Occupancy trends of overwintering coastal waterbird communities reveal guild-specific patterns of redistribution and shifting reliance on existing protected areas.

Climate change and anthropogenic stressors are redistributing species and altering community composition globally. Protected areas (PAs) may not sufficiently protect populations of species undergoing distributional shifts, necessitating that we evaluate existing PAs and identify areas for future protection to conserve biodiversity across regional and temporal scales. Coastal waterbirds are important indicators of marine ecosystem health, representing mobile, long-lived, higher trophic-level consumers. Using a 20-year citizen science dataset (1999-2019) with a before-after control-intervention sampling framework for habitat protection, we applied dynamic occupancy models to assess winter occupancy trends along the Pacific coast of Canada. Specifically, we sought to understand potential drivers of regional declines, spatial commonalities among guilds, and changes in habitat use before and after PA designation, as well as between PAs and non-PAs. Occupancy trends varied regionally, with greater declines in the south compared to the north. Regional differences underlined potential range shifts, particularly for species with traits linked to temperature tolerance, movement, and high productivity foraging, as cold-tolerant, migratory benthivores and piscivores wintered farther north relative to 20 years ago or retreated to cold-water fjords. While 21 of 57 (36.8%) species responded positively to PA designation (before-after), greater occupancy declines tended to occur in PAs established pre-1999 relative to non-PAs (control-intervention). Since PAs are currently concentrated in the south, negative associations were most apparent for species retreating northward, but existing PAs may have a stabilizing or transitory effect on southern wintering species shifting into the region from farther south. We emphasize that conservation strategies must balance persistence of current communities with preserving the climate-adapted biodiversity of tomorrow by accounting for community-level effects of species moving into and out of existing PAs. Incorporating range shifts into PA planning by predicting distributional changes will allow conservation practitioners to identify priority habitats, such as cold-water refugia, for persistent wildlife communities.

Le changement climatique et les facteurs de stress anthropiques redistribuent les espèces et modifient la composition des communautés à l'échelle mondiale. Les zones protégées (ZP) ne protègent peut-être pas suffisamment les populations d'espèces qui subissent des changements de répartition, ce qui nous oblige à évaluer les ZP existantes et à identifier les zones à protéger à l'avenir pour conserver la biodiversité à l'échelle régionale et temporelle. Les oiseaux côtiers sont des indicateurs importants de la santé des écosystèmes marins, car ils représentent des consommateurs mobiles, ont une longue durée de vie et représente le niveau trophique supérieur. En utilisant un ensemble de données de science participative sur 20 ans (1999-2019) avec un échantillonnage avant-après contrôle-intervention (AACI) pour la protection de l'habitat, nous avons appliqué des modèles d'occupation dynamiques pour évaluer les tendances de l'occupation hivernale le long de la côte pacifique du Canada. Plus précisément, nous avons cherché à comprendre les moteurs potentiels des déclins régionaux, les points communs spatiaux entre les guildes et les changements dans l'utilisation de l'habitat avant et après la désignation de le ZP, ainsi qu'entre les ZP et les non-ZP. Les tendances en matière d'occupation varient d'une région à l'autre, avec des déclins plus importants dans le sud que dans le nord. Les différences régionales soulignent les déplacements potentiels de l'aire de répartition, en particulier pour les espèces dont les caractéristiques sont liées à la tolérance à la température, aux déplacements et à la recherche de nourriture à rendement élevé, car les benthivores et les piscivores migrateurs tolérants au froid ont hiverné plus au nord qu'il y a 20 ans ou se sont retirés dans les fjords aux eaux froides. Alors que 21 des 57 (36,8 %) espèces ont réagi positivement à la désignation des aires protégées (avant-après), les baisses d'occupation ont eu tendance à être plus importantes dans les aires protégées créées avant 1999 que dans les aires non protégées (contrôle-intervention). Comme les aires protégées sont actuellement concentrées dans le sud, les associations négatives étaient plus évidentes pour les espèces qui se retirent vers le nord, mais les aires protégées existantes peuvent avoir un effet stabilisateur ou transitoire sur les espèces hivernant dans le sud qui se déplacent dans la région à partir d'une région plus au sud. Nous soulignons que les stratégies de conservation doivent trouver un équilibre entre la persistance des communautés actuelles et la préservation de la biodiversité adaptée au climat de demain, en tenant compte des effets au niveau des communautés des espèces qui entrent dans les aires protégées existantes ou qui en sortent. L'intégration des changements d'aire de répartition dans la planification des aires protégées en prédisant les changements de distribution permettra aux praticiens de la conservation d'identifier les habitats prioritaires, tels que les refuges d'eau froide, pour les communautés d'espèces sauvages persistantes.

