Interventions for preventing relapse or recurrence of major depressive disorder in adults in a primary care setting: a network meta‐analysis

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The aim is to assess, using network meta-analysis (NMA), the effectiveness and safety of interventions for preventing relapse-recurrence of depression in adults in a primary care setting. NMA is a technique for comparing three or more interventions simultaneously in a single analysis by combining both direct and indirect evidence across a network of studies. The objectives are to:. estimate the relative effectiveness of pharmacological, psychological and other interventions to prevent relapse-recurrence, compared with each other and controls (e.g. pill placebo, treatment as usual) on relapse-recurrence outcomes and adverse events; assess the effect of interventions on quality of life outcomes and social and occupational functioning; estimate the relative ranking of included interventions on relapse-recurrence, quality of life, and adverse events; summarise availability and principal findings of eligible economic evaluations

Structural Insights Into the Disruption of Tnf-tnfr1 Signalling by Small Molecules Stabilising a Distorted Tnf

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617. FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49). INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. FUNDING: Cancer Research UK and Blood Cancer UK

Psychological and pharmacological interventions for post-traumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis

Background: Complex traumatic events associated with armed conflict, forcible displacement, childhood sexual abuse and domestic violence are increasingly prevalent. People exposed to complex traumatic events are at not only at risk of post-traumatic stress disorder (PTSD) but also other mental health comorbidities. While evidence-based psychological and pharmacological treatments are effective for single event PTSD it is not known if people who have experienced complex traumatic events can benefit and tolerate these commonly available treatments. Furthermore, it is not known which components of psychological interventions are most effective for managing PTSD in this population. We performed a systematic review and component network meta-analysis to assess the effectiveness of psychological and pharmacological interventions for managing mental health problems in people exposed to complex traumatic events.Methods and Findings: We searched CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Published International Literature on Traumatic Stress, PsycINFO, and Science Citation Index for randomised and non-randomised controlled trials of psychological and pharmacological treatments for PTSD symptoms n people exposed to complex traumatic events, published up to 25th October 2019. We adopted a non-diagnostic approach and included studies of adults who have experienced complex trauma. Complex trauma sub-groups were: veterans; childhood sexual abuse; war-affected; refugees; and domestic violence. The primary outcome was reduction in PTSD symptoms. Secondary outcomes were depressive and anxiety symptoms, quality of life, sleep quality, and positive and negative affect. We included 116 studies, of which 50 were conducted in hospital settings, 24 were delivered in community settings, seven were delivered in military clinics for veterans or active military personnel, five were conducted in refugee camps, four used remote delivery via web based or telephone platforms, four were conducted in specialist trauma clinics, two were delivered in home settings, and two were delivered in primary care clinics; clinical setting was not reported in 17 studies. Ninety-four RCTs for a total of 6158 participants were included in meta-analyses across the primary and secondary outcomes; 19 RCTs for a total of 933 participants were included in the component network meta-analysis. The mean age of participants in the included RCTs was 42.6 ±9.3 years, and 42% were male. Nine non-randomised controlled trials were included. The mean age of participants in the non-randomised controlled trials was 40.6 ±9.4 years, and 47% were male. The average length of follow-up across all included studies at post-treatment for the primary outcome was 11.5 weeks. The pair-wise meta-analysis showed that psychological interventions reduce PTSD symptoms more than inactive control (k=46; n=3389; standardised mean difference, SMD=-0.82, 95% CI: -1.02 to -0.63) and active control (k-9; n=662; SMD=-0.35, 95% CI: -0.56 to -0.14) at post-treatment, and also compared with inactive control at 6-month follow-up (k=10; n=738; SMD=-0.45, 95% CI: -0.82 to -0.08). Psychological interventions reduced depressive symptoms (k=31; n=2075; SMD=-0.87, 95% CI: -1.11 to -0.63; I2=82.7%, p=0.000) and anxiety (k=15; n=1395; SMD=-1.03, 95% CI: -1.44 to -0.61; p=0.000) at post-treatment comparted with inactive control. Sleep quality was significantly improved at post-treatment by psychological interventions compared with inactive control (k=3; n=111; SMD=-1.00, 95% CI: -1.49 to-0.51; p=0.245). There were no significant differences between psychological interventions and inactive control group at post-treatment for quality of life (k=6; n=401; SMD=0.33, 95% CI: -0.01 to 0.66; p=0.021). Antipsychotic medicine (k=5; n=364; SMD=–0.45; –0.85 to –0.05; p=0.085) and Prazosin (k=3; n=110; SMD=-0.52; -1.03 to -0.02; p=0.182) were effective in reducing PTSD symptoms. Phase-based psychological interventions that included skills based strategies along with trauma-focused strategies were the most promising interventions for emotional dysregulation and interpersonal problems. Compared with pharmacological interventions we observed that psychological interventions were associated with greater reductions in PTSD and depression symptoms and improved sleep quality. Sensitivity analysis showed that psychological interventions were acceptable with lower drop out, even in studies rated at low risk of attrition bias. Trauma-focused psychological interventions were superior to non-trauma focused interventions across trauma sub-groups for PTSD symptoms, but effects among veterans and war-affected populations were significantly reduced. The network meta-analysis showed that multi-component interventions that included cognitive restructuring and imaginal exposure were the most effective for reducing PTSD symptoms (k=17; n=1077; mean difference=-37.95, 95% CI: -60.84 to -15.16). Our use of a non-diagnostic inclusion strategy may have over-looked certain complex trauma populations with severe and enduring mental comorbidities. Additionally, the relative contribution of skills-based intervention components were not feasibly evaluated in the network meta-analysis.Conclusions: In this systematic review and meta-analysis we observed that trauma-focused psychological interventions are effective for managing mental health problems and comorbidities in people exposed to complex trauma. Multi-component interventions, which can include phase-based approaches, were the most effective treatment package for managing PTSD in complex trauma. Establishing optimal ways to deliver multicomponent psychological interventions for people exposed to complex traumatic events is a research and clinical priority

