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Introduction The United States opioid epidemic remains responsible for 75,673 overdose deaths in 2021. Self-medication with kratom, a Southeastern Asian plant containing the mu opioid receptor agonists mitragynine and 7-hydroxymitragynine, is becoming increasingly prevalent. Kratom is legally available in most states with purported benefits in the self-treatment of opiate withdrawal and mood disorders. Anecdotal data linking kratom to male sexual health enhancement have not been formally investigated. Objective To objectively investigate the potential effect of kratom use on men's sexual health including ejaculatory and erectile function. Methods Under IRB approval, Twitter and Reddit (r/Kratom) were accessed to disseminate our survey featuring validated instruments (IIEF and the premature ejaculation diagnostic tool, PEDT). Sexual health prior to and after four weeks of kratom use were assessed. Descriptive statistics were used to ascertain differences between ejaculatory and erectile function with kratom use. Results Most males surveyed (n =165) were 18-40 years old (84.9%) and were white (86.7%). When examining kratom use, 82.4% (n= 136) of males used kratom for 1 or more years, with 95.8% using it at least weekly. Reasons for using kratom included an illicit drug dependency (17.6%), a prescription medicine dependency (14.5%), acute or chronic pain (39.4%), a mental health condition (63.6%), and issues with sexual health (4.8%). Of the 156 sexual health responses, 37.7% (n=59) and 20.5% (n=32) reported kratom having a positive and negative impact on their sexual health, respectively. Kratom use lead to increased time to ejaculation in 104 (66.6%) patients which was perceived as positive by 62 (59.6%). A subset of patients (n=78) answered questions about premature ejaculation prior to and after 4 weeks of kratom use. The mean pre and post kratom premature ejaculation diagnostic tool (PEDT) scores were 13.0 +/− 0.6 and 8.3 +/− 0.4 respectively (p < 0.001). Ejaculation prior to 5 minutes was improved after kratom use (n=40; 51.3% vs. n=10; 12.8%) (p < 0.0001). Post kratom use, more patients reported lack of frustration with ejaculation prior to desire (n=17; 21.8 % vs. n=48; 61.5%) (p < 0.001). Kratom users were unlikely to report concerns regarding fertility (n=1, 6.1%), testosterone levels (n=25, 15.2%), libido (n=38, 23.0%), or erectile dysfunction (ED) (n=30, 18.2%). The mean International Index of Erectile Function score was decreased with kratom use (26.6 +/− 0.6 vs. 25.9 +/− 0.5) (p < 0.05). Users rarely stopped kratom due to concerns regarding delayed ejaculation (n=5, 10%), low libido (n=8, 7.5 %), or ED (n=6, 7.9%). Conclusions Kratom users report delayed ejaculation, overall benefits to their sexual health, and a statistically significant impact on erectile function with kratom use. Clinicians treating male sexual health should be aware of kratom and its potential effect on ejaculatory and erectile function. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific.

Introduction Buried penis repairs are complex cases often requiring collaboration between urology and plastic surgery. These surgeries are often extensive, can require split thickness skin grafting (STSG) of the penile shaft, negative pressure wound vac, and have high incidence of wound complications. There are no studies that evaluate perioperative pain in patients undergoing buried penis repair. Objective In the ongoing opioid epidemic, we aim to evaluate patient risk factors and peri-operative elements that can minimize opioid use in buried penis repair. Methods A retrospective chart review of patients who underwent buried penis repair from 7/2012 to 7/2021 was performed. Patient demographics, comorbidities and perioperative data were collected, including history of chronic pain, indications, intraoperative findings, perioperative pain control, and 30-day post-operative encounters. The state’s prescription monitoring program was used to verify use of prescription pain medications prior to surgery, at discharge, and refills, collected as Morphine Equivalent Dose (MED). Results A total of 63 patients were included in analysis. Mean age was 55.9 ± 14.4 with a mean pre-op BMI of 41.99 ± 9.17. 75% required a STSG on the penile shaft. The median discharge MED (dMED) was 150, ranging from 0 to 450 MED. 36.5% required opioid refills within 30 days of surgery. This cohort was further separated into two groups: patients who were discharged with < 150 MED (A) vs ≥ 150 MED (B), based on the median dMED. Three patients were excluded: two were on home opioids, one discharged on benzodiazepines. There were no differences in age, pre-op BMI, medical comorbidities (CAD, PVD, HTN, DM, psychiatric history) or history of chronic pain between the cohorts. Surgery for improvement of hygiene was more likely to have higher dMED, 40.7% (A) vs 69.7% (B), p=0.017. Other surgical indications (sexual health, voiding) showed no difference. Prior surgeries (urethral procedures, circumcision) were statistically more likely to require higher dMED, 48.1% (A) vs 72.7% (B), p=0.033. If a penile skin graft was required, there was no difference in graft size and dMED. Twenty-six patients had a hospital managed wound vac, while 19 patients had home wound vacs, but there was no difference in dMED. Although there was no standardized hospital pain regimen, patients on scheduled acetaminophen were more likely to have a lower dMED, 70.3%(A) vs 42.4% (B), p=0.021. 40.7% (A) vs 36.4% (B) of patients required opioid refills within 30 days of surgery, showing no statistical significance. Conclusions For patients who are embarking on buried penis repair, providers can pre-operatively set pain control expectations, especially for those who require repair for hygiene purposes or have had prior urologic reconstructive surgery. In the perioperative setting, this data supports the use of non-opioids, specifically scheduled acetaminophen, to minimize opioid prescribing at discharge. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific

Background The effectiveness of biologics for improving long-term outcomes in patients with Crohn’s disease [CD] is still controversial. In this nationwide study, we aimed to evaluate trends of long-term outcomes in all CD patients in Israel during the biologics era. Methods Trends of outcomes were analysed using data from the four Israeli health maintenance organisations, covering 98% of the population; joinpoint regression models were used to explore changes of these trends over 2005 to 2019. Results A total of 16 936 patients were diagnosed with CD in Israel since 2005 (2932 [17%] paediatric onset, 14 004 [83%] adult onset) with 114 947 person-years of follow-up. The cumulative rate of any CD related surgery was 5%, 9%, 11%, and 14% at 1, 3, 5, and 10 years from diagnosis. The increase in use of biologics was sharp (from 8.9% to 36%; average annual percent change [AAPC], 14.3%), and the time to biologics was shorter in recent years (median time of 4.8 [1.9–8.1] years in those diagnosed in 2005–2008 compared with 0.5 [0.2–1.1] years in those diagnosed in 2015–2018; p Conclusions The rates of hospitalisations, steroid dependency, and intestinal resections decreased in association with increased use of biologics both in children and in adults, but not the rate of perianal surgeries.

Background In this nationwide study, we aimed to explore health services utilization, medical management, and disease outcomes of inflammatory bowel diseases (IBD) between Jews and Arabs, the two major ethnic groups in Israel. Methods We utilized a cohort including all patients diagnosed with IBD in Israel since 2005. The primary outcome was steroid-dependency, with secondary outcomes including use of biologics, time to surgery, and IBD-related admissions. Outcomes were controlled for possible inherent differences in disease course and phenotype. Results Of the 32,491 included patients, 18,252 (56%) had Crohn’s disease (CD) and 14,239 (44%) had ulcerative colitis (UC); 10% were Arabs and 90% were Jews. Jewish ethnicity was associated with lower rates of steroid-dependency compared to Arab ethnicity in both CD )HR=0.7 [95%CI 0.6-0.8]) and UC (HR=0.7 [95%CI 0.6-0.8]). In addition, Jewish ethnicity was associated with increased use of biologics during the first year from diagnosis in patients with CD (HR=1.3 [95%CI 1.1-1.6]) but not with UC. The risk of IBD-related surgery in CD at 3 and 5 years was higher in the Arab group at all time points (13% vs 10%, 16% vs 14%, respectively, p=0.005). Arabs had higher number of IBD-related hospitalizations than Jews (19% vs. 28% with two or more IBD-related hospitalizations at 5 years, p Conclusion Arab ethnicity is associated with higher rate of hospitalizations, steroid-dependency and surgeries on one hand, and lower utilization of biologics on the other. The results should be considered by policy makers to improve access to medical care across all populations.