Maternal mental health: a key area for future research among women with congenital heart disease.

In this viewpoint, we respond to the recently published national priorities for research in congenital heart disease (CHD) among adults, established through the James Lind Alliance Priority Setting Partnership, with specific attention to priority 3 (mental health) and priority 5 (maternal health). Our recent policy impact project explored how maternal mental health is currently addressed in adult congenital heart disease (ACHD) services in the National Health Service, identified gaps and discussed possible ways forward. Our multidisciplinary discussion groups, which included women with lived experience of CHD and pregnancy, cardiology and obstetrics clinicians and medical anthropologists, found that while pregnancy and the postnatal period increase the mental health challenges faced by women with CHD, current services are not yet equipped to address them. Based on this work, we welcome the prioritisation of both mental health and maternal health in ACHD, and suggest that future research should focus on the overlaps between these two priority areas.

Higher Intra-Abdominal Visceral Adipose Tissue Mass Is Associated With Lower Rates of Clinical and Endoscopic Remission in Patients With Inflammatory Bowel Diseases Initiating Biologic Therapy: Results of the Constellation Study.

BACKGROUND & AIMS: We sought to assess the association between intra-abdominal visceral adipose tissue (IA-VAT) and response to 3 different biologic drugs in patients with inflammatory bowel disease (IBD) and to investigate its effects on inflammatory cytokine expression, pharmacokinetics, and intestinal microbiota. METHODS: We prospectively enrolled subjects with active IBD initiating infliximab, vedolizumab, or ustekinumab and a healthy control group. Baseline body composition (including IA-VAT as percent of total body mass [IA-VAT%]) was measured using GE iDXA scan. Primary outcome was corticosteroid- free deep remission at weeks 14-16, defined as Harvey Bradshaw Index <5 for Crohn's disease and partial Mayo score <2 for ulcerative colitis, with a normal C-reactive protein and fecal calprotectin. Secondary outcomes were corticosteroid-free deep remission and endoscopic remission (Endoscopic Mayo Score ≤1 in ulcerative colitis or Simple Endoscopic Score for Crohn's disease ≤2) at weeks 30-46. RESULTS: A total of 141 patients with IBD and 51 healthy controls were included. No differences in body composition parameters were seen between the IBD and healthy control cohorts. Patients with higher IA-VAT% were less likely to achieve corticosteroid-free deep remission (P < .001) or endoscopic remission (P = .02) vs those with lower IA-VAT%. Furthermore, nonresponders with high IA-VAT% had significantly higher serum interleukin-6 and tumor necrosis factor at baseline compared with responders and patients with low IA-VAT%. Drug pharmacokinetic properties and microbiota diversity were similar when comparing high and low IA-VAT% groups. CONCLUSIONS: Higher IA-VAT% was independently associated with worse outcomes. This association could be driven at least partially by discrete differences in inflammatory cytokine expression.

Assessing Diversity and Inclusivity is the Next Frontier in Mental Health Recovery Narrative Research and Practice.

