NIHR Wellcome Trust Southampton Clinical Research Facility

RATIONALE: Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN RESULTS: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. CONCLUSIONS: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

BACKGROUND: We tested erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, for the prevention of episodic migraine. METHODS: We randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of migraine days per month. Secondary end points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning). RESULTS: A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P<0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P<0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo. CONCLUSIONS: Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE ClinicalTrials.gov number, NCT02456740 .).

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .).

In hospital practice, pleural aspiration (thoracocentesis) and chest drain insertion may be required in many different clinical settings for a variety of indications. Doctors in most specialities will be exposed to patients requiring pleural drainage and need to be aware of safe techniques. There have been many reports of the dangers of large-bore chest drains and it had been anticipated that, with the previous guidelines, better training and the advent of small-bore Seldinger technique chest drains, there would have been an improvement. Unfortunately the descriptions of serious complications continue, and in 2008 the National Patient Safety Agency (NPSA) issued a report making recommendations for safer practice.1 These updated guidelines take into consideration the recommendations from this report and describe the technique of pleural aspiration and Seldinger chest drain insertion and ultrasound guidance. Much of this guideline consists of descriptions of how to do these procedures but, where possible, advice is given when evidence is available. Before undertaking an invasive pleural procedure, all operators should be appropriately trained and have been initially supervised by an experienced trainer. Many of the complications described in the NPSA report were the result of inadequate training or supervision. A recent survey of UK NHS Trusts showed that the majority did not have a formal training policy for chest drain insertion in 2008.2 Studies of clinical practice have shown that there is a wide variation in the knowledge and skills of doctors inserting chest drains. In a published study3 where doctors were asked to indicate where they would insert a chest drain, 45% indicated they would insert the drain outside of the safety triangle, …

