Search

In the coming decades, warming and deoxygenation of marine waters are anticipated to result in shifts in the distribution and abundance of fishes, with consequences for the diversity and composition of fish communities. Here, we combine fisheries-independent trawl survey data spanning the west coast of the USA and Canada with high-resolution regional ocean models to make projections of how 34 groundfish species will be impacted by changes in temperature and oxygen in British Columbia (BC) and Washington. In this region, species that are projected to decrease in occurrence are roughly balanced by those that are projected to increase, resulting in considerable compositional turnover. Many, but not all, species are projected to shift to deeper depths as conditions warm, but low oxygen will limit how deep they can go. Thus, biodiversity will likely decrease in the shallowest waters (less than 100 m), where warming will be greatest, increase at mid-depths (100–600 m) as shallow species shift deeper, and decrease at depths where oxygen is limited (greater than 600 m). These results highlight the critical importance of accounting for the joint role of temperature, oxygen and depth when projecting the impacts of climate change on marine biodiversity. This article is part of the theme issue ‘Detecting and attributing the causes of biodiversity change: needs, gaps and solutions’.

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. Objectives The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. Search methods We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. Selection criteria Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. Data collection and analysis Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. Main results One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. Authors' conclusions High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.

Treatment targets in both randomized controlled trials (RCTs) and daily practice have evolved for patients with ulcerative colitis (UC), motivated by changing regulatory requirements and efforts to alter the disease's natural history. Substantial heterogeneity in outcome definitions has been identified in UC RCTs.1 To harmonize treatment outcomes that should be reported, we proposed the collaborative development of a core outcome set (COS).2 A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials to facilitate reporting consistency, reduce selective reporting bias, and improve quality of evidence synthesis.3.

Approximately half of the patients with ulcerative colitis (UC) who undergo restorative proctocolectomy develop pouchitis within 10 years of surgery. Currently, there are no approved pouchitis treatments. It is important to quantify, and ultimately minimize, placebo rates to design and conduct efficient pouchitis trials. To quantify the placebo rate observed in pouchitis randomized controlled trials (RCTs) in meta-analysis. Embase, MEDLINE, and the Cochrane Library were searched from inception to November 3, 2017, for placebo-controlled RCTs enrolling adult UC patients with, or at risk for developing, pouchitis. A fixed-effect binomial-normal model was used to pool placebo rates on the log-odds (logit) scale. Proportions and 95% confidence intervals were reported. Outcomes of interest included development of pouchitis, induction of remission/response, and maintenance of remission/response. The Cochrane risk of bias tool was used to evaluate study quality. Twelve trials (five prevention, five induction, and two maintenance) enrolling a total of 229 placebo patients were eligible for inclusion. The pooled placebo rates for development of pouchitis and induction of response were 47% (95% CI 39–56%) and 24% (95% CI 14–37%), respectively. An insufficient number of trials prevented additional data pooling and meta-regression analysis and no consistent definitions of outcome were identified. No consistent methods for measuring pouchitis disease activity or defining response and remission were identified, highlighting the need for standardized definitions of outcomes for use in pouchitis trials. Additional high-quality trials are required to evaluate existing and novel therapies in this area.

