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Sickle cell disease is the commonest genetic disorder in Nigeria, affecting 2-3% of an estimated population of 160 million people. The role of genetic mutations in folate cycle genes, and the variable phenotypic expressions constituting disease severity, needs to be critically examined.This study was carried out to establish the pattern of methionine synthase gene mutations (rs1805087 SNP), and its possible association with disease severity in adults with sickle cell anaemia in Lagos, Nigeria.This is a cross-sectional study of seventy (70) subjects with sickle cell disease (HbSS) matched for age and gender with known apparently healthy haemoglobin genotype AA (HbAA) subjects, as cases and controls respectively. Structured questionnaires were used to obtain demographic, clinical and other phenotypic data needed to compute disease severity. Pattern of MTR A2756G gene mutation and homocysteine assay (Hcy) were assessed by Polymerase Chain Reaction and Enzyme- linked Immunosorbent Assay respectively. Full blood count analysis of participants was done using the KX-21 Automated Analyzer (Sysmex Corporation, Japan).The mutant genotypes MTR 2756 AG/GG were recorded in 46.4% (n =55) of subjects with disease severity score7. Elevated plasma homocysteine (HHcy) was significantly associated with disease severity among HbSS subjects (OR=17.2, CI: 3.490-86.079; p=0.0001). Conversely, no significant association was observed with the mutant genotypes MTR 2756 AG/GG and disease severity (p0.05).While HHcy is significantly associated with phenotypic expression of HbSS, the MTR 2756 SNPs did not appear to independently influence homocysteine level or disease severity in HbSS subjects.La drépanocytose est la maladie génétique la plus répandue au Nigeria, affectant 2 à 3 % d’une population estimée à 160 millions de personnes. Le rôle des mutations génétiques dans les gènes du cycle du folate, et les expressions phénotypiques variables constituant la gravité de la maladie, doivent être examinés de façon critique.Cette étude a été menée pour établir le schéma des mutations du gène de la méthionine synthase (rs1805087 SNP), et son association possible avec la gravité de la maladie chez les adultes atteints de drépanocytose à Lagos, au Nigeria.Il s’agit d’une étude transversale de soixantedix (70) sujets atteints de drépanocytose (HbSS) appariés pour l’âge et le sexe avec des sujets connus apparemment sains de génotype d’hémoglobine AA (HbAA), comme cas et contrôles respectivement. Des questionnaires structurés ont été utilisés pour obtenir des données démographiques, cliniques et autres données phénotypiques nécessaires au calcul de la gravité de la maladie. Le profil de la mutation du gène MTR A2756G et le dosage de l’homocystéine (Hcy) ont été évalués respectivement par réaction en chaîne par polymérase et par test immunologique enzymatique. L’analyse de la formule sanguine complète des participants a été effectuée à l’aide de l’analyseur automatisé KX-21 (Sysmex Corporation, Japon).Les génotypes mutants MTR 2756 AG/GG ont été enregistrés chez 46,4 % (n =55) des sujets présentant un score de gravité de la maladie7. L’homocystéine plasmatique élevée (HHcy) était significativement associée à la gravité de la maladie chez les sujets HbSS (OR=17,2, CI : 3,490–86,079 ; p=0,0001). À l’inverse, aucune association significative n’a été observée entre les génotypes mutants MTR 2756 AG/GG et la gravité de la maladie (p0,05).Alors que l’HHcy est significativement associée à l’expression phénotypique de l’HbSS, les SNP MTR 2756 ne semblent pas influencer indépendamment le niveau d’homocystéine ou la gravité de la maladie chez les sujets HbSS.

