Scotland Registry for Ankylosing Spondylitis (SIRAS) – Protocol

Funding SIRAS was funded by unrestricted grants from Pfizer and AbbVie. The project was reviewed by both companies, during the award process, for Scientific merit, to ensure that the design did not compromise patient safety, and to assess the global regulatory implications and any impact on regulatory strategy.Publisher PD

Improving Translatability of Spinal Cord Injury Research by Including Age as a Demographic Variable

Pre-clinical and clinical spinal cord injury (SCI) studies differ in study design, particularly in the demographic characteristics of the chosen population. In clinical study design, criteria such as such as motor scores, neurological level, and severity of injury are often key determinants for participant inclusion. Further, demographic variables in clinical trials often include individuals from a wide age range and typically include both sexes, albeit historically most cases of SCI occur in males. In contrast, pre-clinical SCI models predominately utilize young adult rodents and typically use only females. While it is often not feasible to power SCI clinical trials to test multi-variable designs such as contrasting different ages, recent pre-clinical findings in SCI animal models have emphasized the importance of considering age as a biological variable prior to human experiments. Emerging pre-clinical data have identified case examples of treatments that diverge in efficacy across different demographic variables and have elucidated several age-dependent effects in SCI. The extent to which these differing or diverging treatment responses manifest clinically can not only complicate statistical findings and trial interpretations but also may be predictive of worse outcomes in select clinical populations. This review highlights recent literature including age as a biological variable in pre-clinical studies and articulates the results with respect to implications for clinical trials. Based on emerging unpredictable treatment outcomes in older rodents, we argue for the importance of including age as a biological variable in pre-clinical animal models prior to clinical testing. We believe that careful analyses of how age interacts with SCI treatments and pathophysiology will help guide clinical trial design and may improve both the safety and outcomes of such important efforts

The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer-treatment induced anaemia (including review of TA142): a systematic review and economic model

Background: Anaemia is a common side-effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions (RBCTs) to improve cancer treatment-induced anaemia (CIA). Methods: The clinical effectiveness review followed principles published by NHS CRD. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care (BSC), placebo, or other ESA. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL), and adverse events (AEs) were evaluated. Where appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment to no ESA treatment. The model has two components: one evaluating short-term costs and QALYs (while patients are anaemic); and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% pa. Probabilistic and univariate deterministic sensitivity analyses were performed. Results: Twenty-three studies assessing ESAs within their licensed indication (based on start dose administered) were included. None of the RCTs were completely aligned with current EU licenses. Results suggest that there is clinical benefit from ESAs for anaemia-related outcomes. Data suggest improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain; although point estimates are lower confidence intervals are wide and not statistically significant. Base case incremental cost-effectiveness ratios (ICERs) for ESA treatment versus no ESA treatment ranged from £19,429–£35,018 per quality-adjusted life year (QALY) gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost. Conclusions: ESAs could be cost-effective when used closer to licence but there is considerable uncertainty mainly due to unknown impacts on overall survival

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF

Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.This work was funded by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of patients was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. SRC consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK. In the last three years PJC has served on an advisory board for Lundbeck. NAH consults for GSK. PdB, DJ and WCD are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson

Does safety climate moderate the influence of staffing adequacy and work conditions on nurse injuries?

Hospital nurses have one of the highest work-related injury rates in the United States. Yet, approaches to improving employee safety have generally focused on attempts to modify individual behavior through enforced compliance with safety rules and mandatory participation in safety training. We examined a theoretical model that investigated the impact on nurse injuries (back injuries and needlesticks) of critical structural variables (staffing adequacy, work engagement, and work conditions) and further tested whether safety climate moderated these effects. A longitudinal, non-experimental, organizational study, conducted in 281 medical-surgical units in 143 general acute care hospitals in the United States. Work engagement and work conditions were positively related to safety climate, but not directly to nurse back injuries or needlesticks. Safety climate moderated the relationship between work engagement and needlesticks, while safety climate moderated the effect of work conditions on both needlesticks and back injuries, although in unexpected ways. DISCUSSION AND IMPACT ON INDUSTRY: Our findings suggest that positive work engagement and work conditions contribute to enhanced safety climate and can reduce nurse injuries

Peptides derived from hookworm anti-inflammatory proteins suppress inducible colitis in mice and inflammatory cytokine production by human cells

A decline in the prevalence of parasites such as hookworms appears to be correlated with the rise in non-communicable inflammatory conditions in people from high- and middle-income countries. This correlation has led to studies that have identified proteins produced by hookworms that can suppress inflammatory bowel disease (IBD) and asthma in animal models. Hookworms secrete a family of abundant netrin-domain containing proteins referred to as AIPs (Anti-Inflammatory Proteins), but there is no information on the structure-function relationships. Here we have applied a downsizing approach to the hookworm AIPs to derive peptides of 20 residues or less, some of which display anti-inflammatory effects when co-cultured with human peripheral blood mononuclear cells and oral therapeutic activity in a chemically induced mouse model of acute colitis. Our results indicate that a conserved helical region is responsible, at least in part, for the anti-inflammatory effects. This helical region has potential in the design of improved leads for treating IBD and possibly other inflammatory conditions

A stable aberrant immunophenotype characterizes nearly all cases of cutaneous T-cell lymphoma in blood and can be used to monitor response to therapy

BACKGROUND: Abnormal variations in the expression level of some commonly expressed T-cell antigens are a feature of many T-cell malignancies. METHODS: We sought to assess the frequency of such abnormal antigen expression by flow cytometry in peripheral blood (PB) samples from patients with mycosis fungoides (MF) and Sézary syndrome (SS). We correlated presence of morphologically identifiable tumor cells on PB smear with the frequency of abnormalities in the level of expression of CD3, CD4, CD7, CD8 and CD26. We also examined the degree of stability of these abnormal findings in tumor cells over the course of disease. The flow cytometric findings in 100 PB samples from 44 patients, including 38 who had multiple sequential PB samples (2–8 samples each), were assessed. RESULTS: Abnormalities were seen in the expression level of one or more T-cell markers in 41 cases (93%) including CD3 in 34% of patients, CD4 in 54%, CD26 in 86% and CD 45 in 40% (10 cases tested). In all but 2 cases, the abnormal T-cell immunophenotype remained similar over the course of treatment and correlated with the relative numbers of tumor cells counted on PB smear. CONCLUSIONS: Using a standard T-cell panel, stable phenotypically aberrant T-cell populations representing the tumor are detected in the vast majority of involved PB samples in MF/SS and can be used to monitor response to therapy

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma

BackgroundImage- guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma.ProcedureA multi- institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3- year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children’s Oncology Group for risk stratification.ResultsA total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy.ConclusionsPCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real- time pathology assessment of specimen quality.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154667/1/pbc28153_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154667/2/pbc28153.pd