B-cell depletion in Rheumatoid Arthritis: clinical, biochemical and synovial predictors of response

PhDDespite a growing armamentarium of therapies available to treat rheumatoid arthritis (RA), predicting response to therapy remains a clinical challenge. Witnessed variability in treatment outcomes translates to a large unmet clinical need; with significant risk of disease progression, exposure to side effects and health economic burden. Clinical heterogeneity in RA is reflected at the tissue level as diseased synovium displays variation in both degree and organisation of immune cell infiltration. Transcriptomic analysis suggests that synovial cellular heterogeneity is mirrored by a diversification of molecular profiles which may affect response to therapy. B-cells play a critical role in the pathogenesis and propagation of RA. Treatment response to the B-cell depleting agent rituximab in RA is varied and clear predictors of response are yet to be elucidated. The first aim of this work was to develop a pathological scoring system for the rheumatoid synovium to determine ‘B-cell rich’ and ‘B-cell poor’ pathotypes and investigate whether these subgroups can predict clinical response. I establish that despite the degree of reduction in synovial B-cells following rituximab therapy, clinical response remains indeterminate. The second aim was to investigate whether a molecular signature associated with response to rituximab therapy. Critically, I demonstrate that an upregulation of genes associated with ectopic lymphoid structures (ELS) and those which orchestrate Th17/interleukin 17 (IL-17) pathways are associated with diminished response to rituximab. Furthermore, these genes can be utilised to create a model which has high sensitivity to predict response to rituximab. Finally, I investigate whether changes in synovial cellular infiltration and gene expression are associated with changes in ultrasound (US) synovial thickening (ST) and power doppler (PD) signal, demonstrating a key role of fibroblast and IL-17 associated genes. Synovium remains the site of insult in RA; this work enhances the notion that synovial biopsies may be pivotal stratification tools of the future

The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring

Background Azathioprine is efficacious in the treatment of severe childhood atopic dermatitis; however, robust data on adverse effects in this population are lacking. Objective We sought to assess adverse effects of azathioprine treatment in a pediatric atopic dermatitis cohort, and make recommendations for monitoring based on these data

Statistical inference based on progressively type-II censored data from the Burr X distribution under progressive-stress accelerated life test

[[abstract]]In this article, estimation problems for the Burr X distribution under a progressive-stress accelerated life test with progressive type-II censoring are studied. The stress is assumed to be a linearly increasing function of time. The inverse power law and the cumulative exposure model are considered. The classical and Bayesian estimations for the model parameters are obtained by using maximum likelihood method and Markov chain Monte Carlo technique,respectively. The asymptotic confidence intervals are constructed and highest posterior density intervals are also established. A simulation study is conducted to investigate the performance of the proposed point and interval estimations. Finally, a real data set is analysed for illustration.[[notice]]補正完

Intermediaries and social entrepreneurship identity: implications for business model innovation

Purpose: The authors propose a theoretical basis for understanding the role of ecosystem intermediaries in the configuration of social entrepreneurship identities in social purpose organisations (SPOs) and their business model innovations (BMIs). Design/methodology/approach: Adopting a retrospective multiple-case study, the authors offer insights into the paths/elements that determine the building of 44 social entrepreneurship identities in the context of an emerging economy (Mexico). Findings: The study sheds light on the role of intermediaries in the configuration of the entrepreneurial identities of Mexican SPOs and BMIs, as well as several externalities generated during the process of capturing the social and economic value, especially when social innovations are focussed on solving societal, economic and ecological social problems. Research limitations/implications: The first limitation is related to the analysis of intermediaries within the social entrepreneurship ecosystem, which needs more conceptual and empirical evidence. The second limitation is that the analysis focussed only on intervened SPOs, as the authors did not control for non-intervened SPOs. Thus, this allows for future in-depth analysis of intermediary efficiency in a focus group (intervened SPOs) and a control group (non-intervened SPOs). Practical implications: The study also provides insights for Mexican SPOs on how a social entrepreneurship identity helps to capture the value creation of social innovations within an innovation ecosystem. Indeed, it is strongly aligned with the United Nations' Social Development Goals. Originality/value: The study enhances the discussion about how intermediaries could encourage social entrepreneurial identity, as well as how intermediary intervention could facilitate the design and implementation of BMIs in the innovation ecosystem