Topic Setting up an interface geriatrics service in a seaside area with a large elderly population. Many elderly patients are readmitted due to the challenge of managing their chronic health conditions in the community. These patients are frail, with frequently exacerbated chronic conditions causing regular readmissions. We noted that treatment was rarely changed during these admissions and patients were not uniformly managed. Aims Aims for this project were to improve care for older people, reduce readmissions and produce clear patient care plans. Interventions Our first PDSA cycle involved implementing geriatrician presence at community MDTs (involving social services, GPs, intermediate care teams, and various others). This generated home visits to several patients, with a mix of acute and chronic issues. We offered Advance Care planning where appropriate to these patients. We noted several patients were repeatedly discussed at MDT. This brought into focus frequent attenders who were usually well-known to the community. In the next cycle we introduced ‘frequent attender’ plans for these patients, ensuring a unified approach to their management. Subsequent cycles involved geriatrician presence at the ‘frequent attenders’ steering group, and further links with community teams. Our primary intervention has been Advance care & frequent attender plans offering tailored management for complex patients. These are completed by a geriatrician discussing patients wishes for treatment and future care. Improvements Readmission rates show up to 90% reduction in admissions/ED attendances for patients following care plan implementation. Feedback from families and patients is positive – the service is ‘pragmatic and supportive’, delivering ‘empathetic care’. Discussion Implementing an interface geriatrics service highlights the importance of caring for frail patients in their preferred place of care, reducing unnecessary/inappropriate hospitalisations. Geriatrician presence at community MDTs has improved care by offering prompt access to medical advice and review of complex patients. It highlights patients presenting frequently to services, allowing us to work with patients and families to improve management. A frequent attender list generated by the hospital helps target patients for whom intervention will give significant benefit. We plan to extend this further by working with nursing homes that have high conveyancing rates. The service is being extended to more areas within our region, and we are working with GPs and care homes to further offer advance care planning to vulnerable and frail patients.

Summary Medical procedures can disperse infectious agents and spread disease. Particularly, dental procedures may pose a high risk of disease transmission as they use high-powered instruments operating within the oral cavity that may contain infectious microbiota or viruses. Here we assess the ability of powered dental devices in removing the biofluid films and identified mechanical, hydrodynamic, and aerodynamic forces as the main underlying mechanisms of removal and dispersal processes. Our results indicate that potentially infectious agents can be removed and dispersed immediately after dental instrument engagement with the adherent biofluid film, while the degree of their dispersal is rapidly depleted owing to the removal of the source and dilution by the coolant water. We found that droplets created by high-speed drill interactions typically travel ballistically, while aerosol-laden air tends to flow as a current over surfaces. Our mechanistic investigation offers plausible routes for reducing the spread of infection during invasive medical procedures., Graphical abstract, Highlights • Mechanical, hydrodynamic, and aerodynamic forces drive removal/dispersal processes • The air-rotor has the highest ability to remove and disperse infectious agents • The aerosol cloud flows as a current and continuously settles • Manipulating rheological properties of the fluids can suppress aerosol generation, Dentistry; Therapeutic procedure; Applied physics

BackgroundCOVID-19 has restricted singing in communal worship. We sought to understand variations in droplet transmission and the impact of wearing face masks.MethodsUsing rapid laser planar imaging, we measured droplets while participants exhaled, said ‘hello’ or ‘snake’, sang a note or ‘Happy Birthday’, with and without surgical face masks. We measured mean velocity magnitude (MVM), time averaged droplet number (TADN) and maximum droplet number (MDN). Multilevel regression models were used.ResultsIn 20 participants, sound intensity was 71 Decibels (dB) for speaking and 85 dB for singing (p85% reduction wearing face masks. Droplet transmission varied widely, particularly for singing. Masks decreased TADN by 99% (pConclusionsWide variation exists for droplet production. This significantly reduced when wearing face masks. Singing during religious worship wearing a face mask appears as safe as exhaling or talking. This has implications for UK public health guidance during the COVID-19 pandemic.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb but are not amenable to mass testing as they take several days and require use of viable SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid protein (NP) at predicting the presence and magnitude of NAb determined by PRNT. SARS-CoV-2 IgG ELISA correlated well with NAb and was highly sensitive (93.8% [95% CI 79.2–99.2]) and specific (88.9% [95% CI 51.8–99.7%]) at predicting the presence of NAb. There was not a strong correlation between IgM ELISA and PRNT result. IgG ELISA provides a useful, high throughput method of predicting the presence of neutralising antibodies, with higher ELISA results increasing the likelihood of having a greater NAb titre.

