A supportive self-management program for people with chronic headaches and migraine : a randomized controlled trial and economic evaluation

Background and Objectives: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce burden of headache disability. We tested the effectiveness of a group educational and supportive self-management programme for people living with chronic headaches. Methods: A pragmatic randomised controlled trial. Participants were aged ≥18 years with chronic migraine or chronic tension type headache, with or without medication overuse headache. We primarily recruited from general practices. Participants were assigned to either a two-day group education and self-management programme, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material. The primary outcome was headache related quality of life using the Headache Impact Test (HIT-6) at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data. Results: Between April 2017 and March 2019, we randomised 736 participants. Since only nine participants just had tension type headache our main analyses were on the 727 participants with migraine. Of these 376 were allocated to the self-management intervention 351 to usual care. Data from 586 (81%) participants were analysed for primary outcome. There was no between group difference in HIT-6, (adjusted mean difference = -0·3, 95% CI -1·23 to 0·67), or headache days (0·9, 95% CI -0·29, 2·05), at 12 months. The CHESS intervention generated incremental adjusted costs of £268 (95% CI,£176 to £377) [USD383 (95%CI USD252 to USD539)] and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to .063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained. Discussion: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management programme for people living with chronic migraine or chronic tension type headache with episodic migraine. Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 https://doi.org/10.1186/ISRCTN79708100 The first enrolment was 24th April 2017. Classification of evidence: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache related quality of life in people with chronic migraine

PHACTR1 modulates vascular compliance but not endothelial function: a translational study

Aims The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function. Methods and results Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P

Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia.

BACKGROUND Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses. METHOD We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms. RESULTS Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination. CONCLUSIONS These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort

A supportive self-management program for people with chronic headaches and migraine: A randomized controlled trial and economic evaluation

Background and Objectives: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce burden of headache disability. We tested the effectiveness of a group educational and supportive self-management programme for people living with chronic headaches.Methods: A pragmatic randomised controlled trial. Participants were aged ≥18 years with chronic migraine or chronic tension type headache, with or without medication overuse headache.We primarily recruited from general practices. Participants were assigned to either a two-day group education and self-management programme, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material.The primary outcome was headache related quality of life using the Headache Impact Test (HIT-6) at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data.Results: Between April 2017 and March 2019, we randomised 736 participants. Since only nine participants just had tension type headache our main analyses were on the 727 participants with migraine. Of these 376 were allocated to the self-management intervention 351 to usual care. Data from 586 (81%) participants were analysed for primary outcome. There was no between group difference in HIT-6, (adjusted mean difference = -0·3, 95% CI -1·23 to 0·67), or headache days (0·9, 95% CI -0·29, 2·05), at 12 months. The CHESS intervention generated incremental adjusted costs of £268 (95% CI,£176 to £377) [USD383 (95%CI USD252 to USD539)] and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to .063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained.Discussion: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management programme for people living with chronic migraine or chronic tension type headache with episodic migraine.Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 https://doi.org/10.1186/ISRCTN79708100 The first enrolment was 24th April 2017.Classification of evidence: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache related quality of life in people with chronic migraine

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease