New Cross 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.

PROPHYLAXIS: 1: ESGE recommends routine rectal administration of 100 mg of diclofenac or indomethacin immediately before endoscopic retrograde cholangiopancreatography (ERCP) in all patients without contraindications to nonsteroidal anti-inflammatory drug administration.Strong recommendation, moderate quality evidence. 2: ESGE recommends prophylactic pancreatic stenting in selected patients at high risk for post-ERCP pancreatitis (inadvertent guidewire insertion/opacification of the pancreatic duct, double-guidewire cannulation).Strong recommendation, moderate quality evidence. 3: ESGE suggests against routine endoscopic biliary sphincterotomy before the insertion of a single plastic stent or an uncovered/partially covered self-expandable metal stent for relief of biliary obstruction.Weak recommendation, moderate quality evidence. 4: ESGE recommends against the routine use of antibiotic prophylaxis before ERCP.Strong recommendation, moderate quality evidence. 5: ESGE suggests antibiotic prophylaxis before ERCP in the case of anticipated incomplete biliary drainage, for severely immunocompromised patients, and when performing cholangioscopy.Weak recommendation, moderate quality evidence. 6: ESGE suggests tests of coagulation are not routinely required prior to ERCP for patients who are not on anticoagulants and not jaundiced.Weak recommendation, low quality evidence. TREATMENT: 7: ESGE suggests against salvage pancreatic stenting in patients with post-ERCP pancreatitis.Weak recommendation, low quality evidence. 8: ESGE suggests temporary placement of a biliary fully covered self-expandable metal stent for post-sphincterotomy bleeding refractory to standard hemostatic modalities.Weak recommendation, low quality evidence. 9: ESGE suggests to evaluate patients with post-ERCP cholangitis by abdominal ultrasonography or computed tomography (CT) scan and, in the absence of improvement with conservative therapy, to consider repeat ERCP. A bile sample should be collected for microbiological examination during repeat ERCP.Weak recommendation, low quality evidence.

OBJECTIVES: Detection of dementia is essential for improving the lives of patients but the extent of underdetection worldwide and its causes are not known. This study aimed to quantify the prevalence of undetected dementia and to examine its correlates. METHODS/SETTING/PARTICIPANTS: A systematic search was conducted until October 2016 for studies reporting the proportion of undetected dementia and/or its determinants in either the community or in residential care settings worldwide. Random-effects models calculated the pooled rate of undetected dementia and subgroup analyses were conducted to identify determinants of the variation. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measures of interest were the prevalence and determinants of undetected dementia. RESULTS: 23 studies were eligible for inclusion in this review. The pooled rate of undetected dementia was 61.7% (95% CI 55.0% to 68.0%). The rate of underdetection was higher in China and India (vs Europe and North America), in the community setting (vs residential/nursing care), age of <70 years, male gender and diagnosis by general practitioner. However, it was lower in the studies using Mini-Mental State Examination (MMSE) diagnosis criteria. CONCLUSIONS: The prevalence of undetected dementia is high globally. Wide variations in detecting dementia need to be urgently examined, particularly in populations with low socioeconomic status. Efforts are required to reduce diagnostic inequality and to improve early diagnosis in the community.