Background There is uncertainty about the ability to predict disease course in UC, often since prediction studies are small and include selected population. We aimed to use a large nationwide cohort to explore predictors of disease course in UC. Methods Data of patients diagnosed with UC in the epi-IIRN cohort 2005-2020 were retrieved from the four Israeli Health-Maintenance-Organizations covering 98% of the population. The following potential predictors were explored: demographic data, laboratory results, induction medications, and extra-intestinal manifestations. The primary outcome was complicated disease course defined as colectomy, steroid-dependency, or need for more than one biologic class. Hierarchical clustering categorized disease severity at diagnosis based on available laboratory results into four groups of disease severity (mild, moderate, severe, and extreme). Results A total of 15,111 UC patients with 114,208 person-years of follow-up were included, of whom 2,213 (14%) had complicated disease course. The latter was predicted in a Cox multivariable regression model by induction therapy with biologics (HR 3.84 [2.4-6.12]) and severity of laboratory tests prior to diagnosis (HR 1.41 [1.03-1.92]). The use of topical treatment (5-ASA or steroids enema/suppository) as monotherapy was protective with a decreased risk of complicated disease course (compared with untreated, HR 0.5 [0.38-0.63). Younger age of diagnosis (HR of pediatric-onset compared to adult-onset 1.79 [1.48-2.15]) and recent year of diagnosis (HR 1.03 [1-1.04]) were also associated with complicated outcome. Jews had 23% reduced risk of complicated disease course compared with Arabs (HR 0.77 [0.60-0.97]) (Figure 1). Specifically in the laboratory tests, there was a gradual increase in complicated disease amongst the disease severity clusters (p Conclusion In this nationwide cohort, complicated disease course was apparent in 14% of patients and predicted by serum laboratory tests and induction therapy with biologics. Jewish ethnicity and topic therapy (reflecting proctitis) were associated with better outcomes.

Background Recent studies such as the GEM project have identified microbial, serological and metabolomic markers that may help predict inflammatory bowel disease (IBD) well in advance of diagnosis, with the ultimate goal of pre-disease prevention. In this population-based study, we used the epi-Israeli IBD Research Nucleus (IIRN) validated cohort to explore the utility of routine blood tests as markers for pre-diagnostic IBD prediction. Methods We included all blood tests from all IBD patients diagnosed from 2005-2020 insured in three of the four Israeli health maintenance organizations (HMOs), and individually matched each to two non-IBD controls. Test results were collected and collated by number of months pre-diagnosis, then reported over time until diagnosis. Means were compared using Welch's t-test with false discovery rate correction to account for multiple comparisons. Trends over time were analyzed to detect tests that showed divergence between cases and controls at least one year before diagnosis. Results Pre-diagnosis results from 142 different blood tests were collected for 7,630 Crohn’s disease (CD) patients and 6,026 ulcerative colitis (UC) patients (mean age 33.3±17.4 years for CD and 38 ± 17.9 years for UC). Median duration of pre-diagnosis data collection was 50 (IQR 11-96) months for CD and 48 (IQR11-96) months for UC. Of the 142 tests, 24 (17%) showed significant differences between CD and controls at least one year pre-diagnosis (Figure 1); these included not only inflammation-related tests such as ESR, hemoglobin and albumin, but also seemingly unrelated tests such as bilirubin, cholesterol and creatinine. In UC patients, no tests showed statistically significant differences at least one year pre-diagnosis. Conclusion We were able to detect changes in blood tests collected as part of routine care long before CD diagnosis, opening the possibility of detecting early signals of future CD in patients undergoing routine blood tests. These may be used for developing screening and prediction models for prevention strategies. This research was partially supported by the Israeli Council for Higher Education (CHE) via the Data Science Research Center, Ben-Gurion University of the Negev, Israel. The epi-IIRN project has been funded by an educational grant from the Leona M. and Harry B. Helmsley Charitable Trust.

Background Studies have reported conflicting findings regarding the effect of timing of biologics initiation on disease course, often affected by selection and referral biases. In this nationwide cohort study we aimed to explore whether early initiation of biologics is associated with better disease outcomes in CD and UC. Methods Data of patients diagnosed with IBD in the epi-IIRN cohort from 2005 to 2020 were retrieved from 4 Israeli Health-Maintenance-Organizations covering 98% of the population.The primary analysis was time to steroid-dependency and IBD-related surgery. To control for confounding by indication in which the severity of disease could account both for the timing of biologics and risk of disease outcomes,we compared treatment strategies using the cloning,censoring and weighting method to emulate a target trial. Inverse probability of treatment weights were fitted per patient to adjust by weighting for time varying confounding and selection bias.Survival probabilities(POS) were estimated and compared at 10 years post diagnosis for each strategy through weighted non-parametric Kaplan-Meier estimators. The 95%CIs for survival probabilities were calculated using non-parametric bootstrap with 500 replicates. Results Of the 34,375 patients diagnosed with IBD, 7,452(39%) CD patients and 2,235(15%) UC patients received biologics and included in the analysis. In total,1,139 CD and 206 UC patients received biologics during the first three months after diagnosis,2,108 CD and 450 UC during the 3-12 month period,1,161 CD and 396 UC during 1-2 year period,and 719 CD and 271 UC during 2-3 years post diagnosis. Patients who initiated biologics after 3 years post diagnosis were excluded as they were not considered early biologics initiation.In CD,at 10 years post diagnosis there was a significant but modest decrease in IBD-related surgeries when initiating biologics prior to 3 months compared to the other periods (POS:0-3 months 0.75[CI 0.71- 0.79] vs 2-3 year 0.7[CI 0.66-0.73] ;p Conclusion Our study showed a slight advantage to earlier initiation of biologics,as reflected by longer time to IBD-related surgery and steroid-dependency in CD.In UC, the effect of early biologics was minor and was only apparent for steroid dependency in UC.

Background Studies have shown that exclusive enteral nutrition (EEN) treatment is as effective to corticosteroids (CS) for induction of remission in pediatric Crohn's disease (CD) with fewer side effects, but long-term outcome data are scarce. In this nationwide study we aimed to compare the risk of complicated disease course (CDC) after 2 years of follow-up in children with CD receiving EEN or CS as induction therapy. Methods Data of children diagnosed with CD in the epi-IIRN cohort between 2005-2020 were retrieved from the 4 Israeli Health-Maintenance-Organizations covering 98% of the population. The primary outcome was CDC defined as CD-related surgery, steroid-dependency, or need for more than one biologic class during 2 years post-diagnosis. Secondary outcomes included hospitalizations, and the use of biologics (any). Additionally, anthropometrics, labs reflecting nutrition (i.e., Alb and HGB), and growth were assessed at repeated visits until 2 years thereafter. To account for confounding by indication bias, we compared children with similar baseline characteristics based on Propensity Score (PS) individual matching. Time to CDC outcome was evaluated using Kaplan-Meier survival curves and compared by the log-rank test. A Cox proportional hazard model was sought to assess the relationship between the type of induction and time to CDC outcome. Results A total of 785 children with CD were induced after diagnosis with either EEN (n=410) or CS (n=375); mean age 13.3±3.5 years, 59% males. PS successfully matched 116 pairs of whom 85 (36%) had CDC. The survival probability of CDC at 6, 12,18, and 24 months was higher in the CS group compared to the EEN group at all time points (5%vs4%, 12% vs 10%, 22% vs 3%, and 27% vs.16%, respectively p=0.045; fig. 1). In a Cox multivariable model adjusted by year of diagnosis, CS induction treatment was similarly associated with higher hazard of CDC by 2 years (HR 1.8 [95%CI 1.01-3.25]). The survival probability of hospitalization was also higher in the CS group at 6,12,8, and 24 months (16% vs 9%, 20% vs 12%, 25% vs 14%, and 27% vs. 15%, respectively, p=0.024; fig.2). There was no difference in time to biologics (p=0.96, n=59 (51%) in EEN, n=57 (49%) in CS) and anthropometric data (Table 1). Significant improvements were observed in HGB and Alb levels for the EEN group during the first 3 months from diagnosis compared with the CS (p=0.046 and p=0.035 respectively) (table 1). Conclusion EEN as induction therapy in pediatric CD is associated with a lower long-term risk of complicated disease course and larger improvement in HGB and Alb but not in growth parameters compared with CS, even when adjusting to baseline disease severity and patients characteristics.

