Explore the vast range of titles available.

In two phase 3 trials, mirikizumab, a p19-directed anti–interleukin-23 antibody, was superior to placebo with regard to clinical remission of ulcerative colitis at 12 weeks (induction) and 40 weeks (maintenance).

Patients with moderate-to-severe ulcerative colitis were randomly assigned to receive placebo or induction doses of ustekinumab. Patients who had a response to induction therapy underwent a second randomization to maintenance therapy with ustekinumab or placebo. Ustekinumab was more effective than placebo for inducing and maintaining remission.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

The effects of consumption of n-3 polyunsaturated fatty acids (n-3 PUFAs) enriched hen eggs on endothelium-dependent and endothelium-independent vasodilation in microcirculation, and on endothelial activation and inflammation were determined in young healthy individuals. Control group (N = 21) ate three regular hen eggs/daily (249 mg n-3 PUFAs/day), and n-3 PUFAs group (N = 19) ate three n-3 PUFAs enriched hen eggs/daily (1053 g n-3 PUFAs/day) for 3 weeks. Skin microvascular blood flow in response to iontophoresis of acetylcholine (AChID; endothelium-dependent) and sodium nitroprusside (SNPID; endothelium-independent) was assessed by laser Doppler flowmetry. Blood pressure (BP), body composition, body fluid status, serum lipid and free fatty acids profile, and inflammatory and endothelial activation markers were measured before and after respective dietary protocol. Results: Serum n-3 PUFAs concentration significantly increased, AChID significantly improved, and SNPID remained unchanged in n-3 PUFAs group, while none was changed in Control group. Interferon-γ (pro-inflammatory) significantly decreased and interleukin-10 (anti-inflammatory) significantly increased in n-3 PUFAs. BP, fat free mass, and total body water significantly decreased, while fat mass, interleukin-17A (pro-inflammatory), interleukin-10 and vascular endothelial growth factor A significantly increased in the Control group. Other measured parameters remained unchanged in both groups. Favorable anti-inflammatory properties of n-3 PUFAs consumption potentially contribute to the improvement of microvascular endothelium-dependent vasodilation in healthy individuals.

Early treatment with ibuprofen for a large patent ductus arteriosus did not result in a lower risk of death or moderate or severe bronchopulmonary dysplasia than placebo at 36 weeks of postmenstrual age.

BackgroundThe combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear.MethodsIn a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption.ResultsOut of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156–334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5–4.5), 3 (2–4), 3 (2–6) and 3 (2–5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes.ConclusionsEnteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution.

Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus. The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77. Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events. High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus. Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

ObjectiveThe efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohn's disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success.DesignWe performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort.ResultsFrom January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion.ConclusionsA successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation.Clinical Trial registration numberNCT01183403; Results.

Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT00153660. Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3–9·2) in the celecoxib group and 12·3% (8·8–17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23–0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. The Research Grant Council of Hong Kong.

Several meta-analyses of phase 3 randomized controlled trials (RCTs) were published in 2019, reassessing the safety of most anti-osteoarthritis (OA) medications, mainly on the basis of data from full safety reports. The current systematic review (SR) intends to provide complementary insights into the safety of anti-OA medications, using evidence from post-marketing safety surveillance studies. The review protocol was registered with PROSPERO database (registration no. CRD42021227872). We followed the Cochrane methodology for SRs of interventions and comprehensively searched the Medline, CENTRAL, Scopus and TOXLINE databases from inception to November 2023, to include all post-marketing safety surveillance studies on any anti-OA medications. The outcomes of this SR were any adverse events (AEs) reported in the included studies. The literature search yielded 16,990 studies, of which 59 articles were ultimately included in the review. Most studies investigated non-steroidal anti-inflammatory drugs (NSAIDs, 27 studies, 28 reports) and intra-articular hyaluronic acid (IAHA, 16 studies). Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) were assessed in seven studies (one of which also assessed NSAIDs), and corticosteroid injections in four studies, while opioids and \"herbal mixtures and other compounds\" each were investigated respectively in three and two studies. Most of the studies were cohort studies (n = 44), others were case reports or case series (n = 12), RCTs (n = 2 reports of the same trial), or a case-control study (n = 1). The most commonly reported AEs with NSAIDs from cohort (sample sizes varied between 129 and 22,938 patients), RCT (21,645 patients with OA), and case-control (174 cases and 926 control patients with OA) studies were gastrointestinal (GI) and/or cardiovascular (CV) AEs, with specific AEs varying with individual NSAIDs. Where comparisons between NSAIDs were made, the overall literature shows a better or similar safety profile for celecoxib (at a daily dose of 200 mg, where dosage was reported) compared with other NSAIDs in regards to GI, CV and renal events. Other anti-OA medications with most common AEs reported from cohort studies were: IAHA (injection site pain); diacerein (GI AEs and reddish urine); avocado-soybean unsaponifiables (GI AEs); non-pharmaceutical-grade glucosamine and chondroitin (allergic reactions, GI disorders); opioids (hip fracture associated with long-term tramadol use among older adults; GI and nervous system disorders with hydrocodone); corticosteroid injections (increased risk of OA progression); herbal mixtures and other compounds (GI AEs). There were case reports or case series of specific AEs with various anti-OA medications that require further investigations in well-designed cohort studies before any definitive conclusions can be reached. This SR confirms previous evidence on the safety of anti-OA medications from meta-analyses of phase 3 RCTs. Beyond the evidence here reported, the limitations of this research highlight the urgent need of a reporting guideline for post-marketing safety surveillance studies. Importantly, real-life safety surveillance of anti-OA medications should be strengthened with large cohort studies with control groups, and results should be disaggregated by disease populations for drugs common to several conditions.