Demand for digital health interventions is increasing in many countries. The use of recorded mental health recovery narratives in digital health interventions is becoming more widespread in clinical practice. Mental health recovery narratives are first-person lived experience accounts of recovery from mental health problems, including struggles and successes over time. Helpful impacts of recorded mental health recovery narratives include connectedness with the narrative and validation of experiences. Possible harms include feeling disconnected and excluded from others. Diverse narrative collections from many types of narrators and describing multiple ways to recover are important to maximize the opportunity for service users to benefit through connection and to minimize the likelihood of harm. Mental health clinicians need to know whether narrative collections are sufficiently diverse to recommend to service users. However, no method exists for assessing the diversity and inclusivity of existing or new narrative collections. We argue that assessing diversity and inclusivity is the next frontier in mental health recovery narrative research and practice. This is important, but methodologically and ethically complex. In this viewpoint, we propose and evaluate one diversity and two inclusivity assessment methods. The diversity assessment method involves use of the Simpson Diversity Index. The two inclusivity assessment methods are based on comparator demographic rates and arbitrary thresholds, respectively. These methods were applied to four narrative collections as a case study. Refinements are needed regarding a narrative assessment tool in terms of its practicality and cultural adaptation.

Direct current cardioversion in pregnancy: a multicentre study.

OBJECTIVE: Direct current cardioversion (DCCV) in pregnancy is rarely required and typically only documented in single case reports or case series. A recent UK confidential enquiry reported on several maternal deaths where appropriate DCCV appeared to have been withheld. DESIGN: Retrospective cohort study. SETTING: Seventeen UK and Ireland specialist maternity centres. SAMPLE: Twenty-seven pregnant women requiring DCCV in pregnancy. MAIN OUTCOME MEASURES: Maternal and fetal outcomes following DCCV. RESULTS: Twenty-seven women had a total of 29 DCCVs in pregnancy. Of these, 19 (70%) initial presentations were to Emergency Departments and eight (30%) to maternity settings. There were no maternal deaths. Seventeen of the women (63%) had a prior history of heart disease. Median gestation at DCCV was 28 weeks, median gestation at delivery was 35 weeks, with a live birth in all cases. The abnormal heart rhythms documented at the first cardioversion were atrial fibrillation in 12/27 (44%) cases, atrial flutter in 8/27 (30%), supraventricular tachycardia in 5/27 (19%) and atrial tachycardia in 2/27 (7%). Fetal monitoring was undertaken following DCCV on 14/29 (48%) occasions (10 of 19 (53%) at ≥26 weeks) and on 2/29 (7%) occasions, urgent delivery was required post DCCV. CONCLUSIONS: Direct current cardioversion in pregnancy is rarely required but should be undertaken when clinically indicated according to standard algorithms to optimise maternal wellbeing. Once the woman is stable post DCCV, gestation-relevant fetal monitoring should be undertaken. Maternity units should develop multidisciplinary processes to ensure pregnant women receive the same standard of care as their non-pregnant counterparts.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Distribution, Determinants and Normal Reference Values of Aortic Arch Width: Thoracic Aortic Geometry in the Framingham Heart Study.

Study Objective: Aortic arch geometry changes with age, including an increase in aortic arch width (AAW). High AAW is a predictor of incident adverse cardiovascular disease (CVD) events, but its distribution and determinants are unknown. We hypothesized that traditional CVD risk factors, in addition to age, are associated with increased AAW in community-dwelling adults. Study Design: Framingham Offspring and Third Generation cohort participants (N=3026, 52% Men) underwent thoracic multidetector computed tomography (MDCT). A referent group (733M, 738W) free of clinical CVD, hypertension, dyslipidemia, smoking, and diabetes was used to generate sex and 10-year age-group specific upper 90th percentile (P90) cut-points for AAW. AAW was measured as the distance between the cross-sectional centroids of the ascending and descending thoracic aorta. Multivariable logistic regression models were used to identify clinical correlates of high AAW (≥referent P90) in the overall study group. Results: Among referent participants, AAW increased with greater age-group, p for trend <0.0001 in each sex. Overall and within each age group, AAW was greater in men than women, p<0.0001 all comparisons. Across all participants, high AAW was associated with greater age (odds ratio, OR=1.34/10y; 95% confidence interval 1.20 - 1.50), body surface area (OR=1.97/SD; 1.62 - 2.40), diastolic blood pressure (OR=1.59/10mmHg; 1.40 - 1.81), pack-years smoked (OR=1.07; 1.02 - 1.13), and prevalent CVD (OR=1.64; 1.08 - 2.49). Conclusion: AAW increases with greater age, body size, diastolic blood pressure and burden of smoking. High AAW (≥referent P90) is also associated with prevalent (clinically apparent) CVD. AAW is often seen on and easily measured from tomographic thoracic images and has prognostic value.

Pregnancy outcomes in women following the Ross procedure.

INTRODUCTION: The Ross procedure, where a pulmonary autograft (neoaorta) replaces the aortic valve, has excellent long-term outcomes in patients with congenital aortic valve disease. However, there are reports of neoaortic dilatation and dissection. An increasing number of women are wishing to become pregnant following the Ross procedure, but little is known about the occurrence and risks of neoaortic dilatation and complications in pregnancy. We investigated neoaorta function and outcomes in pregnancy following the Ross procedure. METHODS: This retrospective study investigated women post-Ross procedure at a tertiary ACHD unit between 1997 and 2021. Imaging evaluated neoaortic root dimensions and regurgitation pre-, and post- pregnancy, compared with matched non-pregnant controls. Primary endpoints were change in neoaortic dimensions, degree of regurgitation and adverse maternal outcomes. RESULTS: Nineteen pregnancies in 12 women were included. The mean change in neoaortic root diameter post-pregnancy was 1.8 mm (SD 3.4) (p = 0.017). There was no significant change in neoaortic dimensions in matched controls during follow-up. There were no cases of dissection, arrhythmia, acute coronary syndrome, or maternal mortality. Three deliveries were pre-term, including one emergency Caesarean section due to maternal cardiac decompensation, requiring aortic root replacement post-partum but there were no neonatal deaths. CONCLUSIONS: Pregnancy following the Ross procedure is associated with neoaortic dilatation, and pregnancy is generally well tolerated. Although adverse maternal outcomes are uncommon, there are still rare cases of cardiac complications in and around the time of pregnancy. These findings emphasise the need for accessible pre-pregnancy counselling, risk stratification and careful surveillance through pregnancy by specialist cardio-obstetric multi-disciplinary teams.

An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson's Disease.

BACKGROUND: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD). OBJECTIVE: To explore the use of the electronic medical records (EMRs) to identify participants with PD. METHODS: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. RESULTS: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4%. The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. CONCLUSION: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% -7% (LRRK2) and 4% -11% (GBA). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research.

Pre-conceptual counselling in cardiology patients: still work to do and still missed opportunities. A comparison between 2015 and 2019 in women with cardiac disease attending combined obstetric cardiology clinics. Should the European Guidelines change anything?

Women with underlying cardiac conditions have an increased risk of adverse pregnancy outcomes. Counselling reproductive age women with heart disease is important to assist them in deciding whether to pursue pregnancy, to ensure their best cardiovascular status prior to pregnancy, and that they understand the risks of pregnancy for them and baby. This also provides an opportunity to explore management strategies to reduce risks. For this growing cohort of women, there is a great need for pre-conceptual counselling.This retrospective comparative audit assessed new referrals and pre-conceptual counselling of women attending a joint obstetric-cardiology clinic at a tertiary maternity centre in a 12-month period of 2015-2016 compared with 2018-2019. This reflected the timing of the introduction of a multidisciplinary meeting prior to clinics and assessed the impact on referrals with the introduction of the European Society of Cardiology guidelines.Data were reviewed from 56 and 67 patients in respective audit periods. Patient's risk was stratified using modified World Health Organization classification.Less than 50% of women with pre-existing cardiac conditions had received pre-conceptual counselling, although half of them had risks clearly documented. The majority of patients had a recent electrocardiograph and echocardiogram performed prior to counselling, and there was a modest improvement in the number of appropriate functional tests performed between time points. One-third of patients in both cohorts were taking cardiac medications during pregnancy.There was a significant increase in the number of pregnant women with cardiac disease and in complexity according to modified World Health Organization risk classification. While there have been improvements, it is clear that further work to improve availability and documentation of pre-pregnancy counselling is needed.