At present, the double blind placebo controlled food challenge (DBPCFC) represents the only way to establish or rule out an adverse reaction to a food in older children and adults, whereas an open challenge controlled by trained personnel is sufficient in infants and young children (1). The challenge procedure is not, however, fully developed and no standardised procedure has so far been agreed upon, although a manual describing several of the issues has previously been published (2). For the safety and feasibility of the patient undergoing challenge there is a need for standardisation of the procedures. Standardization also allows for comparison of results between different centers and different populations in scientific protocols. This Position Paper gives advice on how the procedures can be performed, but since there are no direct comparative studies available in the literature directly comparing the various parameters (e.g. timing between two subsequent challenges or increment of the dose for challenge) we have not been able to recommend truly evidence based guidelines. It is also important to realize, that legislative aspects vary in different countries within Europe, and that the guidelines presented herein must be adjusted according to local legislation. Furthermore this guideline does not constitute a guideline for Ethics Committees to decide feasibility of DBPCFC in a scientific protocol. There are several issues to be determined, prior to commencing a challenge in a patient. These can be divided into patient-related parameters, which are parameters concerning the actual patient in question and procedure-related parameters, which deal with the parameters independent of the patient in question (Table 1). Challenge should be performed either for establishment or exclusion of the diagnosis, for scientific reasons in clinical trials or for enabling determination of the sensitivity of the actual patient (threshold value) or for determining the allergenicity of foods. The determination of the sensitivity both enables tailor-made guidelines for the patient and opens the possibility of following sensitivity by repeated challenges especially in children with food allergies normally outgrown during childhood (cow's milk or hen's egg). Patients should be investigated according to the EAACI guidelines (1) using case history combined with in vivo and in vitro testing supplemented with a elimination diet period prior to challenge when necessary. Based on the findings here, the patient-related parameters can be determined. The guidelines in this position paper focus mainly on patients presenting classical immediate type allergic symptoms and signs (IgE-mediated type I allergy), as defined in EAACI position paper (1). Patients of any age with a history of adverse reaction to a food: For establishment or exclusion of the diagnosis of food intolerance/allergy For scientific reasons in clinical trials For determination of the threshold value or degree of sensitivity For assessment of tolerance. Once diagnosed, when a patient is suspected to have outgrown his clinical allergy – especially in children, whose food allergies normally outgrow during childhood, e.g. cow's milk or hen's egg allergies. Patients without specific history of adverse reaction to a food: If any chronic symptom is suspected by the patient or the physician to be food-related If a patient is on an improper elimination diet - without history of adverse food reaction –, the food has to be reintroduced and there are reasons for suspecting that an adverse reaction is possible. If a sensitization to a food is diagnosed and tolerance is not known – for example, sensitization to cross-reactive foods that have not been eaten after the adverse reaction. Eliglible patients for DBPCFC include: All patients with suspicion of an immediate, systemic allergic reaction to a food for establishment or exclusion of the diagnosis in infants and children ≤three years, an open challenge controlled and evaluated by a physician is most often sufficient. Patients with pollen related oral allergy syndrome (5) as their only symptom should only undergo DBPCFC outside scientific protocols in selected cases; for example in cases with discrepancy between case history and outcome of in vivo and/or in vitro tests. An open challenge may precede DBPCFC in older children and adults because a negative result herein renders DBPCFC unnecessary. Open challenges should not be applied in cases with a high probability of a positive outcome or in cases with subjective and/or controversial symptoms only (6). There are, however other types of patients, who also should be investigated in a standardised programme: patients with isolated, late reactions such as a subgroup of patients with atopic eczema dermatitis syndrome (AEDS) (7–12). In the majority of AEDS patients with associated food hypersensitivity an immediate reaction is seen (eg exanthema, flushing, urticaria together with symptoms and signs from the respiratory and gastrointestinal tract), but data are accumulating on a subgroup of patients who only experience exacerbation of their eczema within 24–48 hours after challenge. In such patients, the challenge procedure should be adjusted to meet the demands concerning e.g. timing and settings (11–15). patients with controversial symptoms often of subjective nature such as chronic fatigue syndrome, multiple chemical sensitivities, migraine or joint complaints, who are presenting symptoms which are not in accordance with classical atopic symptoms. Such patients should only be investigated in strict scientific protocols with special attention to the statistical evaluation of the outcome, see ‘‘Statistics section’’(6). patients with chronic urticaria, where a subgroup is reactive to additives or to high doses of special foods (e.g. tomatoes) (16–24). Standardised protocols for DBPCFC in these patients have so far not been fully developed, and the actual incidence of food dependent chronic urticaria remains to be established. patients with isolated late reactions in the gut (25, 26). Also for this group of patients, special attention must be paid to the lack of knowledge of incidence and nature of reaction, since these patients have not been finally classified. Specific guidelines for these four latter groups are not dealt with in this Position Paper. In these patients, the challenge procedures must be adjusted according to the nature and severity of the reactions. Detailed guidelines for such patients have so far not been developed within the EAACI. A detailed position paper which has just been published from the German Society of Allergology and Clinical Immunology for identification of the late reactions in AD is now being modified for the EAACI (13). Challenge is thus performed when the diagnosis is not made by case history and outcome of in vivo/in vitro tests, in scientific protocols for research purposes, or when a patient is suspected to have outgrown his/her clinical allergy. Patients with a clear cut case history of anaphylaxis (or a severe systemic reaction) to one or more specific food items should not be challenged, provided the risk of misinterpretation of a positive skin prick test or specific IgE due to clinically insignificant cross reaction is considered and ruled out - this may be the case for instance in patients with a false positive specific IgE to peanut due to grass pollen sensitization (27). The potential risk to the patient must always be weighed against the risk of misinterpreting e.g. skin prick test results or positive findings in specific IgE. We define Anaphylaxis according to EAACI 2002, comparable to class 3 to 4 in the Müller classification of reactions to bee or wasp (28). In selected cases where positive test results makes challenge unnecessary as is the case in children with positive spt to egg and specific IgE (CAP) above a certain level from ≥0.35 KUA/L to 17.5 ≥ KUA/L, in which the probability of a positive challenge outcome exceeds 95%. At present, such a correlation has only been demonstrated in children with AEDS and allergy to selected foods (29–32). By omitting challenge, determination of the clinical sensitivity (‘‘threshold’’) of the patient is not possible (33). Patients with ongoing disease should not be challenged e.g. patients with acute infection, unstable angina pectoris or patients with seasonal allergy during the season. Patients with chronic atopic disease such as asthma or AEDS should only be challenged when disease activity is at a stable and low level. Pregnant women should not be challenged. Patients taking medication which may enhance, mask, delay or prevent evaluation of a reaction or interfere with treatment of a reaction should not be challenged. Drugs include antihistamines, neuroleptics, oral steroid above 5 mg per day, aspirin and other NSAID's, ACE-inhibitors, beta-blockers and clinical experience and new drugs may extend the list. Medication such as short acting β2-agonists, inhaled or topical steroids can normally be continued during challenge, but the amount used must be kept at a fixed level. Discontinuation of these drugs may interfere with the interpretation of the outcome of the challenge. Double blind challenge (DB) DB is the procedure generally recommended, especially if a positive challenge outcome is expected (for example, when studying an adverse reaction believed to be IgE-mediated, and the food skin test is positive). DB is the method of choice for scientific protocols. DB is the method of choice when studying late reactions or chronic symptoms, such as AEDS, isolated digestive late reactions, or chronic urticaria. DB is the only way to conveniently study subjective food-induced complains, such as acute subjective adverse reactions, chronic fatigue syndrome, multiple chemical sensitivities, migraine or joint complaints. Open challenge A negative DB should always be followed by an open challenge. A positive open challenge could be sufficient when dealing with IgE-mediated acute reactions manifesting with objective signs. For practical reasons, an open challenge can be the first approach when the probability of a negative outcome is estimated to be very high (for example, when studying an adverse reaction believed to be IgE-mediated, and a properly performed food skin test is negative). In infants and children ≤3 years, an open, physician- controlled challenge is often sufficient for suspected immediate type reactions (unless a psychological reaction of the mother is expected). For patients with pollen-related OAS as their only symptom, an open challenge could be sufficient as regular procedure - due to difficulties in blinding fruits and vegetables conserving their allergenicity -. However, in