Antithrombin III Levels and Outcomes Among Patients With Trauma.

Importance: Patients with trauma exhibit a complex balance of coagulopathy manifested by both bleeding and thrombosis. Antithrombin III is a plasma protein that functions as an important regulator of coagulation. Previous studies have found a high incidence of antithrombin III deficiency among patients with trauma. Objective: To assess whether changes in antithrombin III activity are associated with thrombohemorrhagic complications among patients with trauma. Design, Setting, and Participants: This cohort study was conducted from December 2, 2015, to March 24, 2017, at a level I trauma center. A total of 292 patients with trauma were followed up from their arrival through 6 days from admission. Data, including quantification of antithrombin III activity, were collected for these patients. Thromboprophylaxis strategy; hemorrhage, deep vein thrombosis (DVT), and pulmonary embolism screenings; and follow-up evaluations were conducted per institutional protocols. Data analyses were performed from September 28, 2023, to June 4, 2024. Main Outcomes and Measures: The primary study outcome measurements were associations between antithrombin III levels and outcomes among patients with trauma, including ventilator-free days, hospital-free days, intensive care unit (ICU)-free days, hemorrhage, venous thromboembolic events, and mortality. Results: The 292 patients had a mean (SD) age of 54.4 (19.0) years and included 211 men (72.2%). Patients with an antithrombin III deficiency had fewer mean (SD) ventilator-free days (27.8 [5.1] vs 29.6 [1.4]; P = .0003), hospital-free days (20.3 [8.2] vs 24.0 [5.7]; P = 1.37 × 10-6), and ICU-free days (25.7 [4.9] vs 27.7 [2.3]; P = 9.38 × 10-6) compared with patients without a deficiency. Antithrombin III deficiency was also associated with greater rates of progressive intracranial hemorrhage (21.1% [28 of 133] vs 6.3% [10 of 159]; P = .0003) and thrombocytopenia (24.8% [33 of 133] vs 5.0% [8 of 159]; P = 1.94 × 10-6). Although antithrombin III deficiency was not significantly associated with DVT, patients who developed a DVT had a more precipitous decrease in antithrombin III levels that were significantly lower than patients who did not develop a DVT. Conclusions and Relevance: In this cohort study of patients with trauma, antithrombin III deficiency was associated with greater injury severity, increased hemorrhage, and increased mortality, as well as fewer ventilator-free, hospital-free, and ICU-free days. Although this was an associative study, these data suggest that antithrombin III levels may be useful in the risk assessment of patients with trauma.

Discrete and continuous mathematical models of sharp-fronted collective cell migration and invasion.

Mathematical models describing the spatial spreading and invasion of populations of biological cells are often developed in a continuum modelling framework using reaction-diffusion equations. While continuum models based on linear diffusion are routinely employed and known to capture key experimental observations, linear diffusion fails to predict well-defined sharp fronts that are often observed experimentally. This observation has motivated the use of nonlinear degenerate diffusion; however, these nonlinear models and the associated parameters lack a clear biological motivation and interpretation. Here, we take a different approach by developing a stochastic discrete lattice-based model incorporating biologically inspired mechanisms and then deriving the reaction-diffusion continuum limit. Inspired by experimental observations, agents in the simulation deposit extracellular material, which we call a substrate, locally onto the lattice, and the motility of agents is taken to be proportional to the substrate density. Discrete simulations that mimic a two-dimensional circular barrier assay illustrate how the discrete model supports both smooth and sharp-fronted density profiles depending on the rate of substrate deposition. Coarse-graining the discrete model leads to a novel partial differential equation (PDE) model whose solution accurately approximates averaged data from the discrete model. The new discrete model and PDE approximation provide a simple, biologically motivated framework for modelling the spreading, growth and invasion of cell populations with well-defined sharp fronts. Open-source Julia code to replicate all results in this work is available on GitHub.

Natural history and impact of irritable bowel syndrome-type symptoms in inflammatory bowel disease during 12 months of longitudinal follow-up.

