Substance use and mental health factors associated with self-reported higher risk cannabis use among people with HIV screened in primary care.

Background: While cannabis use is prevalent among people with HIV (PWH), factors associated with higher-risk use require further study. We examined factors associated with indicators risk for cannabis use disorder (CUD) among PWH who used cannabis. Methods: Participants included adult (≥18 years old) PWH from 3 HIV primary care clinics in Kaiser Permanente Northern California who reported past three-month cannabis use through the computerized Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) screening. Primary outcome was TAPS cannabis score (range 1-3), categorized as any use (1) and higher risk for CUD (≥2). Measures included sociodemographics (age, sex, race, neighborhood deprivation index [NDI]), Charlson Comorbidity Index (CCI), HIV RNA, CD4 cell counts, higher risk tobacco use (TAPS tobacco score≥2), depression, and anxiety symptoms. Unadjusted and multivariable logistic regression examined factors associated with higher risk for CUD. Results: Of the complete sample (N=978; 94.1% Male; 58.3% White; Age Mode=51-60), 35.8% reported higher risk for CUD. Unadjusted models indicated younger age, Black race, higher CCI, depression, anxiety, and higher risk tobacco use were associated with higher risk, while only Black race (OR=1.84, 95% CI[1.29, 2.63]), anxiety (OR=1.91, 95% CI[1.22, 2.98]), and higher risk tobacco use (OR=2.27, 95% CI[1.47, 3.51]) remained significant in the multivariable model. Conclusions: Black race, anxiety and tobacco use, but not HIV clinical markers, were associated with higher risk for CUD among PWH. Clinical efforts to screen and provide interventions for preventing CUD alongside anxiety and tobacco use among PWH should be evaluated.

The Toronto IBD Global Endoscopic Reporting [TIGER] Score: A Single, Easy to Use Endoscopic Score for Both Crohn's Disease and Ulcerative Colitis Patients.

BACKGROUND AND AIMS: We constructed the Toronto IBD Global Endoscopic Reporting [TIGER] score for inflammatory bowel disease [IBD]. The aim of our study was to develop and validate the TIGER score against faecal calprotectin [FC], C-reactive protein [CRP], and IBD Disk. METHODS: A cross-sectional study was performed among 113 adult patients (60 Crohn's disease [CD] and 53 ulcerative colitis [UC]). In the development and usability phase, blinded IBD experts reviewed and graded ileocolonoscopy videos. In the validity phase the TIGER score was compared with: [1] the Simple endoscopic Score for CD [SES-CD] and the Mayo endoscopic score in CD and UC, respectively; [2] FC and CRP; and [3] IBD Disk. RESULTS: Inter-observer reliability of the TIGER score per segment between reviewers was excellent: interclass correlation coefficient [ICC] = 0.94 [95% CI: 0.92-0.96]. For CD patients, overall agreement per segment between SES-CD and TIGER was 91% [95% CI: 84-95] with kappa coefficient 0.77 [95% CI: 0.63-0.91]. There was a significant correlation between TIGER and CRP [p <0.0083], and TIGER and FC [p <0.0001]. In addition, there was significant correlation between TIGER and IBD Disk [p <0.0001]. For UC patients, overall agreement per segment between Mayo endoscopic score and TIGER was 84% [95% CI: 74%-90%] and kappa coefficient 0.60 [95% CI: 0.42-0.808]. There was a significant correlation between TIGER and FC [p <0.0001]. There was a significant correlation between TIGER and IBD Disk [p <0.0001]. CONCLUSIONS: The TIGER score is a reliable and simple novel endoscopic score that can be used for both CD and UC patients and captures full endoscopic disease burden.

Recurrence after hospitalization for acute coronary syndrome among HIV-infected and HIV-uninfected individuals.

OBJECTIVES: We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. METHODS: We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. RESULTS: Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/µL (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/µL (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ≥ 500 cells/µL (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). CONCLUSIONS: HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.

Acceptability of high-resolution anoscopy for anal cancer screening in HIV-infected patients.

