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Abstract Background The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) questionnaires are commonly used to measure global cognition in clinical trials. Because these scales are discrete and bounded with ceiling and floor effects and highly skewed, their analysis as continuous outcomes presents challenges. Normality assumptions of linear regression models are usually violated, which may result in failure to detect associations with variables of interest. Methods Alternative approaches to analyzing the results of these cognitive batteries include transformations (standardization, square root, or log transformation) of the scores in the multivariate linear regression (MLR) model, the use of nonlinear beta-binomial regression (which is not dependent on the assumption of normality), or Tobit regression, which adds a latent variable to account for bounded data. We aim to empirically compare the model performance of all proposed approaches using four large randomized controlled trials (ORIGIN, TRANSCEND, COMPASS, and NAVIGATE-ESUS), and using as metrics the Akaike information criterion (AIC). We also compared the treatment effects for the methods that have the same unit of measure (i.e., untransformed MLR, beta-binomial, and Tobit). Results The beta-binomial consistently demonstrated superior model performance, with the lowest AIC values among nearly all the approaches considered, followed by the MLR with square root and log transformations across all four studies. Notably, in ORIGIN, a substantial AIC reduction was observed when comparing the untransformed MLR to the beta-binomial, whereas other studies had relatively small AIC reductions. The beta-binomial model also resulted in a significant treatment effect in ORIGIN, while the untransformed MLR and Tobit regression showed no significance. The other three studies had similar and insignificant treatment effects among the three approaches. Conclusion When analyzing discrete and bounded outcomes, such as cognitive scores, as continuous variables, a beta-binomial regression model improves model performance, avoids spurious significance, and allows for a direct interpretation of the actual cognitive measure. Trials registration ORIGIN (NCT00069784). Registered on October 1, 2003; TRANSCEND (NCT00153101). Registered on September 9, 2005; COMPASS (NCT01776424). Registered on January 24, 2013; NAVIGATE-ESUS (NCT02313909). Registered on December 8, 2014.

Abstract Background Mississippi (MS) experiences disproportionally high rates of new HIV infections and limited availability of pre-exposure prophylaxis (PrEP). Federally Qualified Health Centers (FQHCs) are poised to increase access to PrEP. However, little is known about the implementation strategies needed to successfully integrate PrEP services into FQHCs in MS. Purpose The study had two objectives: identify barriers and facilitators to PrEP use and to develop tailored implementation strategies for FQHCs. Methods Semi-structured interviews were conducted with 19 staff and 17 PrEP-eligible patients in MS FQHCs between April 2021 and March 2022. The interview was guided by the integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework which covered PrEP facilitators and barriers. Interviews were coded according to the i-PARIHS domains of context, innovation, and recipients, followed by thematic analysis of these codes. Identified implementation strategies were presented to 9 FQHC staff for feedback. Results Data suggested that PrEP use at FQHCs is influenced by patient and clinic staff knowledge with higher levels of knowledge reflecting more PrEP use. Perceived side effects are the most significant barrier to PrEP use for patients, but participants also identified several other barriers including low HIV risk perception and untrained providers. Despite these barriers, patients also expressed a strong motivation to protect themselves, their partners, and their communities from HIV. Implementation strategies included education and provider training which were perceived as acceptable and appropriate. Conclusions Though patients are motivated to increase protection against HIV, multiple barriers threaten uptake of PrEP within FQHCs in MS. Educating patients and providers, as well as training providers, are promising implementation strategies to overcome these barriers.

