Synaptic signalling in a network of dopamine neurons:What prevents proper inter-cellular crosstalk?

Open access via the Jisc Wiley Agreement Acknowledgements: This work was supported by the Chancellor’s Fellow Grant and the Moray Endowment Grant to SS. YC and TK were supported by Medical Research Council (Award Number: MR/K017276/1) and UK Centre for Mammalian Synthetic Biology. The authors gratefully acknowledge the financial support of NHS Research Scotland (NRS), through Edinburgh Clinical Research Facility. Authors thank Prof. Andrey Abramov (UCL) for his valuable suggestions on design of this study and Scott Denham from the Mass Spectrometry Core for his technical expertise and assistance in this work.Peer reviewedPublisher PD

Adverse pregnancy and neonatal outcomes associated with <i>Neisseria gonorrhoeae:</i> systematic review and meta-analysis.

ObjectiveTo examine associations between Neisseria gonorrhoeae (NG) infection during pregnancy and the risk of preterm birth, spontaneous abortion, premature rupture of membranes, perinatal mortality, low birth weight and ophthalmia neonatorum.Data sourcesWe searched Medline, EMBASE, the Cochrane Library and Cumulative Index to Nursing and Allied Health Literature for studies published between 1948 and 14 January 2020.MethodsStudies were included if they reported testing for NG during pregnancy and compared pregnancy, perinatal and/or neonatal outcomes between women with and without NG. Two reviewers independently assessed papers for inclusion and extracted data. Risk of bias was assessed using established checklists for each study design. Summary ORs with 95% CIs were generated using random effects models for both crude and, where available, adjusted associations.ResultsWe identified 2593 records and included 30 in meta-analyses. Women with NG were more likely to experience preterm birth (OR 1.55, 95% CI 1.21 to 1.99, n=18 studies); premature rupture of membranes (OR 1.41, 95% CI 1.02 to 1.92, n=9); perinatal mortality (OR 2.16, 95% CI 1.35 to 3.46, n=9); low birth weight (OR 1.66, 95% CI 1.12 to 2.48, n=8) and ophthalmia neonatorum (OR 4.21, 95% CI 1.36 to 13.04, n=6). Summary adjusted ORs were, for preterm birth 1.90 (95% CI 1.14 to 3.19, n=5) and for low birth weight 1.48 (95% CI 0.79 to 2.77, n=4). In studies with a multivariable analysis, age was the variable most commonly adjusted for. NG was more strongly associated with preterm birth in low-income and middle-income countries (OR 2.21, 95% CI 1.40 to 3.48, n=7) than in high-income countries (OR 1.38, 95% CI 1.04 to 1.83, n=11).ConclusionsNG is associated with a number of adverse pregnancy and newborn outcomes. Further research should be done to determine the role of NG in different perinatal mortality outcomes because interventions that reduce mortality will have the greatest impact on reducing the burden of disease in low-income and middle-income countries.Prospero registration numberCRD42016050962

Primary trabeculectomy versus primary glaucoma eye drops for newly diagnosed advanced glaucoma: TAGS RCT

Background: Patients diagnosed with advanced primary open-angle glaucoma are at a high risk of lifetime blindness. Uncertainty exists about whether primary medical management (glaucoma eye drops) or primary surgical treatment (augmented trabeculectomy) provide the best and safest patient outcomes. // Objectives: To compare primary medical management with primary surgical treatment (augmented trabeculectomy) in patients with primary open-angle glaucoma presenting with advanced disease in terms of health-related quality of life, clinical effectiveness, safety and cost-effectiveness. // Design: This was a two-arm, parallel, multicentre, pragmatic randomised controlled trial. // Setting: Secondary care eye services. // Participants: Adult patients presenting with advanced primary open-angle glaucoma in at least one eye, as defined by the Hodapp–Parrish–Anderson classification of severe glaucoma. // Intervention: Primary medical treatment – escalating medical management with glaucoma eye drops. Primary trabeculectomy treatment – trabeculectomy augmented with mitomycin C. // Main outcome measures: The primary outcome was health-related quality of life measured with the Visual Function Questionnaire-25 at 2 years post randomisation. Secondary outcomes were mean intraocular pressure; EQ-5D-5L; Health Utilities Index 3; Glaucoma Utility Index; cost and cost-effectiveness; generic, vision-specific and disease-specific health-related quality of life; clinical effectiveness; and safety. // Results: A total of 453 participants were recruited. The mean age of the participants was 67 years (standard deviation 12 years) in the trabeculectomy arm and 68 years (standard deviation 12 years) in the medical management arm. Over 65% of participants were male and more than 80% were white. At 24 months, the mean difference in Visual Function Questionnaire-25 score was 1.06 (95% confidence interval –1.32 to 3.43; p = 0.383). There was no evidence of a difference between arms in the EQ-5D-5L score, the Health Utilities Index or the Glaucoma Utility Index. At 24 months, the mean intraocular pressure was 12.40 mmHg in the trabeculectomy arm and 15.07 mmHg in the medical management arm (mean difference –2.75 mmHg, 95% confidence interval –3.84 to –1.66 mmHg; p < 0.001). Fewer types of glaucoma eye drops were required in the trabeculectomy arm. LogMAR visual acuity was slightly better in the medical management arm (mean difference 0.07, 95% confidence interval 0.02 to 0.11; p = 0.006) than in the trabeculectomy arm. There was no evidence of difference in safety between the two arms. A discrete choice experiment updated the utility values for the Glaucoma Utility Index. The within-trial economic analysis found a small increase in the mean EQ-5D-5L score (0.04) and that trabeculectomy has a higher probability of being cost-effective than medical management. The incremental cost of trabeculectomy per quality-adjusted life-year was £45,456. Therefore, at 2 years, surgery is unlikely to be considered cost-effective at a threshold of £20,000 per quality-adjusted life-year. When extrapolated over a patient’s lifetime in a model-based analysis, trabeculectomy, compared with medical treatment, was associated with higher costs (average £2687), a larger number of quality-adjusted life-years (average 0.28) and higher incremental cost per quality-adjusted life-year gained (average £9679). The likelihood of trabeculectomy being cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life year gained was 73%. // Conclusions: Our results suggested that there was no difference between treatment arms in health-related quality of life, as measured with the Visual Function Questionnaire-25 at 24 months. Intraocular pressure was better controlled in the trabeculectomy arm, and this may reduce visual field progression. Modelling over the patient’s lifetime suggests that trabeculectomy may be cost-effective over the range of values of society’s willingness to pay for a quality-adjusted life-year

