Adverse Events and Serological Responses After SARS-CoV-2 Vaccination in Individuals With Inflammatory Bowel Disease.

INTRODUCTION: We determined adverse events after 4 doses of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine in those with inflammatory bowel disease (IBD), associations between antibodies and injection site reactions (ISR), and risk of IBD flare. METHODS: Individuals with IBD were interviewed for adverse events to SARS-CoV-2 vaccine. Multivariable linear regression assessed the association between antibody titers and ISR. RESULTS: Severe adverse events occurred in 0.03%. ISR were significantly associated with antibody levels after the fourth dose (geometric mean ratio = 2.56; 95% confidence interval 1.18-5.57). No cases of IBD flare occurred. DISCUSSION: SARS-CoV-2 vaccines are safe for those with IBD. ISR after the fourth dose may indicate increased antibodies.

Validation of a new optical diagnosis training module to improve dysplasia characterization in inflammatory bowel disease: a multicenter international study.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) increases risk of dysplasia and colorectal cancer. Advanced endoscopic techniques allow for the detection and characterization of IBD dysplastic lesions, but specialized training is not widely available. We aimed to develop and validate an online training platform to improve the detection and characterization of colonic lesions in IBD: OPtical diagnosis Training to Improve dysplasia Characterization in Inflammatory Bowel Disease (OPTIC-IBD). METHODS: We designed a web-based learning module that includes surveillance principles, optical diagnostic methods, approach to characterization, and classifications of colonic lesions using still images and videos. We invited gastroenterologists from Canada, Italy, and the United Kingdom with a wide range of experience. Participants reviewed 24 educational videos of IBD colonic lesions, predicted histology, and rated their confidence. The primary endpoint was to improve accuracy in detecting dysplastic lesions after training on the platform. Furthermore, participants were randomized 1:1 to get additional training or not, with a final assessment occurring after 60 days. Diagnostic performance for dysplasia and rater confidence were measured. RESULTS: A total of 117 participants completed the study and were assessed for the primary endpoint. Diagnostic accuracy improved from 70.8% to 75.0% (P = .002) after training, with the greatest improvements seen in less experienced endoscopists. Improvements in both accuracy and confidence were sustained after 2 months of assessment, although the group randomized to receive additional training did not improve further. Similarly, participants' confidence in characterizing lesions significantly improved between before and after the course (P < .001), and it was sustained after 2 months of assessment. CONCLUSIONS: The OPTIC-IBD training module demonstrated that an online platform could improve participants' accuracy and confidence in the optical diagnosis of dysplasia in patients with IBD. The training platform can be widely available and improve endoscopic care for people with IBD. (Clinical trial registration number: NCT04924543.).

Embedding the rehabilitation treatment specification system (RTSS) into clinical practice: an evaluation of a pilot teaching programme.

