GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists. Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society

Mapping Systematic Reviews on Forensic Psychiatric Care: A Systematic Review Identifying Knowledge Gaps

Background: Forensic psychiatric care treats mentally disordered offenders who suffer mainly from psychotic disorders, although comorbidities such as personality disorders, neurodevelopmental disorders, and substance abuse are common. A large proportion of these patients have committed violent crimes. Their care is involuntary, and their caregivers' mission is complex: not only to rehabilitate the patient, but also to consider their risk for reoffending and their risk to society. The objective of this overview of systematic reviews is to identify, appraise, and summarize the existing knowledge in forensic psychiatric care and identify knowledge gaps that require further research.Methods: We undertook a systematic literature search for systematic reviews in five defined domains considered important in daily clinical practice within the forensic psychiatric care: (1) diagnostic assessment and risk assessments; (2) pharmacological treatment; (3) psychological interventions; (4) psychosocial interventions, rehabilitation, and habilitation; and (5) restraint interventions. The target population was mentally disordered offenders (forensic psychiatric patients aged >15 years). Each abstract and full text review was assessed by two of the authors. Relevant reviews then were assessed for bias, and those with moderate or low risk of bias were included.Results: Of 38 systematic reviews meeting the inclusion criteria, only four had a moderate risk of bias. Two aimed to incorporate as many aspects of forensic psychiatric care as possible, one investigated non-pharmacological interventions to reduce aggression in forensic psychiatric care, and one focused on women with intellectual disabilities in forensic care. However, most of the primary studies included in these reviews had high risks of bias, and therefore, no conclusions could be drawn. All of our identified domains must be considered knowledge gaps.Conclusion: We could not answer any of our research questions within the five domains because of the high risk of bias in the primary studies in the included systematic reviews. There is an urgent need for more research on forensic psychiatric care since all of our studied domains were considered knowledge gaps

The GRADE Working Group clarifies the construct of certainty of evidence

The authors would like to thank colleagues at the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) who, through participating in a series of seminars, contributed with valuable input on the initial draft of the presented approaches. The authors also thank all GRADE Working Group members who have contributed to the paper during group discussions at Grade Working Group meetings. The Health Services Research Unit, University of Aberdeen, receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. The Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation (OCAY-13-309). SVK is funded by a NRS Scottish Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_12017/13 & MC_UU_12017/15) and Chief Scientist’s Office (SPHSU13 & SPHSU15).Peer reviewedPublisher PD

Interferons in antiviral defense and autoimmunity : Focus on type 1 diabetes

p>Type 1 diabetes (T1D) is a disease characterized by the loss of insulin producing beta-cells in the pancreatic islets of Langerhans. Interferons (IFNs), produced by immune cells and infected parenchymal cells, may be protective or damaging in the pathogenesis of T1D. An intact beta-cell response to IFNs is critical for beta-cell survival and protection from diabetes during a Coxsackievirus B (CVB) infection, a virus associated with T1D in humans. It has also been suggested that IFNs may protect from natural killer (NK) cell dependent destruction. Importantly, while being protective during infection with CVB, the pancreatic beta-cell response to cytokines is crucial for the development of type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse. NOD mice overexpressing the Suppressor of Cytokine Signaling 1 (SOCS-1) specifically in the beta-cells are protected from spontaneous diabetes. The work in this thesis focuses on the mechanisms behind the protective and damaging effects of IFNs in the pathogenesis of T1D. Moreover, it identifies a possible source of IFNgamma during CVB infection. This thesis shows that IFNs trigger an antiviral state in mouse and human islets. Both the RNase L and the dsRNA-dependent protein kinase (PKR) pathways are induced by IFNs in mouse islets and play important roles in providing unique and complementary antiviral activities that regulate the outcome of CVB infection. Moreover, this thesis shows that human islet cells also respond to IFNs by expressing signature genes of antiviral defense. It further demonstrates that human islets express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which contribute to the production of type I IFN in infected cells. These observations suggest that human islet cells have the possibility to detect an invading virus and to produce type I IFNs during an infection. The work presented in this thesis identifies the NK cell as a possible contributor of IFNgamma during CVB infection: it shows that CVB interferes with the expression of NK cell receptor ligands on infected cells and that IFNgamma production, rather than cytotoxicity, marks the early human NK cell response to CVB infection. Finally, this thesis gives new insights into how IFNs, by acting directly on beta-cells, contribute to disease development in the NOD mouse. It demonstrates that the beta-cell, by responding to thepro-inflammatory pancreas milieu, strongly influences the percentage of self-reactive CD8 T-cells in the pancreas. In conclusion, this thesis supports the notion that cytokine-exposed islet cells affect islet infection and inflammation, highlighting an important role for the beta-cell in the local regulation of the diabetogenic process. By providing a basic understanding for how beta-cells respond to IFNs, and how this relates to their defense against CVB and to the accumulation of pathogenic cells in the pancreas, it may contribute to a future unraveling of the mechanisms underlying beta-cell loss in T1D

