The Impact of Biologic Therapies on Rate of Colectomy in Paediatric-onset Ulcerative Colitis - A Population-Based Cohort Study.

AIM: Biologic therapies have been associated with reduced rate of colectomy in ulcerative colitis (UC) in adults, but data are limited in paediatric-onset UC. Our aim was to define the rate of colectomy in paediatric-onset UC, including post-transition into adult care, and to evaluate the impact of biologic therapies on rate of colectomy. METHOD: All prevalent patients diagnosed with paediatric-onset UC in South-East Scotland were identified from a prospectively accrued database at our regional tertiary centre. Patients exposed to biologics or surgery were identified and further data collected from health records. Kaplan-Meier analysis was used to calculate cumulative risk of colectomy over time. RESULTS: 145 prevalent patients were identified between 2000 and 2021. Median follow-up was 7.9 years (IQR 4.1-13.1). 23 patients (16 %) underwent a colectomy. 50/145 (34 %) patients received biologic therapy, and 13/23 (57 %) patients who underwent colectomy received biologics. The cumulative risk of colectomy across the whole cohort at 1, 5, and 10 years was 3 %, 13 % and 16 %, respectively. Patients exposed to biologics had a higher colectomy rate at 5 and 10 years (22 % and 34 %). Patients in the pre-biologic era (2000-2008) had non-significantly reduced time from diagnosis to colectomy (2.4 vs 3.7 years, p = 0.204). CONCLUSION: We have defined the 1-, 5-, and 10-year colectomy rate in a population-based cohort of Paediatric-onset UC patients. Patients who received biologic therapy had a significantly increased risk of colectomy. Increased severity of disease in these patients may account for the greater colectomy risk. LEVEL OF EVIDENCE: Level 1.

Chromatin Landscape Governing Murine Epidermal Differentiation.

Chromatin landscape and regulatory networks are determinants in lineage specification and differentiation. To define the temporospatial differentiation axis in murine epidermal cells in vivo, we generated datasets profiling expression dynamics (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin using sequencing), architecture (Hi-C), and histone modifications (chromatin immunoprecipitation followed by sequencing) in the epidermis. We show that many differentially regulated genes are suppressed during the differentiation process, with superenhancers controlling differentiation-specific epigenomic changes. Our data shows the relevance of the Dlx/Klf/Grhl combinatorial regulatory network in maintaining correct temporospatial gene expression during epidermal differentiation. We determined differential open compartments, topologically associating domain score, and looping in the basal cell and suprabasal cell epidermal fractions, with the evolutionarily conserved epidermal differentiation complex region showing distinct suprabasal cell-specific topologically associating domain and loop formation that coincided with superenhancer sites. Overall, our study provides a global genome-wide resource of chromatin dynamics that define unrecognized regulatory networks and the epigenetic control of Dlx3-bound superenhancer elements during epidermal differentiation.

Intrinsic Networks Regulating Tissue Repair: Comparative Studies of Oral and Skin Wound Healing.

Wound repair is a systematic biological program characterized by four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Notwithstanding differences between species and distinct anatomical sites, the fundamental phases in the wound healing process are conserved among mammalian species. Oral wound healing is defined as an ideal wound healing model because it resolves rapidly and without scar formation. Understanding the regulation and contribution of the different molecular events that drive rapid wound healing in oral mucosa compared with those of the skin will help us define how these lesions heal more efficiently and may provide new therapeutic strategies that can be translated to the clinical settings for patients with chronic nonhealing wounds. Although all epithelial tissues have remarkable ability for tissue repair, the efficiency of such repair differs between epithelia (oral mucosa vs. cutaneous). This prompts the long-standing, fundamental biological and clinically relevant questions as to why and how does the oral mucosa achieve its enhanced wound healing capacity. In this review, we focus on (1) distinct innate wound healing capabilities of the oral mucosa, (2) lessons learned from comparative transcriptomic studies of oral mucosa versus skin, and (3) translation of findings to therapeutics for enhanced wound healing.