Background The population of elderly-onset (diagnosis >=65 years old) inflammatory bowel disease (IBD) is growing worldwide. Management of this population poses challenges, given the overall increased morbidity at the elderly age. Data related to complications in this population are limited. We performed a population-based study of elderly IBD patients to characterize complications compared with non -IBD matched individuals. Methods As part of the validated epidemiological cohort of the Israeli IBD Research Nucleus (epi-IIRN), we included all elderly-onset IBD patients (age at diagnosis >65 years) from the four Israeli health funds diagnosed from 1.1.2005 until 30.06.2020, covering 98% of the Israeli population. Each IBD case was matched at diagnosis to 3 non-IBD individuals by year of birth, sex, geographic district, and health fund. Comparison of incidence of pneumonia, osteoporotic fractures, bacteremia/septicemia and venous thromboembolism events were made. Time to complication was compared using the Kaplan-Meier survival analysis, stratified by IBD subtype, sex and any exposure of >3 months to immunosuppressive IBD medications. Cox proportional hazard models were sought to explore complications risk adjusted by comorbidities (chronic obstructive pulmonary disease, ischemic heart disease and other diseases). Results A total of 2,163 elderly-onset IBD patients were identified (46% males; 48% with Crohn’s disease, median (IQR) age at inclusion 71 [68, 76] years, exposure to >3 months of systemic CS 25%, thiopurines 10%, methotrexate 3.3%, anti-TNF 10.2%, Vedolizumab 5.7%, Ustekinumab 1.7%) and compared to 6,489 matched non-IBD controls. Median (IQR) follow-up time was 74 (40, 118) months. Incidence rates of pneumonia, fractures, bacteremia and venous thromboembolism are shown in table 1. On univariate analysis event-free survival analyses were similar in IBD and controls in pneumonia (p=0.72), osteoporotic fractures (p=0.79), bacteremia (p=0.085) and venous thromboembolism (p=0.14) Figure 1. Survival analysis remained similar when stratified by sex, IBD subtype and drug exposure. Using the comorbidity adjusted Cox model, the overall HR of pneumonia was 1.04 (95% CI 0.835-1.294), for osteoporotic fractures was 1.026 (95% CI 0.815-1.293); of bacteremia 2.161 (95% CI 0.865-5.397) and of venous thromboembolism 0.579 (95% CI 0.272-1.23). Conclusion In this population-based nation-wide study elderly onset IBD was not associated with increased risk of pneumonia, bacteremia, venous thromboembolism, and osteoporotic fractures compared with matched non-IBD elderly individuals. Studies in other populations are still needed to assess complications risk in diverse populations.

Background 5-aminosalicylates (5-ASA) are widely used in Crohn's disease (CD) despite guidelines advising otherwise. In this nationwide study, we aimed to assess the outcomes of first-line 5-ASA-maintenance therapy (5-ASA-MT) compared with no-maintenance treatment (no-MT) in patients with newly diagnosed CD. Methods We utilized data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel between 2005-2020. Outcomes included therapeutic failure, hospitalization, surgeries, steroid dependency, escalation to biologics, and 5-ASA-related adverse events. Propensity-score (PS) matching was utilized to compare outcomes in the 5-ASA-MT vs. no-MT groups. Results Of the 19,264 patients diagnosed with CD, 3,027 (16%) received first-line 5-ASA-MT and 5,583 (29%) received no-MT. Both strategies declined over the years; 5-ASA-MT from 21% in 2005 to 11% in 2019 (p Conclusion First-line 5-ASA-monotherapy was not superior to no-MT but associated with a slightly higher rate of adverse events, while both strategies have declined over the years. These findings suggest that a subset of patients with mild CD may be offered a watchful waiting approach.

Background Identifying prognostic factors of therapeutic failure, may facilitate balancing the risks and benefits of biologic treatment. In this population-based study, we aimed to explore predictors of therapeutic failure of biologics in Ulcerative Colitis (UC). Methods We retrieved data from two of four Health Maintenance Organizations in Israel, covering 38% of the population and part of the validated epi-IIRN IBD cohort. We included an inception cohort of UC patients, diagnosed since 2005, who were commenced on biologics. Those who underwent colectomy within 90 days from diagnosis were excluded. The primary outcome was therapeutic failure (i.e. discontinuation of treatment or need for colectomy or >1 short steroid courses). The secondary outcome was primary non-response (PNR; i.e. therapeutic failure within 4 months of initiation). Predictors were sought through Cox proportional hazard model. Results A total of 910 patients were included (246 [27%] pediatric-onset, 664 [73%] adults) with a median follow-up of 7.9 years (IQR 4.9–12.0). The probability of PNR was 16% and of therapeutic failure 35%, 55% and 63% after one, three and five years after commencing biologics, respectively. Older age at diagnosis (HR 1.01 [95%CI 1.005–1.01]), number of flares prior to initiation of biologics (HR 1.1 [95%CI 1.05–1.2]) and steroid use prior to biologics (HR 1.3 [95%CI 1.1–1.6]) were associated with therapeutic failure. PNR was associated with use of steroids prior to initiation of biologics (HR 2.1 [95%CI 1.4–3.3]). Laboratory blood work, including CRP, ESR, albumin, leukocytes, hemoglobin and platelets did not predict therapeutic failure, whether at diagnosis (HR 1.1 [95%CI 0.6–2.0]) or at initiation of biologics (HR 1.2 [95%CI 0.7–2.1]). Conclusion One third of UC patients failed to response to biologic treatment within one year. Older age at diagnosis and disease severity prior to biologic treatment, reflected by number of flares and steroid use, predicted therapeutic failure.

Background To clarify the risk of lymphoma in patients with inflammatory bowel diseases (IBD) exposed to anti-tumor necrosis factor (anti-TNF) and/or thiopurines we aimed to evaluate the Israeli IBD population. Methods A nested case-control study on the epidemiology cohort of the Israeli IBD Research Nucleus (epi-IIRN) including all 4 Health Maintenance Organizations in Israel linked to the Israeli Cancer Registry. Patients diagnosed since 1.1.2005 until 31.12.2015 (42,954 patients) were included and followed until 31.12.2017. Each lymphoma case was matched to 30 non-lymphoma IBD patients by age, gender, IBD subtype, and date of earliest evidence of IBD in the database. Patients with other risk factors for lymphoma, or lymphoma diagnosis prior to IBD diagnosis were excluded (figure 1). Conditional logistic regression was used to compute the association of drug exposure (anti-TNF, thiopurines and combination) with diagnosis of lymphoma. Patients without exposure to anti-TNF and/or thiopurines in each group served as reference within each group. Additionally, sub-group analyses by gender, age group at inclusion (≤48, 49–64, ≥65), time from last drug exposure (≤90 days, 91–365 days, >365 days) were done. Results The final nested cohort included 5556 IBD patients (185 lymphoma cases matched to 5,371 without lymphoma). Mean follow-up (F/U): 5.5±3.5 years, 50% with Crohn’s disease, mean age at database entry 52.6±17.80 years. Anti-TNF-only exposure was documented in 4.3% (8/185) of lymphoma cases vs. 2.6% (145/5,371) of controls OR 1.97, CI 0.93–4.16, p=0.07; in males the ORs were 2.84 (CI 1.17–6.92 p=0.04) and increased to OR 3.48 (CI 1.55–7.88, p=0.002) for males Conclusion This nationwide study suggests that exposure to anti-TNF therapy alone or in combination with thiopurines may be associated with an increased risk of lymphoma, but only in males, especially when last exposure occurred within 90 days.

Background While short-term safety data of COVID-19 vaccination has been reassuring, it is theoretically possible that the vaccine-associated immune activation could trigger immune dysregulation and thus exacerbation of IBD. We used the epi-Israeli IBD Research Nucleus (IIRN) database to perform a population-based study exploring the effect of COVID-19 vaccination on disease course in IBD patients. Methods We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched to unvaccinated IBD patients by demographics, parameters of disease severity at baseline generated by hierarchical clustering of laboratory data, and length of time from previous exacerbation to baseline. The primary outcome was rate of IBD exacerbation as defined by proxies of hospitalizations, treatment escalation, and commencement of corticosteroid or enema. The study period was December, 2020 to June, 2021 Results 707 pairs of vaccinated and unvaccinated IBD patients were compared. The pairs matched exactly for gender, district, IBD type and disease severity, and ±1 year for age at IBD diagnosis and at vaccination. Mean age was 38.5±13.5 years and median follow-up was 98 days (IQR 16–143). No difference in the outcome was found between the groups from the 2nd vaccination to the end of follow-up, with risk of exacerbation in vaccinated patients of 29% and risk in unvaccinated patients 26% (p=0.3). Conclusion COVID-19 vaccinated IBD patients demonstrated a rate of IBD exacerbation following vaccination that was no different from that of unvaccinated patients. The multifaceted immune activation induced by the vaccine did not result in worsening IBD disease course. These results provide further reassurance for IBD patients receiving the vaccine.