BACKGROUND: Little is known about the natural history and impact of irritable bowel syndrome (IBS)-type symptoms on psychological health and quality of life in inflammatory bowel disease (IBD). We aimed to address this in a 12-month longitudinal follow-up study of secondary care patients. METHODS: We collected demographic, Rome III IBS-type symptom, psychological, and quality of life data, with questionnaires at 3-month intervals, over 12 months of follow-up in patients with IBD in clinical remission at baseline. We assessed the natural history of Rome III IBS-type symptoms over the 12 months of the study and compared psychological and quality of life data between those reporting Rome III IBS-type symptoms at each of the points of follow-up with those not reporting such symptoms. KEY RESULTS: Among 206 patients with IBD in clinical remission at baseline (104 [50.5%] women, mean age 56.9 years [range 18-83 years], 79 [38.3%] Crohn's disease), 33 (16.0%) reported Rome III IBS-type symptoms at baseline and 72 (35.0%) reported Rome III IBS-type symptoms at one or more time points. Among the 33 patients with Rome III IBS-type symptoms at baseline, symptoms resolved in 6 (18.2%) patients, were present throughout in 6 (18.2%) patients, and fluctuated in the remaining 21 (63.6%) patients. Among the 39 patients with new onset of Rome III IBS-type symptoms after baseline, 24 (65.1%) had symptoms at one point in time only, 10 (25.6%) at two points, four (10.3%) at three points, and one (2.6%) at four points. At each point in time, reporting IBS-type symptoms was associated with significantly higher anxiety, depression, or somatoform symptom-reporting scores, and/or lower quality of life scores. CONCLUSIONS & INFERENCES: In this 12-month follow-up study, one-third of patients with IBD reported presence of Rome III IBS-type symptoms at any point in time. Reporting such symptoms was associated with significant impacts on psychological health and/or quality of life.

Impact of Opioid Use on the Natural History of Inflammatory Bowel Disease: Prospective Longitudinal Follow-up Study.

BACKGROUND: Opioid use is increasingly prevalent amongst patients with inflammatory bowel disease (IBD), but whether opioids have deleterious effects, or their use is merely linked with more severe disease, is unclear. We conducted a longitudinal follow-up study examining this issue. METHODS: Data on demographics, gastrointestinal and psychological symptoms, quality of life, and opioid use were recorded at baseline. Data on healthcare use and adverse disease outcomes were obtained from a review of electronic medical records at 12 months. Characteristics at baseline of those using opioids and those who were not were compared, in addition to occurrence of flare, prescription of glucocorticosteroids, treatment escalation, hospitalization, or intestinal resection during the 12 months of follow-up. RESULTS: Of 1029 eligible participants, 116 (11.3%) were taking opioids at baseline. Medium (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.61-13.6) or high (OR, 8.03; 95% CI, 2.21-29.2) levels of somatoform symptom-reporting and use of antidepressants (OR, 2.54; 95% CI, 1.34-4.84) or glucocorticosteroids (OR, 6.63; 95% CI, 2.26-19.5; P < .01 for all analyses) were independently associated with opioid use. Following multivariate analysis, opioid users were significantly more likely to undergo intestinal resection (hazard ratio,  7.09; 95% CI, 1.63 to 30.9; P = .009), particularly when codeine or dihydrocodeine were excluded (hazard ratio, 42.9; 95% CI, 3.36 to 548; P = .004). CONCLUSIONS: Opioid use in IBD is associated with psychological comorbidity and increased risk of intestinal resection, particularly in stronger formulations. Future studies should stratify the risk of individual opioids, so that robust prescribing algorithms can be developed and assess whether addressing psychological factors in routine IBD care could be an effective opioid avoidance strategy.

Of the 1029 patients with IBD in this study, opioid use exceeded 10% and was associated with psychological comorbidity and an increased risk of intestinal resection during longitudinal follow-up, particularly when more potent formulations were used.