The fate of patients with acute aortic syndrome during the coronavirus (COVID-19) pandemic: A UK multicenter study.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has posed challenges to health care services across the world. There has been a significant restructuring of health care resources to protect services for patients with COVID-19-related illness and to maintain emergency and urgent medical and surgical activity. This study assessed access to emergency treatment, logistical challenges, and outcomes of patients with acute aortic syndrome during the early months of the COVID-19 pandemic in the United Kingdom. METHODS: This was a multicenter study, from March 1 to May 20, 2020 that included 19 cardiac centers, was a retrospective analysis of prospectively collected data obtained from individual centers' national cardiac surgical databases. Demographic details, choice of treatment, operative details, and outcomes were collected. COVID-19 screening, timing of surgery, and outcomes of COVID-19-positive and -negative patients were also analyzed. RESULTS: In total, 88 patients presented with acute aortic syndrome to participating centers from March 1 to May 20, 2020. There were 79 aortic dissections (89.8%), 7 intramural hematomas (7.9%), and 2 penetrating aortic ulcers (2.3%). Seventy-nine patients (89.8%) underwent surgery. In-hospital mortality was 25.3% (n = 20). Postoperative complications included 13.9% postoperative stroke (11.4% permanent and 2.3% temporary), 16.5% rate of hemofiltration, and 10.1% rate of tracheostomy. Nine patients were treated conservatively with a mortality of 60%. Seven patients were diagnosed with COVID-19, and there was no associated mortality. CONCLUSIONS: Despite extensive restructuring of health care resources, access to emergency and urgent treatment for patients with acute aortic syndrome was maintained in the early months of the COVID-19 pandemic in the United Kingdom. Clinical outcomes were similar to the prepandemic period.

Early experience of aortic surgery during the COVID-19 pandemic in the UK: A multicentre study.

BACKGROUND: A significant restructuring of the healthcare services has taken place since the declaration of the coronavirus disease 2019 (COVID-19) pandemic, with elective surgery put on hold to concentrate intensive care resources to treat COVID-19 as well as to protect patients who are waiting for relatively low risk surgery from exposure to potentially infected hospital environment. METHODS: Multicentre study, with 19 participating centers, to define the impact of the pandemic on the provision of aortovascular services and patients' outcomes after having adapted the thresholds for intervention to guarantee access to treatment for emergency and urgent conditions. Retrospective analysis of prospectively collected data, including all patients with aortovascular conditions admitted for surgical or conservative treatment from the 1st March to the 20th May 2020. RESULTS: A total of 189 patients were analyzed, and 182 underwent surgery. Diagnosis included: aneurysm (45%), acute aortic syndrome (44%), pseudoaneurysm (4%), aortic valve endocarditis (4%), and other (3%). Timing for surgery was: emergency (40%), urgent (34%), or elective (26%). In-hospital mortality was 12%. Thirteen patients were diagnosed with COVID-19 during the peri-operative period, and this subgroup was not associated with a higher mortality. CONCLUSIONS: There was a significant change in service provision for aortovascular patients in the UK. Although the emergency and urgent surgical activity were maintained, elective treatment was minimal during early months of the pandemic. The preoperative COVID-19 screening protocol, combined with self-isolation and shielding, contributed to the low incidence of COVID-19 in our series and a mortality similar to that of pre-pandemic outcomes.

Hemoglobin A1c Accurately Predicts Continuous Glucose Monitoring-Derived Average Glucose in Youth and Young Adults With Cystic Fibrosis.