BACKGROUND: Ustekinumab (CNTO 1275) is a monoclonal antibody that targets the standard p40 subunit of cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn’s disease. AIMS: To assess the efficacy and safety of anti-IL-12/23p40 antibodies for maintenance of remission in Crohn’s disease. METHODS: A comprehensive search of MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials, and The Cochrane IBD Group Specialized Register through September 2016 was completed. Randomized controlled trials (RCTs) in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in adult patients with active Crohn’s disease were identified for inclusion. RESULTS: Two RCTs (n=542) met the inclusion criteria. However, the two studies were not pooled due to differences in time points for analysis. One study (n=145) compared doses of 1, 3, and 6 mg/kg of ustekinumab to placebo for 22 weeks. There was no statistically significant difference in remission rates in this study (RR=0.80, 95% CI 0.63 to 1.02, low-quality evidence). However, ustekinumab was statistically superior to placebo in rates of clinical response (RR=0.53, 95% CI 0.36 to 0.79, low-quality evidence). The other included study (n=259) compared doses of 90 mg of ustekinumab administered every 8 weeks and every 12 weeks to placebo for 44 weeks. Ustekinumab was shown superior to placebo in maintenance of remission in both 90 mg every 8 weeks and every 12 weeks (RR= 0.73, 95% CI 0.58 to 0.92, moderate-quality evidence and RR=0.80, 95% CI 0.65 to 0.99, moderate quality evidence respectively). Ustekinumab was also shown to be superior to placebo with respect to clinical response in the 8 and 12 week dosing groups (RR=0.73, 95% CI 0.56 to 0.94, low-quality evidence and RR=0.75, 95% CI 0.58 to 0.97, low-quality evidence respectively). Data on adverse effects was pooled from both studies and showed there was no statistically significant differences in incidence of adverse events (AE) or serious adverse events (SAE) (RR=0.94, 95% CI 0.86–1.03, low quality of evidence and RR=0.69, 95% CI 0.42 to 1.15 respectively). CONCLUSIONS: Low to moderate quality evidence suggests that ustekinumab is effective for maintenance of clinical response when administered for 22 and 44 weeks and maintenance of clinical remission when administered for 44 weeks. Ustekinumab appears to be safe with no increased risk of AE’s, SAE’s or withdrawal due to AE’s. Further studies are required to increase the quality of evidence available for the use of ustekinumab in the maintenance of moderate to severe Crohn’s disease. FUNDING AGENCIES: Cochrane IBD Group and Summer Opportunities Research Program, Schulich School of Medicine and Dentistry

