Aneurin Bevan University Health Board

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs 71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Abstract The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF 50 ) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.

BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

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: The COVID-19 pandemic has placed unprecedented strain on health-care systems. Frailty is being used in clinical decision making for patients with COVID-19, yet the prevalence and effect of frailty in people with COVID-19 is not known. In the COVID-19 in Older PEople (COPE) study we aimed to establish the prevalence of frailty in patients with COVID-19 who were admitted to hospital and investigate its association with mortality and duration of hospital stay. METHODS: This was an observational cohort study conducted at ten hospitals in the UK and one in Italy. All adults (≥18 years) admitted to participating hospitals with COVID-19 were included. Patients with incomplete hospital records were excluded. The study analysed routinely generated hospital data for patients with COVID-19. Frailty was assessed by specialist COVID-19 teams using the clinical frailty scale (CFS) and patients were grouped according to their score (1-2=fit; 3-4=vulnerable, but not frail; 5-6=initial signs of frailty but with some degree of independence; and 7-9=severe or very severe frailty). The primary outcome was in-hospital mortality (time from hospital admission to mortality and day-7 mortality). FINDINGS: Between Feb 27, and April 28, 2020, we enrolled 1564 patients with COVID-19. The median age was 74 years (IQR 61-83); 903 (57·7%) were men and 661 (42·3%) were women; 425 (27·2%) had died at data cutoff (April 28, 2020). 772 (49·4%) were classed as frail (CFS 5-8) and 27 (1·7%) were classed as terminally ill (CFS 9). Compared with CFS 1-2, the adjusted hazard ratios for time from hospital admission to death were 1·55 (95% CI 1·00-2·41) for CFS 3-4, 1·83 (1·15-2·91) for CFS 5-6, and 2·39 (1·50-3·81) for CFS 7-9, and adjusted odds ratios for day-7 mortality were 1·22 (95% CI 0·63-2·38) for CFS 3-4, 1·62 (0·81-3·26) for CFS 5-6, and 3·12 (1·56-6·24) for CFS 7-9. INTERPRETATION: In a large population of patients admitted to hospital with COVID-19, disease outcomes were better predicted by frailty than either age or comorbidity. Our results support the use of CFS to inform decision making about medical care in adult patients admitted to hospital with COVID-19. FUNDING: None.

BACKGROUND: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant. METHODS: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages. INTERPRETATION: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. FUNDING: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure: Conversion to objectively defined secondary progressive MS. Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Awake tracheal intubation has a high success rate and a favourable safety profile but is underused in cases of anticipated difficult airway management. These guidelines are a comprehensive document to support decision making, preparation and practical performance of awake tracheal intubation. We performed a systematic review of the literature seeking all of the available evidence for each element of awake tracheal intubation in order to make recommendations. In the absence of high-quality evidence, expert consensus and a Delphi study were used to formulate recommendations. We highlight key areas of awake tracheal intubation in which specific recommendations were made, which included: indications; procedural setup; checklists; oxygenation; airway topicalisation; sedation; verification of tracheal tube position; complications; management of unsuccessful awake tracheal intubation; post-tracheal intubation management; consent; and training. We recognise that there are a range of techniques and regimens that may be effective and one such example technique is included. Breaking down the key practical elements of awake tracheal intubation into sedation, topicalisation, oxygenation and performance might help practitioners to plan, perform and address complications. These guidelines aim to support clinical practice and help lower the threshold for performing awake tracheal intubation when indicated.

