Raigmore Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Health and social care workers (HSCWs) have carried a heavy burden during the COVID-19 crisis and, in the challenge to control the virus, have directly faced its consequences. Supporting their psychological wellbeing continues, therefore, to be a priority. This rapid review was carried out to establish whether there are any identifiable risk factors for adverse mental health outcomes amongst HSCWs during the COVID-19 crisis. METHODS: We undertook a rapid review of the literature following guidelines by the WHO and the Cochrane Collaboration's recommendations. We searched across 14 databases, executing the search at two different time points. We included published, observational and experimental studies that reported the psychological effects on HSCWs during the COVID-19 pandemic. RESULTS: The 24 studies included in this review reported data predominantly from China (18 out of 24 included studies) and most sampled urban hospital staff. Our study indicates that COVID-19 has a considerable impact on the psychological wellbeing of front-line hospital staff. Results suggest that nurses may be at higher risk of adverse mental health outcomes during this pandemic, but no studies compare this group with the primary care workforce. Furthermore, no studies investigated the psychological impact of the COVID-19 pandemic on social care staff. Other risk factors identified were underlying organic illness, gender (female), concern about family, fear of infection, lack of personal protective equipment (PPE) and close contact with COVID-19. Systemic support, adequate knowledge and resilience were identified as factors protecting against adverse mental health outcomes. CONCLUSIONS: The evidence to date suggests that female nurses with close contact with COVID-19 patients may have the most to gain from efforts aimed at supporting psychological well-being. However, inconsistencies in findings and a lack of data collected outside of hospital settings, suggest that we should not exclude any groups when addressing psychological well-being in health and social care workers. Whilst psychological interventions aimed at enhancing resilience in the individual may be of benefit, it is evident that to build a resilient workforce, occupational and environmental factors must be addressed. Further research including social care workers and analysis of wider societal structural factors is recommended.

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

IMPORTANCE: Type 1 diabetes has historically been associated with a significant reduction in life expectancy. Major advances in treatment of type 1 diabetes have occurred in the past 3 decades. Contemporary estimates of the effect of type 1 diabetes on life expectancy are needed. OBJECTIVE: To examine current life expectancy in people with and without type 1 diabetes in Scotland. We also examined whether any loss of life expectancy in patients with type 1 diabetes is confined to those who develop kidney disease. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of all individuals alive in Scotland with type 1 diabetes who were aged 20 years or older from 2008 through 2010 and were in a nationwide register (n=24,691 contributing 67,712 person-years and 1043 deaths). MAIN OUTCOMES AND MEASURES: Differences in life expectancy between those with and those without type 1 diabetes and the percentage of the difference due to various causes. RESULTS: Life expectancy at an attained age of 20 years was an additional 46.2 years among men with type 1 diabetes and 57.3 years among men without it, an estimated loss in life expectancy with diabetes of 11.1 years (95% CI, 10.1-12.1). Life expectancy from age 20 years was an additional 48.1 years among women with type 1 diabetes and 61.0 years among women without it, an estimated loss with diabetes of 12.9 years (95% CI, 11.7-14.1). Even among those with type 1 diabetes with an estimated glomerular filtration rate of 90 mL/min/1.73 m2 or higher, life expectancy was reduced (49.0 years in men, 53.1 years in women) giving an estimated loss from age 20 years of 8.3 years (95% CI, 6.5-10.1) for men and 7.9 years (95% CI, 5.5-10.3) for women. Overall, the largest percentage of the estimated loss in life expectancy was related to ischemic heart disease (36% in men, 31% in women) but death from diabetic coma or ketoacidosis was associated with the largest percentage of the estimated loss occurring before age 50 years (29.4% in men, 21.7% in women). CONCLUSIONS AND RELEVANCE: Estimated life expectancy for patients with type 1 diabetes in Scotland based on data from 2008 through 2010 indicated an estimated loss of life expectancy at age 20 years of approximately 11 years for men and 13 years for women compared with the general population without type 1 diabetes.

