bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uptake of fetal aneuploidy screening after the introduction of the non‐invasive prenatal test: A national population‐based register study
Authors: van der Meij Karuna R. M. , de Groot‐van Mooren Maurike , Carbo Ellen W. S. , Pieters Mijntje J. , Rodenburg Wendy , Sistermans Erik A. , Cornel Martina C. , Henneman Lidewij ,   the Dutch NIPT Consortium
Published: January 2021

AbstractIntroductionThe introduction of the non‐invasive prenatal test (NIPT) has shifted the prenatal screening landscape. Countries are exploring ways to integrate NIPT in their national prenatal screening programs, either as a first‐ or second‐tier test. This study aimed to describe how the uptake of fetal aneuploidy screening changed after the introduction of NIPT as a second‐tier and as a first‐tier test within the national prenatal screening program of the Netherlands.Material and methodsA population‐based register study in the Netherlands, recording uptake of fetal aneuploidy screening. Data from all pregnant women choosing to have the first‐trimester combined test (FCT) or first‐tier NIPT between January 2007 and March 2019 were retrospectively collected using national registration systems. Uptake percentages for fetal aneuploidy screening (FCT and NIPT) were calculated and stratified by region and maternal age. Statistical significance was determined using trend analysis and chi‐squared tests.ResultsBetween 2007 and 2013 FCT uptake increased from 14.8% to 29.5% (P = .004). In April 2014 NIPT was introduced as a second‐tier test for high‐risk women after FCT (TRIDENT‐1 study). FCT uptake rose from 29.5% in 2013 to 34.2% in 2015 (P < .0001). After the introduction of NIPT as a first‐tier test for all women in April 2017 (TRIDENT‐2 study), FCT uptake declined significantly from 35.8% in 2016 to 2.6% in 2018 (P < .0001). NIPT uptake increased to 43.4% in 2018. Regionally, NIPT uptake ranged from 31.8% to 67.9%. Total uptake (FCT and NIPT) between 2007 and 2018 increased significantly from 14.8% to 45.9% (P < .0001). However, total uptake stabilized at 46% for both years of TRIDENT‐2 (April 2017‐March 2019).ConclusionsAn increase in total fetal aneuploidy screening uptake up to 45.9% was observed after the introduction of NIPT. Uptake appears to have stabilized within a year after introducing first‐tier NIPT.
Estimating the potential impact of implementing pre‐emptive pharmacogenetic testing in primary care across the UK
Authors: Youssef Essra , Kirkdale Charlotte L. , Wright David J. , Guchelaar Henk‐Jan , Thornley Tracey 
Published: January 2021

AimsPharmacogenetics (PGx) in the UK is currently implemented in secondary care for a small group of high‐risk medicines. However, most prescribing takes place in primary care, with a large group of medicines influenced by commonly occurring genetic variations. The goal of this study is to quantitatively estimate the volumes of medicines impacted by implementation of a population‐level, pre‐emptive pharmacogenetic screening programme for nine genes related to medicines frequently dispensed in primary care in 2019.MethodsA large community pharmacy database was analysed to estimate the national incidence of first prescriptions for 56 PGx drugs used in the UK for the period 1 January–31 December 2019. These estimated prescription volumes were combined with phenotype frequency data to estimate the occurrence of actionable drug–gene interactions (DGI) in daily practice in community pharmacies.ResultsIn between 19.1 and 21.1% (n = 5 233 353–5 780 595) of all new prescriptions for 56 drugs (n = 27 411 288 new prescriptions/year), an actionable drug–gene interaction (DGI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group and/or the Clinical Pharmacogenetics Implementation Consortium. In these cases, the DGI would result in either increased monitoring, guarding against a maximum ceiling dose or an optional or immediate drug/dose change. An immediate dose adjustment or change in drug regimen accounted for 8.6–9.1% (n = 2 354 058–2 500 283) of these prescriptions.ConclusionsActionable drug–gene interactions frequently occur in UK primary care, with a large opportunity to optimise prescribing.
HIV infection as a risk factor for vaginal dysbiosis, bacterial vaginosis, and candidosis in pregnancy: A matched case‐control study
Authors: Foessleitner Philipp , Petricevic Ljubomir , Boerger Isabell , Steiner Irene , Kiss Herbert , Rieger Armin , Touzeau‐Roemer Veronique , Farr Alex 
Published: January 2021