these patients, DB are recommended for scientific protocols and other selected cases for example, discrepancies between clinical history and outcome of diagnostic tests. Single Blind Challenge Single blind challenge carries the same difficulties for blinding foods as for DB, and introduces subjective biases of the observer. Therefore, with only a minor additional work (cross-over by an external technician), DB can be performed, and the result will be more robust. Therefore, our recommendation is to always use DB instead. The personnel involved in challenge procedure must be specially trained in management of acute allergic reactions and equipment for resuscitation (including adrenaline for injection and oxygen) must be readily available. In cases where a severe reaction is suspected, challenge should be performed in settings with immediate access to intensive care units. A possible need for latex-free surroundings should be considered. Placebo challenge and active challenge should ideally be separated by at least 24 hours, but when late reactions are not expected, both challenges can in many cases of classical type 1 allergy be performed on the same day. If a reaction needing treatment occurs, the next challenge should not be performed until the symptoms have resolved and the quarantine period for the drugs used has expired. Intravenous access should be available before initiation of challenges as a general rule, and always if a severe systemic reaction is expected. In small children, iv access is only necessary in selected cases, but if there is any doubt on the outcome (severity) of a challenge, it is advisable to place a cannula in advance. Patients can be in most cases be challenged as out patients and discharged after an observation period of at least 2 hours after the last dose given, provided no reaction has occurred. The observation period must be adjusted to the expected symptoms and signs in the patient in question. The patient must be discharged with specific information and satisfactory arrangements for care if a late reaction (especially asthma) occurs. In some cases, ‘‘rescue medication’’ consisting of antihistamines, β-agonists and steroids may be given to the patient to take prn after contacting the physician. If a patient experiences a severe reaction needing treatment (asthma, laryngeal oedema, severe urticaria), he/she should be kept under observation at the hospital overnight and treated accordingly. A negative outcome of DBPCFC must always be followed by an open serving of the food in order to avoid possible false negative outcome of DBPCFC due to destruction of allergens during preparation of the challenge (34). For clinical purposes, a patient may thus be classified as positive, or likely positive (only positive in open challenge) whereas as in a scientific protocol a positive open challenge in a DBPCFC negative patient should be considered as a drop-out. If case history is suggestive of reactions in special situations only (reaction elicited only when exercising after eating (food dependent, exercise induced anaphylaxis (3) or with concomitant intake of a drugs (e.g. aspirin (4)) or intake of processed food (35–37)) challenges should first be performed without exercise/drug intake and if negative repeated with exercise/drug intake . Many of these reactions are, however, severe of nature and the use of pharmaceutical ‘‘facilitators’’ such as aspirine may enhance the severity of the reaction resulting in life-threatening situations. Such challenges should always be considered carefully. The challenge protocol should be decided on beforehand. In cases of classical type 1 patients presenting objective signs a protocol using one active and one placebo is normally sufficient due to the low frequency of reactions to placebo in these patients (38–49). In more dubious cases and especially in cases patients presenting with subjective signs only a protocol with repeated challenges should be applied, either using three plus three challenges or three plus two challenges (50–53). The starting dose, ie the amount of food in question administered to the patient as the first dose should be evaluated based on patient's case history and correlated to available data from the literature (Table 2). In published papers, 5% of patients react to less than 1 mg of peanut, whereas 15% of milk allergic patients react to less than 5 ml of cow's milk (43, 54). A computer model for assessment of threshold has recently been published demonstrating a possible threshold for a reaction in one in a hundred patients for milk, egg and peanut of 0,1 mg (55). It is advisable to begin with a starting dose below the expected ‘threshold dose’, because this will enable determination of the actual sensitivity in the patient (low adverse effect level and no observed adverse effect level). There is no correlation between the size of a skin prick test or the level of specific IgE and the clinical sensitivity in individual patients (33, 65). A time interval of 15–30 minutes is in most cases suitable for investigation of IgE associated reactions unless using capsules. In published papers, symptoms most often occur 3 to 15 minutes after intake; especially the severe reactions always occur immediately - if the patient history claims a reaction developed later, time schedule should be adjusted accordingly (39, 42, 43, 45, 50, 56, 66, 67). All patients follow the above incremental scheme if an acute reaction is suspected, patients with suspected isolated late reactions (e.g. exacerbation of AD) continue on another protocol with intake of normal daily amount the following day settings (11–15). The increment may either be a doubling of the dose every 15–30 minutes until top dose has been reached or the patient react, or a increment using logarithmic mean ie 1, 3, 10, 30, 100 etc. No comparative studies comparing these two protocols are available. There is a theoretical risk of passive rush desensitization during the procedure, but evidence for such a phenomenon has not been published and is unlikely since this would result in a positive outcome of the open feeding following a negative DBPCFC. Such reactions have only been seen in cases, where the active substance was destroyed during the blinding procedure (34, 68). If too large increments, on the other hand, are used, the risk of severe reactions increases. Therefore, at the present state of knowledge, either doubling or logarithmic increment is recommended. The top dose ie the maximal amount administered should normally be the normal daily intake in a serving of the food in question, adjusted for the age of the patient. Data concerning the foods most often causing allergic reactions has previously been published (69). Active and placebo challenges should be identical regarding taste, looks, smell, viscosity, texture, structure and volume. Assessment of possible differences between active and placebo should be evaluated by standard procedures such as duo-test and triangle-test, where differences in taste, texture, smell etc. are compared either in pairs or by ability for finding one different between three samples (70). In infants and children liquid foods can be masked in extensive hydrolysed cow's milk based formulas or in amino acid formulas eventually with addition of flavouring agents or colourants. Items with a strong taste such as black currant juice or peppermint oil may help masking an unpleasant taste. Different recipes for masking liquid and solid foods (peanut, soy, wheat, milk, egg, fish, hazelnut, almond, brazil nut, apple, carrot, celery, apricot, banana, zucchini, crustaceans) have been developed and are available on the EAACI homepage (http://www.eaaci.org or http://www.ig-food.org.) It is of crucial importance to ensure presence and stability of the allergenicity of the food in the mixture. In cases with very stable foods such as peanut or cod (42, 71) stability in the serving is not a problem, whereas in other cases especially with foods of vegetable origin (apples) the stability is very low (72). The procedures must be adjusted according to the stability of the food in question (35, 37). Only in cases of a suspected reaction to additives is masking in gelatine capsules recommended. Capsules should else wise be avoided, since reactions in mouth and throat are bypassed (OAS) and since the whole procedure is delayed due to the lag phase when the capsule is dissolved in the stomach. Measures to avoid toxicity from the food administered should be taken (aflatoxins in brazil nuts, salmonella bacteria in eggs, and mites in flour). Different approaches should be taken in patients presenting classical allergic symptoms with objective signs of a reaction on challenge and patients presenting subjective symptoms only. special attention should be made to the statistical evaluation when patients with controversial symptoms. In classical type I allergy with signs (e.g. a in or urticaria), reactions to placebo are and a challenge procedure using one active and one placebo challenge is normally sufficient 42, In the frequency of reactions to placebo seen in patients with subjective symptoms is repeated challenges are normally necessary. statistical approaches different approaches in challenge This is especially for patients only presenting subjective An approach the actual patient The risk of a patient the of challenges by is per if one active and one placebo is repeated challenges must be used to ensure statistical A protocol using three active and three has been published The of a patient the by is a new model has been where using challenges in of where the patient is of the presence of either three active and two placebo challenges or This approach the same statistical as using An approach a of patients In several published patients to placebo challenges are from statistical This approach carries the risk of the actual frequency of patients with actual allergy. a example, the following outcome of a with 100 patients with subjective symptoms only can be used for It is that using the whole no correlation between challenge and outcome is the patients to placebo and however, results in a frequency of in the The frequency of placebo in a must always be taken into and the actual frequency In both cases, a statistical model has been developed The use of such statistical evaluation of the outcome of a is recommended. All challenges should be For comparative reasons, and standardised should be of such are available at The present position paper the present level of knowledge for placebo controlled The use of the guidelines presented will both safety and feasibility for the patient and involved in the challenge procedure and by using enable between results in different