Effecting a national implementation project through distributed leadership in the West Midlands: rising to the spread challenge.

We describe the utility and impact of a distributed leadership model to implement a National Health Service (NHS) England Academic Health Sciences national quality improvement programme, in the West Midlands. This model was adopted to address the inherent difficulties of implementing change in practice in a large geographical region with a diverse population of health service personnel. We report on the inclusion of a senior trainee as part of the implementation team, supported by a multidisciplinary clinical consultant team, with equal agency in decision making, acting as mentors and activators in the background.

Raising the bar: Recovery ambition for species at risk in Canada and the US.

Routinely crossing international borders and/or persisting in populations across multiple countries, species are commonly subject to a patchwork of endangered species legislation. Canada and the United States share numerous endangered species; their respective acts, the Species at Risk Act (SARA) and the Endangered Species Act (ESA), require documents that outline requirements for species recovery. Although there are many priorities for improving endangered species legislation effectiveness, species recovery goals are a crucial component. We compared recovery goal quality, as measured by goal quantitativeness and ambition, for species listed under SARA and ESA. By comparing across ESA and SARA, the intent of the study was to identify differences and similarities that could support the development of stronger species' recovery goals under both legislations. Our results indicated that: (1) overall, only 38% of recovery goals were quantitative, 41% had high ambition, and 26% were both quantitative and with high ambition; (2) recovery goals had higher quantitativeness and ambition under ESA than SARA; (3) recovery goals for endangered species had higher ambition than threatened species under ESA and SARA, and; (4) no recovery goal aimed to restore populations to historic levels. Combined, these findings provide guidance to strengthen recovery goals and improve subsequent conservation outcomes. In particular, species at risk planners should seek to attain higher recovery goal ambition, particularly for SARA-listed species, and include quantitative recovery goals wherever possible.

Development of Risk Prediction Equations for Incident Chronic Kidney Disease.

Importance: Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions. Objective: To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR). Design, Setting, and Participants: Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540). Exposures: Demographic and clinical factors. Main Outcomes and Measures: Incident eGFR of less than 60 mL/min/1.73 m2. Results: Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. Conclusions and Relevance: Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Correction to: Vedolizumab Concentrations Are Associated with Long-Term Endoscopic Remission in Patients with Inflammatory Bowel Diseases.

The original version of the article unfortunately contained a couple of errors. In 'methods' section, in 'Outcomes' subsection, the sentence 'Endoscopic remission was defined as an SESCD ≤ 2 in patients with CD and an EMS ≤ 2 in UC patients while off corticosteroids.'

Comparison of On-Site Versus Remote Mobile Device Support in the Framingham Heart Study Using the Health eHeart Study for Digital Follow-up: Randomized Pilot Study Set Within an Observational Study Design.

BACKGROUND: New electronic cohort (e-Cohort) study designs provide resource-effective methods for collecting participant data. It is unclear if implementing an e-Cohort study without direct, in-person participant contact can achieve successful participation rates. OBJECTIVE: The objective of this study was to compare 2 distinct enrollment methods for setting up mobile health (mHealth) devices and to assess the ongoing adherence to device use in an e-Cohort pilot study. METHODS: We coenrolled participants from the Framingham Heart Study (FHS) into the FHS-Health eHeart (HeH) pilot study, a digital cohort with infrastructure for collecting mHealth data. FHS participants who had an email address and smartphone were randomized to our FHS-HeH pilot study into 1 of 2 study arms: remote versus on-site support. We oversampled older adults (age ≥65 years), with a target of enrolling 20% of our sample as older adults. In the remote arm, participants received an email containing a link to enrollment website and, upon enrollment, were sent 4 smartphone-connectable sensor devices. Participants in the on-site arm were invited to visit an in-person FHS facility and were provided in-person support for enrollment and connecting the devices. Device data were tracked for at least 5 months. RESULTS: Compared with the individuals who declined, individuals who consented to our pilot study (on-site, n=101; remote, n=93) were more likely to be women, highly educated, and younger. In the on-site arm, the connection and initial use of devices was ≥20% higher than the remote arm (mean percent difference was 25% [95% CI 17-35] for activity monitor, 22% [95% CI 12-32] for blood pressure cuff, 20% [95% CI 10-30] for scale, and 43% [95% CI 30-55] for electrocardiogram), with device connection rates in the on-site arm of 99%, 95%, 95%, and 84%. Once connected, continued device use over the 5-month study period was similar between the study arms. CONCLUSIONS: Our pilot study demonstrated that the deployment of mobile devices among middle-aged and older adults in the context of an on-site clinic visit was associated with higher initial rates of device use as compared with offering only remote support. Once connected, the device use was similar in both groups.