BACKGROUND: Incisional hernia is a common complication of abdominal surgery and an important source of morbidity. It may be repaired using open suture, open mesh or laparoscopic mesh techniques. This review examines the results of these methods of repair. METHODS: A Medline literature search was performed to identify articles relating to 'incisional hernia', 'ventral hernia' and 'wound failure'. Relevant papers from the reference lists of these articles were also sought. RESULTS: The recurrence rate after open suture repair may be as high as 31-49 per cent; for open mesh repair it is between 0 and 10 per cent. Comparative studies show that recurrence is significantly more frequent after open suture repair than after open mesh repair; complication rates are similar for both procedures. Recurrence rates after laparoscopic mesh repair vary from 0 to 9 per cent. Comparative studies show that laparoscopic mesh repair is at least as safe and effective as open mesh repair. CONCLUSION: Open suture repair for incisional hernia carries an unacceptably high recurrence rate. The results of open mesh and laparoscopic mesh techniques are encouraging. There is scope for a large multicentre randomized clinical trial to compare laparoscopic and open mesh repair.

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

INTRODUCTION: Clinical and experimental studies have shown that the coronavirus family has a certain tropism for the central nervous system. Seven types of coronavirus can infect humans. DEVELOPMENT: Coronaviruses are not always confined to the respiratory tract, and under certain conditions they can invade the central nervous system and cause neurological pathologies. The potential for neuroinvasion is well documented in most human coronaviruses (OC-43, 229E, MERS and SARS) and in some animal coronaviruses (porcine haemagglutinating encephalomyelitis coronavirus). Neurological symptoms have been reported in patients affected by COVID-19, such as headache, dizziness, myalgia and anosmia, as well as cases of encephalopathy, encephalitis, necrotising haemorrhagic encephalopathy, stroke, epileptic seizures, rhabdomyolysis and Guillain-Barre syndrome, associated with SARS-CoV-2 infection. CONCLUSIONS: Future epidemiological studies and case records should elucidate the real incidence of these neurological complications, their pathogenic mechanisms and their therapeutic options.

INTRODUCTION: The extent to which low sexual function or sexual dissatisfaction in women impacts on well-being remains uncertain, yet this is a critical issue in the controversy as to the benefits of pharmacotherapy for women seeking treatment for female sexual dysfunction. Aim. To explore the relationship between well-being and self-perceived satisfaction with sexual function in women and to determine if there is an independent effect of menopausal status or age. DESIGN: A community-based cross-sectional study. PATIENTS: A total of 421 women, aged 18 to 65 years were recruited from the community. Women were required to self-identify at study outset as being either satisfied or dissatisfied with their sexual life and be premenopausal or postmenopausal. MAIN OUTCOME MEASURES: Scores from the Psychological General Well-Being Index (PGWB), the Beck Depression Index (BDI) and a daily diary of sexual function. RESULTS: A group of 349 women were included in the analysis. Total PGWB and domain scores of positive well-being and vitality were lower in dissatisfied women compared to satisfied women. PGWB total and domain scores of depressed mood, positive well-being and vitality were higher in older women. Menopause did not have an independent effect on well-being. CONCLUSIONS: Women who self-identify as having sexual dissatisfaction have lower psychological general well-being. These findings reinforce the importance of addressing sexual health and well-being in women as an essential component of their health care.

These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address: Which patients should commence surveillance post-polypectomy and post-cancer resection? What is the appropriate surveillance interval? When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG’s guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant. two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either : two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.

