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Summary: Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference −0.17, 95% CI −0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Background The relationship between COVID‐19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID‐19, defined as hospitalization with COVID‐19 requiring respiratory support or resulting in death. Cross‐trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID‐19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID‐19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C‐reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID‐19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID‐19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C‐reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID‐19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID‐19 liability 1.03, 95% CI 1.00–1.06, P‐value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID‐19. Conclusions These data support that liability to critical COVID‐19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID‐19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

Abstract Background Many adverse pregnancy outcomes in the UK could be prevented with better intrapartum care. Training for intrapartum emergencies has been widely recommended but there are conflicting data about their effectiveness. Observational studies have shown sustained local improvements in perinatal outcomes associated with the use of the PRactical Obstetric Multi-Professional Training – (PROMPT) training package. However this effect needs to be investigated in the context of randomised study design in settings other than enthusiastic early adopter single-centres. The main aim of this study is to determine the effectiveness of PROMPT to reduce the rate of term infants born with low APGAR scores. Methods THISTLE (Trial of Hands-on Interprofessional Simulation Training for Local Emergencies) is a multi-centre stepped-wedge clustered randomised controlled superiority trial conducted across 12 large Maternity Units in Scotland. On the basis of prior observational findings all Units have been offered the intervention and have been randomly allocated in groups of four Units, to one of three intervention time periods, each six months apart. Teams of four multi-professional clinicians from each participating Unit attended a two-day PROMPT Train the Trainers (T3) programme prior to the start of their allocated intervention step. Following the T3 training, the teams commenced the implementation of local intrapartum emergency training in their own Units by the start of their allocated intervention period. Blinding has not been possible due to the nature of the intervention. The aim of the study is to follow up each Unit for at least 12-months after they have commenced their local courses. The primary outcome for the study is the proportion of Apgar scores

BackgroundConcerns have been raised that a lack of senior obstetricians ("consultants") on the labour ward outside normal hours may lead to worse outcomes among babies born during periods of reduced cover.Methods and findingsWe carried out a multicentre cohort study using data from 19 obstetric units in the United Kingdom between 1 April 2012 and 31 March 2013 to examine whether rates of obstetric intervention and outcome change "out-of-hours," i.e., when consultants are not providing dedicated, on-site labour ward cover. At the 19 hospitals, obstetric rotas ranged from 51 to 106 h of on-site labour ward cover per week. There were 87,501 singleton live births during the year, and 55.8% occurred out-of-hours. Women who delivered out-of-hours had slightly lower rates of intrapartum caesarean section (CS) (12.7% versus 13.4%, adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.90 to 0.98) and instrumental delivery (15.6% versus 17.0%, adj. OR 0.92; 95% CI 0.89 to 0.96) than women who delivered at times of on-site labour ward cover. There was some evidence that the severe perineal tear rate was reduced in out-of-hours vaginal deliveries (3.3% versus 3.6%, adj. OR 0.92; 95% CI 0.85 to 1.00). There was no evidence of a statistically significant difference between out-of-hours and "in-hours" deliveries in the rate of babies with a low Apgar score at 5 min (1.33% versus 1.25%, adjusted OR 1.07; 95% CI 0.95 to 1.21) or low cord pH (0.94% versus 0.82%; adjusted OR 1.12; 95% CI 0.96 to 1.31). Key study limitations include the potential for bias by indication, the reliance upon an organisational measure of consultant presence, and a non-random sample of maternity units.ConclusionsThere was no difference in the rate of maternal and neonatal morbidity according to the presence of consultants on the labour ward, with the possible exception of a reduced rate of severe perineal tears in out-of-hours vaginal deliveries. Fewer women had operative deliveries out-of-hours. Taken together, the available evidence provides some reassurance that the current organisation of maternity care in the UK allows for good planning and risk management. However there is a need for more robust evidence on the quality of care afforded by different models of labour ward staffing.

Nonnus composed both the Dionysiaca and the Paraphrase of John, and in that order; he is distinct from Nonnus of Edessa and from the Nonnus who appears in the Life of Pelagia the Harlot.

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Meleager’s anthology probably consisted of four books, each on a distinctive theme; Philip’s sequence was alphabetical, but only for the first letter and with some thematic ordering within each alphabetic section.

Background: The incidence of nodular melanoma (NM) has been consistently described as at least 10-15% of total melanomas for over 15 years despite advances in diagnostic algorithms and medical technology. NMs are strongly correlated with faster rates of growth and poorer prognosis and thus provide clinicians with a challenge for early recognition. Objective: To evaluate diagnostic clues of consecutive histopathologically proven NMs in one general practice with particular emphasis on dermatoscopic characteristics and compare this to the published literature. Method: A retrospective observational study was performed of five consecutive histologically proven NM, from a total of 212 consecutive melanomas from a general practice in Brisbane, Queensland, Australia. Dermatoscopic images, both polarized and non-polarized, which appears to be a unique resource, and dermatopathologic slides were available for all lesions. Results: All of the NMs in this series were pigmented although one was hypomelanotic. Two of them were symmetrical. The most highly sensitive clues to NM were gray or blue structures and polarizing-specific white lines. Limitations: Due to the small number of NMs in this report no statistical significance can be attributed to the observational findings. Conclusion: This small series supports what is already known: that a significant proportion of NMs may be dermatoscopically symmetrical but that known clues to melanoma are frequently present.Nodular lesions, pigmented or non-pigmented, should be excised to exclude NM if there is any clue to malignancy, regardless of symmetry, unless a confident specific benign diagnosis can be made.