Objective UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates. Design RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing. Results Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5–7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028). Conclusion Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb, but are not amenable to mass testing as they take several days and require use of SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 receptor binding domain (S1-RBD), and spike subunit 2 (S2) and nucleocapsid protein (NP), at predicting the presence and magnitude of NAb determined by PRNT. IgG S2 + NP ELISA was 96.8% [95% CI 83.8–99.9] sensitive and 88.9% [95% CI 51.8–99.7] specific at predicting the presence of NAbs (PRNT80 > 1:40). IgG and IgM S1-RBD ELISAs correlated with PRNT titre, with higher ELISA results increasing the likelihood of a robust neutralising response. The IgM S1-RBD assay can be used as a rapid, high throughput test to approximate the magnitude of NAb titre.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Urethral stricture is fundamentally a fibrosis of the urethral epithelial and associated corpus spongiosum, which in turn, causes obstruction of the urethral lumen. Patients with urethral stricture most commonly present with lower urinary tract symptoms, urinary retention or urinary tract infection but may also experience a broad spectrum of other signs and symptoms, including genitourinary pain, hematuria, abscess, ejaculatory dysfunction, or renal failure. When urethral stricture is initially suspected based on clinical assessment, cystoscopy is suggested as the modality that most accurately establishes the diagnosis. This recommendation is based on several factors, including the accuracy of cystoscopy, as well as its wide availability, lesser overall cost, and comfort of urologists with this technique. When recurrent urethral stricture is suspected, we suggest performing retrograde urethrography to further stage the length and location of the stricture or referring the patient to a physician with expertise in reconstructive urology. Ultimately, the treatment decision depends on several factors, including the type and acuity of patient symptoms, the presence of complications, prior interventions, and the overall impact of the urethral stricture on the patient’s quality of life. Endoscopic treatment, either as dilation or internal urethrotomy, is suggested rather than urethroplasty for the initial treatment of urethral stricture. This recommendation applies to men with undifferentiated urethral stricture and does not apply to trauma-related urethral injuries, penile urethral strictures (hypospadias, lichen sclerosus), or suspected urethral malignancy. In the setting of recurrent urethral stricture, urethroplasty is suggested rather than repeat endoscopic management but this may vary depending on patient preference and impact of the symptoms on the patient. The purpose of this guideline is to provide a practical summary outlining the diagnosis and treatment of urethral stricture in the Canadian setting.

This book explores the economic evidence for the settlement at Bornais on South Uist. It reports in detail on the large assemblages of material found during the excavations at mounds 2 and 2A. There is important evidence for craft activity, such as bone and antler working and this includes the only comb making workshop from a rural settlement in Britain. A large proportion of the copper alloy, bone and antler assemblages comprise pieces of personal adornment and provide important information on the dress and thereby social relations within the settlement occupation. There is a large assemblage of iron tools and fittings, which provides important information on the activities taking place at the settlement. The information derived from the artefact assemblages is complemented by that provided by the ecofactual material. Large amounts of animal, fish and bird bones plus carbonised plant remains provide detailed information on agricultural practices, and the processing, preparation and consumption of foodstuffs. It is clear that the Norse inhabitants of the settlement had access to a much richer variety of resources than had been exploited before the Viking colonisation of the region. The settlement also had a significantly wider range of connections; material culture indicates contacts to the south with the Irish Sea ports and Bristol, and to the north with Shetland and the Viking homelands of Norway. The evidence produced by these excavations is exceptional and provides an unparalleled opportunity to explore medieval life in the Scandinavian kingdoms of Western Britain.