OBJECTIVE: To identify the number of drug-disease and drug-drug interactions for exemplar index conditions within National Institute of Health and Care Excellence (NICE) clinical guidelines. DESIGN: Systematic identification, quantification, and classification of potentially serious drug-disease and drug-drug interactions for drugs recommended by NICE clinical guidelines for type 2 diabetes, heart failure, and depression in relation to 11 other common conditions and drugs recommended by NICE guidelines for those conditions. SETTING: NICE clinical guidelines for type 2 diabetes, heart failure, and depression MAIN OUTCOME MEASURES: Potentially serious drug-disease and drug-drug interactions. RESULTS: Following recommendations for prescription in 12 national clinical guidelines would result in several potentially serious drug interactions. There were 32 potentially serious drug-disease interactions between drugs recommended in the guideline for type 2 diabetes and the 11 other conditions compared with six for drugs recommended in the guideline for depression and 10 for drugs recommended in the guideline for heart failure. Of these drug-disease interactions, 27 (84%) in the type 2 diabetes guideline and all of those in the two other guidelines were between the recommended drug and chronic kidney disease. More potentially serious drug-drug interactions were identified between drugs recommended by guidelines for each of the three index conditions and drugs recommended by the guidelines for the 11 other conditions: 133 drug-drug interactions for drugs recommended in the type 2 diabetes guideline, 89 for depression, and 111 for heart failure. Few of these drug-disease or drug-drug interactions were highlighted in the guidelines for the three index conditions. CONCLUSIONS: Drug-disease interactions were relatively uncommon with the exception of interactions when a patient also has chronic kidney disease. Guideline developers could consider a more systematic approach regarding the potential for drug-disease interactions, based on epidemiological knowledge of the comorbidities of people with the disease the guideline is focused on, and should particularly consider whether chronic kidney disease is common in the target population. In contrast, potentially serious drug-drug interactions between recommended drugs for different conditions were common. The extensive number of potentially serious interactions requires innovative interactive approaches to the production and dissemination of guidelines to allow clinicians and patients with multimorbidity to make informed decisions about drug selection.

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.

BACKGROUND: Ileocolic anastomoses are commonly performed for right-sided colon cancer and Crohn's disease. The anastomosis may be constructed using a linear cutter stapler or by suturing. Individual trials comparing stapled versus handsewn ileocolic anastomoses have found little difference in the complication rate but they have lacked adequate power to detect potential small difference. This is an update of a Cochrane review first published in 2007. OBJECTIVES: To compare outcomes of ileocolic anastomoses performed using stapling and handsewn techniques. The hypothesis tested was that the stapling technique is associated with fewer complications. SEARCH STRATEGY: MEDLINE, EMBASE, Cochrane Colorectal Cancer Group specialised register SR-COLOCA, Cochrane Library were searched for randomised controlled trials comparing use of a linear cuter stapler with any type of suturing technique for ileocolic anastomoses in adults from 1970 to 2005 and were updated in December 2010. Abstracts presented to the following society meetings between 1970 and 2010 were handsearched: American Society of Colon and Rectal Surgeons, the Association of Coloproctology of Great Britain and Ireland, European Association of Coloproctology. SELECTION CRITERIA: Randomised controlled trials comparing use of linear cutter stapler (isoperistaltic side to side or functional end to end) with any type of suturing technique in adults. DATA COLLECTION AND ANALYSIS: Eligible studies were selected and their methodological quality assessed. Relevant results were extracted and missing data sought from the authors. RevMan 5 was used to perform meta-analysis when there were sufficient data. Sub-group analyses for cancer inflammatory bowel disease as indication for ileocolic anastomoses were performed. MAIN RESULTS: After obtaining individual data from authors for studies that include other anastomoses, seven trials (including one unpublished) with 1125 ileocolic participants (441 stapled, 684 handsewn) were included. The five largest trials had adequate allocation concealment.Stapled anastomosis was associated with significantly fewer anastomotic leaks compared with handsewn (S=11/441, HS=42/684, OR 0.48 [0.24, 0.95] p=0.03). One study performed routine radiology to detect asymptomatic leaks. For the sub-group of 825 cancer patients in four studies, stapled anastomosis led to significantly fewer anastomotic leaks (S=4/300, HS=35/525, OR 0.28 [0.10, 0.75] p=0.01). In subgroup analysis of non-cancer patients (3 studies, 264 patients) there were no differences for any reported outcomes. All other outcomes: stricture, anastomotic haemorrhage, anastomotic time, re-operation, mortality, intra-abdominal abscess, wound infection, length of stay, showed no significant difference. AUTHORS' CONCLUSIONS: Stapled functional end to end ileocolic anastomosis is associated with fewer leaks than handsewn anastomosis.