Internet-delivered psychological treatments for mood and anxiety disorders : a systematic review of their efficacy, safety, and cost-effectiveness

BACKGROUND: Greater access to evidence-based psychological treatments is needed. This review aimed to evaluate whether internet-delivered psychological treatments for mood and anxiety disorders are efficacious, noninferior to established treatments, safe, and cost-effective for children, adolescents and adults. METHODS: We searched the literature for studies published until March 2013. Randomized controlled trials (RCTs) were considered for the assessment of short-term efficacy and safety and were pooled in meta-analyses. Other designs were also considered for long-term effect and cost-effectiveness. Comparisons against established treatments were evaluated for noninferiority. Two reviewers independently assessed the relevant studies for risk of bias. The quality of the evidence was graded using an international grading system. RESULTS: A total of 52 relevant RCTs were identified whereof 12 were excluded due to high risk of bias. Five cost-effectiveness studies were identified and three were excluded due to high risk of bias. The included trials mainly evaluated internet-delivered cognitive behavioral therapy (I-CBT) against a waiting list in adult volunteers and 88% were conducted in Sweden or Australia. One trial involved children. For adults, the quality of evidence was graded as moderate for the short-term efficacy of I-CBT vs. waiting list for mild/moderate depression (d = 0.83; 95% CI 0.59, 1.07) and social phobia (d = 0.85; 95% CI 0.66, 1.05), and moderate for no efficacy of internet-delivered attention bias modification vs. sham treatment for social phobia (d = -0.04; 95% CI -0.24, 0.35). The quality of evidence was graded as low/very low for other disorders, interventions, children/adolescents, noninferiority, adverse events, and cost-effectiveness. CONCLUSIONS: I-CBT is a viable treatment option for adults with depression and some anxiety disorders who request this treatment modality. Important questions remain before broad implementation can be supported. Future research would benefit from prioritizing adapting treatments to children/adolescents and using noninferiority designs with established forms of treatment

Mapping Systematic Reviews on Forensic Psychiatric Care : A Systematic Review Identifying Knowledge Gaps

Background: Forensic psychiatric care treats mentally disordered offenders who suffer mainly from psychotic disorders, although comorbidities such as personality disorders, neurodevelopmental disorders, and substance abuse are common. A large proportion of these patients have committed violent crimes. Their care is involuntary, and their caregivers' mission is complex: not only to rehabilitate the patient, but also to consider their risk for reoffending and their risk to society. The objective of this overview of systematic reviews is to identify, appraise, and summarize the existing knowledge in forensic psychiatric care and identify knowledge gaps that require further research. Methods: We undertook a systematic literature search for systematic reviews in five defined domains considered important in daily clinical practice within the forensic psychiatric care: (1) diagnostic assessment and risk assessments; (2) pharmacological treatment; (3) psychological interventions; (4) psychosocial interventions, rehabilitation, and habilitation; and (5) restraint interventions. The target population was mentally disordered offenders (forensic psychiatric patients aged >15 years). Each abstract and full text review was assessed by two of the authors. Relevant reviews then were assessed for bias, and those with moderate or low risk of bias were included. Results: Of 38 systematic reviews meeting the inclusion criteria, only four had a moderate risk of bias. Two aimed to incorporate as many aspects of forensic psychiatric care as possible, one investigated non-pharmacological interventions to reduce aggression in forensic psychiatric care, and one focused on women with intellectual disabilities in forensic care. However, most of the primary studies included in these reviews had high risks of bias, and therefore, no conclusions could be drawn. All of our identified domains must be considered knowledge gaps. Conclusion: We could not answer any of our research questions within the five domains because of the high risk of bias in the primary studies in the included systematic reviews. There is an urgent need for more research on forensic psychiatric care since all of our studied domains were considered knowledge gaps

Pharmacological Treatment in Forensic Psychiatry-A Systematic Review

Background: Pharmacological treatment is of great importance in forensic psychiatry, and the vast majority of patients are treated with antipsychotic agents. There are several systematic differences between general and forensic psychiatric patients, e.g. severe violent behavior, the amount of comorbidity, such as personality disorders and/or substance abuse. Based on that, it is reasonable to suspect that effects of pharmacological treatments also may differ. The objective of this systematic review was to investigate the effects of pharmacological interventions for patients within forensic psychiatry. Methods: The systematic review protocol was pre-registered in PROSPERO (CRD42017075308). Six databases were used for literature search on January 11, 2018. Controlled trials from forensic psychiatric care reporting on the effects of antipsychotic agents, mood stabilizers, benzodiazepines, antidepressants, as well as pharmacological agents used for the treatment of addiction or ADHD, were included. Two authors independently reviewed the studies, evaluated risk of bias and assessed certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: The literature search resulted in 1783 records (titles and abstracts) out of which 10 studies were included. Most of the studies included were retrospective and non-randomized. Five of them focused on treatment with clozapine and the remaining five on other antipsychotics or mood stabilizers. Five studies with a high risk of bias indicated positive effects of clozapine on time from treatment start to discharge, crime-free time, time from discharge to readmission, improved clinical functioning, and reduction in aggressive behavior. Psychotic symptoms after treatment were more pronounced in the clozapine group. Mainly due to the high risk of bias the reliability of the evidence for all outcomes was assessed as very low. Conclusion: This systematic review highlights the shortage of knowledge on the effectiveness of pharmacological treatment within forensic psychiatry. Due to very few studies being available in this setting, as well as limitations in their execution and reporting, it is challenging to overview the outcomes of pharmacological interventions in this context. The frequent use of antipsychotics, sometimes in combination with other pharmacological agents, in this complex and heterogeneous patient group, calls for high-quality studies performed in this specific setting

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFN gamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1 beta, IFN gamma, TNF alpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFN gamma in beta cells. In summary, we show that interference with IFN gamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death

Internet-delivered psychological treatment as an add-on to treatment as usual for common mental disorders : A systematic review with meta-analysis of randomized trials

Background: Psychological treatments for common mental disorders are increasingly being delivered remotely via the internet. Evidence suggests that internet-delivered cognitive behavioural therapy (iCBT) is superior to waitlist. However, the benefits are unclear of using this treatment modality as an add-on to treatment as usual (TAU) in regular healthcare. Methods: The literature was systematically searched up to August 2021 for randomized trials of internet-delivered psychological treatments using TAU as the comparator. Eligible participants were diagnosed with depressive, anxiety, obsessive-compulsive, or trauma- and stress-related disorders. Outcomes of interest were symptoms, functioning, quality of life, healthcare utilization, and negative effects. Results were synthesized using random-effects meta-analyses. Quality of evidence was assessed using GRADE. Results: The included studies evaluated iCBT for adults with depression (k = 9), depressive or anxiety disorders (k = 4), and post-traumatic stress disorder (k = 2) and were conducted in primary care or similar settings. For depression, low-certainty evidence suggested beneficial short-term effects on symptoms (g = −0.23; 95 % CI: = −0.37, −0.09), response rate (OR = 2.46; 1.31, 4.64), and remission (OR = 1.70; 1.19, 2.42;). The certainty of evidence was very low for long-term effects, other outcomes, and other disorders. Limitations: TAU varied across studies and was often insufficiently described. Conclusions: iCBT as a complement to usual care for adult with depression may result in a small incremental effect, which potentially could be clinically important. Studies are lacking for several common disorders and for children, adolescents, and the elderly. More robust studies of long-term effects are also needed, to better inform clinical decision-making