Introduction: The Royal College of Physicians and Surgeons of Canada’s Competence by Design (CBD) initiative presents curricula challenges to ensure residents gain proficiency while progressing through training. To prepare first-year urology residents (R1s), we developed, implemented, and evaluated a didactic and simulation-focused boot camp to implement the CBD curriculum. We report our experiences and findings of the first three years. Methods: Urology residents from two Canadian universities participated in the two-day boot camp at the beginning of residency. Eleven didactic and six simulation sessions allowed for instruction and deliberate practice with feedback. Pre-and post-course multiple-choice questionnaires (MCQs) and an objective structured clinical exam (OSCE) evaluated knowledge and skills uptake. For initial program evaluation, three R2s served as historical controls in year 1. Results: Nineteen residents completed boot camp. The mean age was 26.4 (±2.8) and 13 were male. Participants markedly improved on the pre- and post-MCQs (year 1: 62% and 91%; year 2: 55% and 89%; year 3: 58% and 86%, respectively). Participants scored marginally higher than the controls on four of the six OSCE stations. OSCE scores remained >88% over the three cohorts. All participants reported higher confidence levels post-boot camp and felt it was excellent preparation for residency. Conclusions: During its first three years, our urology boot camp has demonstrated high feasibility and utility. Knowledge and technical skills uptake were established via MCQ and OSCE results, with participants’ scores near or above those of R2 controls. This boot camp will remain in our CBD curriculum and can provide a framework for other urology residency programs.

We report dynamics of seroconversion to SARS-CoV-2 infections detected by IgG ELISA in 177 individuals diagnosed by RT-PCR. Longitudinal analysis identifies 2-8.5% of individuals who do not seroconvert even weeks after infection. They are younger than seroconverters who have increased co-morbidity and higher inflammatory markers such as C-Reactive Protein. Higher antibody responses are associated with non-white ethnicity. Antibody responses do not decline during follow up almost to 2 months. Serological assays increase understanding of disease severity. Their application in regular surveillance will clarify the duration and protective nature of humoral responses to SARS-CoV-2.

SummaryHere we describe an open and transparent consortium for the rapid development of COVID-19 rapid diagnostics tests. We report diagnostic accuracy data on the Mologic manufactured IgG COVID-19 ELISA on known positive serum samples and on a panel of known negative respiratory and viral serum samples pre-December 2019.In January, Mologic, embarked on a product development pathway for COVID-19 diagnostics focusing on ELISA and rapid diagnostic tests (RDTs), with anticipated funding from Wellcome Trust and DFID.834 clinical samples from known COVID-19 patients and hospital negative controls were tested on Mologic’s IgG ELISA. The reported sensitivity on 270 clinical samples from 124 prospectively enrolled patients was 94% (95% CI: 89.60% - 96.81%) on day 10 or more post laboratory diagnosis, and 96% (95% CI: 84.85% - 99.46%) between 14–21 days post symptom onset. A specificity panel comprising 564 samples collected pre-December 2019 were tested to include most common respiratory pathogens, other types of coronavirus, and flaviviruses. Specificity in this panel was 97% (95% CI: 95.65% - 98.50%).This is the first in a series of Mologic products for COVID-19, which will be deployed for COVID-19 diagnosis, contact tracing and sero-epidemiological studies to estimate disease burden and transmission with a focus on ensuring access, affordability, and availability to low-resource settings.

BackgroundThe best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA.MethodsC-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.5 at any time point) during the double-blind period.ResultsAt Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (pConclusionsPatients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal.Trial registration numberNCT02505542, ClinicalTrials.gov.