BACKGROUND: Deficiency in the provision and quality of treatment specification by rehabilitation clinicians impairs the ability to differentiate effective from ineffective elements of treatment. The standardised language of the rehabilitation treatment specification system (RTSS) has been proposed as a countermeasure. To date, there is no evidence of its use in clinical practice and what effect it may have. This study aimed to assess the ability of a pilot teaching programme to embed the RTSS into the clinical practice of an inpatient oncology physiotherapy team. The objectives were to evaluate the teaching programme's effect on; participants' familiarity and perceived benefit of the RTSS, its uptake, participants' clinical reasoning, and their feelings and attitudes towards adopting the RTSS. This study provides an evaluation of the pilot teaching programme which will subsequently inform a larger iteration in an ongoing Health Education England (HEE) project aiming to disseminate and embed the RTSS into physiotherapy practice to improve physiotherapists' treatment specification. METHODS: A 6-week, multi-modal RTSS pilot teaching programme based upon socio-constructivist theory was delivered to 10 inpatient oncology physiotherapists at a large urban UK trust in 2021. Self-reported measures and clinical case note audits were assessed before and after the RTSS teaching programme to evaluate its effect on RTSS familiarity and perceived benefit, uptake, and clinical reasoning. A post-teaching focus group was undertaken. It was qualitatively analysed using an inductive, independent thematic approach to evaluate clinicians' reflection and adoption. RESULTS: Ten participants (8F, 29.4(±3.5) years) with variable clinical experience completed the RTSS teaching programme (six 1-hour lecture/case-based-learning sessions weekly) with 85% mean attendance. Nine yielded complete data for analyses, and 7 participated in the focus group. There was significant improvements in self-reported familiarity and confidence using the RTSS. Furthermore, there was a significant effect of the teaching on self-reported clinical reasoning overall and specifically in knowledge and theory application. But this was not reflected in clinicians' uptake of RTSS language, nor in the quality of clinical reasoning emergent in their case notes. Qualitative analyses revealed that while clinicians' conceptual understanding and the relative advantage of using the RTSS in practice was pervasive, they articulated that translating its perceived academic disposition into their clinical practice a challenge. CONCLUSIONS: The RTSS teaching programme was shown to be effective in improving self-reported measures of clinical reasoning, despite clinical uptake of the RTSS remaining low. Future iterations should be tested across physiotherapy specialisms and in a larger sample with consideration of pedagogical and cultural measures to support the clinical diffusion of the RTSS.

Weighted Gene Co-Expression Network Analysis Identifies a Functional Guild and Metabolite Cluster Mediating the Relationship between Mucosal Inflammation and Adherence to the Mediterranean Diet in Ulcerative Colitis.

Diet influences the pathogenesis and clinical course of inflammatory bowel disease (IBD). The Mediterranean diet (MD) is linked to reductions in inflammatory biomarkers and alterations in microbial taxa and metabolites associated with health. We aimed to identify features of the gut microbiome that mediate the relationship between the MD and fecal calprotectin (FCP) in ulcerative colitis (UC). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of co-abundant microbial taxa and metabolites correlated with the MD and FCP. The features considered were gut microbial taxa, serum metabolites, dietary components, short-chain fatty acid and bile acid profiles in participants that experienced an increase (n = 13) or decrease in FCP (n = 16) over eight weeks. WGCNA revealed ten modules containing sixteen key features that acted as key mediators between the MD and FCP. Three taxa (Faecalibacterium prausnitzii, Dorea longicatena, Roseburia inulinivorans) and a cluster of four metabolites (benzyl alcohol, 3-hydroxyphenylacetate, 3-4-hydroxyphenylacetate and phenylacetate) demonstrated a strong mediating effect (ACME: -1.23, p = 0.004). This study identified a novel association between diet, inflammation and the gut microbiome, providing new insights into the underlying mechanisms of how a MD may influence IBD. See clinicaltrials.gov (NCT04474561).

Effects on prostate cancer cells of targeting RNA polymerase III.

RNA polymerase (pol) III occurs in two forms, containing either the POLR3G subunit or the related paralogue POLR3GL. Whereas POLR3GL is ubiquitous, POLR3G is enriched in undifferentiated cells. Depletion of POLR3G selectively triggers proliferative arrest and differentiation of prostate cancer cells, responses not elicited when POLR3GL is depleted. A small molecule pol III inhibitor can cause POLR3G depletion, induce similar differentiation and suppress proliferation and viability of cancer cells. This response involves control of the fate-determining factor NANOG by small RNAs derived from Alu short interspersed nuclear elements. Tumour initiating activity in vivo can be reduced by transient exposure to the pol III inhibitor. Untransformed prostate cells appear less sensitive than cancer cells to pol III depletion or inhibition, raising the possibility of a therapeutic window.

Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice.