David John Mott,1 Jake Hitch,1,2 Samantha Nier,3 Zack Pemberton-Whiteley,3,4 Chris Skedgel1 1Office of Health Economics, London, UK; 2Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK; 3Acute Leukemia Advocates Network, Bern, Switzerland; 4Leukemia Care, Worcester, UKCorrespondence: David John Mott, Email dmott@ohe.orgBackground: Acute leukemia is a cancer of the white blood cells which progresses rapidly and aggressively. There are two types: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The latter has a rare subtype: acute promyelocytic leukemia (APL). For some patients, following first-line treatment, remission is not achieved (“refractory disease”), and for others the leukemia returns after achieving remission (“relapse”). For these individuals, outcomes are typically poor. It is, therefore, important to understand patients’ treatment priorities in this context.Methods: Building upon formative qualitative research, an online survey containing a discrete choice experiment (DCE) was designed to explore patients’ treatment preferences in the relapsed/refractory setting. The DCE attributes were mode of administration; quality of life during treatment; chance of response; duration of response; and quality of life during response. Each respondent completed twelve scenarios containing two hypothetical treatments. Participants were eligible if they lived in the United Kingdom and had a diagnosis of acute leukemia. The data were analysed using a latent class model.Results: A total of 95 patients completed the survey. The latent class analysis identified two classes. For both, chance of response was the most important attribute. For class 1, every attribute was important, whereas for class 2, the only important attributes were quality of life (during treatment and response) and chance of response. A greater proportion of respondents would fall into class 1 overall, and those with ALL or APL and those more recently diagnosed were more likely to be in class 2.Conclusion: Our results indicate that patients are strongly concerned about the chance of response, as well as quality of life (to a lesser extent), when faced with different treatment options in the relapsed/refractory setting. However, there is significant preference heterogeneity within the patient population, and other treatment characteristics also matter to many.Keywords: acute leukemia, hematology, oncology, patient preferences, discrete choice experiment

This pilot study investigated the feasibility of using magnetic resonance elastography (MRE) for the non-invasive detection and quantification of liver fibrosis in the Oncopig cancer model. Seven 8-week-old Oncopigs underwent alcoholic liver fibrosis induction and serial MRE imaging and liver biopsy at 1, 2, and 3 months post procedure. MRE was utilized to quantify liver stiffness, and liver fibrosis was histologically graded using the METAVIR system. The primary outcome measure was the capability to detect and quantify liver fibrosis using MRE with radiologic–pathologic correlation. Liver fibrosis induction, MRE imaging, and liver biopsy were successfully performed. MRE liver fibrosis was evident in 57% (4/7), 50% (3/6), and 40% (2/5) animal subjects 1, 2, and 3 months after fibrosis induction, with mean liver stiffness of 2.94, 3.25, and 2.91 kPa, respectively. Histological liver fibrosis was noted in 71% (5/7), 100% (5/5), and 100% (5/5) of animal subjects with available tissue samples. There was no significant statistical correlation between the MRE-measured liver stiffness and the METAVIR fibrosis scores. In conclusion, quantifiable liver fibrosis may be induced in the Oncopig. MRE has potential utility in non-invasively detecting liver stiffness in this large-animal preclinical model, though tissue biopsy was more sensitive in demonstrating disease.

A 42-year-old man presented with very large lower limb varicose veins bilaterally and an 8-month history of fainting when standing up from a squatting position. He had been investigated for syncope by a cardiologist with no abnormality found on electrocardiogram, echocardiogram, 24-h electrocardiogram or 48-h blood pressure monitoring. Venous duplex ultrasonography showed bilaterally great saphenous vein reflux, with each vein having a diameter of 23.5 and 24.0 mm at the groin, and a similar dilation along the whole vein to ankle. These veins were successfully ablated with endovenous laser ablation, immediately following which the syncope disappeared and has not returned. We calculate that before treatment, the patient had approximately 500 ml of blood refluxing passively with gravity from his deep venous system on standing into his incompetent great saphenous veins and associated varicosities, which would account for his postural syncope.

Abstract Background Management of adults with atrial fibrillation (AF) or atrial flutter in the emergency department (ED) includes rate reduction, cardioversion, and stroke prevention. Different approaches to these components of care may lead to variation in frequency of hospitalization and stroke prevention actions, with significant implications for patient experience, cost of care, and risk of complications. Standardization using evidence-based recommendations could reduce variation in management, preventable hospitalizations, and stroke risk. Methods We describe the rationale for our ED-based AF treatment recommendations. We also describe the development of an electronic clinical decision support system (CDSS) to deliver these recommendations to emergency physicians at the point of care. We implemented the CDSS at three pilot sites to assess feasibility and solicit user feedback. We will evaluate the impact of the CDSS on hospitalization and stroke prevention actions using a stepped-wedge cluster randomized pragmatic clinical trial across 13 community EDs in Northern California. Discussion We hypothesize that the CDSS intervention will reduce hospitalization of adults with isolated AF or atrial flutter presenting to the ED and increase anticoagulation prescription in eligible patients at the time of ED discharge and within 30 days. If our hypotheses are confirmed, the treatment protocol and CDSS could be recommended to other EDs to improve management of adults with AF or atrial flutter. Trial registration ClinicalTrials.gov NCT05009225 . Registered on 17 August 2021.