OBJECTIVES: HIV-infected individuals are at increased risk of anal cancer. Screening for anal cancer precursors using high-resolution anoscopy (HRA) may be clinically beneficial. In this study, we examined patient tolerability of this procedure. METHODS: The acceptability of HRA was evaluated among HIV-infected patients who completed a first-time HRA between July 2008 and December 2013 at Kaiser Permanente Northern California. We reviewed electronic medical records to identify lack of HRA acceptability, which was defined as receipt of HRA with sedation, dispensation of opioid analgaesia, and/or an urgent care visit following HRA, and to evaluate factors associated with patients not returning for a recommended repeat HRA (proxy for HRA acceptability). HRA acceptability was also assessed via a survey mailed to patients who completed HRA between January 2014 and August 2014. Logistic regression was used to model lack of acceptability of initial HRA and likelihood of not returning for a repeat HRA. RESULTS: Of 1857 HIV-infected patients, 94 were prescribed opioids and one had an urgent care visit. Lack of HRA acceptability was more likely in patients with pre-existing anal conditions [e.g. warts or fissure; adjusted odds ratio (aOR) 4.02; 95% confidence interval (CI) 2.4-6.7], those who had ever smoked (aOR 1.6; 95% CI 1.0-2.5) and women (aOR 5.3; 95% CI 1.6-17.5). Fifty per cent of patients returned for a repeat HRA, with younger patients less likely to return (per 10-year age interval, aOR 0.8; 95% CI 0.7-0.9). Of 48 survey respondents, 91.7% reported acceptable pain levels and all reported willingness to return for a repeat HRA. CONCLUSIONS: HRA was generally well tolerated and may be an acceptable screening approach for patients at high risk of anal cancer.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors.

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/µL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates.

Ileal pouch-anal anastomosis for ulcerative colitis: a Canadian institution's experience.

BACKGROUND: We aimed to summarize the outcomes of ulcerative colitis (UC) patients receiving an ileal pouch-anal anastamosis (IPAA) over an 11-year period at a high-volume Canadian inflammatory bowel disease (IBD) center. METHODS: A retrospective chart review was performed for subjects with UC who underwent IPAA between 2002 and 2013. Patient charts were reviewed for demographic data, clinical characteristics, preoperative medical treatment, and surgical outcomes. Univariate and multivariate logistic regression modeling were used to determine significant factors in postoperative outcomes. RESULTS: Seven hundred fifty-eight were included from the IBD database. The median age at the time of surgery was 37.1 (±12.1). Mean preoperative disease duration was 8.1 years (±8.7). Three hundred sixty-nine patients (48.7 %) had systemic corticosteroids (>15 mg/day) within 30 days prior to surgery. Of these, 286 patients had high dose (>30 mg/day) corticosteroids within 7 days of their first surgery. One hundred nine (14.0 %) IPAA procedures were performed laparoscopically. Pelvic pouches were created in traditional 2 (n = 460) and 3 (n = 285) stages; the remainder (n = 13) was performed in non-traditional staged operations. Early complications, defined as occurring within the same stay in hospital, consisted of pelvic abscess (n = 135, 17.8 %), small bowel obstruction (n = 134, 17.7 %), wound infection (n = 108, 14.3 %), and deep vein thrombosis (n = 33, 4.4 %). The overall pouch leak rate was 92 (12.1 %). There was one death in our study. The median length of stay was 10.3 days (SD6.0). Late complications, defined as occurring after discharge from hospital, consisted of anal stricture (n = 55, 7.3 %), pouch fistula (n = 26, 3.4 %), and functional pouch failure (n = 7, 0.9 %). CONCLUSIONS: IPAA has been found to be a safe and effective method of surgical management of UC patients in a high-volume IBD center.

Higher Adalimumab Drug Levels are Associated with Mucosal Healing in Patients with Crohn's Disease.