BACKGROUND: Ustekinumab and briakinumab are monoclonal antibodies that target the standard p40 subunit of cytokines interleukin‐12 and interleukin‐23 (IL‐12/23p40), which are involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with Crohn's disease fail conventional therapy or therapy with biologics (e.g. infliximab) or develop significant adverse events. Anti‐IL‐12/23p40 antibodies such as ustekinumab may be an effective alternative for these individuals. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti‐IL‐12/23p40 antibodies for maintenance of remission in CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers from inception to 17 September 2019. We searched references and conference abstracts for additional studies. SELECTION CRITERIA: We considered for inclusion randomized controlled trials in which monoclonal antibodies against IL‐12/23p40 were compared to placebo or another active comparator in participants with quiescent CD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, extracted data, and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome measure was failure to maintain clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to maintain clinical response, adverse events (AE), serious adverse events (SAE), and withdrawals due to AEs. Clinical response was defined as a decrease in CDAI score of ≥ 100 points from baseline score. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. We analyzed all data on an intention‐to‐treat basis. We used GRADE to evaluate the overall certainty of the evidence supporting the outcomes. MAIN RESULTS: Three randomized controlled trials (646 participants) met the inclusion criteria. Two trials assessed the efficacy of ustekinumab (542 participants), and one study assessed the efficacy of briakinumab (104 participants). We assessed all of the included studies as at low risk of bias. One study (N = 145) compared subcutaneous ustekinumab (90 mg) administered at 8 and 16 weeks compared to placebo. Fifty‐eight per cent (42/72) of ustekinumab participants failed to maintain clinical remission at 22 weeks compared to 73% (53/73) of placebo participants (RR 0.80, 95% CI 0.63 to 1.02; moderate‐certainty evidence). Failure to maintain clinical response at 22 weeks was seen in 31% (22/72) of ustekinumab participants compared to 58% (42/73) of placebo participants (RR 0.53, 95% CI 0.36 to 0.79; moderate‐certainty evidence). One study (N = 388) compared subcutaneous ustekinumab (90 mg) administered every 8 weeks or every 12 weeks to placebo for 44 weeks. Forty‐nine per cent (126/257) of ustekinumab participants failed to maintain clinical remission at 44 weeks compared to 64% (84/131) of placebo participants (RR 0.76, 95% CI 0.64 to 0.91; moderate‐certainty evidence). Forty‐one per cent (106/257) of ustekinumab participants failed to maintain clinical response at 44 weeks compared to 56% (73/131) of placebo participants (RR 0.74, 95% CI 0.60 to 0.91; moderate‐certainty evidence). Eighty per cent (267/335) of ustekinumab participants had an AE compared to 84% (173/206) of placebo participants (RR 0.94, 95% CI 0.87 to 1.03; high‐certainty evidence). Commonly reported adverse events included infections, injection site reactions, CD event, abdominal pain, nausea, arthralgia, and headache. Eleven per cent of ustekinumab participants had an SAE compared to 16% (32/206) of placebo participants (RR 0.74, 95% CI 0.48 to 1.15; moderate‐certainty evidence). SAEs included serious infections, malignant neoplasm, and basal cell carcinoma. Seven per cent (5/73) of ustekinumab participants withdrew from the study due to an AE compared to 1% (1/72) of placebo participants (RR 4.93, 95% CI 0.59 to 41.18; low‐certainty evidence). Worsening CD was the most common reason for withdrawal due to an AE. One study compared intravenous briakinumab (200 mg, 400 mg, or 700 mg) administered at weeks 12, 16, and 20 with placebo. Failure to maintain clinical remission at 24 weeks was seen in 51% (32/63) of briakinumab participants compared to 61% (22/36) of placebo participants (RR 0.84, 95% CI 0.58 to 1.20; low‐certainty evidence). Failure to maintain clinical response at 24 weeks was seen in 33% (21/63) of briakinumab participants compared to 53% (19/36) of placebo participants (RR 0.64, 95% CI 0.40 to 1.02; low‐certainty evidence). Sixty‐six per cent (59/90) of briakinumab participants had an AE compared to 64% (9/14) of placebo participants (RR 1.02, 95% CI 0.67 to 1.55; low‐certainty evidence). Common AEs included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. Two per cent (2/90) of briakinumab participants had an SAE compared to 7% (1/14) of placebo participants (RR 0.31, 95% CI 0.03 to 3.21; low‐certainty evidence). SAEs included small bowel obstruction, deep vein thrombosis, and respiratory distress. Withdrawal due to an AE was noted in 2% of briakinumab participants compared to 0% (0/14) of placebo participants (RR 0.82, 95% CI 0.04 to 16.34; low‐certainty evidence). The AEs leading to study withdrawal were not described. AUTHORS' CONCLUSIONS: Moderate‐certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe CD in remission without an increased risk of adverse events (high‐certainty evidence) or serious adverse events (moderate‐certainty evidence) relative to placebo. The effect of briakinumab on maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission was uncertain as the certainty of the evidence was low. The effect of briakinumab on adverse events and serious adverse events was also uncertain due to low‐certainty evidence. Further studies are required to determine the long‐term efficacy and safety of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used by itself or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in CD is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab. This review will be updated when the results of this study become available. The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.

Manila clams ( Venerupis philippinarum ) challenged in laboratory trials via bath exposure proved to be resistant to infections with Mikrocytos mackini (protistan parasite of unknown taxonomic affiliation), while Pacific oysters ( Crassostrea gigas ) challenged simultaneously using identical conditions developed infections. Although M. mackini was detected by a nucleic acid pathogen specific (PCR) assay in 10–30% of the challenged V. philippinarum that were sampled soon after exposure (0–48 h, n = 40), all of the subsequent V. philippinarum ( n = 62) sampled 9–17 weeks post-exposure tested negative for M. mackini by PCR assay. Prevalence of infection for the exposed C. gigas ( n = 100) during this same period ranged from 50% to 100% by PCR assay. Infection was confirmed in the oysters (58%, n = 60) by a digoxigenin-labelled DNA probe designed to detect M. mackini by in situ hybridization, but M. mackini was not found in any of the exposed Manila clams ( n = 63) using this technique.