Madalitso M Mlozen,1,2 Jacqueline Van Marwijk,1 Brendan Shane Wilhelmi,1 Chris Whiteley1 1Department of Biochemistry and Microbiology, Rhodes University, Makhanda (Grahamstown), South Africa; 2Malawi Adventist University, Malamulo Campus, Department of Biomedical Sciences, Makwasa, MalawiCorrespondence: Madalitso M Mlozen, Malawi Adventist University, Malamulo campus, Department of Biomedical Sciences, P.O.Box 55, Makwasa, Tel +265 884628334, Email mlozenim@mchs.advenist.orgBackground: Regardless of the efforts to ease cases of human African trypanosomiasis (HAT), an increased number of cases get reported annually. This is because of drug resistant Trypanosoma brucei (Tb), the causative agent of the illness. This has renewed the need for creative methods to find new anti-trypanosomal drugs. The blood stream form (BSF) of the parasite depends exclusively on the glycolytic pathway for energy production while it is in the human host. Interruptions in this pathway efficiently kills the parasite. Trypanosoma brucei hexokinase (TbHK) is the first enzyme in glycolysis, and any effectors or inhibitors of TbHK would have potential as anti-trypanosomal agents.Methods: TbHK and human glucokinase (hGCK) were over-expressed with a 6 histidine-tag in E. coli BL21(DE3) cells having the pRARE2 plasmid.Results: TbHK had thermal and pH stability between 30°C and 55°C and 7.5 and 8.5, respectively, while hGCK exhibited thermal and pH stability between 30°C and 40°C and 7.0 and 8.0, respectively. Kinetically, TbHK had a Km of 39.3 μM, Vmax of 0.066 μmol.min− 1.mL− 1, kcat of 2.05 min− 1 and kcat/Km of 0.0526 min− 1.μmol− 1. hGCK exhibited a Km of 4.5 μM, Vmax of 0.032 μnmol.min− 1.mL− 1, kcat of 11.25 min− 1, and kcat/Km of 2.5 min− 1.μmol− 1. Interaction kinetic studies of silver nanoparticles (AgNPs) (0.1 μM) of average size of 6 nm with TbHK and hGCK were conducted. AgNPs selectively inhibited TbHK over hGCK. TbHK showed a non-competitive inhibition with a 50% and 28% decrease in Vmax, and kcat/km, respectively. HsGCK showed a 33% increase in affinity, 9% decrease in Vmax, and a 50% increase in enzyme efficiency.Conclusion: The observed pattern of hGCK and AgNPs falls under the uncompetitive inhibition. The observed highly selective inhibitory effects of AgNPs between TbHK and hGCK may be used in development of new anti-trypanosomal drugs.Keywords: nanoparticles, hexokinase, trypanosomiasis, nanomedicine

A 43-year-old woman presented with localised areas of prominent, tender superficial veins in her right arm and both legs, and chest pain, following the second dose of AstraZeneca vaccine and possible contemporaneous Covid-19 infection. Electrocardiogram, troponin and d -dimer had all been normal. However, a venous duplex ultrasound scan showed a perivenous inflammation without thrombosis in the areas of her limbs with prominent tender veins, but not elsewhere. We suggest that patients may present with prominent and tender superficial veins secondary to non-thrombotic phlebitis following Covid-19 infection or the AstraZeneca vaccine, which appears to be self-limiting. In addition, this case raises the possibility that Covid-19 infection or the AstraZeneca vaccine may directly affect cells in the vein wall, resulting in phlebitis without any evidence of thrombosis or microthrombosis. This phenomenon appears to be transient and self-limiting.

Abstract Background Outbreaks of infectious diseases generate outbreaks of scientific evidence. In 2016 epidemics of Zika virus emerged, and in 2020, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of coronavirus disease 2019 (COVID-19). We compared patterns of scientific publications for the two infections to analyse the evolution of the evidence. Methods We annotated publications on Zika virus and SARS-CoV-2 that we collected using living evidence databases according to study design. We used descriptive statistics to categorise and compare study designs over time. Results We found 2286 publications about Zika virus in 2016 and 21,990 about SARS-CoV-2 up to 24 May 2020, of which we analysed a random sample of 5294 (24%). For both infections, there were more epidemiological than laboratory science studies. Amongst epidemiological studies for both infections, case reports, case series and cross-sectional studies emerged first, cohort and case-control studies were published later. Trials were the last to emerge. The number of preprints was much higher for SARS-CoV-2 than for Zika virus. Conclusions Similarities in the overall pattern of publications might be generalizable, whereas differences are compatible with differences in the characteristics of a disease. Understanding how evidence accumulates during disease outbreaks helps us understand which types of public health questions we can answer and when.