Background Emergency abdominal surgery is associated with a high risk of postoperative pulmonary complications (PPCs). The primary aim of this study was to determine whether patients undergoing emergency laparotomy are ventilated using a lung-protective ventilation strategy employing tidal volume ≤8 ml kg−1 ideal body weight−1, PEEP >5 cm H2O, and recruitment manoeuvres. The secondary aim was to investigate the association between ventilation factors (lung-protective ventilation strategy, intraoperative FiO2, and peak inspiratory pressure) and the occurrence of PPCs. Methods Data were collected prospectively in 28 hospitals across London as part of routine National Emergency Laparotomy Audit (NELA). Patients were followed for 7 days. Complications were defined according to the European Perioperative Clinical Outcome definition. Results Data were collected from 568 patients. The median [inter-quartile range (IQR)] tidal volume observed was 500 ml (450–540 ml), corresponding to a median tidal volume of 8 ml kg−1 ideal body weight−1 (IQR: 7.2–9.1 ml). A lung-protective ventilation strategy was employed in 4.9% (28/568) of patients, and was not protective against the occurrence of PPCs in the multivariable analysis (hazard ratio=1.06; P=0.69). Peak inspiratory pressure of Conclusions Both intraoperative peak inspiratory pressure and FiO2 are independent factors significantly associated with development of a postoperative pulmonary complication in emergency laparotomy patients. Further studies are required to identify causality and to demonstrate if their manipulation could lead to better clinical outcomes.

ObjectivesTo report 4-year imaging outcomes in the RAPID-axSpA (NCT01087762) study of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), treated with certolizumab pegol (CZP).MethodsThis phase III, randomised trial was placebo-controlled and double-blind to week 24, dose-blind to week 48 and open-label to week 204. Patients fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria with active disease were stratified (AS/nr-axSpA) according to the modified New York (mNY) criteria at randomisation. Spinal radiographs were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). MRI inflammation used the Spondyloarthritis Research Consortium of Canada (SPARCC) score for sacroiliac joints (SIJ) and the Berlin spinal score (remission defined as SPARCC ResultsMRI improvements from baseline (BL) to week 12 were maintained to week 204 (SPARCC BL: AS=8.5, nr-axSpA=7.5; SPARCC week 204: AS=1.3, nr-axSpA=2.4; Berlin BL: AS=7.4, nr-axSpA=4.4; Berlin week 204: AS=2.6, nr-axSpA=1.9). 66.7% of patients with AS and 69.6% of patients with nr-axSpA with BL SPARCC scores ≥2, and 65.4% of patients with AS and 57.3% of patients with nr-axSpA with BL Berlin score >2, achieved remission at week 204. Mean mSASSS change in AS from BL to week 204 was 0.98 (95% CI 0.34, 1.63); 0.67 (95% CI 0.21,1.13) from BL to week 96; and 0.31 (95% CI 0.02,0.60) from week 96 to week 204. Corresponding nr-axSpA changes were 0.06 (95% CI −0.17,0.28), –0.01 (95% CI −0.19,0.17) and 0.07 (95% CI −0.07,0.20). 4.5% of patients with nr-axSpA fulfilled the mNY criteria at week 204, while 4.3% of patients with AS no longer did so.ConclusionsIn patients with CZP-treated axSpA, rapid decreases in spinal and SIJ MRI inflammation were maintained to week 204. Overall, 4-year spinal progression was low, with less progression during years 2–4 than 0–2. Radiographic SIJ grading changes demonstrated limited progression.Trial registration numberNCT01087762; Post-results.