Background Some studies have shown decreased serological response to vaccination in patients on anti-tumor necrosis factor (TNF) medications. While the large majority of these patients do seroconvert after vaccination, titers have generally been lower and one study showed reduced neutralizing and inhibitory functions. One real-world population-based study compared found no increased infection rate in anti-TNF treated patients, but infection rates were low. The low event rate mandates exploration in longer-term population-based data. We used the epi-Israeli IBD Research Nucleus (IIRN) database to explore the effectiveness of COVID-19 vaccination in IBD patients in Israel. Methods We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched by date of vaccination ±3 days and demographic variables to non-IBD controls. The primary outcome was incidence of positive COVID-19 PCR following vaccination between December, 2020 to June, 2021. Results 12,640 IBD patients received two vaccine doses; the matched cohort included 4,946 matched pairs (total 9,892 subjects). Mean age was 50.5±16.1 years and median follow-up was 22 weeks (range 4.1–24.4). Fifteen (0.3%) vaccinated IBD patients tested positive compared with 15 (0.3%) vaccinated non-IBD controls (OR=1 [95%CI 0.49–2.05], p=1.0). Patients on anti-TNF and/or corticosteroids did not have a higher incidence of positivity – neither compared to the entire group nor to IBD patients treated with vedolizumab/ustekinumab, even after precise matching for demographics, underlying diseases and IBD severity. Conclusion In a large population-based cohort of IBD patients in Israel, vaccine effectiveness was equivalent to non-IBD controls and was not influenced by treatment with anti-TNF or corticosteroids. Notwithstanding previous findings of impaired serological response in anti-TNF treated IBD patients, this real-world large-scale study shows that vaccine protection is robust in IBD patients, including those on immunosuppressive medications.

OBJECTIVES The impact of pediatric-onset inflammatory bowel disease (IBD) on growth is debated. We aimed to investigate the effect of IBD on anthropometric measures at young adulthood. METHODS Children diagnosed with Crohn disease (CD) or ulcerative colitis (UC) (2005-2019) were identified in a national database along with matched non-IBD controls. RESULTS Overall, 2229 IBD cases (68% CD) were matched to 4338 controls. Only females with CD differed in final height from controls (z scores: -0.37 ± 1.09 vs -0.25 ± 1.06, respectively; P = 0.01), corresponding to a mean difference of 0.7 ± 0.2 cm (all females) and 1.2 ± 0.3 cm in females diagnosed

Background Paediatric onset IBD [PIBD] is characterised by a more extensive phenotype than adult-onset IBD and a higher utilisation of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. Methods PIBD patients [ Results In all, 3944 PIBD cases were included (2642 [67%] Crohn’s disease, 1302 [33%] ulcerative colitis) translating into 23 635 person-years of follow-up, individually matched to 13 005 non-IBD children. By 30 years of age, 14 IBD patients [0.35%, 5.9/10 000 patient-years] were diagnosed with cancer and one [0.03%] with haemophagocytic-lymphohistiocytosis [HLH], compared with 14 [0.11%, 1.9/10 000 patient-years] cases of cancer {relative risk (RR) 2.5 (95% confidence interval [CI] 1.05-6.2); p = 0.04} and no HLH in the comparison-group. There were no cases of hepatosplenic T cell lymphoma, adenocarcinoma, or cholangiocarcinoma. Cancer risk was 15.6 cases/10 000 person-years in those treated with thiopurines alone (RR compared with IBD patients never exposed to either thiopurines or anti-tumuor necrosis factor [TNF] 1.8 [95% CI 0.6-6.1]; p = 0.2), 11.1/10 000 in those treated with anti-TNF alone (RR 1.3 [95% CI 0.3-6.6]; p = 0.5), and 23.1/10 000 treated with combination therapy of anti-TNF and thiopurines (RR 2.8 [95% CI 0.6-13.8]; p = 0.2). Conclusions PIBD confers an increased risk for malignancy compared with non-IBD in children. However, the absolute risk is very low and no differences in risk with specific therapies were apparent in our data.

Background: Pediatric-onset IBD (PIBD) is characterized by a more extensive phenotype than adults and a higher utilization of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. Methods: PIBD cases were included from the epi-IIRN cohort , covering 98% of the Israeli population from 2005, linked to the national cancer registry. We matched PIBD cases to non-IBD children for calculating the cumulative incidence of cancer. Finding: 3,944 PIBD cases were included (2,642 [67%] Crohn's disease, 1,302 [33%] ulcerative colitis) translating into 23,635 person-years of follow-up , individually matched to 13,005 non-IBD children. By 30 years of age, 14 IBD patients (0.35%, 5.9/10,000 patient-years) were diagnosed with cancer and one (0.03%) with haemophagocytic-lymphohistiocytosis (HLH), compared with 14 (0.11%, 1.9/10,000 patient-years) cases of cancer (OR 2.5 [95%CI 1.05-6.2]; p=0.04) and no HLH in the comparison-group. There were no cases of hepatosplenic T-cell lymphoma, adenocarcinoma or cholangiocarcinoma. Cancer risk was 15.6 cases/10,000 person-years in those treated with thiopurines alone (OR compared with those never exposed to either thiopurines or anti-tumor necrosis factor (TNF) 1.8 (95%CI 0.6-6.1); p=0.2), 11.1/10,000 in those treated with anti-TNF alone (OR 1.3 [95%CI 0.3-6.6]; p=0.5), and 23.1/10,000 treated with combination therapy of anti-TNF and thiopurines (OR 2.8 [95%CI 0.6-13.8]; p=0.2). Interpretation: PIBD confers an increased risk for malignancy compared with non-IBD children. The risk was not statistically associated with treatment, likely since the absolute risk was very low. Funding Statement: None to declare. Declaration of Interests: ID- Has received consultation fee, research grant or honorarium from Janssen, Pfizer, Abbvie, Takeda, Genentech/Roche, Neopharm, Ferring, Rafa Laboratories, Falk Pharma, Nestle, Given Imaging/Medtronic, Gilead, Celgene, Arena, Sublimity, Celltrion Altman Research; DT - Has received consultation fee, research grant, royalties, or honorarium from Janssen, Pfizer, Hospital for Sick Children, Ferring, Abbvie, Takeda, Biogen, Neopharm, Uniliver, Atlantic Health, Shire, Celgene, Lilly, Roche; all other authors have nothing to declare. Ethics Approval Statement: This study was approved by the local ethics committee.

Background There are currently no nationwide data on the epidemiology of inflammatory bowel diseases (IBD) in Israel. We aimed to determine the population-based epidemiological trends of IBD in the diverse Israeli population. Methods Health-administrative data were retrieved from all 4 Israeli health maintenance organizations, insuring 98% of the population, using validated identification algorithms. National trends were determined using Joinpoint regression analysis calculating annual percent change and average annual percent change (AAPC). Results By 2019, there were 46,074 patients with IBD in Israel, corresponding to a national prevalence of 519/100,000 (0.52%), of whom 54.1% had Crohn disease (CD) and 45.9% had ulcerative colitis (UC). The number of Jewish patients doubled from 18,701 in 2005 (354/100,000) to 38,950 (589/100,000) in 2018 (AAPC, +4.0%; P < 0.05), and the number of Arab patients increased 3-fold from 1096 (102.1/100,000) to 3534 (240.7/100,000; AAPC, +6.8%; P < 0.05) during the same years. However, the increase rate has gradually decelerated over time (annual percent change during 2005-2008, 2009-2014, and 2005-2018 was +6.7%, +4.2%, and +2.3%, respectively; P < 0.05). Pediatric prevalence increased from 37.4 to 52.2/100,000, with CD predominating in both Jews and Arabs. The incidence of CD remained stable (from 15.9/100,000 to 14.9/100,000) and the incidence of UC decreased (15.4/100,000 to 10.5/100,000 (AAPC, –3.2%; P < 0.001)). In contrast, pediatric incidence of CD increased from 7.3/100,000 to 8.3/100,000 (AAPC, +1.9%; P < 0.05) and that of UC increased from 2.6 to 4.4/100,000 (AAPC, +5.8%; P < 0.05). Conclusions The IBD prevalence rate in Israel is still increasing but gradually decelerating, probably due to the decreasing overall IBD incidence. Nonetheless, incidence rate in children is still increasing. Ongoing narrowing in the rates between Jews and Arabs over time may indicate shared environmental factors.