OBJECTIVE: In cystic fibrosis (CF), hemoglobin A1c (HbA1c) is thought to underestimate glycemia. However, few studies have directly assessed the relationship between HbA1c and average glucose in CF. We determined the relationships among glycemic markers-HbA1c, fructosamine (FA), glycated albumin (%GA), and 1,5-anhydroglucitol (1,5-AG)-and continuous glucose monitoring (CGM) in CF, hypothesizing that alternate markers would better predict average sensor glucose (ASG) than HbA1c. RESEARCH DESIGN AND METHODS: CF participants and a group of healthy control subjects (HCs), ages 6-25 years, wore CGM for up to 7 days. Pearson correlations assessed the relationships between CGM variables and HbA1c, FA, %GA, and 1,5-AG. The regression line between HbA1c and ASG was compared in CF versus HC. Linear regressions determined whether alternate markers predicted ASG after adjustment for HbA1c. RESULTS: CF (n = 93) and HC (n = 29) groups wore CGM for 5.2 ± 1 days. CF participants were 14 ± 3 years of age and 47% were male, with a BMI z score -0.1 ± 0.8 and no different from HCs in age, sex, or BMI. Mean HbA1c in CF was 5.7 ± 0.8% (39 ± 9 mmol/mol) vs. HC 5.1 ± 0.2% (32 ± 2 mmol/mol) (P < 0.0001). All glycemic markers correlated with ASG (P ≤ 0.01): HbA1c (r = 0.86), FA (r = 0.69), %GA (r = 0.83), and 1,5-AG (r = -0.26). The regression line between ASG and HbA1c did not differ in CF versus HC (P = 0.44). After adjustment for HbA1c, %GA continued to predict ASG (P = 0.0009) in CF. CONCLUSIONS: HbA1c does not underestimate ASG in CF as previously assumed. No alternate glycemic marker correlated more strongly with ASG than HbA1c. %GA shows strong correlation with ASG and added to the prediction of ASG beyond HbA1c. However, we are not advocating use of HbA1c for diabetes screening in CF based on these results. Further study will determine whether glycemic measures other than ASG differ among different types of diabetes for a given HbA1c.

Identifying English Practices that Are High Antibiotic Prescribers Accounting for Comorbidities and Other Legitimate Medical Reasons for Variation.

BACKGROUND: Seeing one's practice as a high antibiotic prescriber compared to general practices with similar patient populations can be one of the best motivators for change. Current comparisons are based on age-sex weighting of the practice population for expected prescribing rates (STAR-PU). Here, we investigate whether there is a need to additionally account for further potentially legitimate medical reasons for higher antibiotic prescribing. METHODS: Publicly available data from 7376 general practices in England between April 2014 and March 2015 were used. We built two different negative binomial regression models to compare observed versus expected antibiotic dispensing levels per practice: one including comorbidities as covariates and another with the addition of smoking prevalence and deprivation. We compared the ranking of practices in terms of items prescribed per STAR-PU according to i) conventional STAR-PU methodology, ii) observed vs expected prescribing levels using the comorbidity model, and iii) observed vs expected prescribing levels using the full model. FINDINGS: The median number of antibiotic items prescribed per practice per STAR-PU was 1.09 (25th-75th percentile, 0.92-1.25). 1133 practices (76.8% of 1476) were consistently identified as being in the top 20% of high antibiotic prescribers. However, some practices that would be classified as high prescribers using the current STAR-PU methodology would not be classified as high prescribers if comorbidity was accounted for (n = 269, 18.2%) and if additionally smoking prevalence and deprivation were accounted for (n = 312, 21.1%). INTERPRETATION: Current age-sex weighted comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. This new metric that accounts for legitimate medical reasons for higher antibiotic prescribing may have more credibility among general practitioners and, thus, more likely to be acted upon. OUTSTANDING QUESTIONS: Findings of this study indicate that the antibiotic prescribing metric by which practices are measured (and need to implement interventions determined) may be inadequate, and therefore raises the question of how they should be measured. Substantial variation between practices remains after accounting for comorbidities, deprivation and smoking. There is a need for a better understanding of why such variation remains and, more importantly, what can be done to reduce it. While antibiotics are more frequently indicated in patients with comorbidities, it is unclear to what extent antibiotic prescribing can be lowered among that patient population and how this could be achieved.