A 70-year-old man presented to our vein clinic with intermittent and recurrent left testicular and groin pain, clinically resembling epididymo-orchitis. He had never had any genitourinary problems until contracting a severe flu-like illness in January 2020, strongly suspected to have been Covid-19. He had failed to respond on four separate occasions to antibiotics prescribed by his GP and had only responded on these occasions to aspirin. Duplex ultrasonography at our clinic showed thrombosis of the left testicular vein with venous collateral formation. The testicle itself showed mild oedema, but a reduced arterial flow supporting the pain to be secondary to thrombosis. Covid-19 is known to be associated with venous thromboembolic disease, but usually in patients sick enough to be hospitalised and particularly in those requiring intensive care. This man appears to have had a left testicular vein thrombosis secondary to relatively mild Covid-19 infection, as he did not require hospitalisation.

Abstract Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet therapy modifies the risks of recurrent ICH, major haemorrhagic events, major occlusive vascular events, or a composite of all major vascular events compared to avoiding antiplatelet therapy. Methods/design The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet therapy for adults surviving antithrombotic-associated ICH. Recruitment began on 22 May 2013 and ended on 31 May 2018. Follow-up ended on 30 November 2018. This update to the protocol describes the statistical analysis plan (version 1.7, finalised on 25 January 2019). Database lock and un-blinding occurred on 29 January 2019, after which the un-masked trial statistician conducted the final analyses according to this statistical analysis plan. Discussion Final results of RESTART will be analysed and disseminated in May 2019. Trial registration ISRCTN registry 71907627. Prospectively registered on 25 April 2013.

A 48-year-old woman attended to discuss a dilemma. She had suffered a cardiac arrest immediately following microsclerotherapy of leg telangiectasia with 0.3% aethoxysklerol. She had successful defibrillation and been transferred to hospital. In hospital, despite normal cardiac tests, she was diagnosed as having idiopathic cardiac arrest. The exposure to aethoxysklerol was discounted by her cardiologists as a cause of her arrest. Following the hospital protocol, she was strongly advised to have an implantable defibrillator. Cardiac arrest and myocardial infarction are documented after aethoxysklerol injection with proposed mechanisms being anaphylaxis, direct cardiotoxicity or endothelin-1 release. Before consenting to an implantable defibrillator, which may have its own complications in the long term, doctors and the patient need to be certain that this arrest was not due to a reaction to aethoxysklerol.

Objective Anterior cruciate ligament reconstruction (ACLR) predisposes footballers for subsequent ACL and hamstring (HS) injury. This case series examines HS muscle activation patterns during the running in ACLR patients (bone-patellar tendon-bone (BTB) and (HS) graft) after completion of functional criteria allowing return to training.Methods Electromyography (EMG) recorded from medial and lateral HS bilaterally during treadmill running (12, 14 and 16 km/hour) from 21 male ACLR patients on average 7 months from surgery (5-9) that underwent (HS) (n=12) or BTB reconstruction (n=9) were compared with 19 healthy runners. Main outcome measures: EMG signal was normalised to peak during the running. Pairwise comparisons were made for each muscle group examining stance and swing activation for mean and peak EMG for each patient group and leg.Results Significantly lower relative peak activation in stance (not swing) phase for medial HS was seen for all conditions with effect sizes ranging from −0.63 (controls, BTB non-injured leg) to −1.09 (HS injured). For lateral HS only BTB injured were significantly lower in stance phase (−1.05)Conclusion ACLR patients show neuromuscular alterations during different phases of running. The finding of reduced medial HS activity in stance phase might have implications for knee instability and HS muscle injury on resumption of sport.