AIM: To study the availability and quality of adult and paediatric colonoscopy in three National Health Service (NHS) regions. METHOD: A prospective four month study of colonoscopies in North East Thames, West Midlands, and East Anglia. PATIENTS: Subjects undergoing colonoscopy in 68 endoscopy units. RESULTS: A total of 9223 colonoscopies were studied. The mean number of colonoscopies performed over the four month period was 142 in district general hospitals and 213 in teaching hospitals. Intravenous sedation was administered in 94.6% of procedures, but 2.2% and 11.4% of "at risk" patients did not have continuous venous access or did not receive supplemental oxygen, respectively. Caecal intubation was recorded in 76.9% of procedures but the adjusted caecal intubation rate was only 56.9%. Reasons for failing to reach the caecum included patient discomfort (34.7%), looping (29.7%), and poor bowel preparation (19.6%). A normal colonoscopy was reported in 42.1%. The most common diagnosis was polyps (22.5%) followed by diverticular disease (14.9%). Inflammatory bowel disease was recorded in 13.9% and carcinoma in 3.8%. Only half of the patients remembered being told of possible adverse events prior to the procedure. Rectal bleeding requiring admission following colonoscopy was reported in six patients. The overall perforation rate was 1:769 and colonoscopy was considered a possible factor in six deaths occurring within 30 days of the procedure. Only 17.0% of colonoscopists had received supervised training for their first 100 colonoscopies and only 39.3% had attended a training course. CONCLUSION: There is serious under provision of colonoscopy service in most NHS hospitals. Endoscopy sedation guidelines are not always adhered to and there is a wide variation in practice between units. Colonoscopy is often incomplete and does not achieve the target 90% caecal intubation rate. Serious complications of colonoscopy were comparable with previous studies. Training in colonoscopy is often inadequate and improved practice should result from better training.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers. Because anecdotal reports suggest that smoking and nicotine may improve the symptoms of the disease, we examined the effect of nicotine as a supplemental treatment for ulcerative colitis. METHODS: We treated 72 patients with active ulcerative colitis with either transdermal nicotine patches or placebo patches for six weeks in a randomized, double-blind study. Incremental doses of nicotine were given; most patients tolerated doses of 15 to 25 mg per 24 hours. All the patients had been taking mesalamine, and 12 were receiving low doses of glucocorticoids; these medications were continued without change during the study. Clinical, sigmoidoscopic, and histologic assessments were made at base line and at the end of the study; symptoms were recorded daily on a diary card, and the clinician made a global assessment. Side effects and plasma nicotine and cotinine concentrations were monitored throughout the study. RESULTS: Seventeen of the 35 patients in the nicotine group had complete remissions, as compared with 9 of the 37 patients in the placebo group (P = 0.03). The patients in the nicotine group had greater improvement in the global clinical grade of colitis (P < 0.001) and the histologic grade (P = 0.03), lower stool frequency (a difference of 1.6 stools daily; P = 0.008), less abdominal pain (P = 0.05), and less fecal urgency (P = 0.009). More patients in the nicotine group had side effects (23, vs. 11 in the placebo group; P = 0.002), the most common of which were nausea, lightheadedness, headache, and sleep disturbance. Withdrawals due to ineffective therapy were more common in the placebo group (3 vs. 8, P = 0.12). CONCLUSIONS: The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.

Blood nicotine and carboxyhaemoglobin (COHb) concentrations were studied in 330 smokers (206 women and 124 men). Blood nicotine concentrations in individual smokers varied from 25 to 444 nmol/l (4 to 72 ng/ml). The average concentration, 203 nmol/l (33 ng/ml), was the same in the men and the women, although cigarette consumption was higher in the men. Despite large differences in nicotine yield, there was no relation between blood nicotine concentration and the type of cigarette smoked: smokers of plain, untipped cigarettes (1.9 mg nicotine), cigarettes with unventilated filters (1.3 mg nicotine), and cigarettes with ventilated filters (0.8 mg nicotine) had similar blood nicotine concentrations. Cigarette consumption was also similar in these three groups. The correlation between blood nicotine concentration and nicotine yield of cigarette, though significant, was low (0.21, p < 0.001), showing that the nicotine yield of the cigarettes accounted for only 4.4% of the variation in blood nicotine concentrations. Similarly, the low correlation of 0.30 between COHb concentration and cigarette consumption suggests that cigarette consumption accounted for only 9% of the variation in the amount of smoke taken into the smokers' lungs. These results suggest that the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation. The findings of epidemiological studies showing lower risks with filter-tipped cigarettes may be attributable to other factors such as biases in the samples and changes in the quality and carcinogenicity of tobacco tar, rather than to reduced tar intake.