Novel symptom clusters predict disease impact and healthcare utilisation in inflammatory bowel disease: Prospective longitudinal follow-up study.

BACKGROUND: Predicting adverse disease outcomes and high-volume users of healthcare amongst patients with inflammatory bowel disease (IBD) is difficult. AIMS: The aim of this study is to use latent class analysis to create novel clusters of patients and to assess whether these predict outcomes during 6.5 years of longitudinal follow-up. METHODS: Baseline demographic features, disease activity indices, anxiety, depression, and somatoform symptom-reporting scores were recorded for 692 adults. Faecal calprotectin (FC) was analysed at baseline in 348 (50.3%) patients (<250 mcg/g defined biochemical remission). Using baseline gastrointestinal and psychological symptoms, latent class analysis identified specific patient clusters. Rates of glucocorticosteroid prescription or flare, escalation, hospitalisation, or intestinal resection were compared between clusters using multivariate Cox regression. RESULTS: A three-cluster model was the optimum solution; 132 (19.1%) patients had below-average gastrointestinal and psychological symptoms (cluster 1), 352 (50.9%) had average levels of gastrointestinal and psychological symptoms (cluster 2), and 208 (30.1%) had the highest levels of both gastrointestinal and psychological symptoms (cluster 3). Compared with cluster 1, cluster 3 had significantly increased risk of flare or glucocorticosteroid prescription (hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.46-3.10), escalation (HR: 1.92; 95% CI: 1.34-2.76), a composite of escalation, hospitalisation, or intestinal resection (HR: 2.05; 95% CI: 1.45-2.88), or any of the endpoints of interest (HR: 2.06; 95% CI: 1.45-2.93). Healthcare utilisation was highest in cluster 3. CONCLUSIONS: Novel model-based clusters identify patients with IBD at higher risk of adverse disease outcomes who are high-volume users of healthcare.

Combined anti-S1 and anti-S2 antibodies from hybrid immunity elicit potent cross-variant ADCC against SARS-CoV-2.

Antibodies capable of neutralizing SARS-CoV-2 are well studied, but Fc receptor-dependent antibody activities that can also significantly impact the course of infection have not been studied in such depth. Since most SARS-CoV-2 vaccines induce only anti-spike antibodies, here we investigated spike-specific antibody-dependent cellular cytotoxicity (ADCC). Vaccination produced antibodies that weakly induced ADCC; however, antibodies from individuals who were infected prior to vaccination (hybrid immunity) elicited strong anti-spike ADCC. Quantitative and qualitative aspects of humoral immunity contributed to this capability, with infection skewing IgG antibody production toward S2, vaccination skewing toward S1, and hybrid immunity evoking strong responses against both domains. A combination of antibodies targeting both spike domains support strong antibody-dependent NK cell activation, with 3 regions of antibody reactivity outside the receptor-binding domain (RBD) corresponding with potent anti-spike ADCC. Consequently, ADCC induced by hybrid immunity with ancestral antigen was conserved against variants containing neutralization escape mutations in the RBD. Induction of antibodies recognizing a broad range of spike epitopes and eliciting strong and durable ADCC may partially explain why hybrid immunity provides superior protection against infection and disease compared with vaccination alone, and it demonstrates that spike-only subunit vaccines would benefit from strategies that induce combined anti-S1 and anti-S2 antibody responses.

Characteristics and Effect of Anxiety and Depression Trajectories in Inflammatory Bowel Disease.