Endovenous thermal ablation is a first-line treatment for symptomatic varicose veins due to truncal vein reflux. Ablation of an incompetent great saphenous vein is usually performed from distally, with the vein access at the lowest point of reflux, or just below the knee. Occasionally there are patients in whom the great saphenous vein is difficult to access distally for reasons such as small vein diameter, scar tissue, vasospasm, difficult anatomy or multiple attempts with haematoma formation. In such cases, we access the great saphenous vein in a retrograde fashion by percutaneous cannulation of the superficial inferior epigastric vein, passing the catheter into the great saphenous vein just distal to the saphenofemoral junction and then down the vein to the required distal position. Ablation can then be performed, stopping the ablation in the great saphenous vein just distal to the junction of superficial inferior epigastric vein and great saphenous vein. We present a patient to illustrate our technique.

Abstract Background Anxiety affects a quarter of strokes. It can be disabling even after mild stroke and transient ischaemic attack (TIA). It is not feasible to deliver conventional psychological therapies to the large population of anxious stroke and TIA patients. We are testing the feasibility of a web-enabled randomised controlled trial (RCT) to compare an individualised telemedicine cognitive behavioural therapy (CBT)-based intervention with a self-guided web-based relaxation programme. This study aims to evaluate the feasibility of novel trial procedures and the delivery of the TASK interventions in stroke and TIA patients. Methods We aim to recruit 40 community-based stroke and TIA patients experiencing anxiety at least 1 month post-discharge in Lothian, Scotland. We will assess the (1) recruitment number per month; (2) percentage completion of electronic consent; (3) time taken for remote eligibility confirmation; (4) percentage completion of follow-up surveys: modified Rankin scale, EuroQol-5D5L, 7-item generalised anxiety disorder, Patient Health Questionnaire-2 and modified fear questionnaire; (5) data capture of intervention fidelity and (6) use of actigraph smartwatches to obtain continuous data of rest/activity. Discussion The current study will provide feasibility data on streamlined web-enabled trial procedures and the use of smartwatches to obtain objective measures in stroke and TIA patients, offering potential for large efficient RCTs to be conducted centrally and remotely with far fewer resources in the future. This study will inform further refinements of the TASK interventions before evaluation in a definitive RCT. Trial registration Clinicaltrials.gov NCT03439813. Retrospectively registered on 20/2/2018.

A 56-year-old woman presented in 2006 with symptomatic primary varicose veins in her right leg. Venous duplex ultrasonography at that time showed what appeared to be “neovascular tissue” around the saphenofemoral junction. However, there had been no previous trauma or surgery in this area. This appearance has subsequently been described as primary avalvular varicose anomalies. She underwent endovenous treatment at that time. In 2018, she presented with symptomatic recurrent varicose veins of the same leg. Venous duplex ultrasonography showed successful ablation of the great saphenous and anterior accessory saphenous veins. All of the recurrent venous reflux was arising from the primary avalvular varicose anomalies. This report shows that primary avalvular varicose anomalies is a previously unreported cause of recurrent varicose veins and leads us to suggest that if found, treatment of the primary avalvular varicose anomalies should be considered at the primary procedure.

Objectives To examine the association between generalised joint laxity (GJL) and injury rates in Middle Eastern male youth athletes.Design Prospective observational study consisting of GJL screen and injury audit (season 2009/2010).Setting Aspire Sports Academy Doha, Qatar.Participants A total of 226 adolescent male athletes (mean age: 14.2 years; SD: 1.7; range: 10–18) involved in 15 sporting activities were grouped into contact and non-contact sports. All available athletes were included in this study.Outcome measures A seasonal injury audit, athletes’ anthropometric characteristics, for example, weight, height and body mass index and screen for GJL to determine Beighton Score (BS).Results The 226 athletes sustained 596 injuries and 75% reported at least one injury over a seasonal injury audit. Players in contact sports were injured more often than players in non-contact sports (more frequent injuries than injury-free time in contact sports; 127 days (95% CI 93 to 160) vs 176 days in non-contact sports (95% CI 118 to 234) (p

