 % проти 24,8 %, р<0,01, разом 39,7 %), з епізодичним та частим вживанням алкоголю (відповідно 53,3 % і 33,8 %, р<0,01, разом 42,5 %, та 21,1 % і 1,8 %, р<0,01, разом 10,5 %).
Висновки. Хворим з первинним епізодом БАР притаманні невисокий освітній та професійний рівень, погана сімейна реалізація, поширеність куріння; для чоловіків характерні нижчий рівень освіти з більшою професійною спрямованістю, вищий рівень інвалідизації, гірша сімейна реалізація, а також більший рівень ураження аддикціями. Ці дані можуть бути використані для ранньої діагностики та профілактики БАР.
ТРОМБОФІЛІЯ, УСКЛАДНЕНА ГОСТРИМ ІНФАРКТОМ МІОКАРДА: КЛІНІЧНИЙ ВИПАДОК ІЗ АНАЛІЗОМ СУЧАСНИХ ДІАГНОСТИЧНО-ЛІКУВАЛЬНИХ АЛГОРИТМІВ ВЕДЕННЯ ХВОРИХ
Authors: Shved M. I. , Yastremska I. O. , Pizhytska K. B. , Kovbasa N. M. , Zubanyuk V. M. , Dobrianskyi T. O. 
Published: November 2019

Діагностика тромбофілії та патогенетичне лікування її клінічних проявів супроводжується рядом труднощів, що зумовлено без- або малосимптомним перебігом хвороби та недостатньою обізнаністю лікарів щодо критеріїв діагностики цієї патології.
Мета – підвищення рівня діагностики і вибору адекватного лікування пацієнтів з тромбофілією, ускладненою гострим інфарктом міокарда, шляхом детального аналізу та клініко-лабораторного розбору власного клінічного випадку.
Матеріал і методи. Системний аналіз, бібліосемантика та аналіз випадку захворювання конкретного пацієнта з тромбофілією, дослідження генетичного поліморфізму, асоційованого з тромбофілією. Пошук джерел здійснювався за допомогою науково-статистичної бази даних медичної інформації PubMed-NCBI.
Результати. При відсутності чітких причинних факторів високого ризику розвитку гострого інфаркту міокарда (стенозуючого атеросклерозу) та при наявності рецидивних тромбозів різної локалізації пацієнтам показане обов’язкове обстеження з метою підтвердження (виключення) вродженої або набутої тромбофілії, що в подальшому визначає програму профілактики повторних епізодів спонтанного тромбозу. З цією метою було проведено дослідження генетичного поліморфізму, асоційованого з ризиком тромбофілії, у хворого з рецидивними венозними (ілеофеморальним) та артеріальними (коронарним) тромбозами. Прогностично найнесприятливішою була наявність у хворого поліморфізму алелів 4G/4G гена серпін-1 (РАІ-1), який є антагоністом тканинного активатора плазміногену і сприяє зниженню фібринолітичної активності крові, що підвищує ризик коронарних порушень в 1,3 раза. Одночасно у хворого діагностовано поліморфізм алелів С/Т гена ITGA2 (інтегрину альфа-2), який відповідає за функцію тромбоцитарного рецептора до колагену і сприяє збільшенню швидкості адгезії тромбоцитів, що підвищує ризик інфаркту міокарда в 2,8 раза. Також важливо вказати на таку особливість генетичних порушень у даного пацієнта, як поліморфізм алелів G/T гена F13, для якого характерне зниження фактора VIII згортання крові, що в кінцевому результаті призводить до зменшення ризику венозного тромбозу, але на фоні антикоагулянтної терапії цей ризик може суттєво зростати (12–20 %).
Отримані результати обґрунтували переведення хворого з прийому ксарелто на довготривале вживання прямих низькомолекулярних гепаринів (фондапаринукс).
Висновки. У хворих з діагностованою тромбофілією необхідно використовувати персоніфікований підхід до вибору антитромботичних засобів лікування та профілактики повторних тромбозів шляхом визначення у пацієнта певного поліморфізму генів та форми тромбофілії.