BACKGROUND AND AIMS: The current approach to managing the loss of response to anti-tumour necrosis factor (TNF) agents is generally empirical. Prior studies have suggested that adalimumab levels of >4.9 µg/mL are required to achieve clinical remission. Our aim was to identify an optimal adalimumab level to achieve endoscopic healing in Crohn's disease (CD). METHODS: A cohort of 60 CD patients treated with adalimumab between 2005 and 2013 were reviewed for the study. Demographic and clinical information was obtained from chart review and patient interview. Disease activity was determined using the Harvey-Bradshaw index (HBI), ileocolonoscopy reports and C-reactive protein (CRP) levels. Clinical remission was defined as HBI <5. Endoscopic remission/mucosal healing (MH) was defined as the absence of any ulceration in all ileocolonic segments. Trough adalimumab levels and adalimumab antibody levels were tested using a liquid-phase mobility shift assay. RESULTS: Lower median CRP was significantly associated with MH 1.2mg/dl vs no MH 14.4mg/dl (p = 6.93×10(-6)). Higher adalimumab trough level was significantly associated with MH (median 14.7 µg/mL in those with MH vs 3.4 µg/mL in those without, p = 6.25×10(-5)). Higher adalimumab trough level was also significantly associated with the combined outcome of clinical and endoscopic remission (median 13.0 vs 4.8 µg/mL, p = 5.36×10(-3)). A cut-off of 8.14 µg/ml best discriminated subjects with MH from those without MH, with sensitivity and specificity of 91.4 and 76.0%, respectively (positive and negative predictive values 84.2 and 86.4%, respectively). CONCLUSIONS: Higher adalimumab levels were significantly associated with MH. This study suggests that attaining MH alone or a combined outcome of clinical and endoscopic remission is more likely to occur in those patients who achieve an adalimumab trough level of at least 8.14 µg/mL.

Characterization of Intestinal Microbiota in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: There is an unexplained association between ulcerative colitis [UC] and primary sclerosing cholangitis [PSC], with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. METHODS: UC patients with PSC [PSC-UC] and without PSC [UC] were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units [OTUs] using Quantitative Insights Into Microbial Ecology [QIIME]. Microbial alpha diversity, beta diversity, and relative abundance were compared between PSC-UC and UC phenotypes. RESULTS: In all, 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis [PCoA] demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort, Chao 1 index was modestly decreased in PSC-UC compared with UC [p = 0.04] but did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, but results were not robust to false-discovery rate correction. CONCLUSIONS: No strong PSC-specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment centre had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors.

A validated web-based tool to display individualised Crohn's disease predicted outcomes based on clinical, serologic and genetic variables.

BACKGROUND: Early treatment for Crohn's disease (CD) with immunomodulators and/or anti-TNF agents improves outcomes in comparison to a slower 'step up' algorithm. However, there remains a limited ability to identify those who would benefit most from early intensive therapy. AIM: To develop a validated, individualised, web-based tool for patients and clinicians to visualise individualised risks for developing Crohn's disease complications. METHODS: A well-characterised cohort of adult patients with CD was analysed. Available data included: demographics; clinical characteristics; serologic immune responses; NOD2 status; time from diagnosis to complication; and medication exposure. Cox proportional analyses were performed to model the probability of developing a CD complication over time. The Cox model was validated externally in two independent CD cohorts. Using system dynamics analysis (SDA), these results were transformed into a simple graphical web-based display to show patients their individualised probability of developing a complication over a 3-year period. RESULTS: Two hundered and forty three CD patients were included in the final model of which 142 experienced a complication. Significant variables in the multivariate Cox model included small bowel disease (HR 2.12, CI 1.05-4.29), left colonic disease (HR 0.73, CI 0.49-1.09), perianal disease (HR 4.12, CI 1.01-16.88), ASCA (HR 1.35, CI 1.16-1.58), Cbir (HR 1.29, CI 1.07-1.55), ANCA (HR 0.77, CI 0.62-0.95), and the NOD2 frameshift mutation/SNP13 (HR 2.13, CI 1.33-3.40). The Harrell's C (concordance index for predictive accuracy of the model) = 0.73. When applied to the two external validation cohorts (adult n = 109, pediatric n = 392), the concordance index was 0.73 and 0.75, respectively, for adult and pediatric patients. CONCLUSIONS: A validated, web-based tool has been developed to display an individualised predicted outcome for adult patients with Crohn's disease based on clinical, serologic and genetic variables. This tool can be used to help providers and patients make personalised decisions about treatment options.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Body mass index and early CD4 T-cell recovery among adults initiating antiretroviral therapy in North America, 1998-2010.