INTRODUCTION: Symptoms of common mental disorders, such as anxiety or depression, are associated with adverse clinical outcomes in inflammatory bowel disease (IBD). We report trajectories of these symptoms in IBD, patient characteristics associated with different trajectories, and effects on healthcare utilization and prognosis. METHODS: We collected demographic, symptom, psychological, and quality-of-life data, with questionnaires at 3-month intervals, over 12 months of follow-up. We collected healthcare utilization and IBD outcomes through notes review. We compared characteristics of those with persistently normal or improving anxiety or depression scores with those with persistently abnormal or worsening scores and the number of flares, glucocorticosteroid prescriptions, escalations of therapy, hospitalizations, or intestinal resections due to IBD activity. RESULTS: Among 771 and 777 patients, respectively, worsening or persistently abnormal anxiety or depression scores were associated with increased antidepressant (28.6% vs 12.3% anxiety, 35.8% vs 10.1% depression, P < 0.001) and opiate use (19.0% vs 7.8% anxiety, P = 0.001 and 34.0% vs 7.4% depression, P < 0.001), compared with those with persistently normal or improving scores. These individuals were also more likely to have been diagnosed with IBD in the last 12 months (16.3% vs 5.0% anxiety, P = 0.001, and 15.1% vs 5.5% depression, P = 0.006), to have clinically active disease at baseline (57.1% vs 26.6% anxiety and 71.7% vs 29.1% depression, P < 0.001) and lower quality-of-life scores ( P < 0.001). Individuals with worsening or persistently abnormal trajectories of anxiety or depression required significantly more outpatient appointments, radiological investigations, and endoscopic procedures for IBD-related symptoms. DISCUSSION: In this 12-month follow-up study, patients with IBD with worsening or persistently high anxiety or depression scores were higher utilizers of health care but were not at an increased risk of future adverse disease outcomes.

Natural history and impact of irritable bowel syndrome-type symptoms in inflammatory bowel disease during 6 years of longitudinal follow-up.

BACKGROUND: The long-term natural history and impact of irritable bowel syndrome (IBS)-type symptoms on outcomes in inflammatory bowel disease (IBD) are uncertain. AIM: To assess this in a longitudinal follow-up study of patients in secondary care METHODS: We assessed the natural history of IBS-type symptoms in IBD via Rome III criteria applied at baseline, and 2 and 6 years. We defined longitudinal disease activity as the need for glucocorticosteroids or flare, escalation, hospitalisation or intestinal resection. To assess healthcare utilisation, we recorded the number of outpatient clinic attendances and investigations. We also collected anxiety, depression and somatoform symptom scores and quality of life scores during follow-up. RESULTS: Among 125 individuals with Rome III data at all three time points, only 41 (32.8%) never reported IBS-type symptoms. Fifteen patients (12.0%) had IBS-type symptoms at baseline that resolved, 19 (15.2%) had fluctuating symptoms, 35 (28.0%) had new-onset symptoms, and 15 (12.0%) had persistent symptoms. Among more than 300 patients with IBD activity data, IBS-type symptoms were not associated with an increased likelihood of the need for glucocorticosteroids or flare, escalation, hospitalisation or intestinal resection. However, the mean numbers of outpatient appointments and endoscopic investigations were significantly higher among those with IBS-type symptoms. Anxiety, depression and somatoform symptom scores were significantly higher, and quality of life scores were significantly lower, in those reporting IBS-type symptoms at least once during the study. CONCLUSIONS: IBS-type symptoms affected more than two-thirds of patients with IBD during >6 years of follow-up and were associated with increased healthcare utilisation, and worse anxiety, depression, somatoform symptom and quality of life scores, but not adverse disease activity outcomes.

Relative Contribution of Disease Activity and Psychological Health to Prognosis of Inflammatory Bowel Disease During 6.5 Years of Longitudinal Follow-Up.