Objectives To assess time trends in colorectal cancer screening uptake, time-to-colonoscopy completion following a positive fecal occult blood test and associated patient factors, and the extent and predictors of longitudinal screening adherence in Israel. Setting Nation-wide population-based study using data collected from four health maintenance organizations for the Quality Indicators in Community Healthcare Program. Methods Screening uptake for the eligible population (aged 50–74) was recorded 2003–2018 using aggregate data. For a subcohort (2008–2012, N = 1,342,617), time-to-colonoscopy following a positive fecal occult blood test and longitudinal adherence to screening guidelines were measured using individual-level data, and associated factors assessed in multivariate models. Results The annual proportion screened rose for both sexes from 11 to 65%, increasing five-fold for age group 60–74 and >six-fold for 50–59 year olds, respectively. From 2008 to 2012, 67,314 adults had a positive fecal occult blood test, of whom 71% eventually performed a colonoscopy after a median interval of 122 (95% confidence interval 110.2–113.7) days. Factors associated with time-to-colonoscopy included age, socioeconomic status, and comorbidities. Only 25.5% of the population demonstrated full longitudinal screening adherence, mainly attributable to colonoscopy in the past 10 years rather than annual fecal occult blood test performance (83% versus 17%, respectively). Smoking, diabetes, lower socioeconomic status, cardiovascular disease, and hypertension were associated with decreased adherence. Performance of other cancer screening tests and frequent primary care visits were strongly associated with adherence. Conclusions Despite substantial improvement in colorectal cancer screening uptake on a population level, individual-level data uncovered gaps in colonoscopy completion after a positive fecal occult blood test and in longitudinal adherence to screening, which should be addressed using focused interventions.

Mira Y Friedman,1,2 Maya Leventer-Roberts,3 Joseph Rosenblum,4 Nir Zigman,4 Iris Goren,4 Vered Mourad,4 Natan Lederman,5 Nurit Cohen,5 Eran Matz,6 Doron Z Dushnitzky,6 Nirit Borovsky,6 Moshe B Hoshen,3 Gili Focht,1 Malka Avitzour,1 Yael Shachar,1 Yehuda Chowers,7 Rami Eliakim,8 Shomron Ben-Horin,8 Shmuel Odes,9 Doron Schwartz,9 Iris Dotan,10 Eran Israeli,11 Zohar Levi,10 Eric I Benchimol,12–14 Ran D Balicer,3 Dan Turner1 On behalf of the Israeli IBD Research Nucleus (IIRN) 1The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; 2Braun School of Public and Community Medicine, The Hebrew University– Hadassah Medical Center, Jerusalem, Israel; 3Clalit Research Institute, Chief’s Office, Clalit Health Services, Tel Aviv, Israel; 4Maccabi Healthcare Services, Tel Aviv, Israel; 5Meuhedet Health Services, Tel Aviv, Israel; 6Leumit Health Services, Tel Aviv, Israel; 7Department of Gastroenterology, Rambam Health Care Campus, Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel; 8Department of Gastroenterology, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 9Department of Gastroenterology and Hepatology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel; 10Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel; 11Institute of Gastroenterology and Liver Diseases, Hadassah Medical Center, Hebrew University, Jerusalem, Israel; 12CHEO Inflammatory Bowel Disease Centre, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; 13Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada; 14Institute for Clinical Evaluative Sciences, Ottawa, ON, Canada Background: Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn’s disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. Methods: Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. Results: The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2–5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). Conclusion: The application of the validated algorithms to Israel’s administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies. Keywords: inflammatory bowel diseases, Crohn’s disease, ulcerative colitis, search algorithms, validation, case ascertainment, Israel, administrative database research

Background 25% of UC patients fail to respond to induction therapy with biologics. In this nationwide study we aimed to evaluate trends in biologics utilization and sustainability in UC during the last 15 years. Methods This study was performed on data from four the four Israeli Health Maintenance Organizations, covering 98% of the population. Sustainability was defined as continuous treatment without IBD-related surgeries and at most one short steroid course. Sustainability was compared across different biologics utilizing a propensity score (PS) weighted analysis, estimated by generalized boosted modeling (GBM). Results 13,231 patients were diagnosed with UC in Israel since 2005 (1,426 [11%] pediatric-onset,11,805 [89%] adult-onset), of whom 1,692 (13%) were ever treated with biologics (400 [24%] pediatric-onset, 1,292 adults [76%], OR 3.2 [95%CI 2.8–3.6]; p The sustainability rate in those treated with infliximab was 52% at one year from initiation of biologics, and 37% and 34% at three and five years, thereafter; compared to 55%, 43% and 40% with adalimumab and 72% and 67% after one and two years with vedolizumab. The primary non-response rate was 30% with infliximab, 31% with adalimumab and 16% with vedolizumab. Sustainability was associated with earlier initiation of biologics during the disease course (HR 0.9 [95%CI 0.85–0.95]). In the PS-adjusted model where vedolizumab served as the reference, the sustainability of both infliximab (HR 0.7 [95%CI 0.6–0.95]) and adalimumab (HR 0.8 [95%CI 0.6–0.99]) were lower. Compared with monotherapy, combination therapy increased the sustainability rate with both adalimumab (HR 0.3 [95%CI 0.2–0.6]) and infliximab (HR 0.4 [95%CI 0.-0.6]), but not with vedolizumab (HR 1.4 [95%CI 0.98–2.1]). Conclusion Biologics are being increasingly used in UC but only half of patients sustain treatment at one year. Treatment is commenced earlier during the disease course, and this is associated with improved sustainability. Sustainability rate is higher with vedolizumab, and in combination therapy of IMM and infliximab or adalimumab.

Background Total colectomy (TC) is often considered a curative procedure for patients with chronic refractory ulcerative colitis (UC) or acute severe colitis. Chronic pouchitis and de novo Crohn’s disease (CD) are well recognized sequelae following TC, yet the true incidence of these are poorly characterized in large population models. We assessed the rate of subsequent utilization of IBD medications as a proxy marker of clinically significant pouchitis or de novo CD following TC for UC. Methods This study utilized data from the Epi-IIRN project, a meta-database incorporating patient data from all four health maintenance organisations (HMO) in Israel, representing 98% of the population. We included all patients identified in the prevalence cohort with an initial diagnosis of UC who underwent TC from January 2000, with ≥ 6 month follow-up. Primary outcome was utilization of IBD medications (including thiopurines, methotrexate, infliximab, adalimumab, vedolizumab, ustekinumab and tofacitinib) following TC. Secondary outcomes were time to commencement of medications, hospitalizations and repeated surgery. Potential predictors of IBD medication use were identified using multivariable models. Results Overall 23,506 patients with UC were identified in the prevalence cohort of whom 456 patients underwent TC for UC and were included in our analysis. 51% of our sample were female, with a median follow up of 8.5 years (IQR 3.8–13.2) and 3956 patient-years. Median age at UC diagnosis was 44.1 (26.5–56.2) years and at TC was 50.2 (34.2–61.7). IBD medications were commenced in 88 (19%) of patients, including 54 (12%) biologics, 56 (12%) immunomodulators and 3 (1%) tofacitinib. A diagnosis of CD was formally assigned to 65 (75%) of these patients. The need for IBD medications was gradual (figure 1). Patients recommenced on IBD medications were younger at diagnosis (30.3 years (18.3–49.7) vs 41.4 (24.2–55.6), p Conclusion In this nationwide analysis we show that almost 20% of patients require ongoing IBD medications following TC for UC. Younger age is associated with higher rate of subsequent medication use. Patient expectations need be adjusted to account for the potential ongoing requirement of long-term medication following TC.

Background Therapy in IBD is recommended in order to treat or prevent complications. In this nationwide study we aimed to assess the incidence of patients with IBD who were not receiving maintenance treatment after diagnosis and the duration of non-treatment. Methods This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all patients with IBD diagnosed from 2005 to 2019. Non-treatment was defined as lack of drug prescription of maintenance medication for at least six months from diagnosis. Sustainability was defined as lack of maintenance medications and without IBD-related surgeries. Cox regression model was used to explore estimated predictors of sustainability. Results A total of 30,168 patients were diagnosed with IBD in Israel since 2005 (16,936 [56%] Crohn’s disease [CD] and 13,231 [44%] ulcerative colitis [UC]). A total of 5,448 (32%) patients with CD were untreated, compared to 5,158 (39%) with UC (OR 1.35 [95%CI 1.3–1.4]; p Conclusion Most patients with IBD eventually require maintenance therapy. Lack of maintenance treatment is more common in UC. Nevertheless, a third of patients with CD and one quarter with UC who had no medical treatment at six months from diagnosis remained untreated for five years, especially in older patients with CD and those who did not require induction therapy, suggesting milder disease.