Analysis of Blunt Abdominal Trauma with Respect to Associated Injuries, Period of Survival And Mechanism of Death Among Autopsies Conducted in Dept. of FMT, RIMS, Ranchi

Abstract : Introduction: Since the abdominal cavity contains the vital organs like liver, spleen, kidney, stomach, intestines etc, traum

<i>Pseudomonas aeruginosa</i> in Nepali hospitals: poor outcomes amid 10 years of increasing antimicrobial resistance

ObjectiveTo determine antimicrobial resistance patterns and prevalence of multi- (MDR, i.e., resistant to ⩾3 classes of antimicrobial agents) and extensively (XDR, i.e., resistant to ⩾3, susceptible to ⩽2 groups of antibiotics) drug-resistant strains of Pseudomonas aeruginosa.MethodsThis was a cross-sectional study conducted in Nepal Mediciti Hospital, Lalitpur, Nepal, using standard microbiological methods with Kirby Bauer disc diffusion to identify antimicrobial susceptibility.ResultsP. aeruginosa (n = 447) were most frequently isolated in respiratory (n = 203, 45.4%) and urinary samples (n = 120, 26.8%). AWaRe Access antibiotics showed 25-30% resistance, Watch antibiotics 30-55%. Susceptibility to AWaRe Reserve antibiotics remains high; however, 32.8% were resistant to aztreonam. Overall, 190 (42.5%) were MDR and 99 (22.1%) XDR (first Nepali report) based on mainly non-respiratory samples. The majority of infected patients were >40 years (n = 229, 63.2%) or inpatients (n = 181, 50.0%); 36 (15.2%) had an unfavourable outcome, including death (n = 25, 10.5%). Our larger study showed a failure of improvement over eight previous studies covering 10 years.ConclusionAntibiotic resistance in P. aeruginosa occurred to all 19 AWaRe group antibiotics tested. Vulnerable patients are at significant risk from such resistant strains, with a high death rate. Sustainable and acceptable antibiotic surveillance and control are urgently needed across Nepal, as antimicrobial resistance has deteriorated over the last decade

Performance evaluation of different coating materials in delamination for micro-milling applications on high-speed steel substrate.

This is the final version. Available from MDPI via the DOI in this record. The objective of the present work is to carry out analytical and finite element analysis for commonly used coating materials for micro-milling applications on high-speed steel substrate and evaluate the effects of different parameters. Four different coating materials were selected for micro-milling applications: titanium nitride (TiN), diamond-like carbon (DLC), aluminium titanium nitride (AlTiN) and titanium silicon nitride (TiSiN). A 3D finite element model of coating and substrate assembly was developed in Abaqus to find the Hertzian normal stress when subjected to normal load of 4 N, applied with the help of a rigid ball. The radius of the rigid ball was 200 µm. For all the coating materials, the length was 3 mm, the width was 1 mm, and the thickness was 3 µm. For the high-speed steel substrate, the length was 3 mm, the width was 1 mm, and the thickness was 50 µm. Along the length and width, coating and substrate both were divided into 26 equal parts. The deformation behaviour of all the coating materials was considered as linear-elastic and that of the substrate was characterized as elastic-plastic. The maximum normal stress developed in the FEA model was 12,109 MPa. The variation of the FEA result from the analytical result (i.e., 12,435.97 MPa is 2.63%) which is acceptable. This confirms that the FEA model of coating-substrate assembly is acceptable. The results shows that the TiSiN coating shows least plastic equivalent strain in the substrate, which serves the purpose of protecting the substrate from plastic deformation and the TiSiN of 3 micron thickness is the most optimum coating thickness for micro-milling applications

High antibiotic resistance and mortality with <i>Acinetobacter</i> species in a tertiary hospital, Nepal