This study was undertaken to perform a systematic review and meta-analysis of studies of mortality in Parkinson's disease (PD) and to investigate which factors were associated with mortality. We conducted comprehensive searches of studies reporting a ratio of mortality in PD versus controls, descriptive survival measures, or factors predicting survival; assessed study quality; and extracted relevant data. Descriptive analysis, meta-analysis, and meta-regression were performed as appropriate. Eighty-eight studies were included in the review with variable study methods and quality. Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity. Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5. Inception cohorts, measurements at longer follow-up duration, and older study recruitment year were associated with lower mortality ratios, but these findings were not robust in sensitivity analyses. Within studies, mortality ratios increased over time. No robust evidence was found that mortality has decreased after the introduction of levodopa (L-dopa). On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity. In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years. Increasing age and presence of dementia were most commonly associated with increased mortality. Parkinson's disease is associated with increased mortality, but major heterogeneity is seen in estimates of mortality, which is probably explained by variable methodology and patient selection. Individual-patient-data meta-analysis of high-quality inception studies with long-term follow-up would be the optimal way to investigate the factors influencing mortality.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: The primary aim of this review was to establish whether health literacy interventions, in adults, are effective for improving health literacy. Two secondary aims assessed the impact of health literacy interventions on health behaviours and whether health literacy interventions have been conducted in cardiovascular patients. METHODS: A systematic review (Prospero registration: CRD42018110772) with no start date running through until April 2020. Eligible studies were conducted in adults and included a pre/post measure of health literacy. Medline, Embase, Eric, PsychINFO, CINAHL, Psychology and Behavioural Science, HMIC, Web of Science, Scopus, Social Care Online, NHS Scotland Journals, Social Policy and Practice, and Global Health were searched. Two thousand one hundred twenty-seven papers were assessed, and 57 full text papers screened to give 22 unique datasets from 23 papers. Risk of bias was assessed regarding randomisation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting and other biases. Intervention reporting quality was assessed using the TIDieR checklist. RESULTS: Twenty-two studies were included reporting on 10,997 participants in nine countries. The majority of studies (14/22) were published in 2018 or later. Eight studies (n = 1268 participants) also reported on behavioural outcomes. Health literacy interventions resulted in improvements in at least some aspect of health literacy in 15/22 studies (n = 10,180 participants) and improved behavioural outcomes in 7/8 studies (n = 1209 participants). Only two studies were conducted with cardiovascular patients. All studies were at risk of bias with 18 judged as high risk. In addition, there was poor reporting of intervention content with little explication of the theoretical basis for the interventions. CONCLUSIONS: Health literacy interventions can improve health literacy and can also lead to changes in health behaviours. Health literacy interventions offer a way to improve outcomes for populations most at risk of health inequalities. Health literacy is a developing field with very few interventions using clear theoretical frameworks. Closer links between health literacy and behaviour change theories and frameworks could result in higher quality and more effective interventions. PROSPERO REGISTRATION: Prospero registration: CRD42018110772.

Summary Intravenous lidocaine is used widely for its effect on postoperative pain and recovery but it can be, and has been, fatal when used inappropriately and incorrectly. The risk‐benefit ratio of i.v. lidocaine varies with type of surgery and with patient factors such as comorbidity (including pre‐existing chronic pain). This consensus statement aims to address three questions. First, does i.v. lidocaine effectively reduce postoperative pain and facilitate recovery? Second, is i.v. lidocaine safe? Third, does the fact that i.v. lidocaine is not licensed for this indication affect its use? We suggest that i.v. lidocaine should be regarded as a ‘high‐risk’ medicine. Individual anaesthetists may feel that, in selected patients, i.v. lidocaine may be beneficial as part of a multimodal peri‐operative pain management strategy. This approach should be approved by hospital medication governance systems, and the individual clinical decision should be made with properly informed consent from the patient concerned. If i.v. lidocaine is used, we recommend an initial dose of no more than 1.5 mg.kg ‐1 , calculated using the patient’s ideal body weight and given as an infusion over 10 min. Thereafter, an infusion of no more than 1.5 mg.kg ‐1 .h ‐1 for no longer than 24 h is recommended, subject to review and re‐assessment. Intravenous lidocaine should not be used at the same time as, or within the period of action of, other local anaesthetic interventions. This includes not starting i.v. lidocaine within 4 h after any nerve block, and not performing any nerve block until 4 h after discontinuing an i.v. lidocaine infusion.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) comprise a spectrum of acute inflammatory pulmonary oedema resulting in refractory hypoxaemia in the absence of an underlying cardiogenic cause. There are multiple pulmonary and extrapulmonary causes and ALI/ARDS patients are a clinically heterogeneous group with associated high morbidity and mortality. Inflammatory injury to the alveolar epithelial and endothelial capillary membrane is a central event in the pathogenesis of ALI/ARDS, and involves degradation of the basement membrane. Matrix metalloproteinases (MMPs) have been implicated in a wide variety of pulmonary pathologies and are capable of degrading all components of the extracellular matrix including the basement membrane and key non-matrix mediators of lung injury such as chemokines and cell surface receptors. While many studies implicate MMPs in the injurious process, there are significant gaps in our knowledge of the role of specific proteases at different phases of injury and repair. This article examines the role of MMPs in injury and repair of the alveolar epithelial-endothelial capillary barrier and discusses the potential for MMP modulation in the prevention and treatment of ALI. The need for further mechanistic and in vivo studies to inform appropriate subsequent clinical trials of MMP modulation will be highlighted.