Genetic diversity and connectivity of southern right whales (Eubalaena australis) found in the Brazil and Chile-Peru wintering grounds and the South Georgia (Islas Georgias del Sur) feeding ground

As species recover from exploitation, continued assessments of connectivity and population structure are warranted to provide information for conservation and management. This is particularly true in species with high dispersal capacity, such as migratory whales, where patterns of connectivity could change rapidly. Here we build on a previous long-term, large-scale collaboration on southern right whales (Eubalaena australis) to combine new (nnew) and published (npub) mitochondrial (mtDNA) and microsatellite genetic data from all major wintering grounds and, uniquely, the South Georgia (Islas Georgias del Sur: SG) feeding grounds. Specifically, we include data from Argentina (npub mtDNA/microsatellite=208/46), Brazil (nnew mtDNA/microsatellite=50/50), South Africa (nnew mtDNA/microsatellite=66/77, npub mtDNA/microsatellite=350/47), Chile-Peru (nnew mtDNA/microsatellite=1/1), the Indo-Pacific (npub mtDNA/microsatellite=769/126), and SG (npub mtDNA/microsatellite=8/0, nnew mtDNA/microsatellite=3/11) to investigate the position of previously unstudied habitats in the migratory network: Brazil, SG and Chile-Peru. These new genetic data show connectivity between Brazil and Argentina, exemplified by weak genetic differentiation and the movement of one genetically identified individual between the South American grounds. The single sample from Chile-Peru had a mtDNA haplotype previously only observed in the Indo-Pacific and had a nuclear genotype that appeared admixed between the Indo-Pacific and South Atlantic, based on genetic clustering and assignment algorithms. The SG samples were clearly South Atlantic, and were more similar to the South American than the South African wintering grounds. This study highlights how international collaborations are critical to provide context for emerging or recovering regions, like the SG feeding ground, as well as those that remain critically endangered, such as Chile-Peru

Small Molecules That Inhibit Tnf Signalling by Stabilising an Asymmetric Form of the Trimer

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn\u27s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions

The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales

Background The COVID-19 pandemic has affected all our lives, not only through the infection itself but also through the measures taken to control the spread of the virus (e.g. lockdown). Aims Here, we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. Method We compared the mental health symptoms of up to 4773 twins in their mid-20s in 2018 prior to the COVID-19 pandemic (T1) and during four-wave longitudinal data collection during the pandemic in April, July and October 2020, and in March 2021 (T2-T5) using phenotypic and genetic longitudinal designs. Results The average changes in mental health were small to medium and mainly occurred from T1 to T2 (average Cohen d = 0.14). Despite the expectation of catastrophic effects of the pandemic on mental health, we did not observe trends in worsening mental health during the pandemic (T3-T5). Young people with pre-existing mental health problems were disproportionately affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences in mental health symptoms did not change during the lockdown (average heritability 33%); the average genetic correlation between T1 and T2-T5 was 0.95, indicating that genetic effects before the pandemic were substantially correlated with genetic effects up to a year later. Conclusions We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]