The prescribing of many drugs in pregnancy is complicated by a lack of knowledge regarding their compatibility leading to patient misinformation and withdrawal/denial of disease-ameliorating therapies. This situation should be avoided because active rheumatic disease is associated with adverse pregnancy outcomes [ 1 ] and there is growing evidence of drug safety in pregnancy. To provide evidence-based recommendations, which do not imply a legal obligation, for clinicians when prescribing anti-rheumatic drugs before/during pregnancy and breastfeeding that update previous recommendations [ 2 , 3 ]. For recommendations on prescribing other drugs in pregnancy and breastfeeding see the British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) guidelines part II [ 4 ]. Health professionals directly involved in managing patients with rheumatic disease in the UK who are (or planning to become) pregnant and/or breastfeeding, men planning to conceive and patients who have accidentally conceived while taking these medications. This guideline does not cover the management of infertility or the indications for these drugs in specific rheumatic diseases in pregnancy. Specific questions were considered in relation to each drug. Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastfeeding? Where possible, recommendations are made regarding compatibility with paternal exposure. These findings are summarized in Table 1 . A description of evidence and full recommendations are given in the full guideline provided as supplementary data , available at Rheumatology Online. Summary of drug compatibility in pregnancy and breastfeeding For further information and caveats, see relevant recommendations and main text in executive summary and full guideline. a Data are limited. b In healthy full-term infants only. c Conception may be enhanced by stopping SSZ for 3 months prior to conception. d Suggested monitoring of maternal blood pressure, renal function, blood glucose and drug levels. e Only consider in severe or life-/organ-threatening maternal disease. f Unintentional first trimester exposure is unlikely to be harmful. g Unlikely to be harmful. Prednisolone is compatible with each trimester of pregnancy [level of evidence (LOE) 1 ++, grade of recommendation (GOR) A, strength of agreement (SOA) 100%]. Prednisolone is compatible with breastfeeding (LOE 2−, GOR D, SOA 98.9%). Prednisolone is compatible with paternal exposure (LOE 2+, GOR D, SOA 98.9%). Methylprednisolone has rates of placental transfer similar to prednisolone with equivalent anti-inflammatory effects at 80% of prednisolone dose and would therefore be expected to be compatible with pregnancy, breastfeeding and paternal exposure (LOE 4, GOR D, SOA 93.7%). HCQ remains the antimalarial of choice in women planning a pregnancy with rheumatic disease in need of treatment and should be continued during pregnancy (LOE 1 ++, GOR A, SOA 100%). HCQ is compatible with breastfeeding (LOE 4, GOR D, SOA 98.9%). Men should not be discouraged from taking HCQ while trying to conceive (LOE 2−, GOR D, SOA 98.9%). MTX at any dose should be avoided in pregnancy and stopped 3 months in advance of conception (LOE 2−, GOR D, SOA 100%). In women treated with low-dose MTX within 3 months prior to conception, folate supplementation (5 mg/day) should be continued prior to and throughout pregnancy (LOE 1, GOR B, SOA 98.4%). In the case of accidental pregnancy on low-dose MTX, the drug should be stopped immediately, folate supplementation (5 mg/day) continued and a careful evaluation of foetal risk carried out by local experts (LOE 4, GOR D, SOA 100%). MTX cannot be recommended in breastfeeding because of theoretical risks and insufficient outcome data (LOE 4, GOR D, SOA 100%). Based on limited evidence, low-dose MTX may be compatible with paternal exposure (LOE 2+, GOR D, SOA 95.8%). SSZ with folate supplementation (5 mg/day) is compatible throughout pregnancy (LOE 2+, GOR C, SOA 100%). SSZ is compatible with breastfeeding in healthy, full-term infants (LOE 4, GOR D, SOA 100%). Men taking SSZ may have reduced fertility. There is no evidence, however, that conception is enhanced by stopping SSZ for 3 months prior to conception unless conception is delayed >12 months when other causes of infertility should also be considered (LOE 3, GOR D, SOA 97.4%). Based on limited evidence, LEF may not be a human teratogen but it is still not recommended in women planning pregnancy (LOE 2+, GOR C, SOA 100%). Women on LEF considering pregnancy should stop and undergo cholestyramine washout before switching to alternative medication compatible with pregnancy (LOE 2+, GOR C, SOA 100%). There is no human evidence of increased congenital abnormalities on LEF if washout is given. Therefore, if accidental conception occurs on LEF, the drug should be stopped immediately and cholestyramine washout given until plasma levels are undetectable (LOE 2+, GOR C, SOA 98.9%). No data exist on excretion into breast milk, therefore breastfeeding is not recommended (LOE 4, GOR D, SOA 100%). Based on very limited evidence, LEF may be compatible with paternal exposure (LOE 4, GOR D, SOA 98.9%). AZA is compatible throughout pregnancy at ⩽2 mg/kg/day (LOE 2 ++, GOR B, SOA 100%). AZA is compatible with breastfeeding (LOE 2−, GOR D, SOA 99.5%). AZA is compatible with paternal exposure (LOE 2+, GOR D, SOA 100%). CSA is compatible throughout pregnancy at the lowest effective dose (LOE 1, GOR B, SOA 100%). Mothers on CSA should not be discouraged from breastfeeding (LOE 3, GOR D, SOA 100%). Based on limited evidence, CSA