Objective Evaluate plantar loading during ‘on-field’ common football movements in players after fifth metatarsal (MT-5) stress fracture and compare with matched healthy players.Methods Fourteen elite male soccer players participated in the study conducted on a natural grass playing surface using firm ground football boots. Seven players who had suffered a primary stress fracture (MT-5 group) and seven matched healthy players (controls, CON) performed three common football movements while in-shoe plantar loading data were collected.Results Large between-group differences exist for maximal vertical force normalised to bodyweight (Fmax) at the lateral toes (2-5) of the stance leg during a set-piece kick (MT-5: 0.2±0.06 bodyweight (BW), CON: 0.1±0.05 BW, effect size (ES) 1.4) and the curved run where the MT-5 group showed higher Fmax with very large effect size at the lateral forefoot of the injured (closest to curve) limb when running a curve to receive a pass (MT-5 injured−CON=0.01 BW, ES 1.5). Small between-group differences were evident during straight-line running. However, between-limb analysis of MT-5 group showed significant unloading of the lateral forefoot region of the involved foot.Conclusions Elite male football players who have returned to play after MT-5 stress fracture display significantly higher maximum plantar force at the lateral forefoot and lateral toes (2-5) compared with healthy matched control players during two football movements (kick and curved run) with the magnitude of these differences being very large. These findings may have important implications for manipulating regional load during rehabilitation or should a player report lateral forefoot prodromal symptoms.

Objectives To determine whether a dual-camera markerless motion capture system can be used for lower limb kinematic evaluation in athletes in a preseason screening setting.Design Descriptive laboratory study.Setting Laboratory setting.Participants Thirty-four (n=34) healthy athletes.Main outcome measures Three dimensional lower limb kinematics during three functional tests: Single Leg Squat (SLS), Single Leg Jump, Modified Counter-movement Jump. The tests were simultaneously recorded using both a marker-based motion capture system and two Kinect v2 cameras using iPi Mocap Studio software.Results Excellent agreement between systems for the flexion/extension range of motion of the shin during all tests and for the thigh abduction/adduction during SLS were seen. For peak angles, results showed excellent agreement for knee flexion. Poor correlation was seen for the rotation movements.Conclusions This study supports the use of dual Kinect v2 configuration with the iPi software as a valid tool for assessment of sagittal and frontal plane hip and knee kinematic parameters but not axial rotation in athletes.

The role of incompetent perforating veins in the aetiology of varicose veins is not well understood. Anecdotally, competitive cyclists appeared to be more prone to varicose veins than the general population. We present a case of a 63-year-old amateur competitive cyclist who acutely developed a painful varicosity of her left calf while straining during a hill climb in 106-mile cycle race. Duplex ultrasonography has shown an underlying incompetent perforating vein, feeding the varicosity directly through the underlying muscle. With no other significant venous reflux in either leg, we believe this case shows a clear causative association between the stresses put across the lower leg during competitive cycling and developing a varicose vein via an incompetent perforating vein. We believe this should lead to further investigations as to any link between cycling, perforator vein incompetence and the development of varicose veins.

A 40-year-old woman with a history of alopecia areata related to stress or hormonal changes was treated for bilateral primary symptomatic varicose veins (CEAP clinical score C2S) of pelvic origin, using a staged procedure. Her first procedure entailed pelvic vein embolisation of three pelvic veins using 14 coils and including foam sclerotherapy of the tributaries, using 3% sodium tetradecyl sulphate. Following this procedure, she had an exacerbation of alopecia areata with some moderate shedding of hair. Subsequently, she underwent endovenous laser ablation under local anaesthetic without incident. Seven months after the pelvic vein embolisation, she underwent foam sclerotherapy of leg and labial varicose veins using sodium tetradecyl sulphate. Two days following this procedure, she had a severe exacerbation of alopecia areata with gross shedding of hair. These two episodes of exacerbation of alopecia areata appear to be associated with sodium tetradecyl sulphate foam sclerotherapy of veins.

Abstract Placental abnormalities are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting ∼5% of all pregnancies. An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human and mouse placenta show structural similarities, but there have been no systematic attempts to assess their molecular similarities or differences. We collected protein and mRNA expression data through shot‐gun proteomics and microarray expression analysis of the highly vascular exchange region, microdissected from the human and mouse near‐term placenta. Over 7000 ortholog genes were detected with 70% co‐expressed in both species. Close to 90% agreement was found between our human proteomic results and 1649 genes assayed by immunohistochemistry for expression in the human placenta in the Human Protein Atlas. Interestingly, over 80% of genes known to cause placental phenotypes in mouse are co‐expressed in human. Several of these phenotype‐associated proteins form a tight protein–protein interaction network involving 15 known and 34 novel candidate proteins also likely important in placental structure and/or function. The entire data are available as a web‐accessible database to guide the informed development of mouse models to study human disease.