BACKGROUND & AIMS: Symptoms of common mental disorders, such as anxiety or depression, are common in inflammatory bowel disease (IBD) and may affect prognosis. However, unlike clinical or biochemical markers of disease activity, psychological health is not a recommended therapeutic target. We assessed relative contribution of poor psychological health and clinical or biochemical activity to prognosis. METHODS: Demographic features, IBD subtype, treatments, and anxiety and depression scores were recorded at baseline for 760 adults, with clinical activity determined using validated scoring systems. Fecal calprotectin was analyzed in 379 (49.9%) patients (≥250 µg/g used to define biochemical activity). Glucocorticosteroid prescription or flare, escalation, hospitalization, intestinal resection, or death were assessed during 6.5 years of follow-up. Occurrence was compared using multivariate Cox regression across 4 patient groups according to presence of disease remission or activity, with or without symptoms of a common mental disorder, at baseline. RESULTS: In total, 718 (94.5%) participants provided data. Compared with clinical remission without symptoms of a common mental disorder at baseline, need for glucocorticosteroid prescription or flare (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.58-3.54), escalation (HR, 1.65; 95% CI, 1.14--2.40), and death (HR, 4.99; 95% CI, 1.80-13.88) were significantly higher in those with clinical activity and symptoms of a common mental disorder. Rates in those with clinical remission and symptoms of a common mental disorder at baseline or those with clinical activity without symptoms of a common mental disorder were not significantly higher. Similarly, with biochemical activity and symptoms of a common mental disorder, rates of glucocorticosteroid prescription or flare (HR, 2.48; 95% CI, 1.38-4.46), escalation (HR, 2.97; 95% CI, 1.74-5.06), hospitalization (HR, 3.10; 95% CI, 1.43-6.68), and death (HR, 6.26; 95% CI, 2.23-17.56) were significantly higher. CONCLUSIONS: Psychological factors are important determinants of poor prognostic outcomes in IBD and should be considered as a therapeutic target.

Few SARS-CoV-2 infections detected in Newfoundland and Labrador in the absence of Public Health Laboratory-based confirmation.

OBJECTIVE: To assess the incidence of COVID-19 infection in the absence of a confirmatory test in persons suspecting they contracted COVID-19 and elucidate reasons for their belief. METHODS: We recruited persons with a confirmed COVID-19 diagnosis and persons who believed they may have contracted COVID-19 between December, 2019 and April, 2021 into a study of immunity against SARS-CoV-2. An intake questionnaire captured their perceived risk factors for exposure and symptoms experienced, including symptom duration and severity. ELISA testing against multiple SARS-CoV-2 antigens was done to detect antibodies against SARS-CoV-2. No participant had received COVID-19 vaccination prior to the time of testing. RESULTS: The vast majority of study subjects without Public Health confirmation of infection had no detectable antibodies against SARS-CoV-2. Suspected infection with SARS-CoV-2 generally involved experiencing symptoms common to many other respiratory infections. Unusually severe or persistent symptoms often supported suspicion of infection with SARS-CoV-2 as did travel or contact with travelers from outside Newfoundland and Labrador. Rare cases in which antibodies against SARS-CoV-2 were detected despite negative results of Public Health testing for SARS-CoV-2 RNA involved persons in close contact with confirmed cases. CONCLUSIONS: Broad public awareness and declaration of pandemic status in March, 2020 contributed to the perceived risk of contracting COVID-19 in Newfoundland and Labrador from late 2019 to April 2021 and raised expectation of its severity. Serological testing is useful to diagnose past infection with SARS-CoV-2 to accurately estimate population exposure rates.

Prevalence and impact of Rome IV versus Rome III irritable bowel syndrome in patients with inflammatory bowel disease.