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.

BACKGROUND: The DNA methylation-based 'epigenetic clock' correlates strongly with chronological age, but it is currently unclear what drives individual differences. We examine cross-sectional and longitudinal associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability. METHODS: DNA methylation-based age acceleration (residuals of the epigenetic clock estimate regressed on chronological age) were estimated in the Lothian Birth Cohort 1936 at ages 70 (n = 920), 73 (n = 299) and 76 (n = 273) years. General cognitive ability, walking speed, lung function and grip strength were measured concurrently. Cross-sectional correlations between age acceleration and the fitness variables were calculated. Longitudinal change in the epigenetic clock estimates and the fitness variables were assessed via linear mixed models and latent growth curves. Epigenetic age acceleration at age 70 was used as a predictor of longitudinal change in fitness. Epigenome-wide association studies (EWASs) were conducted on the four fitness measures. RESULTS: Cross-sectional correlations were significant between greater age acceleration and poorer performance on the lung function, cognition and grip strength measures (r range: -0.07 to -0.05, P range: 9.7 x 10(-3) to 0.024). All of the fitness variables declined over time but age acceleration did not correlate with subsequent change over 6 years. There were no EWAS hits for the fitness traits. CONCLUSIONS: Markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration). However, age acceleration does not associate with decline in these measures, at least over a relatively short follow-up.