Background Real-world studies demonstrate that ~33% of CD patients fail to respond to induction therapy with biologics. In this nationwide study we aimed to evaluate trends in biologics utilization and sustainability in CD during the last 15 years. Methods This study was performed on data from the four Israeli Health Maintenance Organizations, covering 98% of the population. Sustainability was defined as continuous treatment without IBD-related surgeries and at most one short steroid course. Sustainability was compared across different biologics utilizing a propensity score (PS) weighted analysis, estimated by generalized boosted modeling (GBM). Results 16,936 patients were diagnosed with CD in Israel since 2005 (2,932 [17%] pediatric-onset, 14,004 [83%] adult-onset), of whom 5,804 (34%) were ever treated with biologics (1,659 [57%] pediatric-onset, 4,145 adults [30%], OR 3.1 [95%CI 2.9–3.4]) with a median of 6.4 years follow up (IQR 3.4–9.9). Infliximab was the most common first-line treatment in children (58%, p Sustainability was associated with male sex (HR 0.9 [95%CI 0.8–0.95]) and earlier initiation of biologics (HR 0.92 [95%CI 0.9–0.95]). In the PS-adjusted model the sustainability of both infliximab (HR 0.7 [95%CI 0.6–0.8]) and vedolizumab (HR 0.8 [95%CI 0.7–0.95]) were lower than adalimumab. Compared with monotherapy, combination therapy did not change significantly the sustainability rate of all three biologics (adalimumab: HR 1.3 [95%CI 0.8–2.1], infliximab: HR 1.2 [95%CI 0.7–1.9], and vedolizumab: HR 0.8 [95%CI 0.5–1.3]). Conclusion Biologics are being increasingly used in CD and earlier during the disease course, but most patients do not sustain treatment at five years. Sustainability rate was higher with adalimumab compared with either infliximab or vedolizumab

Background Thiopurines have been long used to maintain remission in ulcerative colitis (UC) but are also associated with toxicity and therapeutic failure. We aimed to assess the sustainability rate of thiopurines commenced as monotherapy in UC, and to explore predictors of sustainability. Methods This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all biologic-naïve UC patients diagnosed after 2005 and treated with thiopurines monotherapy for at least three months. Treatment with 5- aminosalicylic acid (ASA) was allowed if initiated prior to or during the first three months from initiation of thiopurines. Sustainability was defined as continued thiopurines treatment without switching therapy, adding biologics or requiring surgery. At most one short steroid course was allowed. Cox regression model was used to explore estimated predictors to sustainability. Results A total of 1,897 (370 [20%] pediatric-onset and 1,527 [80%] adults) thiopurines-treated patients were included with a 15,033 person-years of follow-up. The median time from UC diagnosis to initiation of thiopurines was 12.7 months (IQR 4.6–30.9), and the median treatment duration was 13.0 months (6.3–28.4). Sustainability rate was evident in 92% of patients after 6 months from initiation of thiopurines and 83%, 65% and 42% at one, three and five years, thereafter. Sustainability was associated with early initiation of thiopurines during disease course (HR 0.99 [95%CI 0.985–0.995]) and lack of 5-ASA at initiation of thiopurines (HR 0.7 [95%CI 0.6–0.8]). Conclusion As many as two thirds of biologic-naïve UC patients treated with thiopurines monotherapy sustain this treatment after five years, especially when initiated early and without 5-ASA.

Background Immunomodulators (IMM), including thiopurines and methotrexate (MTX), have been long used to maintain remission in Crohn’s disease (CD), both associated with remission, but also with toxicity and therapeutic failure. We aim to compare the sustainability of thiopurines and MTX commenced as monotherapy in patients with CD, and to explore predictors of sustainability. Methods This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all biologic-naïve CD patients diagnosed after 2005 and treated with IMM monotherapy for at least three months. Sustainability was defined as continues IMM treatment without switching therapy, adding biologics or requiring surgery. In addition, at most one short steroid course was allowed. Cox regression model was used to explore estimated predictors to sustainability. To compare sustainability rate between thiopurines and MTX we used propensity score (PS) matching, and thereafter Cox regression model. Results A total of 4,891 (1,551 [32%] pediatric-onset and 3,340 [68%] adults) IMM-treated patients were included with 37,825 person-years of follow up, of whom 4,339 (89%) were treated with thiopurines and 552 (11%) with MTX. The median time from CD diagnosis to initiation of IMM was 6.1 months (IQR 1.7–19.7), and the median course duration was 11.9 months (6.1–25.3). Sustainability rate was recorded in 92% of patients after 6 months from initiation of IMM and 81%, 69% and 65% at one, three and five years, thereafter. The most common type of failure was escalation to biologics (67%), while 17% required repeated steroid courses and 15% underwent surgery. Sustainability was associated with earlier initiation of IMM during the disease course (HR 0.98 [95%CI 0.97–0.985]) and lack of steroids at initiation of IMM (HR 0.7 [95%CI 0.6–0.8]). A PS adjusted analysis that included 337 thiopurnes-treated patients individually matched with 337 MTX-treated patients, showed sustainability was significantly better with thiopurines (HR 0.7 [95%CI 0.5–0.8]). Conclusion Two thirds of biologic-naïve CD patients treated with IMM monotherapy sustain this treatment after five years, especially when initiated early during the disease course. Sustainability was more likely in those treated with thiopurines compared with MTX.

Background Despite ongoing improvements in Inflammatory Bowel Disease (IBD) therapeutics, timely access to quality medical care likely impacts patient outcomes. Physical distance from specialty care and socioeconomic status (SES) may impact quality of care. In a nationwide population study we aimed to assess the impact of patient location and SES on IBD outcomes. Methods This Epi-IIRN project utilized a meta-database incorporating patient data of all four health maintenance organisations (HMO) in Israel, representing 98% of the population. All patients identified on the incidence cohort were followed from diagnosis until end of 2018. Regions in Israel were defined as central (coastal plain and Jerusalem corridor), northern region and southern region. SES class were defined by postcode as per Israel bureau of statistics data from SES 1 (lowest) to SES 4 (highest). Primary outcome was steroid dependency, with secondary outcomes of biologic therapy use during first year of diagnosis, surgery, gastroenterology visits, hospitalizations and mortality. Analysis was performed separately for Crohn’s disease (CD) and ulcerative colitis (UC). Results A total of 30,167 IBD patients (16,936 (56%) CD and 13,231 (44%) UC) were included: 74% of patients were in central region, 12% southern region and 14% northern region. 21% were in SES class 1 and 12% in SES 4. In CD, lower SES was associated with higher steroid dependency (37% vs 30%, p=0.002), higher surgery rates (21% vs 12%, p In UC, lower SES was associated with lower frequency of gastrointestinal clinic visits (5.0 vs 8.5, p Conclusion In this nationwide analysis we show deleterious impact of both lower SES and peripheral residence on outcomes of CD and UC. Policy makers should consider these data to facilitate improved access to medical care and maximize IBD outcomes in a standardized way.

BACKGROUND AND AIMS There are conflicting data on the association between inflammatory bowel diseases [IBD] and autoimmunity disorders. The aim of this study was to explore this association including the effect of medications. METHODS We utilized health administrative data collected by three of the four health maintenance organizations [HMOs] in Israel, covering 52% of the country's population. We explored the prevalence of the following autoimmune disorders: insulin-dependent diabetes mellitus [IDDM], psoriasis, Sjogren syndrome, coeliac disease, systemic lupus erythematosus [SLE], primary sclerosis cholangitis [PSC] and autoimmune thyroiditis, among all IBD patients vs non-IBD controls. Case ascertainment was determined according to validated computerized algorithms. RESULTS In total, 12625 IBD patients were compared to 12625 controls. A total of 1395 [11.1%] IBD patients had at least one autoimmune disease compared with 740 [5.9%] of non-IBD controls (odds ratio [OR] = 1.99 [95% confidence interval 1.81-2.19]; p < 0.05); all autoimmune diseases, except for thyroiditis, were more prevalent among IBD patients. Adjusted for confounding variables, anti-tumour necrosis factor [anti-TNF] medications were associated with a higher prevalence of psoriasis (54 [5.7%] in IBD vs 177 [4.1%] in controls; OR = 1.50 [1.07-2.08]; p < 0.05) but lower prevalence of Sjogren (1 [0.1%] vs 39 [0.9%]; OR [95% CI] = 0.13 [0.02-0.94]; p < 0.05) and coeliac disease (11 [1.2%] vs 68 [1.6%]; OR [95% CI] = 0.51 [0.27-0.99]; p < 0.05). Thiopurines and 5-aminosalicylates were not associated with any autoimmune disorder. CONCLUSION IBD is associated with all autoimmune diseases explored here except for thyroiditis. Anti-TNF users have a higher prevalence of psoriasis, and lower prevalence of Sjogren and coeliac disease.

