The contribution of depressive ‘disorder characteristics’ to determinations of prognosis for adults with depression : an individual patient data meta-analysis

This is the final version. Available on open access from Cambridge University Press via the DOI in this record.The supplementary material for this article can be found at https://doi.org/10.1017/S0033291721001367Background This study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care. Methods We searched Medline, Embase, PsycINFO and Cochrane Central (inception to 12/01/2020) for RCTs that included the most commonly used comprehensive measure of depressive and anxiety disorder symptoms and diagnoses, in primary care depression RCTs (the Revised Clinical Interview Schedule: CIS-R). Two-stage random-effects meta-analyses were conducted. Results. Twelve (n = 6024) of thirteen eligible studies (n = 6175) provided individual patient data. There was a 31% (95%CI: 25 to 37) difference in depressive symptoms at 3–4 months per standard deviation increase in baseline depressive symptoms. Four additional factors: the duration of anxiety; duration of depression; comorbid panic disorder; and a history of antidepressant treatment were also independently associated with poorer prognosis. There was evidence that the difference in prognosis when these factors were combined could be of clinical importance. Adding these variables improved the amount of variance explained in 3–4 month depressive symptoms from 16% using depressive symptom severity alone to 27%. Risk of bias (assessed with QUIPS) was low in all studies and quality (assessed with GRADE) was high. Sensitivity analyses did not alter our conclusions. Conclusions. When adults seek treatment for depression clinicians should routinely assess for the duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment alongside depressive symptom severity. This could provide clinicians and patients with useful and desired information to elucidate prognosis and aid the clinical management of depression. IntroductionMedical Research Council (MRC)Wellcome TrustMQ FoundationNational Institute of Health Research (NIHR)University College LondonUniversity of PennsylvaniaUniversity of SouthamptonUniversity of YorkUniversity of Exete

Mechanisms of injury in experimental glomerulonephritis

Proliferative glomerulonephritis (GN), seen in patients with Goodpasture’s disease or systemic lupus erythematosus (SLE), is characterised by glomerular infiltration of macrophages and T cells as well as proliferation of intrinsic renal cells. Significant insights into the pathogenesis of GN have been obtained through the use of experimental rodent models, such as nephrotoxic nephritis (NTN). In this thesis I have investigated the role of two important immunological molecules in NTN: Fas ligand (FasL) and Fc gamma receptor IIB (FcγRIIB). FasL is a well-known inducer of apoptosis in cells expressing its receptor Fas; however FasL also mediates non-apoptotic pro-inflammatory responses. FasL is widely expressed throughout the hematopoietic system but is also expressed within healthy and diseased kidney. I describe a novel role for FasL in the promotion of NTN independent from antibody and T cell responses. This pathological effect correlates with enhanced glomerular inflammation and appears to be dependent on FasL expression on both circulating leukocytes and intrinsic renal cells. Additionally, I have shown FasL-defective mesangial cells have impaired signalling through the IL-1R with a reduction in MCP-1 production. FcγRIIB is the sole inhibitory Fc receptor for IgG and is involved in the negative regulation of B cells and cellular activation. FcγRIIB is widely expressed throughout the hematopoietic system but is also expressed on mesangial cells within the kidney. FcγRIIB deficiency greatly exacerbates NTN. Here I use cell-specific deletion to demonstrate the critical importance of FcγRIIB expressed on myeloid cells rather than B cells in the protection from NTN. Further to this, I highlight a role for FcγRIIB on intrinsic renal cells, possibly mesangial cells, in the protection from NTN. Overall, these data widen our knowledge on the pathogenesis of GN and open up possibilities for finding future novel treatments.Open Acces

Lessons learned from implementing remotely invigilated online exams

This paper outlines the key issues of remotely invigilated online exams (RIOEs) and presents ways to avoid and resolve the issues for educators who are considering implementing them. The purpose of this paper is to share the lessons learned during the process of implementing and evaluating RIOEs and highlight the key considerations required to conduct RIOEs more seamlessly, whilst minimising students’ cognitive load. With the continued growth, and future importance of online tertiary education, this paper provides an important contribution to the understanding of the best methods and practices by which to conduct online examinations and provides a foundation for continued research and enhancement of effective RIOEs. The paper follows an extensive Action Learning process to develop and present a case study that was conducted across nine fully online business courses in a start-up venture for the University of South Australia. Cognitive load theory underpins the case study, which enabled the researchers to gain profound understanding into the RIOE process, identify issues and offer resolutions. RIOEs require more systematic and effective design compared to traditional paper-based exams and should be supplemented by early and clear communication with students. Educators should enable and encourage students to rehearse the exam service access procedures prior to their exams and students should be provided with real-time responsive technical support for any ad hoc issues that may present during the exam. These factors play a critical role in ensuring the successful implementation of RIOEs

The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis

Abstract Background Cardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T cells is seen mainly in cytomegalovirus (CMV)-seropositive individuals and has been linked to increased cardiovascular disease risk in other conditions. The aims of this study were to phenotype CD4+CD28null T cells in AAV with respect to their pro-inflammatory capacity and ability to target and damage the endothelium and to investigate their relationship to arterial stiffness, a marker of cardiovascular mortality. Methods CD4+CD28null T cells were phenotyped in 53 CMV-seropositive AAV patients in stable remission and 30 age-matched CMV-seropositive healthy volunteers by flow cytometry following stimulation with CMV lysate. The expression of endothelial homing markers and cytotoxic molecules was evaluated in unstimulated CD4+CD28null T cells. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) in patients with AAV. Results CD4+CD28null T cells were CMV-specific and expressed a T helper 1 (Th1) phenotype with high levels of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) secretion. They also co-expressed the endothelial homing markers CX3CR1, CD49d and CD11b and cytotoxic molecules perforin and granzyme B. CD4+CD28null T cells were phenotypically similar in patients with AAV and healthy volunteers but their proportion was almost twice as high in patients with AAV (11.3% [3.7–19.7] versus 6.7 [2.4–8.8]; P = 0.022). The size of the CD4+CD28null T-cell subset was independently linked to increased PWV in AAV (0.66 m/s increase per 10% increase in CD4+CD28null cells, 95% confidence interval 0.13–1.19; P = 0.016). Conclusion The host cellular immune response to CMV leads to the expansion of cytotoxic CD4+CD28null T cells that express endothelial homing markers and are independently linked to increased arterial stiffness, a marker of cardiovascular mortality. Suppression of CMV in AAV may be of therapeutic value in reducing the risk of cardiovascular disease

FcγRIIb on myeloid cells and intrinsic renal cells rather than B cells protects from nephrotoxic nephritis

FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the Fc γRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIB fl/fl/CD19Cre+) or myeloid cells (FcγRIIB fl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-typ