BACKGROUND: Asthma is characterized pathologically by structural changes in the airway, termed airway remodeling. These changes are associated with worse long-term clinical outcomes and have been attributed to eosinophilic inflammation. In vitro studies indicate, however, that the compressive mechanical forces that arise during bronchoconstriction may induce remodeling independently of inflammation. We evaluated the influence of repeated experimentally induced bronchoconstriction on airway structural changes in patients with asthma. METHODS: We randomly assigned 48 subjects with asthma to one of four inhalation challenge protocols involving a series of three challenges with one type of inhaled agent presented at 48-hour intervals. The two active challenges were with either a dust-mite allergen (which causes bronchoconstriction and eosinophilic inflammation) or methacholine (which causes bronchoconstriction without eosinophilic inflammation); the two control challenges (neither of which causes bronchoconstriction) were either saline alone or albuterol followed by methacholine (to control for nonbronchoconstrictor effects of methacholine). Bronchial-biopsy specimens were obtained before and 4 days after completion of the challenges. RESULTS: Allergen and methacholine immediately induced similar levels of bronchoconstriction. Eosinophilic inflammation of the airways increased only in the allergen group, whereas both the allergen and the methacholine groups had significant airway remodeling not seen in the two control groups. Subepithelial collagen-band thickness increased by a median of 2.17 μm in the allergen group (interquartile range [IQR], 0.70 to 3.67) and 1.94 μm in the methacholine group (IQR, 0.37 to 3.24) (P<0.001 for the comparison of the two challenge groups with the two control groups); periodic acid-Schiff staining of epithelium (mucus glands) also increased, by a median of 2.17 percentage points in the allergen group (IQR, 1.03 to 4.77) and 2.13 percentage points in the methacholine group (IQR, 1.14 to 7.96) (P=0.003 for the comparison with controls). There were no significant differences between the allergen and methacholine groups. CONCLUSIONS: Bronchoconstriction without additional inflammation induces airway remodeling in patients with asthma. These findings have potential implications for management.