OBJECTIVES: Adipose tissue affects several aspects of the cellular immune system, but prior epidemiological studies have differed on whether a higher body mass index (BMI) promotes CD4 T-cell recovery on antiretroviral therapy (ART). The objective of this analysis was to assess the relationship between BMI at ART initiation and early changes in CD4 T-cell count. METHODS: We used the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data set to analyse the relationship between pre-treatment BMI and 12-month CD4 T-cell recovery among adults who started ART between 1998 and 2010 and maintained HIV-1 RNA levels < 400 copies/mL for at least 6 months. Multivariable regression models were adjusted for age, race, sex, baseline CD4 count and HIV RNA level, year of ART initiation, ART regimen and clinical site. RESULTS: A total of 8381 participants from 13 cohorts contributed data; 85% were male, 52% were nonwhite, 32% were overweight (BMI 25-29.9 kg/m(2) ) and 15% were obese (BMI > 30 kg/m(2) ). Pretreatment BMI was associated with 12-month CD4 T-cell change (P < 0.001), but the relationship was nonlinear (P < 0.001). Compared with a reference of 22 kg/m(2) , a BMI of 30 kg/m(2) was associated with a 36 cells/µL [95% confidence interval (CI) 14, 59 cells/µL] greater CD4 T-cell count recovery among women and a 19 cells/µL (95% CI 9, 30 cells/µL) greater recovery among men at 12 months. At a BMI > 30 kg/m(2) , the observed benefit was attenuated among men to a greater degree than among women, although this difference was not statistically significant. CONCLUSIONS: A BMI of approximately 30 kg/m(2) at ART initiation was associated with greater CD4 T-cell recovery at 12 months compared with higher or lower BMI values, suggesting that body composition may affect peripheral CD4 T-cell recovery.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Predicting complicated Crohn's disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population-based cohort.

BACKGROUND: Predictors of complicated Crohn's disease (CD), defined as stricturing or penetrating behaviour, and surgery have largely been derived from referral centre populations. AIM: To investigate whether serological markers, susceptibility genes or psychological characteristics are associated with complicated CD or surgery in a population-based cohort. METHODS: One hundred and eighty-two members of the Manitoba IBD Cohort with CD phenotyped using the Montreal classification underwent genetic and serological analysis at enrolment and after 5 years. One hundred and twenty-seven had paired sera at baseline and 5 years later and their data were used to predict outcomes at a median of 9.3 years. Serological analysis consisted of a seven antibody panel, and DNA was tested for CD-associated NOD2 variants (rs2066845,rs2076756,rs2066847), ATG16L1 (rs3828309, rs2241880) and IL23R (rs11465804). Psychological characteristics were assessed using semi-structured interviews and validated survey measures. RESULTS: Sixty-five per cent had complicated CD and 42% underwent surgery. Multivariate analysis indicated that only ASCA IgG-positive serology was predictive of stricturing/penetrating behaviour (OR = 3.01; 95% CI: 1.28-7.09; P = 0.01) and ileal CD (OR = 2.2; 95% CI: 1.07-4.54, P = 0.03). Complicated CD behaviour was strongly associated with surgery (OR = 5.6; 95% CI: 2.43-12.91; P < 0.0001), whereas in multivariate analysis, only ASCA IgG was associated (OR = 2.66; 95% CI, 1.40-5.06, P = 0.003). ASCA titre results were similar at baseline and follow-up. Psychological characteristics were not significantly associated with disease behaviour, serological profile or genotype. CONCLUSIONS: ASCA IgG at baseline was significantly associated with stricturing/penetrating disease at 9-10 years from diagnosis. Stricturing/penetrating disease was significantly associated with surgery. In a model including serology, the genotypes assessed did not significantly associate with complicated disease or surgery.

Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Trends in annual incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in HIV-infected and HIV-uninfected patients.

We describe trends in incidence rates of methicillin-resistant Staphylococcus aureus (MRSA) in HIV-infected and HIV-uninfected patients enrolled in a large northern California Health Plan, and the ratio of MRSA to methicillin-susceptible S. aureus (MSSA) case counts. Between 1995 and 2010, 1549 MRSA infections were diagnosed in 14060 HIV-infected patients (11·0%) compared to 89546 MRSA infections in 6597396 HIV-uninfected patients (1·4%) (P = 0·00). A steady rise in MRSA infection rates began in 1995 in HIV-uninfected patients, peaking at 396·5 infections/100000 person-years in 2007. A more rapid rise in MRSA infection rates occurred in the HIV-infected group after 2000, peaking at 3592·8 infections/100000 in 2005. A declining trend in MRSA rates may have begun in 2008-2009. Comparing the ratio of MRSA to MSSA case counts, we observed that HIV-infected patients shouldered a greater burden of MRSA infection during most years of study follow-up compared to HIV-uninfected patients.

Characterisation of complementary and alternative medicine use and its impact on medication adherence in inflammatory bowel disease.

BACKGROUND: Complementary and alternative medicine (CAM) use among inflammatory bowel disease (IBD) patients is common. We characterised CAM utilisation and assessed its impact on medical adherence in the IBD population. AIM: To characterise CAM utilisation and assess its impact on medical adherence in the IBD population. METHODS: Inflammatory bowel disease patients recruited from an out-patient clinic at a tertiary centre were asked to complete a questionnaire on CAM utilisation, conventional IBD therapy, demographics and communication with their gastroenterologist. Adherence was measured using the self-reported Morisky scale. Demographics, clinical characteristics and self-reported adherence among CAM and non-CAM users were compared. RESULTS: We recruited prospectively 380 IBD subjects (57% Crohn's disease; 35% ulcerative colitis, and 8% indeterminate colitis). The prevalence of CAM use was 56% and did not significantly vary by type of IBD. The most common reason cited for using CAM was ineffectiveness of conventional IBD therapy (40%). The most popular form of CAM was probiotics (53%). CAM users were younger than non-CAM users at diagnosis (21.2 vs. 26.2, P < 0.0001) and more likely than non-CAM users to have a University-level education or higher (75% vs. 62% P = 0.006). There was no overall difference in adherence between CAM and non-CAM users (Morisky score: 1.0 vs. 0.9, P = 0.26). CONCLUSIONS: The use of complementary and alternative medicine is widely prevalent among IBD patients, and is more frequent among those with experience of adverse effects of conventional medications. From this cross-sectional analysis, complementary and alternative medicine use does not appear to be associated with reduced overall adherence to medical therapy.

Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.

BACKGROUND AND AIMS: Antibodies to infliximab reduce serum infliximab with loss of clinical benefit, but undetectable trough serum concentrations of infliximab may occur without antibody formation. The relationship between trough serum infliximab and clinical outcomes was evaluated in acute ulcerative colitis. METHODS: In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance infliximab, rates of clinical remission, colectomy, antibodies to infliximab and trough serum infliximab were determined. RESULTS: Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR 1.9-12.1) months. Detectable trough serum infliximab was present in 39% of patients and, among patients with undetectable infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum infliximab was associated with higher rates of remission (69% vs 15%; p<0.001) and endoscopic improvement (76% vs 28%, p<0.001). An undetectable serum infliximab predicted an increased risk for colectomy (55% vs 7%, OR 9.3; 95% CI 2.9 to 29.9; p<0.001). Concurrent immunosuppression was not associated with clinical outcomes. CONCLUSIONS: For patients with ulcerative colitis treated with infliximab, a detectable trough serum infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum infliximab, irrespective of antibody status, is associated with less favourable outcomes.