BACKGROUND: Irritable bowel syndrome (IBS)-type symptoms are common in inflammatory bowel disease (IBD), but few studies have examined the prevalence and impact of IBS-type symptoms in IBD according to Rome IV criteria. METHODS: We collected demographic, symptom (Rome III, Rome IV, and clinical disease activity indices), psychological (anxiety, depression, and somatization), and quality of life data from 973 IBD patients. Medical records were reviewed to document disease type, extent/location, behavior, medical therapy, and antidepressant or opioid use. We compared characteristics of individuals with no IBS-type symptoms, Rome III IBS-type symptoms, and Rome IV IBS-type symptoms. KEY RESULTS: In total, 302 (31.0%) patients met the Rome III criteria for IBS, and 172 (17.7%) met Rome IV criteria. Those with IBS-type symptoms were younger, more likely to be female, and had higher rates of antidepressant (p = 0.006) or opioid use (p = 0.001). Rome IV IBS-type symptoms were associated with symptoms of mood disorders, flare of disease activity, and lower quality of life scores (p < 0.001 for all analyses). Compared with Rome III criteria, those with Rome IV IBS-type symptoms had significantly higher rates of anxiety (p < 0.001), depression (p = 0.002), and somatization (p < 0.001), lower quality of life scores (p < 0.001) and were more likely to have CD (p = 0.011), with ileal distribution (p = 0.006). CONCLUSIONS AND INFERENCES: Rome IV IBS-type symptoms are associated with increased psychological co-morbidity, lower quality of life scores, and higher rates of antidepressant or opioid use. This is a cohort potentially at risk of adverse clinical outcomes and should be a focus for future research.

Bidirectional brain-gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis.

OBJECTIVE: The role of the brain-gut axis is of increasing interest in IBD, as the link between common mental disorders and GI inflammation may be bidirectional. We performed a systematic review examining these issues. DESIGN: We searched EMBASE Classic and EMBASE, Medline, and APA PsychInfo (to 11 July 2021) for longitudinal follow-up studies examining effect of symptoms of anxiety or depression on subsequent adverse outcomes in IBD, or effect of active IBD on subsequent development of symptoms of anxiety or depression. We pooled relative risks (RRs) and HRs with 95% CIs for adverse outcomes (flare, escalation of therapy, hospitalisation, emergency department attendance, surgery or a composite of any of these) according to presence of symptoms of anxiety or depression at baseline, or RRs and HRs with 95% CIs for new onset of symptoms of anxiety or depression according to presence of active IBD at baseline. RESULTS: We included 12 separate studies, recruiting 9192 patients. All 12 studies examined brain-to-gut effects. Anxiety at baseline was associated with significantly higher risks of escalation of therapy (RR=1.68; 95% CI 1.18 to 2.40), hospitalisation (RR=1.72; 95% CI 1.01 to 2.95), emergency department attendance (RR=1.30; 95% CI 1.21 to 1.39), or a composite of any adverse outcome. Depression at baseline was associated with higher risks of flare (RR=1.60; 95% CI 1.21 to 2.12), escalation of therapy (RR=1.41; 95% CI 1.08 to 1.84), hospitalisation (RR=1.35; 95% CI 1.17 to 1.57), emergency department attendance (RR=1.38; 95% CI 1.22 to 1.56), surgery (RR=1.63; 95% CI 1.19 to 2.22) or a composite of any of these. Three studies examined gut-to-brain effects. Active disease at baseline was associated with future development of anxiety or depression (RR=2.24; 95% CI 1.25 to 4.01 and RR=1.49; 95% CI 1.11 to 1.98, respectively). CONCLUSION: Bidirectional effects of the brain-gut axis are present in IBD and may influence both the natural history of the disease and psychological health.

Longitudinal follow-up study: effect of psychological co-morbidity on the prognosis of inflammatory bowel disease.