is compatible with paternal exposure (LOE 2−, GOR D, SOA 98.9%). Tacrolimus is compatible throughout pregnancy at the lowest effective dose (LOE 2−, GOR D, SOA 99.5%). Mothers on tacrolimus should not be discouraged from breastfeeding (LOE 3, GOR D, SOA 99.5%). Based on limited evidence, tacrolimus is compatible with paternal exposure (LOE 2−, GOR D, SOA 98.4%). CYC is teratogenic and gonadotoxic, therefore it should only be considered in pregnancy in life-/organ-threatening maternal disease (LOE 2, GOR C, SOA 100%). There is no evidence to recommend the use of CYC in breastfeeding (LOE 4, GOR D, SOA 100%). Paternal exposure to CYC is not recommended (LOE 4, GOR D, SOA 98.4%). MMF remains contraindicated during pregnancy (LOE 2−, GOR D, SOA 100%). Treatment with MMF should be stopped at least 6 weeks before a planned pregnancy (LOE 3, GOR D, SOR 100%). No data exist on excretion into breast milk, therefore breastfeeding is not recommended (LOE 4, GOR D, SOA 99.5%). Based on very limited evidence, MMF is compatible with paternal exposure (LOE 2−, GOR D, SOA 98.9%). IVIG is compatible with pregnancy (LOE 1 ++, GOR A, SOA 100%). IVIG is compatible with breastfeeding (LOE 4, GOR D, SOA 98.9%). Based on maternal compatibility, IVIG is unlikely to be harmful (LOE 4, GOR D, SOA 98.9%). Infliximab (IFX) may be continued until 16 weeks and etanercept (ETA) and adalimumab (ADA) may be continued until the end of the second trimester (LOE 2−, GOR D, SOA 98.9%). To ensure low/no levels of drug in cord blood at delivery, ETA and ADA should be avoided in the third trimester and IFX stopped at 16 weeks. If these drugs are continued later in pregnancy to treat active disease, then live vaccines should be avoided in the infant until 7 months of age (LOE 3, GOR D, SOA 98.9%). Certolizumab pegol is compatible with all three trimesters of pregnancy and has reduced placental transfer compared with other TNF inhibitors (TNFis) (LOE 2−, GOR D, SOA 97.9%). Golimumab is unlikely to be harmful in the first trimester (LOE 4, GOR D, SOA 97.9%) Women should not be discouraged from breastfeeding on TNFis, but caution is recommended until further information is available (LOE 3, GOR D, SOA 98.4%). Based on limited evidence IFX, ETA and ADA are compatible with paternal exposure (LOE 2−, GOR D, SOA 98.9%). RTX should be stopped 6 months before conception. Limited evidence has not shown RTX to be teratogenic and only second-/third-trimester exposure is associated with neonatal B cell depletion. Therefore, unintentional RTX exposure early in the first trimester is unlikely to be harmful (LOE 2−, GOR D, SOA 97.9%). There are no data on RTX use in breastfeeding (SOA 100%). Based on limited evidence, RTX is compatible with paternal exposure (LOE 2−, GOR D, SOA 98.4%). TCZ should be stopped at least 3 months before conception, but unintentional exposure early in the first trimester is unlikely to be harmful (LOE 3, GOR D, SOA 96.8%). There are no data on TCZ use in breastfeeding (SOA 99.5%). There are no data relating to paternal exposure to TCZ, but it is unlikely to be harmful (LOE 4, GOR D, SOA 97.9%). There is limited evidence on which to base a recommendation for anakinra in pregnancy, but unintentional exposure in the first trimester is unlikely to be harmful (LOE 2−, GOR D, SOA 96.8%). There are no data on anakinra use in breastfeeding (SOA 100%). There are no data relating to paternal exposure to anakinra, but it is unlikely to be harmful (LOE 4, GOR D, SOA 98.9%). There are insufficient data to recommend ABA in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful (LOE 3, GOR D, SOA 98.9%). There are no data on ABA use in breastfeeding (SOA 100%). There are no data relating to paternal exposure to ABA, but it is unlikely to be harmful (LOE 4, GOR D, SOA 98.9%). There are insufficient data to recommend BEL in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful (LOE 3, GOR D, SOA 100%). There are no data on BEL use in breastfeeding (SOA 100%). There are no data relating to paternal exposure to BEL, but it is unlikely to be harmful (LOE 4, GOR D, SOA 98.9%). Funding : No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement : K.S. has received educational support from Daiichi Sankyo. C.G. has undertaken consultancies and received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, Merck Serono and UCB, has been a member of speakers’ bureau for GlaxoSmithKline, UCB and Lilly and has received research grant support from UCB, but none of these activities have been related to the use of any specific drug in pregnancy. L.M. has received support from AbbVie and Pfizer to attend education meetings and received participation honoraria from MSD. I.G. has received unit support from AbbVie, MSD, Roche, Bristol-Myers Squibb and Sobi, participated on advisory boards for Pfizer and received fees for participation in an educational meeting by UCB. D.W. has received financial support for an independent PhD studentship from GlaxoSmithKline and Alere and acted as a consultant for Roche Diagnostics. M.N. has received unit and individual support to attend meetings from UCB and Jansen UK and participated on an expert panel for UCB. M.K. has received individual support to attend meetings from GlaxoSmithKline, UCB and Astra-Zeneca, chairing fees from Bristol-Myers Squibb and honoraria from GlaxoSmithKline/Human Genome Sciences, Medimmune, INOVA Diagnostics and Merck. M.G. has received individual support to attend a meeting from Roche. All others have declared no conflicts of interest.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