AbstractBackgroundThis study aimed to evaluate the vaginal microbiota of HIV‐positive pregnant women relative to HIV‐negative controls, and to compare their risk of vaginal dysbiosis, bacterial vaginosis, and vulvovaginal candidosis (VVC).MethodsThis is a nested matched case‐control study that analyzed data from women who received pregnancy care at our center from 2003 to 2014. Women routinely underwent screening for asymptomatic vaginal infections using phase microscopy on Gram‐stained smears. HIV‐positive women were assigned to the case group, and HIV‐negative women were assigned to the control group. Cases and controls were matched in a 1:4 ratio. Logistic regression was used to test whether HIV infection was associated with vaginal dysbiosis (Nugent score 4‐6), BV (Nugent score 7‐10), or VVC.ResultsOne hundred and twenty‐seven women were assigned to the case group, and 4290 were assigned to the control group (including 508 matched controls). Dysbiosis or BV was found in 29.9% of the cases and 17.6% of the controls. Women in the case group had increased risk of vaginal dysbiosis or BV (odds ratio [OR] 2.09, 95% confidence interval [CI], 1.30‐3.32, P = .002). The risk of VVC was also higher in the case group (OR 2.14, 95% CI, 1.22‐3.77, P = .008). The incidence of preterm birth did not differ significantly between the groups (cases: 8.7%; controls: 10%, P = .887).ConclusionsHIV‐positive women are at risk of vaginal dysbiosis, BV, and VVC during pregnancy. As imbalances of the vaginal microbiota can lead to preterm birth, screening and treatment of HIV‐positive pregnant women are warranted.
The human G protein‐coupled ATP receptor P2Y11 is a target for anti‐inflammatory strategies
Authors: Gruenbacher Georg , Gander Hubert , Dobler Gabriele , Rahm Andrea , Klaver Dominik , Thurnher Martin 
Published: January 2021

Background and PurposeThe ATP receptor P2Y11, which couples to Gq and Gs proteins, senses cell stress and promotes cytoprotective responses. P2Y11 receptors are upregulated during differentiation of M2 macrophages. However, it is unclear whether and how P2Y11 receptors contribute to the anti‐inflammatory properties of M2 macrophages.Experimental ApproachTranscriptome and secretome profiling of ectopic P2Y11 receptors was used to analyse their signalling and function. Findings were validated in human monocyte‐derived M2 macrophages. The suramin analogue NF340 and P2Y11 receptor‐knockout cells confirmed that agonist‐mediated responses were specific to P2Y11 receptor stimulation.Key ResultsTemporal transcriptome profiling of P2Y11 receptor stimulation showed a strong and tightly controlled response of IL‐1 receptors, including activation of the IL‐1 receptor target genes, IL6 and IL8. Secretome profiling confirmed the presence of IL‐6 and IL‐8 proteins and additionally identified soluble tumour necrosis factor receptor 1 and 2 (sTNFR1 and sTNFR2) as targets of P2Y11 receptor activation. Raised levels of intracellular cAMP in M2 macrophages, after inhibition of phosphodiesterases (PDE), especially PDE4, strongly increased P2Y11 receptor‐induced release of sTNFR2 through ectodomain shedding mediated by TNF‐α converting enzyme (TACE/ADAM17). Both IL‐1α and IL‐1ß synergistically enhanced P2Y11 receptor‐ induced IL‐6 and IL‐8 secretion and release of sTNFR2. During lipopolysaccharide‐induced activation of TLR4, which shares the downstream signalling pathway with IL‐1 receptors, P2Y11 receptors specifically prevented secretion of TNF‐α.Conclusions and ImplicationsTargeting P2Y11 receptors activates IL‐1 receptor signalling to promote sTNFR2 release and suppress TLR4 signalling to prevent TNF‐α secretion, thus facilitating resolution of inflammation.
A Little Autonomy Support Goes a Long Way: Daily Autonomy‐Supportive Parenting, Child Well‐Being, Parental Need Fulfillment, and Change in Child, Family, and Parent Adjustment Across the Adaptation to the COVID‐19 Pandemic
Authors: Neubauer Andreas B. , Schmidt Andrea , Kramer Andrea C. , Schmiedek Florian 
Published: January 2021