Background Up to 25% of patients with ulcerative colitis (UC) may undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Pouchitis may occur in 50–70% of patients, and ~30% may develop chronic pouchitis (CP) or Crohn’s-like disease of the pouch (CLDP). We aimed to identify predictors for the development of CP or CLDP during a long follow-up period. Methods Patients followed prospectively at the pouch clinic at Rabin Medical Center, were cross-referenced with data from the validated epiIIRN cohort which includes all IBD patients in Israel (n = 45 074). All patients had at least one year of follow-up since ileal continuity (i.e., ileostomy closure after pouch formation). CP was defined as an active flare of pouchitis for >4 weeks and being treated with antibiotics or anti-inflammatory therapy, or >4 episodes of acute pouchitis/year. CLDP was defined as having one or more of the following: pouch-related fistula (>1 year after ileostomy closure), inflammation of the afferent limb, or fibrostenotic disease of the pouch. For the analysis, the cohort was further categorised into favourable pouch outcomes (sustained normal pouch, acute pouchitis) vs. unfavourable pouch outcomes (CP, CLDP or pouch failure). Logistic regression included gender, age, previous therapies, disease duration before pouch surgery, surgical technique and number of previous non-IBD related abdominal operations. Results We included 182 patients (55% females; median age at IPAA: 32 years (IQR 23–45); median disease duration until pouch surgery 6 years (3–11); two-staged surgery 69%). The median follow up time was 14 years (IQR 7–22). Before surgery, 37% of patients had been exposed to immunomodulators (either thiopurines or methotrexate), 24% were exposed to anti-TNF therapy and 5% were previously treated with vedolizumab. An unfavourable pouch phenotype was noted in 48% of patients. On multivariate logistic regression, anti-TNF therapy and older age at pouch surgery were associated with decreased odds of an unfavourable pouch outcome (OR 0.3 95% CI 0.11–0.69, p = 0.007 and OR 0.96 95% CI 0.93–0.98, p = 0.005, respectively). Conclusion Therapy of UC with an anti-TNF and older age were associated with a favourable pouch outcome. These may be surrogates for patients with longer follow up as well as indication for IPAA. Such factors should be taken into consideration in clinical decision making.

Background Elevation in liver enzymes (ELE) is often seen in patients with inflammatory bowel disease (IBD). The aim of this study is to assess the incidence, character, chronicity, degree, and etiology of ELE in within the validated epiIIRN cohort which includes all IBD patients in Israel (n = 45,074). Methods We current analysis was performed on data from three of four Health Maintenance Organisations (HMOs), covering 48% of the Israeli population. The identification of Crohn’s disease (CD) and ulcerative colitis (UC) utilised previously validated algorithms. Retrieved data included demographics, anthropometric measures, liver enzymes, medications and other diagnoses codes. Mild ELE was defined from upper normal limit (UNL) to X2 UNL, moderate X3 UNL and severe elevation ≥X4 UNL). The pattern of elevation was defined as hepatocellular (isolated elevation of ALT and/or AST), cholestatic (elevated GGT and/or ALK and bilirubin) and mixed pattern. Chronicity of ELE was defined as brief (180 days). Results The total incidence (ever) of ELE in CD patients was 33% (3098/9421) and 28% in UC (2001/7040); p < 0.001. The mean age at ELE was 29.9 years (IQR 17.2–47.5) in CD and 37.9 years (23.2–53.8) in UC (p < 0.001). Hepatocellular pattern had more commonly in UC (54% vs. 47%, p < 0.001) as mixed pattern (22% vs. 20%, p = 0.01), while cholestatic pattern had more commonly in CD (31% vs. 26%, p < 0.001). The ELE was transient in 609 (9%) patients, while 4054 (62%) had chronic ELE. Mild ELE was recorded in 860 (22%) CD patients and 460 (19%) UC, and severe in 328 (8%) CD and 253 (10%) UC. ELE was recorded during the first three months after initiation of thiopurines in 604 (15%) CD and 201 (8%) UC patients (p < 0.001), after biologics in 346 (9%) CD and 62 (3%) UC (p < 0.001), after steroids in 538 (14%) and 272 (11%), respectively (p = 0.01) and after methotrexate in 76 (2%) and 15 (0.6%), respectively (p = 0.001). The incidence of fatty liver was most common in UC (5% vs. 3%, p = 0.006). Conclusion ELE is common complication in IBD patients, more so in UC. When enzymes do increase in CD they tend to reach higher levels. Drug induced liver injury was more common in CD. This study was supported by a grant from the Leona M. and Harry B. Helmsley Charitable Trust.

An increasing number of laboratory tests are available for diagnosis of gastrointestinal tract diseases in dogs and cats. Use of these tests can lead to more accurate and rapid diagnoses. This review discusses laboratory tests, both new and old, and the role they currently play in the evaluation of animals presented with gastrointestinal problems. A minimum database helps assess the severity of the disorder, detect extra-gastrointestinal causes of problems and assists in formulating diagnostic and therapeutic plans. Faecal examination remains one of the most important diagnostic procedures in the investigation of gastrointestinal problems. Zinc sulphate faecal flotation is an excellent routine screening technique for helminth and protozoal infections, including giardiasis. Rectal cytology can assist in the diagnosis of large bowel disorders. Interpretation of faecal immunodiagnostic tests is hampered by insufficient knowledge of test sensitivities and specificities. Routine faecal cultures are not warranted and faecal occult blood tests are rarely indicated. Serum tests for gastric inflammation are now under development. The serum trypsin-like immunoreactivity test remains the gold standard technique for the diagnosis of exocrine pancreatic insufficiency. Breath hydrogen tests can be helpful in assessing the functional relevance of mild abnormalities in small-bowel biopsy specimens. Subnormal concentrations of serum cobalamin appear to be more specific indicators of gastrointestinal disease in cats than in dogs. Tests for small intestinal bacterial overgrowth remain controversial and assessment of gastrointestinal permeability has yet to prove its value in the diagnostic assessment of companion animals with gastrointestinal problems. Faecal alpha1-protease inhibitor shows promise for the diagnosis of protein-losing enteropathy.

In electron-beam solid freeform fabrication (EBSFF), material in wire form is fed into a melt pool maintained on the surface of the part by the electron beam, and controlled rapid movement of the part deposits metal selectively in a layer-by-layer fashion. Solidification occurs at a high rate, forming a fine dispersion of primary carbides in Alloy 718. Growth of the carbide particles has been modeled, assuming diffusion control and a linear change in the driving force for precipitation with temperature. The model predicts the maximum carbide size as a function of EBSFF operating parameters and alloy composition. For the material and conditions used experimentally in this work, the model predicts a maximum diameter of approximately 1.0 µm. Extraction-replica transmission electron microscopy of EBSFF samples identified carbides in the 300 to 600 nm range, consistent with a population having the predicted maximum size. Control material from a conventional vacuum-arc remelted ingot was also examined, and platelike carbides up to 40 µm in length were noted. This is an indication of the potential of EBSFF to refine the carbide morphology and size distribution.

Originally published in Contemporary Psychology: APA Review of Books, 2001, Vol 46(4), 409–412. The broad range of body image problems experienced by persons without eating disorders is addressed in Exacting Beauty: Theory, Assessment, and Treatment of Body Image Disturbance, by J. Kevin Thompson, L

A 4-year-old castrated male mixed-breed dog with a history of coccidioidomycosis was referred for evaluation of abdominal and pleural effusion. Results of radiography, ultrasonography, cytologic evaluation of thoracic fluid, and serologic testing supported a diagnosis of constrictive pericarditis secondary to infection with Coccidioides immitis. Aggressive treatment for presumptive coccidioidomycosis was begun, but the dog's condition continued to deteriorate, and the dog was euthanatized. At necropsy, the pericardium was thicker than normal and fibrotic and adhered to the epicardium. Microscopically, the pericardium and 1 section of epicardium contained lymphoplasmacytic infiltrates with a few macrophages and neutrophils. Coccidioides immitis was cultured from pericardial fluid. A search of records from the Arizona Veterinary Diagnostic Laboratory for 1988 through 1998 revealed that of 46 dogs in which a diagnosis of coccidioidomycosis was confirmed at necropsy, 13 had involvement of the heart or pericardium.