Abstract Mesenchymal stromal cells (MSCs) have emerged as candidate cells with therapeutic potential to treat different pathologies. The underlying mechanism is paracrine signaling. The cells secrete proteins that can impact inflammation, apoptosis, angiogenesis, and cell proliferation. All are important in wound healing and tissue regeneration. Although the bone marrow has been the most widely used source of MSCs, umbilical cord tissue (CT) presents a source that is just starting to be used in the clinic, yet can be obtained with more ease and easily stored. Here, we characterize CT‐MSCs obtained from multiple donors by analyzing cell surface proteins, differentiation capacity, and proteome profile. Analysis of low, medium, and high passage cells indicates that the morphology and proliferation rate stay constant and with the exception of cluster of differentiation (CD) 105 at late passage, there are no changes in the cell surface protein characteristics, indicating the population does not change with passage. TNF‐stimulated gene 6 protein was measured in a subset of samples and variable expression was observed, but this did not impact the ability of the cells to enhance skin regeneration. In conclusion, CT‐MSC represents a consistent, easily accessible source of cells for cell therapy. Stem Cells Translational Medicine 2019;8:1041–1054

Summary: Reproducibility in molecular and cellular studies is fundamental to scientific discovery. To establish the reproducibility of a well-defined long-term neuronal differentiation protocol, we repeated the cellular and molecular comparison of the same two iPSC lines across five distinct laboratories. Despite uncovering acceptable variability within individual laboratories, we detect poor cross-site reproducibility of the differential gene expression signature between these two lines. Factor analysis identifies the laboratory as the largest source of variation along with several variation-inflating confounders such as passaging effects and progenitor storage. Single-cell transcriptomics shows substantial cellular heterogeneity underlying inter-laboratory variability and being responsible for biases in differential gene expression inference. Factor analysis-based normalization of the combined dataset can remove the nuisance technical effects, enabling the execution of robust hypothesis-generating studies. Our study shows that multi-center collaborations can expose systematic biases and identify critical factors to be standardized when publishing novel protocols, contributing to increased cross-site reproducibility. : In this article, Lakics and colleagues show that, while individual laboratories are able to identify consistent molecular and seemingly statistically robust differences between iPSC neuronal models, cross-site reproducibility is poor. Their findings support multi-center collaborations to expose systematic biases and identify critical factors to be standardized to improve reproducibility in iPSC-based molecular experiments. Keywords: induced pluripotent stem cell, reproducibility, cross-site experimental variation, cortical neurons, gene expression profile, proteomic profiles, single-cell sequencing, molecular profiling, stembancc, public-private partnership

Abstract Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. Methods/design The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). Discussion Final results of RESTART will be analysed and disseminated in 2019. Trial registration ISRCTN71907627 (www.isrctn.com/ISRCTN71907627). Prospectively registered on 25 April 2013.

Abstract Background Routinely collected health data (RCD) are increasingly used for randomized controlled trials (RCTs). This can provide three major benefits: increasing value through better feasibility (reducing costs, time, and resources), expanding the research agenda (performing trials for research questions otherwise not amenable to trials), and offering novel design and data collection options (e.g., point-of-care trials and other designs directly embedded in routine care). However, numerous hurdles and barriers must be considered pertaining to regulatory, ethical, and data aspects, as well as the costs of setting up the RCD infrastructure. Methodological considerations may be different from those in traditional RCTs: RCD are often collected by individuals not involved in the study and who are therefore blinded to the allocation of trial participants. Another consideration is that RCD trials may lead to greater misclassification biases or dilution effects, although these may be offset by randomization and larger sample sizes. Finally, valuable insights into external validity may be provided when using RCD because it allows pragmatic trials to be performed. Methods We provide an overview of the promises, challenges, and potential barriers, methodological implications, and research needs regarding RCD for RCTs. Results RCD have substantial potential for improving the conduct and reducing the costs of RCTs, but a multidisciplinary approach is essential to address emerging practical barriers and methodological implications. Conclusions Future research should be directed toward such issues and specifically focus on data quality validation, alternative research designs and how they affect outcome assessment, and aspects of reporting and transparency.

