bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentially repurposable drugs for schizophrenia identified from its interactome
Authors: Karunakaran Kalyani B. , Chaparala Srilakshmi , Ganapathiraju Madhavi K. 
Published: October 2018

AbstractFrom the schizophrenia drug-target interactome,1we studied the drugs that targeted multiple proteins in the interactome, or those that target proteins with many targets, or those that target novel (computationally predicted) interactors of schizophrenia associated proteins. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the selected drugs using the NextBio software suite, and shortlisted those that had a negative correlation with gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes which were differentially expressed on drug treatment, and had an anti-correlation with gene expression in schizophrenia, were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had pathophysiological overlap with schizophrenia. Drugs that are structurally similar to the shortlisted drugs, or targeted the same genes as these drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis may help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development, facing a high failure rate.
Retracted: Nifedipine alone or combined with sildenafil citrate for management of threatened preterm labour: a randomised trial
Authors: Maher MA , Sayyed TM , El‐khadry SW 
Published: October 2018

ObjectiveTo study the tocolytic action of nifedipine combined with sildenafil citrate (SC) and if the combination is superior to nifedipine alone in inhibiting threatened preterm labour (PTL).DesignProspective randomised study.SettingAn Egyptian university hospital.PopulationWomen with threatened PTL who received either nifedipine with SC or nifedipine alone.MethodsPatients were randomly allocated to receive either (1) nifedipine 20 mg orally (stat dose), followed by 10 mg orally every 6–8 hours at the same time as vaginal administration of SC (25 mg at 8‐hourly intervals) or (2) nifedipine alone. Medications were continued for 48–72 hours.Main outcome measuresThe percentage of women who remained undelivered during hospitalisation.ResultsFrom January 2015 to November 2016, 239 women were randomised. The baseline characteristics of participants were similar. Nifedipine combined with SC was associated with more women remaining undelivered (81.8 versus 68.6%; P = 0.018) during hospitalisation. Regarding secondary outcomes, the addition of SC was also associated with fewer deliveries within 7 days of admission (9.1 versus 20.3%; P = 0.014), prolonged latency (29 versus 7 days; P = 0.002), fewer admissions to neonatal intensive care units (31.4 versus 44.1%; P = 0.043), fewer very preterm deliveries (from 28 to <32 weeks, 20.7 versus 38.1%; P = 0.043), and increased neonatal birthweight (1900 versus 1500 g; P = 0.018).ConclusionsVaginal SC combined with nifedipine is an effective option for tocolytic therapy during threatened PTL.Tweetable abstractVaginal SC enhances the tocolytic effect of nifedipine.
Environmental impact assessments can misrepresent species distributions: a case study of koalas in Queensland, Australia
Authors: Cristescu R. H. , Scales K. L. , Schultz A. J. , Miller R. L. , Schoeman D. S. , Dique D. , Frère C. H. 
Published: October 2018

AbstractVegetation clearing has been implicated as a major contributor to biodiversity loss. It therefore stands to reason that developers should face a regulatory requirement to assess potential impacts and to avoid, mitigate and compensate for loss of vegetation wherever proposed infrastructure developments impact on vegetation considered to be habitat for threatened species. Environmental Impact Assessments (EIA) rely on accurate information to describe the distributions of threatened species within the footprint of proposed infrastructure developments, which is critical to ensuring appropriate mitigation of potentially deleterious impacts on these populations. EIA survey guidelines seek to determine species’ presence accurately, while acknowledging the limits imposed by time and budget constraints. As such, the EIA guidelines may recommend: (1) stratifying the landscape based on previous knowledge of habitat variables relevant to a species; and (2) targeting survey effort to strata with high probability of occupancy. Here, we use koala Phascolarctos cinereus surveys as a case study to explore the extent to which application of EIA guidelines result in accurate occupancy estimates. We compared the presence/absence distribution across one landscape survey and three EIA surveys, and found that koala occupancy was not well predicted by koala habitat criteria widely used to inform sampling design. In the context of EIA, we provide an example of how targeting survey effort to strata with high probability of occupancy risks misrepresenting true occurrence patterns. A general issue with survey designs that rely on previous knowledge is that they self‐reinforce erroneous assumptions. Our findings stand as a warning that EIA might neither quantify the impact of proposed infrastructure developments adequately, nor inform the ensuing mitigation measures. Threatened species’ protection in the face of infrastructure development will require new approaches to EIAs to ensure that providers are enabled to undertake comprehensive environmental surveys capable of detecting priority species.
Comparison of nicotine exposure during pregnancy when smoking and abstinent with nicotine replacement therapy: systematic review and meta‐analysis
Authors: Hickson Charlotte , Lewis Sarah , Campbell Katarzyna Anna , Cooper Sue , Berlin Ivan , Claire Ravinder , Oncken Cheryl , Coleman‐Haynes Tom , Coleman Tim 
Published: October 2018