Children with a peanut allergy (PA) are faced with food and social restrictions due to the potentially life-threatening nature of their disease, for which there is no cure or treatment. This inevitably impacts upon their quality of life (QoL). QoL of 20 children with PA and 20 children with insulin-dependent diabetes mellitus (IDDM) was measured using two disease-specific QoL questionnaires (higher scores correspond to a poorer QoL). One questionnaire was designed by us and the other was adapted from the Vespid Allergy QoL questionnaire. We gave subjects cameras to record how their QoL is affected over a 24-h period. Response rates for both questionnaires were 100%. Mean ages were 9.0 and 10.4 years for PA and IDDM subjects, respectively. Children with a PA reported a poorer quality of life than children with IDDM: mean scores were 54.85 for PA subjects and 46.40 for diabetics (p = 0.004) in questionnaire 1 and 54.30 and 34.50 (p</=0.001) in questionnaire 2. PA children reported more fear of an adverse event and more anxiety about eating, especially when eating away from home. Photographs fell into seven common categories: food, management, environment, away from home, physical activities, restaurant and people. Most photographs related to food and management issues and revealed difficulties for both groups regarding food restrictions. PA subjects felt more threatened by potential hazards within their environment, felt more restricted by their PA regarding physical activities, and worried more about being away from home. However, they felt safe when carrying epinephrine kits and were positive about eating at familiar restaurants. The QoL in children with PA is more impaired than in children with IDDM. Their anxiety may be considered useful in some situations, promoting better adherence to allergen avoidance advice and rescue plans.

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.

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents.

Biofilms associated with the human body, particularly in typically sterile locations, are difficult to diagnose and treat effectively because of their recalcitrance to conventional antibiotic therapy and host immune responses. The study of biofilms in medicine today requires a translational approach, with examination of clinically relevant biofilms in the context of specific anatomic sites, host tissues, and diseases, focusing on what can be done to mitigate their pathologic consequences. This review, which grew out of a discussion session on clinical biofilms at the 5th ASM Biofilm Conference in Cancun, Mexico, is designed to give an overview of biofilm-associated infections (BAI) and to propose a platform for further discussion that includes clinicians, medical microbiologists, and biofilm researchers who are stakeholders in advancing the scientific pursuit of better diagnosis and treatment of BAI to mitigate their human and healthcare costs. It also highlights the need for better diagnostic markers, which exploit the difference between planktonic and biofilm cells.

OBJECTIVE: To observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet. DESIGN: Prospective cohort study. SETTING: Outpatient department and the clinical research facility based at two separate hospitals within the United Kingdom. PARTICIPANTS: 25 women with body mass index (BMI) >25, with active (papilloedema and intracranial pressure >25 cm H(2)O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded. INTERVENTION: Stage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months. MAIN OUTCOME MEASURE: The primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months. RESULTS: All variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P<0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H(2)O, P<0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) micro, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained. CONCLUSION: Women with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.