BACKGROUND: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation. METHODS: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention. RESULTS: The analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization. CONCLUSION: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

OBJECTIVE: To examine the associations between a biomarker of overall passive exposure to tobacco smoke (serum cotinine concentration) and risk of coronary heart disease and stroke. DESIGN: Prospective population based study in general practice (the British regional heart study). PARTICIPANTS: 4729 men in 18 towns who provided baseline blood samples (for cotinine assay) and a detailed smoking history in 1978-80. MAIN OUTCOME MEASURE: Major coronary heart disease and stroke events (fatal and non-fatal) during 20 years of follow up. RESULTS: 2105 men who said they did not smoke and who had cotinine concentrations < 14.1 ng/ml were divided into four equal sized groups on the basis of cotinine concentrations. Relative hazards (95% confidence intervals) for coronary heart disease in the second (0.8-1.4 ng/ml), third (1.5-2.7 ng/ml), and fourth (2.8-14.0 ng/ml) quarters of cotinine concentration compared with the first (> or = 0.7 ng/ml) were 1.45 (1.01 to 2.08), 1.49 (1.03 to 2.14), and 1.57 (1.08 to 2.28), respectively, after adjustment for established risk factors for coronary heart disease. Hazard ratios (for cotinine 0.8-14.0 nu > or = 0.7 ng/ml) were particularly increased during the first (3.73, 1.32 to 10.58) and second five year follow up periods (1.95, 1.09 to 3.48) compared with later periods. There was no consistent association between cotinine concentration and risk of stroke. CONCLUSION: Studies based on reports of smoking in a partner alone seem to underestimate the risks of exposure to passive smoking. Further prospective studies relating biomarkers of passive smoking to risk of coronary heart disease are needed.

This document represents the first position statement produced by the British Society of Gastroenterology and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, setting out the minimum expected standards in diagnostic upper gastrointestinal endoscopy. The need for this statement has arisen from the recognition that while technical competence can be rapidly acquired, in practice the performance of a high-quality examination is variable, with an unacceptably high rate of failure to diagnose cancer at endoscopy. The importance of detecting early neoplasia has taken on greater significance in this era of minimally invasive, organ-preserving endoscopic therapy. In this position statement we describe 38 recommendations to improve diagnostic endoscopy quality. Our goal is to emphasise practices that encourage mucosal inspection and lesion recognition, with the aim of optimising the early diagnosis of upper gastrointestinal disease and improving patient outcomes.

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.

One hundred non-smoking patients attending hospital outpatient clinics reported their degree of passive exposure to tobacco smoke over the preceding three days and provided samples of blood, expired air, saliva, and urine. Although the absolute levels were low, the concentration of cotinine in all body compartments surveyed was systematically related to self reported exposure. Salivary nicotine concentration also showed a linear increase with degree of reported exposure, although this measure was sensitive only to exposure on the day of testing. Measures of carbon monoxide, thiocyanate, and plasma nicotine concentrations were unrelated to exposure. The data indicate that cotinine provides a valid marker of the dose received from passive smoke exposure. The non-invasive samples of urine and saliva are particularly suited to epidemiological investigations. Detailed questionnaire items may also give valuable information.

BACKGROUND AND STUDY AIMS: Upper gastrointestinal (UGI) cancer in the Western world usually presents at an advanced stage, when opportunities for curative therapy are limited. The failure to detect subtle, early-stage UGI cancer at endoscopy may contribute to a poor prognosis. We undertook a meta-analysis of studies of endoscopic miss rates for UGI cancer to quantify how often opportunities to diagnose cancer at an earlier stage are missed. PATIENTS AND METHODS: A MEDLINE search was conducted to identify relevant studies, and a meta-analysis was conducted. "Missed" UGI cancer was defined as cancer that had not been diagnosed by UGI endoscopy performed within 3 years before the diagnosis. Random effects meta-analysis was used to determine the event rate of missed UGI cancer. RESULTS: Ten studies were identified that included 3,787 patients with UGI cancer. Four hundred eighty-seven UGI cancers were missed at endoscopy within 3 years before diagnosis. Marked heterogeneity was observed between studies (I (2), 94.4 %; P < 0.001). On random effects meta-analysis, the pooled miss rates were 6.4 % (95 % confidence interval [CI], 4.3 % - 9.5 %) within 1 year and 11.3 % (95 % CI, 7.5 % - 16.6 %) within 3 years before diagnosis. There appeared to be no difference between the miss rates of oesophageal (44 %) and gastric (51 %) cancer (P = 0.42). Conclusion It appears that 11.3 % of UGI cancers are missed at endoscopy up to 3 years before diagnosis. To ameliorate the poor prognosis of patients with UGI cancer in the Western world, efforts should be made to improve the quality of UGI endoscopy and create opportunities for earlier diagnosis.