AbstractBackground and aimsSmoking during pregnancy is strongly associated with negative pregnancy and perinatal outcomes. Some guidelines recommend nicotine replacement therapy (NRT) for smoking cessation during pregnancy, but adherence with NRT is generally poor and could be partially explained by nicotine‐related safety concerns. We compared pregnant women's cotinine and nicotine exposures from smoking with those when they were abstinent from smoking and using NRT.DesignSystematic review with meta‐analysis and narrative reporting. Twelve studies were included: in most, only one type of NRT was used. Seven were quality‐assessed and judge of variable quality.SettingStudies from any setting that reported nicotine or cotinine levels when smoking and later when abstinent and using NRT.ParticipantsPregnant women who smoked and became abstinent but used NRT either in a cessation study or in a study investigating other impacts of NRT.MeasurementsWe quality‐assessed longitudinal cohort studies using a modified version of the Newcastle–Ottawa scale. For meta‐analysis, we used mean within‐person differences in cotinine or nicotine levels when smoking and at later follow‐up when abstinent and using NRT. Where such data were not available, we calculated differences in group mean levels and reported these narratively, indicating where data were not completely longitudinal.FindingsOf the 12 included studies, four cotinine‐measuring studies (n = 83) were combined in a random effects meta‐analysis; the pooled estimate for the mean difference (95% confidence intervals) in cotinine levels between when women were smoking and abstinent but using NRT was 75.3 (57.1 to 93.4) ng/ml (I2 = 42.1%, P = 0.11). Of eight narratively‐described studies, six reported lower cotinine and/or nicotine levels when abstinent and using NRT; two had mixed findings, with higher levels when abstinent but using NRT reported from at least one assay time‐point.ConclusionsPregnant women who use nicotine replacement therapy instead of smoking reduce their nicotine exposure.
Implications of deranged activated partial thromboplastin time for anaesthesia and surgery
Authors: Loizou E. , Mayhew D. J. , Martlew V. , Murthy B. V. S. 
Published: October 2018

SummaryBleeding during and after surgery ranges from trivial to fatal. Bleeding is in part determined by the patient's coagulation status. The UK National Institute for Health and Care Excellence recommends a pre‐operative clotting test for patients with a history of abnormal bleeding. Anaesthetists are familiar with the prothrombin time assay, used to monitor warfarin effect, but anaesthetists may be less familiar with the activated partial thromboplastin time (APTT), which tests the function of the ‘intrinsic’ clotting pathway. The activated partial thromboplastin time may be prolonged due to contamination, anticoagulant therapy, clotting factor deficiencies, lupus anticoagulant or acquired inhibitors of specific clotting factors. A prolonged activated partial thromboplastin time should lead to: further testing to exclude heparin contamination or therapy, mixing studies to identify factor deficiencies and if necessary dynamic studies, such as the dilute Russell's viper venom time and the Actin FS‐activated partial thromboplastin time, to identify direct factor inhibitors. These tests identify abnormalities and their implications for bleeding, helping anaesthetists and haematologists to manage haemostasis for individual patients.
Body temperature, cutaneous heat loss and skin blood flow during epidural anaesthesia for emergency caesarean section
Authors: Mullington C. J. , Low D. A. , Strutton P. H. , Malhotra S. 
Published: October 2018