Objective Early identification of patients unlikely to achieve good long‐term disease control with anti–tumor necrosis factor therapy in axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) is important for physicians following treat‐to‐target recommendations. Here we assess associations between disease activity or clinical response during the first 12 weeks of treatment and attainment of treatment targets at week 48 in axial SpA and PsA patients receiving certolizumab pegol. Methods The relationship between disease activity or clinical response during the first 12 weeks of treatment and achievement of week‐48 targets (for axial SpA: inactive disease based on Ankylosing Spondylitis Disease Activity Score [ASDAS] using the C‐reactive protein [CRP] level, or Bath Ankylosing Spondylitis Disease Activity Index 5.1 at week 12, compared to 73% of patients (57 of 78) with DAS28‐CRP

Objective The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

To reduce reliance on fossil fuels there has been a global push to minimise fuel consumption, and incorporate the use of bio-derived fuels. In practical combustion systems that use liquid fuels, observing the spray behaviour of these biofuels is key in understanding fuel performance; in particular, droplet size distribution is known to have a strong influence on the fuel energy release and pollutant formation processes. This paper is aimed at the use of the TSI Global Sizing Velocimetry (GSV) interferometric technique as a method to gain detailed understanding of droplet number and size distribution, with a particular focus on ethanol-gasoline fuel blends. The imaging system for the GSV technique consisted of a Nd:YAG laser and a 4 MP (million pixel) camera, and the spray was generated using a generic automotive port fuel injector. The results showed that the GSV technique was able to effectively measure droplet concentration and diameters for all the fuel blends tested in this study. Ethanol was observed to have larger droplet diameters (both D10 and D32) as compared to fossil gasoline, with droplet diameters generally increasing as the proportion of ethanol in the gasoline was increased. The droplet concentration reduced with increasing radial distance from the spray centreline, but no appreciable change was observed with axial displacement from the nozzle tip. Degradation in the image quality was observed for fuel blends with less than 40% ethanol content. The GSV drop sizing measurements were validated using a mono-disperse droplet generator, and an excellent agreement (within 2%) was observed.

Genitourinary (GU) injury is present in approximately 10% of cases of abdominal trauma.1 Of those GU injuries, up to 67% involve the external genitalia.2,3 GU trauma is more common in males, especially in the instance of genital injury. This increased incidence in males is secondary to both anatomical considerations and increased participation in activities such as contact sports, violent interaction, and war activities.2 The lower urinary tract is susceptible to traumatic injury by way of various mechanisms. These injuries, and their sequelae, can affect patients of any age or background. Though lower urinary tract trauma rarely results in life-threating pathology, appropriate management of these injuries is pivotal in decreasing long-term morbidity.4 Although the external genitalia in males are at high risk of injury in trauma because of their extracorporeal location, the scrotum and testes are relatively well-protected from severe damage for the following reasons: 1) the testes are inherently mobile within the scrotum; 2) the scrotal skin provides reasonable elasticity allowing for internal structures to slip away from the point of contact in blunt trauma; 3) the cremasteric reflex offers a protective reflex mechanism; and 4) the tunica albuginea serves as a tough fibrous physical defense with its tensile strength.4–6 Resultantly, the incidence of scrotal or testicular injury in a trauma activation is generally considered to be less than one percent. However, the associated morbidity to the patient (including psychological effects of testicular injury or loss) and health system costs associated with these injuries warrant special attention.5,7–9 In general, there are two broad domains to consider when evaluating scrotal trauma: blunt vs. penetrating injury. Historically, blunt injury has been thought to comprise the significant majority (i.e., 75–80%) of genital trauma.2,4 A recent analysis of the National Trauma Data Bank in the U.S. described a more balanced distribution of penetrating vs. blunt scrotal trauma, with both representing nearly half of all injuries.5 However, this significant difference in reported mechanism may be attributable to input biases and geopolitical determinants (e.g., increased incidence of gunshot wound [penetrating] injuries in the U.S. compared to other nations). The importance of categorizing these these types of injuries into broad classes lies in the special diagnostic and management considerations for each type of injury (Fig. 2). For example, while just 1.5% of blunt testicular injury involves the gonads bilaterally, approximately 30% of penetrating scrotal injury will involve both testes. Additionally, penetrating injury occurs with associated injuries in approximately 70% of patients, decreasing the threshold of suspicion of damage to neighboring structures, such as the penis, bladder, urethra, and femoral vessels.2,4 However, workup for associated injury should not be neglected in the setting of blunt trauma either, and nearby structures should be appropriately investigated when clinical suspicion is present (e.g., blood at the urethral meatus suggesting urethral injury).4 Other domains of scrotal trauma, including thermal and degloving/scrotal wall avulsion injuries, are described in the literature as well and will be discussed here briefly. Open in a separate window Fig. 2 Simplified diagnostic and management pathway in blunt and penetrating scrotal trauma.

