TNF promoter hypomethylation is associated with mucosal inflammation in IBD and anti-TNF response.

Background and aims: Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders. Methods: We obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1, one of which had reduced function in vivo. Conclusions: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

Health Economic Impact of a Multicenter Quality-of-Care Initiative for Reducing Unplanned Healthcare Utilization Among Patients With Inflammatory Bowel Disease.

INTRODUCTION: A multicenter adult inflammatory bowel disease learning health system (IBD Qorus) implemented clinical care process changes for reducing unplanned emergency department visits and hospitalizations using a Breakthrough Series Collaborative approach. METHODS: Using Markov decision models, we determined the health economic impact of participating in the Collaborative from the third-party payer perspective. RESULTS: Across all 23 sites, participation in the Collaborative was associated with lower annual costs by an average of $2,528 ± $233 per patient when compared with the baseline period. DISCUSSION: Implementing clinical care process changes using a Collaborative approach was associated with overall cost savings. Future work should examine which specific interventions are most effective and whether such cost savings are sustainable.

A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn's Disease.

BACKGROUND & AIMS: This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS: Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 µg/g and reduction by >50% among those with baseline FC >250 µg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS: The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). CONCLUSIONS: The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679.

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.

Preventing and responding to depression, self-harm, and suicide in older people living in long term care settings: a systematic review.

Objective: The well documented demographic shift to an aging population means that more people will in future be in need of long term residential care. Previous research has reported an increased risk of mental health issues and suicidal ideation among older people living in residential care settings. However, there is little information on the actual prevalence of depression, self-harm, and suicidal behavior in this population, how it is measured and how care homes respond to these issues. Method: This systematic review of international literature addressed three research questions relating to; the prevalence of mental health problems in this population; how they are identified and; how care homes try to prevent or respond to mental health issues. Results: Findings showed higher reported rates of depression and suicidal behavior in care home residents compared to matched age groups in the community, variation in the use of standardised measures across studies and, interventions almost exclusively focused on increasing staff knowledge about mental health but with an absence of involvement of older people themselves in these programmes. Conclusion: We discuss the implications of these findings in the context of addressing mental health difficulties experienced by older people in residential care and future research in this area.

Chromoendoscopy for Dysplasia Surveillance in Inflammatory Bowel Disease.

Long-standing ulcerative colitis (UC) and extensive Crohn's colitis confer increased risk for development of colorectal cancer. Screening and surveillance colonoscopy programs aim to identify, resect, or detect dysplasia or colorectal cancer. Dysplastic lesions can be removed by endoscopic resection and patients with unresectable lesions can be referred for colectomy at an earlier stage, with the goal of reducing overall morbidity and mortality from colorectal cancer. Surveillance colonoscopy for patients with inflammatory bowel disease (IBD) is endorsed by multiple specialty societies. High-definition endoscopy systems provide improved image resolution, and application of dilute indigo carmine or methylene blue for chromoendoscopy can provide increased contrast. International specialty society guidelines differ in their recommendations regarding use of chromoendoscopy for dysplasia surveillance, with some guidelines advocating a risk-stratified surveillance strategy. In this review, we discuss chromoendoscopy technique, training, implementation, yield as compared with standard-definition and high-definition white light colonoscopy, and positioning of this technique in clinical practice.

Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.

OBJECTIVES: There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. METHODS: CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 µg/mL). RESULTS: Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0-49.4] µg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 µg/mL), and 1 had a minimal CZP level of 0.042 µg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 µg/mL). CONCLUSIONS: There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. TRIAL REGISTRATION NUMBER: NCT02019602; Results.

Update on the Diagnosis and Management of Colon Ischemia.

OPINION STATEMENT: Colonic ischemia is the most common ischemic disorder of the gastrointestinal tract. The condition occurs more commonly in women, and risk increases with advancing age. Presenting symptoms include abdominal pain, bowel urgency, and passage of bloody diarrhea; however, nearly one half of patients do not present with this classic triad of symptoms. Abdominal pain without bloody diarrhea or non-bloody diarrhea should raise concern for an isolated right colon pattern of ischemia. An isolated right colon distribution is associated with more severe outcomes, including need for surgical intervention and increased mortality. Patients that present with symptoms concerning for ischemia should undergo computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast and laboratory testing. Colonoscopy should be performed in patients without evidence of peritonitis. Medical history should be obtained to identify possible etiologies of ischemia. Thrombophilia workup should be considered in young patients and those with recurrent ischemia, but is not required universally. In cases of isolated right colon ischemia, evaluation of the mesenteric vasculature is particularly important, for exclusion of concurrent acute mesenteric ischemia. Treatment of ischemic colitis is supportive in less severe cases, with intravenous fluids and bowel rest. Broad-spectrum antibiotics should be initiated, and surgical consultation should be obtained in cases of severe disease, pancolonic ischemia, and isolated right colonic ischemia. Surgery should be performed for peritonitis, hemodynamic instability, or failure of non-operative management. This article will review colonic ischemia diagnosis, evaluation, and treatment.

Reproductive Planning and Contraception for Women with Inflammatory Bowel Diseases.