SummaryIt is not clear how converting epidural analgesia for labour to epidural anaesthesia for emergency caesarean section affects either cutaneous vasomotor tone or mean body temperature. We hypothesised that topping up a labour epidural blocks active cutaneous vasodilation (cutaneous heat loss and skin blood flow decrease), and that as a result mean body temperature increases. Twenty women in established labour had body temperature, cutaneous heat loss and skin blood flow recorded before and after epidural top‐up for emergency caesarean section. Changes over time were analysed with repeated measures ANOVA. Mean (SD) mean body temperature was 36.8 (0.5)°C at epidural top‐up and 36.9 (0.6)°C at delivery. Between epidural top‐up and delivery, the mean (SD) rate of increase in mean body temperature was 0.5 (0.5) °C.h−1. Following epidural top‐up, chest (p < 0.001) and forearm (p = 0.004) heat loss decreased, but head (p = 0.05), thigh (p = 0.79) and calf (p = 1.00) heat loss did not change. The mean (SD) decrease in heat loss was 15 (19) % (p < 0.001). Neither arm (p = 0.06) nor thigh (p = 0.10) skin blood flow changed following epidural top‐up. Despite the lack of change in skin blood flow, the most plausible explanation for the reduction in heat loss and the increase in mean body temperature is blockade of active cutaneous vasodilation. It is possible that a similar mechanism is responsible for the hyperthermia associated with labour epidural analgesia.
Activin A target genes are differentially expressed between normal and neoplastic adult human testes: clues to gonocyte fate choice
Authors: Szarek M. , Bergmann M. , Konrad L. , Schuppe H.‐C. , Kliesch S. , Hedger M. P. , Loveland K. L. 
Published: October 2018

AbstractBackgroundHuman testicular germ cell tumours (TGCT) arise from germ cell neoplasia in situ (GCNIS) cells that originate from foetal germ cell precursors. Activin A is central to normal foetal testis development, and its dysregulation may contribute to TGCT aetiology.Objective(i) To test whether the expression profiles of activin A targets in normal and neoplastic human testes indicates functional links with TGCT progression. (ii) To investigate whether activin A levels influence MMP activity in a neoplastic germ cell line.Materials and Methods(1) Bouin's fixed, paraffin‐embedded human testes were utilized for PCR‐based transcript analysis and immunohistochemistry. Samples (n = 5 per group) contained the following: (i) normal spermatogenesis, (ii) GCNIS or (iii) seminoma. CXCL12, CCL17, MMP2 and MMP9 were investigated. (2) The human seminoma‐derived TCam‐2 cell line was exposed to activin A (24 h), and target transcripts were measured by qRT‐PCR (n = 4). ELISA (n = 4) and gelatin zymography (n = 3) showed changes in protein level and enzyme activity, respectively.Results(i) Cytoplasmic CXCL12 was detected in Sertoli and other somatic cells, including those surrounding seminoma cells. Anti‐CCL17 labelled only the cytoplasm of Sertoli cells surrounding GCNIS, while anti‐MMP2 and anti‐MMP9 labelled germline and epithelial‐like cells in normal and neoplastic testes. (ii) Exposing TCam‐2 cells to activin A (50 ng/mL) elevated MMP2 and MMP9 transcripts (fourfold and 30‐fold), while only MMP2 protein levels were significantly higher after activin A (5 ng/mL and 50 ng/mL) exposure. Importantly, gelatin zymography revealed activin A increased production of activated MMP2.DiscussionDetection of CCL17 only in GCNIS tumours may reflect a change in Sertoli cell phenotype to a less mature state. Stimulation of MMP2 activity by activin A in TCam‐2 cells suggests activin influences TGCT by modulating the tumour niche.ConclusionThis knowledge provides a basis for understanding how physiological changes that influence activin/TGF‐β superfamily signalling may alter germ cell fate.
Heterogeneity in arterial hypertension and ocular perfusion pressure definitions: Towards a consensus on blood pressure‐related parameters for glaucoma studies
Authors: Barbosa‐Breda João , Abegão‐Pinto Luis , Van Keer Karel , Jesus Danilo A. , Lemmens Sophie , Vandewalle Evelien , Rocha‐Sousa Amândio , Stalmans Ingeborg 
Published: October 2018