The association between poor paternal diet, perturbed embryonic development, and adult offspring ill health represents a new focus for the Developmental Origins of Health and Disease hypothesis. However, our understanding of the underlying mechanisms remains ill-defined. We have developed a mouse paternal low-protein diet (LPD) model to determine its impact on semen quality, maternal uterine physiology, and adult offspring health. We observed that sperm from LPD-fed male mice displayed global hypomethylation associated with reduced testicular expression of DNA methylation and folate-cycle regulators compared with normal protein diet (NPD) fed males. Furthermore, females mated with LPD males display blunted preimplantation uterine immunological, cell signaling, and vascular remodeling responses compared to controls. These data indicate paternal diet impacts on offspring health through both sperm genomic (epigenetic) and seminal plasma (maternal uterine environment) mechanisms. Extending our model, we defined sperm- and seminal plasma-specific effects on offspring health by combining artificial insemination with vasectomized male mating of dietary-manipulated males. All offspring derived from LPD sperm and/or seminal plasma became heavier with increased adiposity, glucose intolerance, perturbed hepatic gene expression symptomatic of nonalcoholic fatty liver disease, and altered gut bacterial profiles. These data provide insight into programming mechanisms linking poor paternal diet with semen quality and offspring health.

Discovery of hydroxy pyrimidine Factor IXa inhibitors.

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

Experiences of using vedolizumab in the treatment of inflammatory bowel disease in the East Midlands UK - a retrospective observational study.

PURPOSE: Clinical trials have demonstrated efficacy of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD). Further real-world data is needed to inform clinical practice. The primary outcome was to assess corticosteroid-free and clinical remission after vedolizumab initiation. Secondary outcomes included effect on disease activity scores, biochemical markers, concomitant drug use, endoscopic remission, surgical intervention, hospital admissions and adverse events. MATERIALS AND METHODS: A multi-centre retrospective observational study was conducted with patients initiated on vedolizumab across seven UK hospitals 1/11/14-30/11/16. Clinical disease activity was assessed using the partial Mayo Scores (pMS) and Harvey Bradshaw Index (HBI). Clinical remission was defined as HBI ≤4 or pMS <2 with a combined stool frequency and rectal bleeding sub score of ≤1. Clinical response was defined as ≥2-point decrease from baseline in pMS and ≥3-point decrease from baseline in HBI. RESULTS: One hundred ninety-two patients were included in the final analysis. 45% of UC and 10% of CD patients were anti-TNF naive. Over the observation period corticosteroid-free remission rates for UC and CD were 46% and 45%, while clinical remission rates were 52% and 44%, respectively. Time to corticosteroid free remission for UC and CD was 17.6 [IQR: 8.7-29.6] and 14.1 [QR: 6.0-21.7] weeks, respectively. Time to clinical response for UC was 9.4 [IQR: 5.7-15.4] and CD was 9.5 [IQR: 6.1-18.2] weeks. There was a substantial decrease in the concomitant use of immunomodulators and a similar decrease in concomitant corticosteroid use over the study period. CONCLUSIONS: Results in this predominately anti-TNF experienced population mirror other published real-world data, demonstrating good clinical effectiveness and a comparable safety profile.

Changes in Local Public Health System Performance Before and After Attainment of National Accreditation Standards.

OBJECTIVE: The aim of this study is to investigate the impact of Public Health Accreditation Board (PHAB) accreditation on the delivery of public health services and on participation from other sectors in the delivery of public health services in local public health systems. DESIGN: This study uses a longitudinal repeated measures design to identify differences between a cohort of public health systems containing PHAB-accredited local health departments and a cohort of public health systems containing unaccredited local health departments. It uses data spanning from 2006 to 2016. SETTING: This study examines a cohort of local public health systems that serves large populations and contains unaccredited and PHAB-accredited local health departments. PARTICIPANTS: Data in this study were collected from the directors of health departments that include local public health systems followed in the National Longitudinal Study of Public Health Systems. INTERVENTION: The intervention examined is PHAB accreditation. MAIN OUTCOME MEASURES: The study focuses on 4 areas: the delivery of core public health services, local health department contribution toward these services, participation in the delivery of these services by other members of the public health system, and public health system makeup. RESULTS: Prior to the advent of accreditation, public health systems containing local health departments that were later accredited by PHAB appear quite similar to their unaccredited peers. Substantial differences between the 2 cohorts appear to manifest themselves after the advent of accreditation. Specifically, the accredited cohort seems to offer a broader array of public health services, involve more partners in the delivery of those services, and enjoy a higher percentage of comprehensive public health systems. CONCLUSIONS: The results of this study suggest that accreditation may yield significant benefits and may help public health systems develop the public health system capital necessary to protect and promote the public's health.

RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis.

Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a Runx1-/- embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPß and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies.

Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography.

The symptoms of Clostridium difficile infections are caused by two exotoxins, TcdA and TcdB, which target host colonocytes by binding to unknown cell surface receptors, at least in part via their combined repetitive oligopeptide (CROP) domains. A combination of the anti-TcdA antibody actoxumab and the anti-TcdB antibody bezlotoxumab is currently under development for the prevention of recurrent C. difficile infections. We demonstrate here through various biophysical approaches that bezlotoxumab binds to specific regions within the N-terminal half of the TcdB CROP domain. Based on this information, we solved the x-ray structure of the N-terminal half of the TcdB CROP domain bound to Fab fragments of bezlotoxumab. The structure reveals that the TcdB CROP domain adopts a ß-solenoid fold consisting of long and short repeats and that bezlotoxumab binds to two homologous sites within the CROP domain, partially occluding two of the four putative carbohydrate binding pockets located in TcdB. We also show that bezlotoxumab neutralizes TcdB by blocking binding of TcdB to mammalian cells. Overall, our data are consistent with a model wherein a single molecule of bezlotoxumab neutralizes TcdB by binding via its two Fab regions to two epitopes within the N-terminal half of the TcdB CROP domain, partially blocking the carbohydrate binding pockets of the toxin and preventing toxin binding to host cells.

Public health departments and accountable care organizations: finding common ground in population health.

We examined areas of potential collaboration between accountable care organizations and public health agencies, as well as perceived barriers and facilitators. We interviewed 9 key informants on 4 topics: advantages of public health agency involvement in accountable care organizations; services public health agencies could provide; practical, cultural, and legal barriers to accountable care organization-public health agency involvement; and business models that facilitate accountable care organization-public health agency collaboration. Public health agencies could help accountable care organizations partner with community organizations and reach vulnerable patients, provide population-based services and surveillance data, and promote policies that improve member health. Barriers include accountable care organizations' need for short-term financial yield, limited public health agency technical and financial capacity, and the absence of a financial model.

Population health, public health, and accountable care: emerging roles and relationships.

To identify roles for public health agencies (PHAs) in accountable care organizations (ACOs), along with their obstacles and facilitators, we interviewed individuals from 9 ACOs, including Medicare, Medicaid, and commercial payers. We learned that PHAs participate in ACO-like partnerships with state Medicaid agencies, but interviewees identified barriers to collaboration with Medicare and commercial ACOs, including Medicare participation requirements, membership cost, risk-bearing restrictions, data-sharing constraints, differences between medicine and public health, and ACOs' investment yield needs. Collaboration was more likely when organizations had common objectives, ACO sponsors had substantial market share, PHA representatives served on ACO advisory boards, and there were preexisting contractual relationships. ACO-PHA relationships are not as straightforward as their shared use of the term "population health" would suggest, but some ACO partnerships could give PHAs access to new revenue streams.

A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach.

Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA(+) background.

CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa.

BACKGROUND: Helicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important. OBJECTIVE: To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses. DESIGN: Gastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4(+)CD25(hi) Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro. RESULTS: CCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-κB signalling. Foxp3(+), but not Foxp3(-), CD4 cells from infected mice migrated towards recombinant CCL20 in vitro. CONCLUSIONS: As well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.

A consensus-based approach to national public health accreditation.