This case study reports the diagnosis and treatment of a lower limb venous ulcer with abnormal underlying venous pathology. One male patient presented with bilateral varicose veins and a right lower limb ulcer. Upon investigation, full-leg duplex ultrasonography revealed total incompetence of the great saphenous vein in the left leg. In the right leg, duplex ultrasonography showed proximal incompetence of the small saphenous vein, and dilation of the anterior accessory saphenous vein, which remained competent. Incidentally, two venous collaterals connected onto the distal region of both these segments, emerging from a scarred, atrophic popliteal–femoral segment. An interventional radiologist performed venoplasty to this popliteal–femoral venous segment. Intervention was successful and 10 weeks post procedure ulceration healed. Popliteal–femoral venous stenosis may be associated with venous ulceration in some cases and may be successfully treated with balloon venoplasty intervention.

Suprapubic varicose veins are usually indicative of unilateral iliac vein occlusion and venous collateralisation. We report two cases of suprapubic varicose veins following pelvic vein embolisation and subsequent pregnancy; both presented without residual pelvic venous reflux or pelvic venous obstruction. In both cases, there was no significant flow in the suprapubic veins indicating that they were not acting as a collateral post-pregnancy. One patient had this venous abnormality treated successfully with TRansluminal Occlusion of Perforators, followed by foam sclerotherapy to the main part of the suprapubic vein. This patient has since completed the reminder of her lower limb varicose vein treatment. We suggest that pregnancy may have caused prolonged intermittent compression of the left common iliac vein, and that this, together with the physiological impact of previous embolisation procedures, obstructed venous drainage from the left leg resulting in collateral vein formation within the 9-month gestation period.

Objectives: Pelvic congestion syndrome (PCS) is associated with pelvic vein reflux (PVR), occasionally secondary to venous compression. Its symptoms, usually intra-pelvic, are alleviated following the abolition of this reflux by pelvic vein embolisation (PVE). The objective of this report is to present two cases of left hip pain, erroneously diagnosed as osteoarthritis, which disappeared after successful PVE and abolition of PVR. Methods: Two females presented with lower limb varicose veins, and also had a history of left-sided hip pain. Both had previously been investigated for the hip pain and diagnosed as osteoarthritis despite minimal arthritic changes on pelvic X-rays. During investigation for lower limb varicose veins, both showed a pelvic origin for their leg veins and hence underwent transvaginal duplex ultrasound. This revealed PVR, and PVE was planned in both patients. Results: Both patients underwent PVE and reported ‘miraculous’ resolution of left hip pain and also PCS symptoms including pelvic pain, irritable bowel issues and the disappearance of pelvic dragging, with almost immediate disappearance of vulval and vaginal varicosities. One patient also noted reduced clitoral sensitivity. Conclusion: Manifestations of PCS may vary in terms of intra- or extra-pelvic signs. PCS and PVR should be considered in the differential diagnosis of patients with arthritic symptoms in the hip without evident radiographic evidence.

Abstract Background Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit. Design International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics. Results The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials. Conclusion The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials. Trial registration ISRCTN25765518

Abstract Background Approximately 70,000 patients/year undergo surgery for repair of a fractured hip in the United Kingdom. This is associated with 30-day mortality of 9% and survivors have a considerable length of acute hospital stay postoperatively (median 26 days). Use of oesophageal Doppler monitoring to guide intra-operative fluid administration in hip fracture repair has previously been associated with a reduction in hospital stay of 4-5 days. Most hip fracture surgery is now performed under spinal anaesthesia. Oesophageal Doppler monitoring may be unreliable in the presence of spinal anaesthesia and most patients would not tolerate the probes. An alternative method of guiding fluid administration (minimally-invasive arterial pulse contour analysis) has been shown to reduce length of stay in high-risk surgical patients but has never been studied in hip fracture surgery. Methods Single-centre randomised controlled parallel group trial. Randomisation by website using computer generated concealed tables. Setting: University hospital in UK. Participants: 128 patients with acute primary hip fracture listed for operative repair under spinal anaesthesia and aged > 65 years. Intervention: Stroke volume guided intra-operative fluid management. Continuous measurement of SV recorded by a calibrated cardiac output monitor (LiDCOplus). Maintenance fluid and 250 ml colloid boluses given to achieve sustained 10% increases in stroke volume. Control group: fluid administration at the responsible (blinded) anaesthetist's discretion. The intervention terminates at the end of the surgical procedure and post-operative fluid management is at the responsible anaesthetist's discretion. Primary outcome: length of acute hospital stay is determined by a blinded team of clinicians. Secondary outcomes include number of complications and total cost of care. Funding NIHR/RfPB: PB-PG-0407-13073. Trial registration number Trial registration: Current Controlled Trials ISRCTN88284896.