AbstractPurposeGlaucoma studies have long taken into account the blood pressure (BP) status of patients. This study summarizes and evaluates the impact of the different criteria that have been used for BP‐related variables in glaucoma research.MethodsStudies included in two meta‐analyses that reviewed the role of BP in glaucoma were analyzed. Additional studies published after the search periods of the meta‐analyses were also included. Criteria for the definition of arterial hypertension and other BP‐related variables, such as mean arterial pressure (MAP) and mean ocular perfusion pressure (MOPP), were retrieved.ResultsSixty‐four studies were evaluated. One‐third used 140 mmHg as a systolic BP cut‐off to define hypertension, 20% used 160 mmHg and the remaining half used various other criteria. Less than 20% of studies reported MAP and/or MOPP. While eight of the ten studies reporting MAP used a correct formula that only happened for five of the eleven studies reporting MOPP. Using as an example average blood pressure values, incorrectly used formulas could have led to an overestimation of more than 100% of the expected values.ConclusionConsiderable heterogeneity exists in BP‐related variables in glaucoma research and different definitions can lead to large disparities. Glaucoma research would benefit from a consensus regarding blood pressure parameters.
Acceleration of cancer science with genome editing and related technologies
Authors: Sakuma Tetsushi , Yamamoto Takashi 
Published: October 2018

Genome editing includes various edits of the genome, such as short insertions and deletions, substitutions, and chromosomal rearrangements including inversions, duplications, and translocations. These variations are based on single or multiple DNA double‐strand break (DSB)‐triggered in cellulo repair machineries. In addition to these “conventional” genome editing strategies, tools enabling customized, site‐specific recognition of particular nucleic acid sequences have been coming into wider use; for example, single base editing without DSB introduction, epigenome editing with recruitment of epigenetic modifiers, transcriptome engineering using RNA editing systems, and in vitro detection of specific DNA and RNA sequences. In this review, we provide a quick overview of the current state of genome editing and related technologies that multilaterally contribute to cancer science.
Role of triggering receptor expressed on myeloid cells 2 in neuroinflammation and neurodegeneration of the central nervous system
Authors: Takahashi Kazuya 
Published: October 2018

AbstractTriggering receptor expressed on myeloid cells 2 (TREM2) is a member of the TREM family of innate immune receptors. It is expressed on the cell membrane of myeloid lineage cells including osteoclasts and microglia. Since it was reported that rare TREM2 variants, such as R47H and R62H, increase the risk of late‐onset Alzheimer's disease, it has been pointed out that many TREM2 variants relate to other neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and frontotemporal dementia. Although there are still conflicting reports as to whether TREM2 promotes or suppresses neurodegenerative or neuroinflammatory diseases, TREM2 has recently been considered to play a key role in the concept of disease‐associated microglia. In disease‐associated microglia induction, TREM2 might have a role as a microglia‐specific checkpoint.
Early development of visual attention in infants in rural Malawi
Authors: Pyykkö Juha , Forssman Linda , Maleta Kenneth , Ashorn Per , Ashorn Ulla , Leppänen Jukka M. 
Published: October 2018