Although a link between primary cutaneous B-cell lymphoma (PCBCL) and Borrelia burgdorferi infection has long been suspected, previous studies have not demonstrated a significant association. The authors looked for evidence of B. burgdorferi in 20 cases of PCBCL from the Scottish Highlands, an area with endemic Lyme disease, and compared their findings with those in 40 control patients (20 undergoing wide reexcision at sites of malignant melanoma and 20 biopsies of inflammatory dermatoses). All studies were performed on formalin-fixed, paraffin-embedded tissues. The cases of PCBCL were classified according to criteria described by the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group using a combination of morphology, immunohistochemistry, and seminested polymerase chain reaction (PCR) for immunoglobulin heavy chain gene rearrangement. A nested PCR was performed on deoxyribonucleic acid (DNA) extracts from the lymphoma and control cases using primers to a unique conserved region of the B. burgdorferi flagellin gene. B. burgdorferi-specific DNA was detected in seven of 20 lymphoma cases (five of 12 marginal zone lymphomas, one of five primary cutaneous follicle center cell lymphomas, one of three diffuse, large B-cell lymphomas of the leg) and in one melanoma reexcision patient of 40 control subjects. The relationship between B. burgdorferi and PCBCL was significant when compared with the control groups separately (p <0.05) or in combination (p <0.01). These results provide strong evidence to support the concept of B. burgdorferi-driven lymphomagenesis in the skin.

INTRODUCTION: Many patients with mild or severe COVID-19 do not make a full recovery and have a wide range of chronic symptoms for weeks or months after infection, often of a neurological, cognitive or psychiatric nature. The epidemiological evidence, diagnostic criteria and pathogenesis of post-COVID-19 syndrome are reviewed. DEVELOPMENT: Post-COVID-19 syndrome is defined by persistent clinical signs and symptoms that appear while or after suffering COVID-19, persist for more than 12 weeks and cannot be explained by an alternative diagnosis. The symptoms can fluctuate or cause relapses. It is a heterogeneous condition that includes post-viral chronic fatigue syndrome, sequelae in multiple organs and the effects of severe hospitalisation/post-intensive care syndrome. It has been reported in patients with mild or severe COVID-19 and irrespective of the severity of the symptoms in the acute phase. Between 10% and 65% of survivors who had mild/moderate COVID-19 present symptoms of post-COVID-19 syndrome for 12 weeks or more. At six months, subjects report an average of 14 persistent symptoms. The most common symptoms are fatigue, dyspnoea, anxiety, depression, and impaired attention, concentration, memory and sleep. The underlying biological mechanisms are unknown, although an abnormal or excessive autoimmune and inflammatory response may play an important role. CONCLUSIONS: Clinical manifestations are diverse, fluctuating and variable, although fatigue and neurocognitive complaints predominate. There is no defined consensus on post-COVID-19 syndrome and its diagnostic criteria have not been subjected to adequate psychometric evaluation.