Psychological interventions for post-traumatic stress disorder (PTSD) in people with severe mental illness

BACKGROUND: Increasing evidence indicates that individuals who develop severe mental illness (SMI) are also vulnerable to developing post-traumatic stress disorder (PTSD), due to increased risk of exposure to traumatic events and social adversity. The effectiveness of trauma-focused psychological interventions (TFPIs) for PTSD in the general population is well-established. TFPIs involve identifying and changing unhelpful beliefs about traumatic experiences, processing of traumatic memories, and developing new ways of responding to cues associated with trauma. Little is known about the potential feasibility, acceptability and effectiveness of TFPIs for individuals who have a SMI and PTSD. OBJECTIVES: To evaluate the effectiveness of psychological interventions for PTSD symptoms or other symptoms of psychological distress arising from trauma in people with SMI. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Study-Based Register (up until March 10, 2016), screened reference lists of relevant reports and reviews, and contacted trial authors for unpublished and/or specific outcome data. SELECTION CRITERIA: We included all relevant randomised controlled trials (RCTs) which investigated TFPIs for people with SMI and PTSD, and reported useable data. DATA COLLECTION AND ANALYSIS: Three review authors (DS, MF, IN) independently screened the titles and abstracts of all references identified, and read short-listed full text papers. We assessed risk of bias in each case. We calculated the risk ratio (RR) and 95% confidence interval (CI) for binary outcomes, and the mean difference (MD) and 95% CI for continuous data, on an intention-to-treat basis. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and created 'Summary of findings' tables. MAIN RESULTS: Four trials involving a total of 300 adults with SMI and PTSD are included. These trials evaluated three active intervention therapies: trauma-focused cognitive behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing (EMDR), and brief psychoeducation for PTSD, all delivered via individual sessions. Our main outcomes of interest were PTSD symptoms, quality of life/well-being, symptoms of co-morbid psychosis, anxiety symptoms, depressive symptoms, adverse events and health economic outcomes. 1. TF-CBT versus usual care/waiting list Three trials provided data for this comparison, however, continuous outcome data available were more often found to be skewed than unskewed, leading to the necessity of conducting analyses separately for the two types of continuous data. Using the unskewed data only, results showed no significant differences between TF-CBT and usual care in reducing clinician-rated PTSD symptoms at short term (1 RCT, n =13, MD 13.15, 95% CI -4.09 to 30.39,low-quality evidence). Limited unskewed data showed equivocal results between groups in terms of general quality of life (1 RCT, n = 39, MD -0.60, 95% CI -4.47 to 3.27, low-quality evidence), symptoms of psychosis (1 RCT, n = 9, MD -6.93, 95% CI -34.17 to 20.31, low-quality evidence), and anxiety (1 RCT, n = 9, MD 12.57, 95% CI -5.54 to 30.68, very low-quality evidence), at medium term. The only available data on depression symptoms were skewed and were equivocal across groups at medium term (2 RCTs, n = 48, MD 3.26, 95% CI -3.66 to 10.18, very low-quality evidence). TF-CBT was not associated with more adverse events (1 RCT, n = 100, RR 0.44, 95% CI 0.09 to 2.31, low-quality evidence) at medium term. No data were available for health economic outcomes. Very limited data for PTSD and other symptoms were available over the long term. 2. EMDR versus waiting listOne trial provided data for this comparison. Favourable effects were found for EMDR in terms of PTSD symptom severity at medium term but data were skewed (1 RCT, n = 83, MD -12.31, 95% CI -22.72 to -1.90, very low-quality evidence). EMDR was not associated with more adverse events (1 RCT, n = 102, RR 0.21, 95% CI 0.02 to 1.85, low-quality evidence). No data were available for quality of life, symptoms of co-morbid psychosis, depression, anxiety and health economics.3. TF-CBT versus EMDROne trial compared TF-CBT with EMDR. PTSD symptom severity, based on skewed data (1 RCT, n = 88, MD -1.69, 95% CI -12.63 to 9.23, very low-quality evidence) was similar between treatment groups. No data were available for the other main outcomes.4. TF-CBT versus psychoeducationOne trial compared TF-CBT with psychoeducation. Results were equivocal for PTSD symptom severity (1 RCT, n = 52, MD 0.23, 95% CI -14.66 to 15.12, low-quality evidence) and general quality of life (1 RCT, n = 49, MD 0.11, 95% CI -0.74 to 0.95, low-quality evidence) by medium term. No data were available for the other outcomes of interest. AUTHORS' CONCLUSIONS: Very few trials have investigated TFPIs for individuals with SMI and PTSD. Results from trials of TF-CBT are limited and inconclusive regarding its effectiveness on PTSD, or on psychotic symptoms or other symptoms of psychological distress. Only one trial evaluated EMDR and provided limited preliminary evidence favouring EMDR compared to waiting list. Comparing TF-CBT head-to-head with EMDR and brief psychoeducation respectively, showed no clear effect for either therapy. Both TF-CBT and EMDR do not appear to cause more (or less) adverse effects, compared to waiting list or usual care; these findings however, are mostly based on low to very low-quality evidence. Further larger scale trials are now needed to provide high-quality evidence to confirm or refute these preliminary findings, and to establish which intervention modalities and techniques are associated with improved outcomes, especially in the long term

Sex differences in frontal lobe connectivity in adults with autism spectrum conditions

Autism spectrum conditions (ASC) are more prevalent in males than females. The biological basis of this difference remains unclear. It has been postulated that one of the primary causes of ASC is a partial disconnection of the frontal lobe from higher-order association areas during development (that is, a frontal ‘disconnection syndrome’). Therefore, in the current study we investigated whether frontal connectivity differs between males and females with ASC. We recruited 98 adults with a confirmed highfunctioning ASC diagnosis (61 males: aged 18–41 years; 37 females: aged 18–37 years) and 115 neurotypical controls (61 males: aged 18–45 years; 54 females: aged 18–52 years). Current ASC symptoms were evaluated using the Autism Diagnostic Observation Schedule (ADOS). Diffusion tensor imaging was performed and fractional anisotropy (FA) maps were created. Mean FA values were determined for five frontal fiber bundles and two non-frontal fiber tracts. Between-group differences in mean tract FA, as well as sex-by-diagnosis interactions were assessed. Additional analyses including ADOS scores informed us on the influence of current ASC symptom severity on frontal connectivity. We found that males with ASC had higher scores of current symptom severity than females, and had significantly lower mean FA values for all but one tract compared to controls. No differences were found between females with or without ASC. Significant sex-by-diagnosis effects were limited to the frontal tracts. Taking current ASC symptom severity scores into account did not alter the findings, although the observed power for these analyses varied. We suggest these findings of frontal connectivity abnormalities in males with ASC, but not in females with ASC, have the potential to inform us on some of the sex differences reported in the behavioral phenotype of ASC.This work was supported by grant GO 400061 (to DGMM) from the UK Medical Research Council (http://www.mrc.ac.uk/index.htm). The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care—East of England (CLAHRC-EoE) also supported the project. This paper represents independent research (part) funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. During the period of the study M-CL and AR were supported by the William Binks Autism Neuroscience Fellowship and Autism Research Trust, and M-CL was also supported by the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto. The Autism Research Trust supported SB-C, BC and ML

Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

Objectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52\u200aweeks in PWH. Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420\u200amg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24\u200aweeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART. Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined. Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4\u200ayears, 82.5% male, mean duration with HIV of 17.4\u200ayears). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP. Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events. Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).National Institutes of Health; National Cancer Institute; U.S. Department of Health and Human Services

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570