This study examined the effects of daily parental autonomy support on changes in child behavior, family environment, and parental well‐being across 3 weeks during the COVID‐19 pandemic in Germany. Day‐to‐day associations among autonomy‐supportive parenting, parental need fulfillment, and child well‐being were also assessed. Parents (longitudinal N = 469; Mage = 42.93, SDage = 6.40) of school children (6–19 years) reported on adjustment measures at two measurement occasions and completed up to 21 daily online questionnaires in the weeks between these assessments. Results from dynamic structural equation models suggested reciprocal positive relations among autonomy‐supportive parenting and parental need fulfillment. Daily parental autonomy support, parental need fulfillment, and child well‐being partially predicted change in adjustment measures highlighting the central role of daily parenting for children’s adjustment during the pandemic.
Pure red cell aplasia and re‐aggravation of myasthenia gravis as a result of early reduction of steroid and immunosuppressant after starting eculizumab: A case report
Authors: Yamazaki Jun , Ueta Yuki , Akiba Yuki , Taguchi Takeshi , Masuda Masayuki , Aizawa Hitoshi 
Published: January 2021

AbstractBackgroundEculizumab, a humanized monoclonal antibody against complement protein C5, has been approved for the treatment of myasthenia gravis (MG) in Japan since 2017. However, there are few reports on reducing the dose of prednisolone (PSL) and immunosuppressants after eculizumab administration.Case presentationA 78‐year‐old woman with thymoma‐associated MG received an extended thymectomy, and was subsequently treated with PSL and tacrolimus (TAC) for 5 years. She was admitted to the hospital for dysarthria and dysphagia. She developed dyspnea and required mechanical ventilation. High‐dose immunoglobulin therapy, high‐dose methylprednisolone therapy and plasmapheresis were carried out. She was weaned off the ventilator, but dysarthria and dysphagia remained. Meanwhile, eculizumab improved her symptoms significantly. A month after reducing the dosage of PSL and TAC, cervical muscle weakness was observed, followed by pure red cell aplasia. After increasing her PSL and TAC dosage, the patient’s symptoms improved.ConclusionsEculizumab might improve the acute phase of MG symptoms, but early reduction of PSL and TAC can aggravate MG pathology and lead to pure red cell aplasia. Autoimmune mechanisms other than the complement‐mediated mechanism might be involved in the development of pure red cell aplasia. We suggest that physicians should not reduce PSL and immunosuppressants quickly after eculizumab administration.
The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility
Authors: Cavarocchi Emma , Whitfield Marjorie , Chargui Ahmed , Stouvenel Laurence , Lorès Patrick , Coutton Charles , Arnoult Christophe , Santulli Pietro , Patrat Catherine , Thierry‐Mieg Nicolas , Ray Pierre F. , Dulioust Emmanuel , Touré Aminata 
Published: January 2021

AbstractAsthenozoospermia, defined by the absence or reduction of sperm motility, constitutes the most frequent cause of human male infertility. This pathological condition is caused by morphological and/or functional defects of the sperm flagellum, which preclude proper sperm progression. While in the last decade many causal genes were identified for asthenozoospermia associated with severe sperm flagellar defects, the causes of purely functional asthenozoospermia are still poorly defined. We describe here the case of an infertile man, displaying asthenozoospermia without major morphological flagellar anomalies and carrying a homozygous splicing mutation in SLC9C1 (sNHE), which we identified by whole‐exome sequencing. SLC9C1 encodes a sperm‐specific sodium/proton exchanger, which in mouse regulates pH homeostasis and interacts with the soluble adenylyl cyclase (sAC), a key regulator of the signalling pathways involved in sperm motility and capacitation. We demonstrate by means of RT‐PCR, immunodetection and immunofluorescence assays on patient's semen samples that the homozygous splicing mutation (c.2748 + 2 T > C) leads to in‐frame exon skipping resulting in a deletion in the cyclic nucleotide‐binding domain of the protein. Our work shows that in human, similar to mouse, SLC9C1 is required for sperm motility. Overall, we establish a homozygous truncating mutation in SLC9C1 as a novel cause of human asthenozoospermia and infertility.
Are marginal bone level changes around dental implants due to infection?
Authors: Coli Pierluigi , Jemt Torsten 
Published: January 2021