This paper provides a preliminary typology of divorcing couples in order to help predict which couples will benefit from divorce mediation. The typology focuses on the couple dynamics during the divorce process. It suggests seven different types of divorcing couples, based on differences in five dimensions: their commitment to divorce, prior litigation, relationship at the time, ability to communicate, and commitment to their children's well-being. A picture of each type of couple is drawn and the couple's ability to benefit from mediation discussed. The typology is aimed mainly at judges, lawyers, and persons in the helping professions who may refer divorcing couples to mediation.

Purpose of Study Limited models exist to investigate the airway epithelium9s role in repair, regeneration, and pathology of chronic obstructive lung diseases. We introduce a human asthmatic airway epithelial xenograft system integrating a proliferating and differentiating airway epithelium with an actively remodeling rodent mesenchyme in an immunocompromised murine host. We hypothesized that epithelial regeneration in asthma induces underlying matrix fibrosis. Methods Used Human airway epithelial cells from asthmatic and non-asthmatic donors (n=5 per group) were seeded into decellularized rat tracheas. Tracheas were ligated to a sterile tubing cassette and implanted subcutaneously in the flanks of athymic nude mice. Grafts were harvested at 2, 4, or 6 weeks for analysis of tissue histology, fibrillar collagen deposition, and TGFβ1 activation. Non-transplantable human lungs from asthmatic and non-asthmatic donor FFPE sections were analyzed using similar methods. Summary of Results Grafted epithelial cells generated a differentiated epithelium with basal, ciliated, and mucus cells. By 4 weeks post-engraftment, asthmatic-derived epithelia showed decreased numbers of ciliated cells and E-cadherin expression compared to non-asthmatic controls, similar to human lung biopsy tissue. While there was no evidence of matrix remodeling in acellular xenografts, grafts seeded with asthmatic-derived epithelial cells had 3 times as much fibrillar collagen at 6 weeks post-engraftment as non-asthmatic epithelial seeded grafts. This was accompanied by a >2-fold induction of matrix TGFβ1 [with evidence of pSMAD3 activity] in asthmatic grafts at 4 weeks (positive pixels/total field pixels=0.12±0.001 vs. 0.05±0.001; p=0.003) and 6 weeks (0.09±0.02 vs. 0.04±0.01; p=0.044) post-engraftment. Conclusions We show in this model that asthmatic epithelium alone is sufficient to drive aberrant mesenchymal remodeling, specifically with fibrillar collagen deposition in asthmatic-derived xenografts.These xenografts are a major advance over current animal models of asthma in that they permit direct assessment of the epithelial-mesenchymal trophic unit.

Missions to the Martian surface will require electric power. Of the several possibilities, photovoltaic power system can offer many advantages. Photovoltaic cell performance increases with decreasing temperatures. The present paper deals with the calculation of the operating temperature of a e exible photovoltaic array needed for the determination of the electric output power from the array. The diurnal temperature variation was determined based on the solution of the heat-balance equation considering radiation, free and forced convection, and conduction. The photovoltaic array was divided into three layers (cover glass, solar cells, and substrate ), for which three differential equations were obtained and solved. The solution takes into account the special atmospheric condition prevailing on Mars, considering the diurnal variation of the ambient and surface temperatures, diurnal variation of direct beam, diffuse and albedo irradiances, variation of wind speed, and variation of various Mars atmospheric parameters with temperature.

Background The National Program for Quality Indicators in Community Healthcare in Israel (QICH) was developed to provide policy makers and consumers with information on the quality of community healthcare in Israel. In what follows we present the most recent results of the QICH indicator set for 2009 and an examination of changes that have occurred since 2007. Methods Data for 28 quality indicators were collected from all four health plans in Israel for the years 2007-2009. The QICH indicator set examined six areas of healthcare: asthma, cancer screening, cardiovascular health, child health, diabetes and immunizations for older adults. Results Dramatic increases in the documentation of anthropometric measures were observed over the measurement period. Documentation of BMI for adolescents and adults increased by 30 percentage points, reaching rates of 61% and 70%, respectively, in 2009. Modest increases (3%-7%) over time were observed for other primary prevention quality measures including immunizations for older adults, cancer screening, anemia screening for young children, and documentation of cardiovascular risks. Overall, rates of recommended care for chronic diseases (asthma, cardiovascular disease and diabetes) increased over time. Changes in rates of quality care for diabetes were varied over the measurement period. Conclusions The overall quality of community healthcare in Israel has improved over the past three years. Future research should focus on the adherence to quality indicators in population subgroups and compare the QICH data with those in other countries. In addition, one of the next steps in assessing and further improving healthcare quality in Israel is to relate these process and performance indicators to health outcomes.

Clinical, radiological and ultrasonographic findings from 22 cats with gastrointestinal lymphosarcoma were reviewed. The most common clinical findings were anorexia, weight loss, vomiting, lethargy, depression, fever, anemia and a palpable abdominal mass. Abdominal radiographs of 12 cats revealed a mass associated with the gastrointestinal tract and/or mesentery, and decreased serosal detail, suggestive of peritoneal effusion. The most common ultrasonographic finding was transmural gastric or intestinal thickening associated with loss of normal wall layering, reduced wall echogenicity and localized hypomotility. As is noted in people, other patterns such as transmural-segmental, transmural-nodular, transmural-bulky and mucosal infiltration were represented. In 3 cats, mesenteric lymph-adenopathy was responsible for most of the mass-effect. Fine-needle aspiration biopsy, automated microcore biopsy, endoscopic biopsy or necropsy confirmed the diagnosis of lymphosarcoma in all cats. Chemotherapy was instituted in 19 cats. Only 6 cats had a complete response to treatment. The results of this study indicate that ultrasonography is a valuable tool for the diagnosis of feline alimentary lymphosarcoma and that biopsies can be obtained under ultrasonographic guidance.

Techniques for obtaining percutaneous ultrasound-guided biopsies of the gastrointestinal tract were evaluated. The efficacity of ultrasonographic detection of gastrointestinal lesions has been established in veterinary medicine. Percutaneous ultrasound-guided aspiration biopsies were performed using either a 22 gauge spinal needle or a 20 gauge Westcott needle. The microcore automated biopsy was performed using a 18 gauge Tru-cut-like needle, assisted by an automated biopsy gun. These techniques are rapid, and easily performed. The techniques were considered safe for the patient, no complications such as hemorrhage, peritonitis or abscessation have occured in our study. These techniques are of particular interest when lesion can not be biopsied successfully by endoscopy and when surgical resection is not recommended.

The purpose of this study was to evaluate the usefulness of ultrasound-guided fine-needle aspiration biopsy and core biopsy in the diagnosis of infiltrative gastrointestinal diseases. Six dogs and seven cats with clinical signs of gastrointestinal disease underwent ultrasonography and intestinal lesions were identified. One or more ultrasound-guided fine-needle aspiration biopsy and/or core biopsy procedures were performed in each patient. Each patient also underwent one of the following additional procedures for comparison of results: 1) surgery (n=4), 2) endoscopy (n=2), 3) post mortem exam (n=3), and, 4) for lymphoma diagnosed with ultrasound-guided procedures, response to chemotherapy (n=4). Correct diagnoses were obtained in nine of the 13 patients, incorrect diagnoses in two of the 13 patients, and inconclusive diagnoses in two of the thirteen patients. Of the 16 total ultrasound-guided procedures performed, ten were confirmed as correct, three as incorrect, and three were non-diagnostic. Intestinal lesions with bowel wall thickness greater than 2.0 cm had a higher percentage of correct diagnoses than lesions of lesser wall thickness. Gastric lesions had a higher percentage of correct diagnoses than small and large intestinal lesions. Malignant lesions had a higher percentage of correct diagnoses than benign lesions. There were no complications. Ultrasound-guided gastrointestinal fine-needle aspiration biopsy and core biopsy appears to be a safe, accurate, and rapid procedure for use in the diagnosis of infiltrative gastrointestinal disease.