Balloon cell melanoma is a rare melanoma subtype, with only one previous case with dermatoscopy published. It is often non-pigmented, leading to diagnostic difficulty, and there is a tendency for lesions to be thick at diagnosis. We report a case of balloon cell melanoma on the forearm of a 61-year-old man with both polarized and non-polarized dermatoscopy and dermatopathology. It presented as a firm pale nodule with focal eccentric pigmentation. The clinical images evoke a differential diagnosis of dermatofibroma, dermal nevus, Spitz nevus and basal cell carcinoma as well as melanoma. This melanoma was partially pigmented due to a small, pigmented superficial spreading component on the edge of the non-pigmented balloon cell nodule, prompting further evaluation. In retrospect there was the clue to malignancy of polarizing-specific white lines (chrysalis structures) and polymorphous vessels, including a pattern of dot vessels. The reticular lines exclude basal cell carcinoma, polarizing-specific white lines are inconsistent with the diagnosis of dermal nevus and their eccentric location is inconsistent with both Spitz nevus and dermatofibroma. Excision biopsy was performed, revealing a superficial spreading melanoma with two distinct invasive components, one of atypical non-mature epithelioid cells and the other an amelanotic nodular component, comprising more than 50% of the lesion, characterized by markedly distended epithelioid melanocytes showing pseudo-xanthomatous cytoplasmic balloon cell morphology. A diagnosis of balloon cell melanoma, Breslow thickness 1.9 mm, mitotic rate 3 per square millimeter was rendered. Wide local excision was performed, as was sentinel lymph node biopsy, which was negative.

While there are several published comprehensive stepwise algorithmic methods for diagnosing pigmented skin malignancy, only limited material has been published for the stepwise assessment of non-pigmented lesions. We present a method based on pattern analysis, with a stepwise assessment, first, for ulceration, second, for white clues (defined as white lines, or in the case of a raised lesion any of the keratin clues: dermatoscopic white circles, dermatoscopic white structureless areas or surface keratin), and third, if no ulceration or white clues are present, proceed to vessel pattern analysis. This is a novel method, and apart from the assessment of white clues in raised lesions, it has not been formally tested. The priority of keratin clues in raised lesions over vessel pattern analysis has, however, been verified. It is conceded that this method is less specific than methods which have clues of pigmented structures, and accepting these limitations, Prediction without Pigment is a decision algorithm intended to guide the clinician in the decision as to whether to perform a biopsy rather than consistently leading to a specific diagnosis. Reaching a more specific diagnosis at the end of our flowchart can be achieved by weighing of clues both clinical and dermatoscopic, and that ability can be expected to improve with both knowledge and experience, but no diagnostic method, including this one, can be 100% sensitive in diagnosing malignancy, in particular, melanoma. Taking these limitations into account, any non-pigmented lesion, regardless of pattern analysis, which is raised and firm (nodular) and for which a confident, specific benign diagnosis cannot be made, should be excised to exclude the nodular variant of amelanotic melanoma.

The incidence of gastroschisis, a congenital anomaly where the infant abdominal wall is defective and intestines protrude from the abdominal cavity, is increasing in many countries. The role of maternal stress in some adverse birth outcomes is now well established. We tested the hypothesis that major stressful life events in the first trimester are risk factors for gastroschisis, and social support protective, in a case-control study in the United Kingdom.Gastroschisis cases and three controls per case (matched for maternal age) were identified at routine 18-20 week fetal anomaly ultrasound scan, in 2007-2010. Face to face questionnaire interviews were carried out during the antenatal period (median 24 weeks gestation) asking about serious stressful events and social support in the first trimester. Data were analysed using conditional logistic regression.Two or more stressful life events in the first trimester (adjusted OR 4.9; 95% CI 1.2-19.4), and moving address in the first trimester (aOR 4.9; 95% CI 1.7-13.9) were strongly associated with risk of gastroschisis, independent of behavioural risk factors including smoking, alcohol, and poor diet. Perceived availability of social support was not associated with reduced risk of gastroschisis (aOR 0.8; 95% CI 0.2-3.1).Stressful maternal life events in the first trimester of pregnancy including change of address were strongly associated with a substantial increase in the risk of gastroschisis, independent of stress related high risk behaviours such as smoking, alcohol consumption and poor diet. This suggests that stress pathways are involved in the aetiology of gastroschisis.