Higher Trough Vedolizumab Concentrations During Maintenance Therapy are Associated With Corticosteroid-Free Remission in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Vedolizumab is an anti-α4ß7 biologic approved for ulcerative colitis [UC] and Crohn's disease [CD]. We aimed to examine the association of maintenance vedolizumab concentrations with remission. METHODS: We performed a cross-sectional multi-centre study of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. RESULTS: In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs. CONCLUSIONS: In a large real-world cohort of vedolizumab maintenance concentrations, IBD patients with remission defined by objective measures [CRP and endoscopy] had significantly higher trough vedolizumab concentrations and immunogenicity was uncommon.

Vedolizumab Concentrations Are Associated with Long-Term Endoscopic Remission in Patients with Inflammatory Bowel Diseases.

BACKGROUND: The aim of this study was to assess the relationship of serum vedolizumab concentrations (SVC) during induction and endoscopic remission in patients with inflammatory bowel diseases (IBD) after 52 weeks of therapy with vedolizumab. We also sought to assess the incidence of antibody to vedolizumab (ATV) formation, the effect of ATV on drug pharmacokinetics and efficacy, and identify variables associated with SVC through the first 30 weeks of treatment. METHODS: This is a prospective cohort study of patients with active IBD initiating standard therapy with vedolizumab. Collected variables included demographics, clinical disease activity, biomarkers, pre-infusion SVC, and ATV measured at weeks 2, 6, 14, 22, and 30. Primary outcome was steroid-free endoscopic remission at week 52. RESULTS: Fifty-five patients were included. Patients that achieved steroid-free endoscopic remission by week 52 had higher SVC at weeks 2, 6, 14, 22, and 30, but only achieved statistical significance at weeks 2 and 6. Only 3 out of the 55 study subjects (5.5%) had detectable ATV through the follow-up. Overall, there were a positive correlation between SVC and serum albumin and a negative correlation with C-reactive protein, fecal calprotectin, and body mass. Vedolizumab concentrations ≥ 23.2 mcg/ml at week 2 were associated with endoscopic remission at week 52 (OR 8.8 [95% CI 2.6-29.7], p < 0.001). CONCLUSIONS: Vedolizumab concentrations during induction were associated with endoscopic remission at week 52. Interventional studies looking into improved efficacy with higher drug exposure are warranted.

Using Human Genetics to Drive Drug Discovery: A Perspective.

The probability of success of developing medicines to treat human disease can be improved by leveraging human genetics. Different types of genetic data and techniques, including genome-wide association, whole-exome sequencing, and whole-genome sequencing, can be used to gain insight into human disease. Layering different types of genetic evidence from Mendelian disease, coding variants, and common variation can bolster support for a genetic target. Human knockouts offer the potential to perform reverse genetic screens in humans to identify physiologically relevant targets. Other components of a good genetic target include protective loss-of-function mutations, some degree of known biology, tractability, and a clean on-target safety profile. In addition to using human genetics to inspire new drug programs, phenome-wide association studies can be used to identify alternative indications or repurposing opportunities. This information can be combined into a 5-step approach for selecting a genetic target for validation, which is presented in detail in this review. Finally, current challenges in leveraging human genetics are highlighted, including the difficulties translating certain types of genetic data, relatively small number of bona fide disease-associated coding rare variants, and current sample sizes of large well-curated biobanks linked to comprehensive genetic information.