CT scanning for diagnosing blunt ureteral and ureteropelvic junction injuries

<p>Abstract</p> <p>Background</p> <p>Blunt ureteral and ureteropelvic (UPJ) injuries are extremely rare and very difficult to diagnose. Many of these injuries are missed by the initial trauma evaluation.</p> <p>Methods</p> <p>Trauma registry data was used to identify all blunt trauma patients with ureteral or UPJ injuries, from 1 April 2001 to 30 November 2006. Demographics, injury information and outcomes were determined. Chart review was then performed to record initial clinical and all CT findings.</p> <p>Results</p> <p>Eight patients had ureteral or UPJ injuries. Subtle findings such as perinephric stranding and hematomas, and low density retroperitoneal fluid were evident on all initial scans, and prompted delayed excretory scans in 7/8 cases. As a result, ureteral and UPJ injuries were diagnosed immediately for these seven patients. These findings were initially missed in the eighth patient because significant associated visceral findings mandated emergency laparotomy. All ureteral and UPJ injuries have completely healed except for the case with the delay in diagnosis.</p> <p>Conclusion</p> <p>Most blunt ureteral and UPJ injuries can be identified if delayed excretory CT scans are performed based on initial CT findings of perinephric stranding and hematomas, or the finding of low density retroperitoneal fluid.</p

Reciprocity as a foundation of financial economics

This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics

Satisfação materna com o cuidado da enfermeira materno-infantil em Campeche, México

OBJECTIVE: Evaluate and compare maternal-satisfaction (global and areas) with maternal-child nursing care (MSMINC) and to explore the relationship of MSMINC with wait time, length of visit, and maternal age and education. METHODS: Cross-sectional descriptive study comprising 213 mothers. Group 1 (n = 84), mothers of children agedEl objetivo de este estudio fue evaluar y comparar la satisfacción materna (global/áreas) con el cuidado de la enfermera materno infantil (MSMINC) y explorar la relación de MSMINC con el tiempo de espera, duración de la visita, edad y educación materna. Se trata de un estudio descriptivo transversal. Participaron 213 madres. Grupo 1, n = 84 madres de niñosOBJETIVO: Avaliar e comparar a satisfação materna (global e áreas) com o cuidado da enfermeira materno-infantil (SMAEMI) e explorar a relação da SMAEMI com o tempo de espera e duração da visita, idade e educação da mãe. MÉTODOS: ESTUdo descritivo-transversal com a participação de 213 mães. Grupo 1, n = 84 mães de criança

The RESPITE trial: remifentanil intravenously administered patient-controlled analgesia (PCA) versus pethidine intramuscular injection for pain relief in labour: study protocol for a randomised controlled trial

Background The commonest opioid used for pain relief in labour is pethidine (meperidine); however, its effectiveness has long been challenged and the drug has known side effects including maternal sedation, nausea and potential transfer across the placenta to the foetus. Over a third of women receiving pethidine require an epidural due to inadequate pain relief. Epidural analgesia increases the risk of an instrumental vaginal delivery and its associated effects. Therefore, there is a clear need for a safe, effective, alternative analgesic to pethidine. Evidence suggests that remifentanil patient-controlled analgesia (PCA) reduces epidural conversion rates compared to pethidine; however, no trial has yet investigated this as a primary endpoint. We are, therefore, comparing pethidine intramuscular injection to remifentanil PCA in a randomised controlled trial. Methods/design Women in established labour, requesting systemic opioid pain relief, will be randomised to either intravenously administered remifentanil PCA (intervention) or pethidine intramuscular injection (control) in an unblinded, 1:1 individual randomised trial. Following informed consent, 400 women in established labour, who request systemic opioid pain relief, from NHS Trusts across England will undergo a minimised randomisation by a computer or automated telephone system to either pethidine or remifentanil. In order to balance the groups this minimisation is based on four parameters; parity (nulliparous versus multiparous), maternal age (<20, 20 < 30, 30 < 40, 40+ years), ethnicity (South Asian (Pakistani/Indian/Bangladeshi) versus Other) and induced versus spontaneous labour. The effectiveness of pain relief provided by each technique will be recorded every 30 min after time zero, until epidural placement, delivery or transfer to theatre, quantified by Visual Analogue Scale. Incidence of maternal side effects including sedation, delivery mode, foetal distress requiring delivery, neonatal status at delivery and rate of initiation of breastfeeding within the first hour of birth will also be recorded. Maternal satisfaction with her childbirth experience will be determined by a postpartum questionnaire prior to discharge from the delivery ward. Discussion The RESPITE trial’s primary outcome is the proportion of women who have an epidural placed for pain relief in labour in each arm. Trial Registration Current Controlled Trials registration number: ISRCTN29654603. Registered on 23 July 2013

Routes for breaching and protecting genetic privacy

We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.Comment: Draft for comment