A classical inventory problem is studied from the perspective of embedded options, reducing inventory-management to the design of optimal contracts for forward delivery of stock (commodity). Financial option techniques a la Black-Scholes are invoked to value the additional ‘option to expand stock’. A simplified approach which ignores distant time effects identifies an optimal ‘time to deliver’ and an optimal ‘amount to deliver’ for a production process run in continuous time modelled by a Cobb-Douglas revenue function. Commodity prices, quoted in initial value terms, are assumed to evolve as a geometric Brownian process with positive (inflationary) drift. Expected revenue maximization identifies an optimal ‘strike price’ for the expansion option to be exercised and reveals the underlying martingale in a truncated (censored) commodity price. The paper establishes comparative statics of the censor, using sensitivity analysis on the related censor functional equation; key here is that the censor, as a function of the drift and volatility of price, is the solution of a functional equation. Asymptotic approximation allows a tractable analysis of the optimal timing.

Contains fulltext : 177598.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis. DESIGN: Observational cohort study. SETTING: Seven hundred and thirty ICUs in 84 countries. PATIENTS: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock. CONCLUSIONS: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.

Background:Several disease activity measures and thresholds have been recommended as psoriatic arthritis (PsA) treatment targets, although consensus on the most appropriate assessment tool is lacking.1Reports suggest low disease activity (LDA) and remission may be associated with minimal structural progression in PsA.2Objectives:To report the relationship between PsA disease activity and structural progression over 216 weeks’ (wks) treatment with certolizumab pegol (CZP), an Fc-free, PEGylated, tumour necrosis factor inhibitor (TNFi) that has shown long-term efficacy and safety in PsA.3Methods:Patients (pts) enrolled in RAPID-PsA (NCT01087788) with active PsA (≥3 tender joints; ≥3 swollen joints; ESR ≥28 mm/hour and/or CRP >upper limit of normal) who had failed treatment with ≥1 csDMARD were randomised 1:1:1 to CZP 200 mg every 2 wks (Q2W), CZP 400 mg every 4 wks (Q4W), or placebo (PBO). All CZP pts received CZP 400 mg at Wks 0/2/4. PBO pts were re-randomised to CZP 200 mg Q2W or 400 mg Q4W at Wk 16 or 24.3Pts were heterogenous for structural damage and disease duration at baseline. Disease activity was assessed using minimal disease activity (MDA) criteria (MDA: 5–6/7 criteria; very LDA [VLDA]: 7/7 criteria), Psoriatic Arthritis Disease Activity Score (PASDAS) (LDA: >1.9–≤3.2; remission: ≤1.9), or Disease Activity Index for Psoriatic Arthritis (DAPSA) (LDA: >4–≤14; remission: ≤4). Radiographs were read in four reading campaigns using the van der Heijde modified Total Sharp Score (mTSS) for PsA. A risk of structural progression (RSP) subgroup (baseline mTSS >median for all pts) was also assessed. Mean change from baseline (CFB) in mTSS and associations with disease activity states were estimated using a hierarchical linear mixed effects model (fixed effects: reading campaign/interactions of concurrent disease activity levels with time; random effects: pt/reading campaign nested within pt) which allowed mean mTSS trajectory, and impact of disease activity levels on this, to differ over time.Results:407/409 randomised pts were assessed for mTSS at least once. At Wk 0, mean (standard deviation) DAPSA=44.5 (22.7), PASDAS=6.0 (1.1). 3/409 (0.7%) pts reported MDA. The proportion of pts achieving remission/VLDA states increased to Wk 216, as did estimated mean mTSS. Estimated mean mTSS CFB remained low overall (0.46 at Wk 216; standard error 0.16;Figure). Across disease activity measures, remission/VLDA states were associated with mTSS estimated mean CFB ≤0 in both the overall group and RSP subgroup (Table).Conclusion:These data indicate that achievement of remission in PsA is important to prevent further structural damage, particularly in pts with pre-existing structural changes. This supports the rationale for strict disease activity targets.References:[1]Coates L. Arthritis Rheumatol 2018;70:345–55;2.Tucker LJ. Curr Rheumatol Rep 2018;20:71;3.van der Heijde D. RMD Open 2018;4:e000582.Table.Estimated mTSS (mixed effects model)mTSS estimated mean CFB (standard error)All patients(N=407)RSP(n=202)PASDASRemission-0.20 (0.25)-0.55 (0.49)LDA0.01 (0.23)-0.07 (0.47)>LDA1.31 (0.22)2.54 (0.43)DAPSARemission-0.34 (0.23)-0.67 (0.46)LDA0.40 (0.22)0.81 (0.44)>LDA1.37 (0.24)2.46 (0.48)MDAVLDA-0.40 (0.28)-0.84 (0.55)MDA0.39 (0.24)0.55 (0.48)>MDA0.89 (0.20)1.73 (0.39)mTSS estimated mean CFB: ≤0; ≤0.5; >0.5. Data to Wk 216 pooled for all pts randomised.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Laura C Coates: None declared, Joseph F. Merola Consultant of: Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Owen Davies Employee of: UCB Pharma, Oscar Irvin-Sellers Employee of: UCB Pharma, Tommi Nurminen Employee of: UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV

Part 1 Scene setting: is health care a business? an analysis of health care, and its considerations as a business, John L. Deffenbaugh managing the design of health care services, Moira Fischbacher and Arthur Francis. Part 2 Quality in health care: towards critical quality, Mike Walsh whose quality? different interest groups' perspectives on health care quality, Juan I. Baeza and Michael Calnan the quantification of patient satisfaction, Mike Hart managing clinical audit - diagnozing the problems and designing solutions, Gail Johnston et al improving child dental health in Scotland - an audit in primary care, Chris Southwick et al human resource management audits - contributions to quality, Sandra Nutley. Part 3 Using performance indicators: what are we counting with hospital episode statistics (HES)?, Richard Wilson clinical outcomes indicators in Scotland - lessons and prospects, Steve Kendrick et al what do managers and physicians prefer as indicators of clinical outcome?, Regis Blais et al performance indicators - a patient-centred approach, Anne Ludbrook and Colin Gordon is indicator use for quality improvement and performance measurement compatible?, Joanne Lally and Richard Thomson published health outcomes - guiding lights or wreckers' lanterns?, Huw T.O. Davies et al.

Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH(+))] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH(+) neurons in populations that constitutively add new neurons (e.g., diencephalic population 5/6). Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of TH(+) neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH(+) axons, as well as permanent deficits in shoaling and reproductive behavior. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation. SIGNIFICANCE STATEMENT Despite the fact that zebrafish show a high propensity to regenerate neurons in the brain, this study reveals that not all types of dopaminergic neurons are functionally regenerated after specific ablation. Hence, in the same adult vertebrate brain, mechanisms of successful and incomplete regeneration can be studied. We identify progenitor cells for dopaminergic neurons and show that activating the immune system promotes the proliferation of these cells. However, in some areas of the brain this only leads to insufficient replacement of functionally important dopaminergic neurons that later disappear. Understanding the mechanisms of regeneration in zebrafish may inform interventions targeting the regeneration of functionally important neurons, such as dopaminergic neurons, from endogenous progenitor cells in nonregenerating mammals.