Cotinine elimination from plasma, saliva, and urine was studied over 11 days in five subjects (three nonsmokers and two occasional smokers). Half-lives for cotinine averaged 16-19 hours in the different body fluids (range 10 to 27 hours between subjects). There was no tendency for the half-life in saliva to be longer than in plasma or urine. We conclude that choice of body fluid for cotinine assay in smoking studies should depend on practical rather than pharmacokinetic considerations.

This is the first UK national guideline to concentrate on acute lower gastrointestinal bleeding (LGIB) and has been commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). The Guidelines Development Group consisted of representatives from the BSG Endoscopy Committee, the Association of Coloproctology of Great Britain and Ireland, the British Society of Interventional Radiology, the Royal College of Radiologists, NHS Blood and Transplant and a patient representative. A systematic search of the literature was undertaken and the quality of evidence and grading of recommendations appraised according to the GRADE(Grading of Recommendations Assessment, Development and Evaluation) methodology. These guidelines focus on the diagnosis and management of acute LGIB in adults, including methods of risk assessment and interventions to diagnose and treat bleeding (colonoscopy, computed tomography, mesenteric angiography, endoscopic therapy, embolisation and surgery). Recommendations are included on the management of patients who develop LGIB while receiving anticoagulants (including direct oral anticoagulants) or antiplatelet drugs. The appropriate use of blood transfusion is also discussed, including haemoglobin triggers and targets.

A rapid method is described for the simultaneous measurement of nicotine and cotinine in biological fluids using capillary column gas-liquid chromatography. Using 100 microliters sample volume the lower limit of detection for both nicotine and cotinine was 100 pg mL-1, allowing the method to be used for the measurement of these compounds in both smokers and non-smokers. The extraction time is 3 min per sample, and by using multi-pipetting and vortexing systems 250 samples can be extracted per day. The average coefficient of variation over the nicotine range 1.0 to 100 ng mL-1 was 3.9% and for cotinine over the range 1.0 to 1000 ng mL-1 was 2.2%. Saliva cotinine concentrations were quantitatively related to passive exposure to parental smoking in a population study of 1118 non-smoking schoolchildren.

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.

The risk of endoscopy in patients on antithrombotics depends on the risks of procedural haemorrhage versus thrombosis due to discontinuation of therapy. P2Y12 RECEPTOR ANTAGONISTS CLOPIDOGREL, PRASUGREL, TICAGRELOR: For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or dual antiplatelet therapy (low quality evidence, strong recommendation); For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists five days before the procedure (moderate quality evidence, strong recommendation). In patients on dual antiplatelet therapy, we suggest continuing aspirin (low quality evidence, weak recommendation). For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a cardiologist about the risk/benefit of discontinuation of P2Y12 receptor antagonists (high quality evidence, strong recommendation). WARFARIN: The advice for warfarin is fundamentally unchanged from British Society of Gastroenterology (BSG) 2008 guidance. DIRECT ORAL ANTICOAGULANTS DOAC: For low-risk endoscopic procedures we suggest omitting the morning dose of DOAC on the day of the procedure (very low quality evidence, weak recommendation); For high-risk endoscopic procedures, we recommend that the last dose of DOAC be taken ≥48 h before the procedure (very low quality evidence, strong recommendation). For patients on dabigatran with CrCl (or estimated glomerular filtration rate, eGFR) of 30-50 mL/min we recommend that the last dose of DOAC be taken 72 h before the procedure (very low quality evidence, strong recommendation). In any patient with rapidly deteriorating renal function a haematologist should be consulted (low quality evidence, strong recommendation).