AbstractEye tracking research has shown that infants develop a repertoire of attentional capacities during the first year. The majority of studies examining the early development of attention comes from Western, high‐resource countries. We examined visual attention in a heterogeneous sample of infants in rural Malawi (N = 312–376, depending on analysis). Infants were assessed with eye‐tracking‐based tests that targeted visual orienting, anticipatory looking, and attention to faces at 7 and 9 months. Consistent with prior research, infants exhibited active visual search for salient visual targets, anticipatory saccades to predictable events, and a robust attentional bias for happy and fearful faces. Individual variations in these processes had low to moderate odd‐even split‐half and test‐retest reliability. There were no consistent associations between attention measures and gestational age, nutritional status, or characteristics of the rearing environment (i.e., maternal cognition, psychosocial well‐being, socioeconomic status, and care practices). The results replicate infants’ early attentional biases in a large, unique sample, and suggest that some of these biases (e.g., bias for faces) are pronounced in low‐resource settings. The results provided no evidence that the initial manifestation of infants’ attentional capacities is associated with risk factors that are common in low‐resource environments.
Average e′ velocity on transthoracic echocardiogram is a novel predictor of left atrial appendage sludge or thrombus in patients with atrial fibrillation
Authors: Garshick Michael S. , Mulliken Jennifer , Schoenfeld Matthew , Riedy Katherine , Guo Yu , Zhong Judy , Dodson John A. , Saric Muhamed , Skolnick Adam H. 
Published: October 2018

BackgroundStudies have demonstrated the value of transthoracic echocardiogram (TTE) diastolic parameters in predicting left atrial appendage (LAA) thrombus; however, these studies have been small. We aim to clarify the relationship between TTE diastolic parameters, in particular average e′, and LAA thrombus or sludge.MethodsA case‐control review was conducted of subjects with non‐valvular atrial fibrillation (n = 2263) who had undergone TEE (transesophageal echocardiogram) and had a TTE within 1 year of TEE. Cases of LAA sludge or thrombus were matched to controls by age, sex, left ventricular ejection fraction (LVEF), and anticoagulation status.ResultsForty‐three subjects (mean age 73 ± 12, 65% male, LVEF 47%, 44% on anticoagulation) with LAA sludge or thrombus were identified. Compared to matched controls, average TTE e′ (7.3 ± 2.1 cm/s vs 8.7 ± 2.1 cm/s, P < 0.001) and the E:e′ ratio (15 ± 7 cm/s vs 12 ± 5 cm/s; P = 0.005) were significant predictors of LAA sludge or thrombus. Average TTE e′ value of >11 cm/s had 100% sensitivity for ruling out LAA sludge or thrombus.ConclusionIn individuals with atrial fibrillation, average e′ >11 cm/s on TTE is a promising independent predictor of the absence of LAA sludge or thrombus on TEE.
Right atrial to left atrial volume index ratio is associated with increased mortality in patients with pulmonary hypertension
Authors: Mysore Manu M. , Bilchick Kenneth C. , Ababio Priscilla , Ruth Benjamin K. , Harding William C. , Breathett Khadijah , Chadwell Kimberley , Patterson Brandy , Mwansa Hunter , Jeukeng Christiana M. , Kwon Younghoon , Kennedy Jamie L. W. , Mihalek Andrew D. , Mazimba Sula 
Published: October 2018

BackgroundPulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance leading to right heart failure. Elevated right atrial (RA) pressure reflects right ventricular (RV) pressure overload and is an established risk factor for mortality in PH. We hypothesized that PH patients with an increased ratio of RA to LA volume index (RAVI/LAVI), would have increased mortality.MethodsWe evaluated the association of RAVI/LAVI with mortality in 124 patients seen at a single academic center's PH clinic after adjusting for the REVEAL risk score, an established risk score in PH. LA and RA volume indices were measured in the four‐and two‐chamber views by two independent researchers. Multivariable logistic regression was used to model the independent association of RAVI/LAVI with survival.ResultsAmong 124 patients (mean age 62 ± 12.7 years, 68.6% female), each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.91, 95% CI: 1.20–3.04). In a multivariable logistic regression, each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.73, 95% CI: 1.003–2.998). Furthermore, RAVI/LAVI in the highest quartile (>1.42) was significantly associated with elevated right atrial pressure (RAP) to pulmonary artery wedge pressure ratio (RAP/PAWP) (0.76 ± 0.41, P = 0.02) compared with the lowest quartile (<0.77), suggesting an interaction between invasive hemodynamic data, atrial structural changes, and mortality in PH.ConclusionsIncreased RAVI/LAVI in PH is associated with decreased survival and accounts for atrial structural remodeling related to invasive hemodynamics. These findings support further study of this index in predicting outcomes in PH.