BACKGROUND: Psychological co-morbidity is more common in patients with inflammatory bowel disease (IBD), compared with the general population, but little is known about the cumulative effect of increasing psychological burden on disease behaviour. AIMS: To examine the effect of psychological co-morbidity on inflammatory bowel disease in a longitudinal follow-up study. METHODS: We collected complete demographic, symptom and psychological co-morbidity data (anxiety, depression and somatisation scores) at baseline from adults with IBD in biochemical remission (faecal calprotectin <250 µg/g). Objective markers of disease activity, including glucocorticosteroid prescription or flare of disease activity, escalation of therapy, hospitalisation or intestinal resection, were reviewed ≥2 years of follow-up. We performed multivariate Cox regression, controlling for patient characteristics and follow-up duration, to examine cumulative effect of psychological co-morbidities on subsequent IBD behaviour. RESULTS: Among 218 participants, 48 (22.0%) had one, 13 (6.0%) two and nine (4.1%) three psychological co-morbidities at baseline. Following multivariate Cox regression analysis, glucocorticosteroid prescription or flare, and escalation of medical therapy were significantly higher among those with two (hazard ratio [HR] = 3.18; 95% confidence interval [CI] 1.44-7.02, and HR = 2.48; 95% CI 1.03-5.93, respectively) or three (HR = 3.53; 95% CI 1.26-9.92, and HR = 8.19; 95% CI 2.88-23.23, respectively) psychological co-morbidities. Occurrence of at least one endpoint of interest was significantly higher with increasing psychological co-morbidity (HR = 1.74; 95% CI 1.07-2.82 for one, HR = 2.47; 95% CI 1.12-5.46 for two and HR = 4.93; 95% CI 1.84-13.17 for three psychological co-morbidities). CONCLUSIONS: Individuals with IBD in biochemical remission experienced a worse disease course with increasing psychological co-morbidity at baseline.

Prevalence of irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease in remission: a systematic review and meta-analysis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) often report symptoms compatible with irritable bowel syndrome (IBS), which might have an effect on psychological health. However, previous estimates of the magnitude of this issue have not accounted for ongoing inflammation as the potential cause. We updated a previous systematic review and meta-analysis to determine prevalence of IBS-type symptoms in patients with IBD in remission to better quantify the magnitude of this issue. METHODS: In this systematic review and meta-analysis, Embase, Embase Classic, and MEDLINE were searched (from Jan 1, 2012, to May 11, 2020) to identify prospective case-control or cross-sectional studies reporting prevalence of symptoms meeting diagnostic criteria for IBS in adults with IBD in remission. Studies were required to have recruited an unselected adult population (more than 90% of participants aged ≥16 years) with histologically or radiologically confirmed IBD and include at least 50 participants. Pooled prevalence and odds ratios (ORs) with 95% CIs were calculated according to the definition of remission, criteria used to define IBS-type symptoms, and type of IBD. The association between IBS-type symptom reporting and psychological comorbidity was examined using weighted mean difference (WMD) or standardised mean difference (SMD) in anxiety and depression scores between those reporting IBS-type symptoms and those not, for cases in which these data were available. FINDINGS: Of 3370 studies identified, 27 were eligible, of which 18 were newly identified. Among 3169 patients with IBD in remission, pooled prevalence of IBS-type symptoms was 32·5% (95% CI 27·4-37·9; I2=90·1%). Prevalence was lower when remission was defined by endoscopic assessment (23·5%, 95% CI 17·9-29·6; I2=59·9%) or histological assessment (25.8%, 95% CI 20.2-31.7; I2=not applicable) than when defined by validated clinical disease activity index (33·6%, 26·3-41·2; I2=91·8%) and higher in Crohn's disease than in ulcerative colitis (36·6%, 29·5-44·0; I2=82·9% vs 28·7%, 22·9-34·8; I2=87·2%). Anxiety (WMD 2·5; 95% CI 0·8-4·3) and depression (SMD 0·64; 0·44-0·84) scores were significantly higher among those who reported IBS-type symptoms than in those who did not. INTERPRETATION: Prevalence of symptoms compatible with IBS in patients with IBD varied according to how remission was defined. However, even when stringent criteria such as endoscopic or histological remission were used, about a quarter of patients reported these symptoms. Such symptoms were more common in patients with Crohn's disease and were associated with psychological comorbidity. Addressing psychological wellbeing might improve outcomes in this specific group of patients. FUNDING: None.

Anti-Tau Trials for Alzheimer's Disease: A Report from the EU/US/CTAD Task Force.

Efforts to develop effective disease-modifying treatments for Alzheimer's disease (AD) have mostly targeted the amyloid ß (Aß) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aß protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.