High-intensity eccentric contractions induce performance decrements and delayed onset muscle soreness. The purpose of this investigation was to study the magnitude and time course of such decrements and their interrelationships in 26 young women of mean(s.d.) age 21.4(3.3) years. Subjects performed 70 maximal eccentric contractions of the elbow flexors on a pulley system, specially designed for the study. The non-exercised arm acted as the control. Measures of soreness, tenderness, swelling (SW), relaxed elbow joint angle (RANG) and isometric strength (STR) were taken before exercise, immediately after exercise (AE), analysis of variance and at 24-h intervals for 11 days. There were significant (P < 0.01, analysis of variance) changes in all factors. Peak effects were observed between 24 and 96 h AE. With the exception of STR, which remained lower (P < 0.01), all variables returned to baseline levels by day 11. A non-significant correlation between pain and STR indicated that pain was not a major factor in strength loss. Also, although no pain was evident, RANG was decreased immediately AE. There was no relationship between SW, RANG and pain. The prolonged nature of these symptoms indicates that repair to damaged soft tissue is a slow process. Strength loss is considered particularly important as it continues when protective pain and tenderness have disappeared. This has implications for the therapeutic management of patients with myopathologies and those receiving eccentric exercise for rehabilitation.

OBJECTIVE: The COVID-19 pandemic has had a major global impact on endoscopic services. This reduced capacity, along with public reluctance to undergo endoscopy during the pandemic, might result in excess mortality from delayed cancer diagnosis. Using the UK's National Endoscopy Database (NED), we performed the first national analysis of the impact of the pandemic on endoscopy services and endoscopic cancer diagnosis. DESIGN: We developed a NED COVID-19 module incorporating procedure-level data on all endoscopic procedures. Three periods were designated: pre-COVID (6 January 2020 to 15 March), transition (16-22 March) and COVID-impacted (23 March-31 May). National, regional and procedure-specific analyses were performed. The average weekly number of cancers, proportion of missing cancers and cancer detection rates were calculated. RESULTS: A weekly average of 35 478 endoscopy procedures were performed in the pre-COVID period. Activity in the COVID-impacted period reduced to 12% of pre-COVID levels; at its low point, activity was only 5%, recovering to 20% of pre-COVID activity by study end. Although more selective vetting significantly increased the per-procedure cancer detection rate (pre-COVID 1.91%; COVID-impacted 6.61%; p<0.001), the weekly number of cancers detected decreased by 58%. The proportion of missing cancers ranged from 19% (pancreatobiliary) to 72% (colorectal). CONCLUSION: This national analysis demonstrates the remarkable impact that the pandemic has had on endoscopic services, which has resulted in a substantial and concerning reduction in cancer detection. Major, urgent efforts are required to restore endoscopy capacity to prevent an impending cancer healthcare crisis.

Of the 605 patients seen since 1973, 336 patients have been treated with sodium valproate (VPA) alone or in combination with drugs other than carbamazepine (CBZ). Of these 336, 240 have been on monotherapy, of whom 200 are seizure-free. Follow up has been longer than 3 years in 78%. Complete control of seizures has been achieved in more than 80% of patients with absence, myoclonic, and primary tonic-clonic seizures, in 72% of those with photosensitive epilepsy including eyelid myoclonia, and in 47% of partial epilepsies, for which carbamazepine was the initial drug of choice. Only 21% of those with myoclonic astatic epilepsy have become free from seizures. At first VPA was given twice daily, but in recent years it was given once daily, as this was more effective. Reasons for failure of VPA therapy are given. Side effects in 436 patients (100 more patients were added for this assessment only) were uncommon, though where they did occur, weight increase was the most frequent. Platelets were reduced without clinical problems. There were no severe hepatic disorders. Serum levels were assessed in seizure-free patients, and the optimum level was between 60 and 120 mg/L (most patients received between 20 and 30 mg/kg). VPA was given during 30 pregnancies, and there was no evidence of teratogenicity on monotherapy. VPA is most effective in primary generalized epilepsy, especially if given as the sole antiepileptic drug. If the daily dose does not exceed 40 mg/kg or 2.5 g, it is singularly free from serious side effects.