Women with chronic medical conditions, such as inflammatory bowel diseases, are at increased risk for adverse pregnancy outcomes. Pregnancy outcomes for these conditions are best during stable disease remission. Unfortunately, women with inflammatory bowel disease are equally as likely as the general population to have unintended pregnancies. Patients look to their gastroenterologist for contraceptive counseling; however, the current standards for disease management do not prioritize this topic. Guidelines based on available evidence and expert opinion, such as the Centers for Disease Control U.S. Medical Eligibility Criteria for Contraceptive Use, exist to help practitioners provide safe and effective contraception to women with chronic medical conditions. If health care providers were to educate themselves and screen women with inflammatory bowel disease for risk of unintended pregnancy, there would be a reduction in the number of unintended pregnancies and subsequent adverse neonatal and maternal outcomes.

Mucosal healing in Crohn's disease and ulcerative colitis: what does it tell us?

PURPOSE OF REVIEW: To provide a critical review of the literature concerning the significance of mucosal healing as a predictor of future clinical and endoscopic course in patients with inflammatory bowel disease. Particular focus is given to articles published within the last year. RECENT FINDINGS: In patients with Crohn's disease, mucosal healing appears to predict future endoscopic activity. The ability to predict future clinical activity is uncertain, likely limited by present techniques for assessment of clinical activity. Recent studies provide support for escalation of treatment in response to ongoing endoscopic disease activity. However, guidance regarding de-escalation of medical therapy is lacking. In patients with ulcerative colitis, mucosal healing appears to be an important predictor of future endoscopic and clinical activity. Recent evidence suggests that mucosal healing is also an important predictor of long-term outcomes such as need for future colectomy. SUMMARY: Assessment of mucosal healing is an important tool in the management of patients with inflammatory bowel disease. The pursuit of endoscopic remission has a clear role in the management of patients with ulcerative colitis, but the application of this parameter to the care of patients with Crohn's disease requires further research.

Cognitive and functional outcome in spina bifida-Chiari II malformation.

PURPOSE: The long-term outcome in spina bifida-Chiari II-hydrocephalus complex is poorly understood. Traditional neurosurgical outcome measures are crude. Neuropsychological testing is increasingly important in outcome assessment. We investigated the health, disability, lifestyle and cognitive function in adults who had myelomeningocoele closure at birth. METHODS: Adult patients under routine follow-up were assessed in a joint neurosurgery/neuropsychology clinic. Patients completed lifestyle questionnaires, the hydrocephalus outcome questionnaire (HOQ) and underwent cognitive testing. Clinical variables including number of shunt revisions, shunt infection and surgical decompression of foramen magnum, which may influence outcome, were investigated. RESULTS: Twenty-one adults with a median age of 35 years were investigated. All had treated hydrocephalus, and eight had foramen magnum decompression for headache or progressive brainstem symptoms with stabilisation of symptoms in seven and improvement in one. Only eight patients were living independently, five were in paid employment and five work voluntarily. HOQ scores for cognitive function were lower (0.56 ± 0.20; mean ± standard deviation (SD)) than those for physical (0.64 ± 0.15) and social-emotional (0.65 ± 0.17) health. Cognitive function varied across the cohort with attention most severely affected (73.9 ± 17.0; mean ± SD). Repeated episodes of shunt malfunction or foramen magnum decompression were not associated with a worse cognitive function. CONCLUSIONS: Despite intervention in childhood and adequate cerebrospinal fluid diversion the prognosis for independent living into adulthood remains poor. All patients have elements of cognitive impairment. Structural brain abnormalities may be more important determinants of cognitive outcome than shunt malfunction.

Digital transformation in home care. A case study.

Simply implementing software and technology does not assure that an organization's targeted clinical and financial goals will be realized. No longer is it possible to roll out a new system--by solely providing end user training and overlaying it on top of already inefficient workflows and outdated roles--and know with certainty that targets will be met. At Virtua Health's Home Care, based in south New Jersey, implementation of their electronic system initially followed this more traditional approach. Unable to completely attain their earlier identified return on investment, they enlisted the help of a new role within their health system, that of the nurse informaticist. Knowledgeable in complex clinical processes and not bound by the technology at hand, the informaticist analyzed physical workflow, digital workflow, roles and physical layout. Leveraging specific tools such as change acceleration, workouts and LEAN, the informaticist was able to redesign workflow and support new levels of functionality. This article provides a view from the "finish line", recounting how this role worked with home care to assimilate information delivery into more efficient processes and align resources to support the new workflow, ultimately achieving real tangible returns.

Coronary embolism causing myocardial infarction in a patient with mechanical aortic valve prosthesis.

Coronary embolism as a cause of myocardial infarction is an uncommon but important entity both in terms of aetiology and treatment. Previous cases of coronary emboli in association with prosthetic mechanical valves have been reported previously but the mechanism of pharmacology and lack of patient awareness of medication importance is quite unique in this case. A 65-year-old male presented to the emergency room with an anterior ST elevation myocardial infarction after 14 h of symptoms. Past medical history included aortic valve replacement with a mechanical tilting-disc valve 18 months earlier for symptomatic severe calcific aortic stenosis. Pre-operative coronary angiography revealed normal coronary arteries. On this occasion, coronary angiography revealed an occluded LAD with an embolic occlusion at the midpoint of the vessel. Successful PTCA and stenting of the lesion were performed. Amazingly, the patient had decided 1 year earlier to stop taking his warfarin medication. He had begun taking a new "herbal remedy" which was helping with his joint pains but the combination with warfarin was causing excessive bleeding each day after facial shaving. He therefore decided to abruptly stop taking his warfarin without any medical advice. Embolic myocardial infarction is underdiagnosed and it is important to diagnose the source of embolism and treat the cause. Patient education is vital in our battle to prevent this entity in high-risk patients as in our case.