SettingNepal Mediciti Hospital, Bhainsepati, Lalitpur, Nepal.ObjectivesTo determine antimicrobial resistance patterns, and the number and proportion of multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) cases among all patients with Acinetobacter isolates between September 2018 and September 2019.DesignThis was a hospital laboratory-based, cross-sectional study.ResultsAcinetobacter spp. (n = 364) were more common in respiratory (n = 172, 47.3%) and invasive samples such as blood, body fluids (n = 95, 26.1%). Sensitivity to AWaRe (Access, Watch and Reserve) Group antibiotics (tigecycline, polymyxin B, colistin) remained high. MDR (resistance to at least three classes of antimicrobial agents) (n = 110, 30.2%) and XDR (MDR plus carbapenem) (n = 87, 23.9%) isolates were most common in the Watch Group of antibiotics and found in respectively 99 (31.0%) and 78 (24.5%) patients (n = 319). Infected patients were more likely to be aged >40 years (n = 196, 61.4%) or inpatients (n = 191, 59.9%); 76 (23.8%) patients had an unfavourable outcome, including death (n = 59, 18.5%).ConclusionA significant proportion of MDR and XDR isolates was found; nearly one patient in five died. Robust hospital infection prevention and control measures (particularly for respiratory and invasive procedures) and routine surveillance are needed to reduce infections and decrease the mortality rate. Tigecycline, polymyxin B and colistin should be cautiously used only in MDR and XDR cases

A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNF alpha-Blockade in Rheumatoid Arthritis Patients

Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment. Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune). Results: At baseline, as per inclusion criteria, DAS28 mean was 6.4 \ub1 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho- and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), p = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho- and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks. Conclusions: The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNF\u3b1-blockade

Quad element MIMO antenna for C, X, Ku, and Ka-band applications

This article presents a quad-element MIMO antenna designed for multiband operation. The prototype of the design is fabricated and utilizes a vector network analyzer (VNA-AV3672D) to measure the S-parameters. The proposed antenna is capable of operating across three broad frequency bands: 3–15.5 GHz, encompassing the C band (4–8 GHz), X band (8–12.4 GHz), and a significant portion of the Ku band (12.4–15.5 GHz). Additionally, it covers two mm-wave bands, specifically 26.4–34.3 GHz and 36.1–48.9 GHz, which corresponds to 86% of the Ka-band (27–40 GHz). To enhance its performance, the design incorporates a partial ground plane and a top patch featuring a dual-sided reverse 3-stage stair and a straight stick symmetrically placed at the bottom. The introduction of a defected ground structure (DGS) on the ground plane serves to provide a wideband response. The DGS on the ground plane plays a crucial role in improving the electromagnetic interaction between the grounding surface and the top patch, contributing to the wideband characteristics of the antenna. The dimensions of the proposed MIMO antenna are 31.7 mm × 31.7 mm × 1.6 mm. Furthermore, the article delves into the assessment of various performance metrics related to antenna diversity, such as ECC, DG, TARC, MEG, CCL, and channel capacity, with corresponding values of 0.11, 8.87 dB, −6.6 dB, ±3 dB, 0.32 bits/sec/Hz, and 18.44 bits/sec/Hz, respectively. Additionally, the equivalent circuit analysis of the MIMO system is explored in the article. It’s worth noting that the measured results exhibit a strong level of agreement with the simulated results, indicating the reliability of the proposed design. The MIMO antenna’s ability to exhibit multiband response, good diversity performance, and consistent channel capacity across various frequency bands renders it highly suitable for integration into multi-band wireless devices. The developed MIMO system should be applicable on n77/n78/n79 5G NR (3.3–5 GHz); WLAN (4.9–5.725 GHz); Wi-Fi (5.15–5.85 GHz); LTE5537.5 (5.15–5.925 GHz); WiMAX (5.25–5.85 GHz); WLAN (5.725–5.875 GHz); long-distance radio telecommunication (4–8 GHz; C-band); satellite, radar, space communications and terrestrial broadband (8–12 GHz; X-band); and various satellite communications (27–40 GHz; Ka-band)