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.

Anaemia is a commonly diagnosed complication among patients suffering with chronic kidney disease. If left untreated, it may affect patient quality of life. There are several causes for anaemia in this patient population. As the kidney function deteriorates, together with medications and dietary restrictions, patients may develop iron deficiency, resulting in reduction of iron supply to the bone marrow (which is the body organ responsible for the production of different blood elements). Chronic kidney disease patients may not be able to utilise their own body's iron stores effectively and hence, many patients, particularly those receiving haemodialysis, may require additional iron treatment, usually provided by infusion.With further weakening of kidney function, patients with chronic kidney disease may need additional treatment with a substance called erythropoietin which drives the bone marrow to produce its own blood. This substance, which is naturally produced by the kidneys, becomes relatively deficient in patients with chronic kidney disease. Any patients will eventually require treatment with erythropoietin or similar products that are given by injection.Over the last few years, several iron and erythropoietin products have been licensed for treating anaemia in chronic kidney disease patients. In addition, several publications discussed the benefits of each treatment and possible risks associated with long term treatment. The current guidelines provide advice to health care professionals on how to screen chronic kidney disease patients for anaemia, which patients to investigate for other causes of anaemia, when and how to treat patients with different medications, how to ensure safe prescribing of treatment and how to diagnose and manage complications associated with anaemia and the drugs used for its treatment.

Plain language summary available online

Linked Comment:Ormerod. Br J Dermatol 2020; 183:604. Plain language summary available online

Introduction While most people who are involved in disasters recover with the support of their families, friends and colleagues, the effects on some people's health, relationships and welfare can be extensive and sustained. Flooding can pose substantial social and mental health problems that may continue over extended periods of time. Flooding can challenge the psychosocial resilience of the hardiest of people who are affected. Methods The Health Protection Agency (HPA) undertook a review of the literature published from 2004 to 2010. It is intended to: assess and appraise the epidemiological evidence on flooding and mental health; assess the existing guidance on emergency planning for the impacts of flooding on psychosocial and mental health needs; provide a detailed report for policymakers and services on practical methods to reduce the impacts of flooding on the mental health of affected people; and identify where research can support future evidence-based guidance. The HPA identified 48 papers which met its criteria. The team also reviewed and discussed relevant government and non-government guidance documents. This paper presents a summary of the outcomes and recommendations from this review of the literature. Results The review indicates that flooding affects people of all ages, can exacerbate or provoke mental health problems, and highlights the importance of secondary stressors in prolonging the psychosocial impacts of flooding. The distressing experiences that the majority of people experience transiently or for longer periods after disasters can be difficult to distinguish from symptoms of common mental disorders. This emphasises the need to reduce the impact of primary and secondary stressors on people affected by flooding and the importance of narrative approaches to differentiate distress from mental disorder. Much of the literature focuses on post-traumatic stress disorder; diagnosable depressive and anxiety disorders and substance misuse are under-represented in the published data. Most people's psychosocial needs are met through their close relationships with their families, friends and communities; smaller proportions of people are likely to require specialised mental healthcare. Finally, there are a number of methodological challenges that arise when conducting research and when analysing and comparing data on the psychosocial and mental health impacts of floods. Conclusions The HPA's findings showed that a multi-sector approach that involves communities as well as agencies is the best way to promote wellbeing and recovery. Agreeing and using internationally understood definitions of and the thresholds that separate distress, mental health and mental ill health would improve the process of assessing, analysing and comparing research findings. Further research is needed on the longitudinal effects of flooding on people's mental health, the effects of successive flooding on populations, and the effects of flooding on the mental health of children, young people and older people and people who respond to the needs of other persons in the aftermath of disasters. Corresponding author: Carla Stanke Address: Health Protection Agency 151 Buckingham Palace Road London SW1W 9SZ E-mail: carla.stanke@hpa.org.uk Fax: 020 7811 7759 Telephone: 020 7811 7161.

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

The Nature of Children With Developmental Coordination Disorder. Motor Impairment in DCD and Activities of Daily Living. Cognitive Explanations of The Planning and Organization of Movement. A Dynamical Systems Perspective of Developmental Coordination Disorder. DCD and Overlapping Conditions, progression and Development in Developmental Coordination Disorder. Assessment of Developmental Coordination Disorder. Early Identification of Children With developmental Coordination Disorder. Assessment of Handwriting in Children With developmental Coordination Disorder. Models of Intervention. Towards an eco--developmental Approach. Neuromotor Task Training. A new Approach to Treat children With Dcd. A Cognitive Perspective on Intervention for Children With developmental Coordination Disorder. The Co--op Experience. Overlapping conditions. Overlapping Management Services for Individuals With Developmental coordination Disorder. References