BACKGROUND: Clinicians use fibrosis in a liver biopsy to predict clinical outcomes of chronic liver disease. The performance of non-invasive tests has been evaluated against histological assessment of fibrosis but use of clinical outcomes as the reference standard would be ideal. The enhanced liver fibrosis (ELF) test was derived and validated in a large cohort of patients and shown to have high diagnostic accuracy (area under the curve (AUC)=0.80 95% CI 0.76 to 0.85) in identification of significant fibrosis on biopsy. OBJECTIVE: To evaluate ELF performance in predicting clinical outcomes by following up the original ELF cohort. METHODS: Patients recruited to the ELF study at seven English centres were followed up for liver morbidity and mortality by examination of clinical data. Defaulting/discharged patients were followed up by family practitioner questionnaires. Primary outcome measure was liver-related morbidity/liver-related death. RESULTS: 457 patients were followed up (median 7 years), with ascertainment of clinical status in 92%. There were 61 liver-related outcomes (39 deaths). Survival analysis showed that the ELF score predicts liver outcomes, with people having the highest ELF scores being significantly more likely to have clinical outcomes than those in lower-score groups. A Cox proportional hazards model showed fully adjusted HRs of 75 (ELF score 12.52-16.67), 20 (10.426-12.51) and 5 (8.34-10.425) compared with patients with ELF <8.34. A unit change in ELF is associated with a doubling of risk of liver-related outcome. CONCLUSIONS: An ELF test can predict clinical outcomes in patients with chronic liver disease and may be a useful prognostic tool in clinical practice.

BACKGROUND: There is growing evidence that schizophrenia is a disorder of cortical connectivity. Specifically, frontotemporal and frontoparietal connections are thought to be functionally impaired. Diffusion tensor magnetic resonance imaging (DT-MRI) is a technique that has the potential to demonstrate structural disconnectivity in schizophrenia. AIMS: To investigate the structural integrity of frontotemporal and frontoparietal white matter tracts in schizophrenia. METHOD: Thirty patients with DSM-IV schizophrenia and thirty matched control subjects underwent DT-MRI and structural MRI. Fractional anisotropy - an index of the integrity of white matter tracts - was determined in the uncinate fasciculus, the anterior cingulum and the arcuate fasciculus and analysed using voxel-based morphometry. RESULTS: There was reduced fractional anisotropy in the left uncinate fasciculus and left arcuate fasciculus in patients with schizophrenia compared with controls. CONCLUSIONS: The findings of reduced white matter tract integrity in the left uncinate fasciculus and left arcuate fasciculus suggest that there is frontotemporal and frontoparietal structural disconnectivity in schizophrenia.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

In this article, the European League Against Rheumatism (EULAR) standardised operating procedures for the elaboration, evaluation, dissemination and implementation of recommendations endorsed by the EULAR standing committees published in 2004 have been updated. The various steps from the application to implementation have been described in detail.

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OBJECTIVE: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. METHODS: Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks. RESULTS: At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (-0.20) versus placebo (-0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ≥3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT01212770.

PURPOSE: This review provides an update on the current clinical, epidemiological and pathophysiological evidence alongside the diagnostic, prevention and treatment approach to chemotherapy-induced peripheral neuropathy (CIPN). FINDINGS: The incidence of cancer and long-term survival after treatment is increasing. CIPN affects sensory, motor and autonomic nerves and is one of the most common adverse events caused by chemotherapeutic agents, which in severe cases leads to dose reduction or treatment cessation, with increased mortality. The primary classes of chemotherapeutic agents associated with CIPN are platinum-based drugs, taxanes, vinca alkaloids, bortezomib and thalidomide. Platinum agents are the most neurotoxic, with oxaliplatin causing the highest prevalence of CIPN. CIPN can progress from acute to chronic, may deteriorate even after treatment cessation (a phenomenon known as coasting) or only partially attenuate. Different chemotherapeutic agents share both similarities and key differences in pathophysiology and clinical presentation. The diagnosis of CIPN relies heavily on identifying symptoms, with limited objective diagnostic approaches targeting the class of affected nerve fibres. Studies have consistently failed to identify at-risk cohorts, and there are no proven strategies or interventions to prevent or limit the development of CIPN. Furthermore, multiple treatments developed to relieve symptoms and to modify the underlying disease in CIPN have failed. IMPLICATIONS: The increasing prevalence of CIPN demands an objective approach to identify at-risk patients in order to prevent or limit progression and effectively alleviate the symptoms associated with CIPN. An evidence base for novel targets and both pharmacological and non-pharmacological treatments is beginning to emerge and has been recognised recently in publications by the American Society of Clinical Oncology and analgesic trial design expert groups such as ACTTION.