The Public Health Accreditation Board (PHAB) solicited (and continues to solicit) the input of more than 400 subject matter experts in various areas of public health during the development and ongoing revision of the accreditation standards and measures. This process is designed to ensure that the standards and measures remain relevant and accommodate the various contexts under which public health departments practice in the United States. One way PHAB gathers feedback is convening a series of discussion meetings, or think tanks, with thought leaders in specific areas of public health, that focus on specific programmatic areas of public health, on the broader context of public health practice, or on emerging issues, such as public health informatics. The think tanks complement other mechanisms to assure that standards and measures are relevant, including gathering input from the practice community, receiving recommendations from public health departments that have undergone the accreditation process, and reviewing relevant literature. While this process allows PHAB to demonstrate its commitment to continuous quality improvement by modifying and improving the standards and measures, it also serves as a communication vehicle for PHAB to educate thought leaders and public health practitioners about the national accreditation program.

The relationship between local public health agency administrative variables and county health status rankings in Kentucky.

OBJECTIVES: The purpose of this research study was to determine whether specific local public health agency (LPHA) characteristics were associated with favorable county health status. Specifically, financial and administrative comparisons were made to determine whether variables such as budget size or number of employees, among others, were associated with community health status among the 120 counties in Kentucky. Other financial and administrative variables collected from LPHA data were also investigated in this study. METHODS: Administrative and financial data were collected for each local public health agency in Kentucky. This was matched with data on the health status of Kentucky counties from the 2010 University of Wisconsin MATCH (Mobilizing Action Towards Community Health Assessment) counties in select measures of health. MATCH data used included measures of health outcomes, specifically socioeconomic status (SES), mortality, and morbidity. Logistic regressions were used to determine the relationship, if any, between variations in the health agency data variables, SES, and health status. RESULTS: Analysis suggests that SES is the strongest link to county health status. Several other variables that appear to have statistically significant association with health status include the education level of the director, whether the LPHA employees received a raise, whether the LPHA had an associated Home Health agency, and the amount of money used from their reserve account to balance the LPHA budget. CONCLUSIONS: For many years, public health in Kentucky has measured the number of clinical visits and other LPHA services but failed to determine specific characteristics and variables that influence community health status. This study suggests that LPHAs in Kentucky can advance public health practice by having well-educated directors, giving annual incremental raises, and utilizing the agency reserve funds to meet budget shortfalls in the short run. Furthermore, LPHAs with an associated home health agency may need to reassess their impact and need in their community, considering the negative effect it may have on county health status.

Effectiveness of eHealth weight management interventions in overweight and obese adults from low socioeconomic groups: a systematic review.

BACKGROUND: Low socioeconomic status (SES) is associated with increased rates of overweight and obesity. Proponents of electronic health (eHealth) hypothesise that its inclusion in weight management interventions can improve efficacy by mitigating typical barriers associated with low SES. OBJECTIVES: To establish the scope of eHealth weight management interventions for people with overweight and obesity from a low SES. Secondary objectives were to determine the efficacy of eHealth interventions in facilitating weight loss, physical activity and fitness improvements. METHODS: Four databases and grey literature were systematically searched to identify eligible studies published in English from inception to May 2021. Studies examining an eHealth intervention with low SES participants were included. Outcomes included temporal change in weight and BMI, anthropometry, physiological measures and physical activity levels. The number and heterogeneity of studies precluded any meta-analyses; thus, a narrative review was undertaken. RESULTS: Four experimental studies with low risk of bias were reviewed. There was variance in how SES was defined. Study aims and eHealth media also varied and included reducing/maintaining weight or increasing physical activity using interactive websites or voice responses, periodic communication and discourse via telephone, social media, text messaging or eNewsletters. Irrespectively, all studies reported short-term weight loss. eHealth interventions also increased short-term physical activity levels where it was assessed, but did not change anthropometry or physiological measures. None reported any effect on physical fitness. CONCLUSIONS: This review revealed short-term effects of eHealth interventions on weight loss and increased physical activity levels for low SES participants. Evidence was limited to a small number of studies, with small to moderate sample sizes. Inter-study comparison is challenging because of considerable variability. Future work should prioritise how to utilise eHealth in the longer term either as a supportive public health measure or by determining its long-term efficacy in engendering volitional health behaviour changes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021243973.