AbstractBackgroundPeri‐implant bone level values have been used as the clinical standard of reference to describe the status of a dental implant. Reduction of marginal bone levels in association with bleeding on probing have been claimed to be a sign of pathology and an indication of treatment needs.PurposeTo assess the available evidence that peri‐implant bone loss is caused by infection.Materials and methodsThis article is a narrative review on the interpretation of marginal bone level changes around dental implants as a consequence of infection.Results and conclusionsThere is evidence that plaque accumulation induces an inflammatory reaction in the peri‐implant soft tissues and that resumption of plaque control measures results in the reduction of the inflammation. Since plaque is always present in the oral cavity, a cause‐effect relationship between plaque accumulation and peri‐implantitis, defined as inflammation of the peri‐implant soft tissues associated with marginal bone loss has been difficult to validate and has not been proven so far. There is no evidence of the mechanisms involved in the tissue reactions resulting in the conversion from a state of an inevitable inflammation contained in the soft tissues to a state of inflammation involving the loss of peri‐implant marginal bone. There is today no consensus whether implants should be expected to be surrounded by tissues which are completely free from inflammation, or that an “immune‐driven”, chronic, subclinical inflammation should be expected at the foreign body implant. The infectious origin theory appears to be mainly supported by ligature‐induced experimental peri‐implantitis investigations in animal models that suffer of several methodological problems, and therefore, provide misleading information with regards to human clinical applications in large, routine populations.
Epilepsy enhance global efficiency of language networks in right temporal lobe gliomas
Authors: Fang Shengyu , Wang Yinyan , Jiang Tao 
Published: January 2021

AbstractAimsWe analyzed the resting state functional magnetic resonance images to investigate the alterations of neural networks in patients with glioma‐related epilepsy (GRE).MethodsFifty‐six patients with right temporal lower‐grade glioma were divided into GRE (n = 28) and non‐GRE groups. Twenty‐eight healthy subjects were recruited after matching age, sex, and education level. Sensorimotor, visual, language, and left executive control networks were applied to generate functional connectivity matrices, and their topological properties were investigated.ResultsNo significant alterations in functional connectivity were found. The least significant discovery test revealed differences only in the language network. The shortest path length, clustering coefficient, local efficiency, and vulnerability were greater in the non‐GRE group than in the other groups. The nodal efficiencies of two nodes (mirror areas to Broca and Wernicke) were weaker in the non‐GRE group than in the other groups. The node of degree centrality (Broca), nodal local efficiency (Wernicke), and nodal clustering coefficient (temporal polar) were greater in the non‐GRE group than in the healthy group.ConclusionDifferent tumor locations alter different neural networks. Temporal lobe gliomas in the right hemisphere altered the language network. Glioma itself and GRE altered the network in opposing ways in patients with right temporal glioma.
Gut dysbiosis in stroke and its implications on Alzheimer’s disease‐like cognitive dysfunction
Authors: Cho Justin , Park You Jeong , Gonzales‐Portillo Bella , Saft Madeline , Cozene Blaise , Sadanandan Nadia , Borlongan Cesar V. 
Published: January 2021

AbstractVarious neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut‐brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut‐brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell‐based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut‐microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes.
Gene therapy for diabetic peripheral neuropathy: A randomized, placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor
Authors: Kessler John A. , Shaibani Aziz , Sang Christine N. , Christiansen Mark , Kudrow David , Vinik Aaron , Shin Nari ,   the VM202 study group
Published: January 2021

AbstractVM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study.
Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN.

WHAT QUESTION DID THIS STUDY ADDRESS?
Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Nonviral gene therapy can be used safely and practically to treat DPN.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.
Safety and effectiveness of linagliptin in Korean patients with type 2 diabetes: A postmarketing surveillance study
Authors: Bae Jaehyun , Song Kee‐Ho , Park Jong Suk , Lee Jae Hyuk , Jeong In‐Kyung , Kim Hyun Jin , Lim Young‐Hyo , Cho Jae‐Hyoung , Choi Sung Hee , Chung Yoon‐Sok , Kang Eun Seok 
Published: January 2021

AbstractWe designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was −0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.