Severe Colitis in 2 Patients with Melanoma Treated with BRAF/MEK Inhibitors: Case Report and Literature Review.

Introduction: Encorafenib and binimetinib, a combination of BRAF and MEK inhibitors, is a standard of care for patients with advanced BRAFV600-mutant melanoma. This combination is known to have gastrointestinal side effects, most of which are mild and managed symptomatically. However, very few studies have reported severe colitis. Case Presentation: We report here 2 patients with advanced melanoma who developed severe ulcerated right colitis manifested by diarrhea and hematochezia while being treated with encorafenib and binimetinib after immune checkpoint therapy. Conclusion: This rare but serious adverse event was not described in early phase 3 trials but has emerged in recent years, particularly with the sequential use of immune checkpoint inhibitors followed by BRAF/MEK inhibitors. In a comprehensive review of the existing literature, we identified 20 cases of severe colitis due to BRAF/MEK inhibitors. Clinical, endoscopic, and histological features are described to provide insight into the current understanding of this poorly understood clinical entity.

Dietary index based on the Food Standards Agency nutrient profiling system and risk of Crohn's disease and ulcerative colitis.

BACKGROUND: Nutri-score is now widely available in food packages in Europe. AIM: To study the overall nutritional quality of the diet in relation to risks of Crohn's disease (CD) and ulcerative colitis (UC), in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort METHODS: We collected dietary data at baseline from validated food frequency questionnaires. We used a dietary index based on the UK Food Standards Agency modified nutrient profiling system (FSAm-NPS-DI) underlying the Nutri-Score label, to measure the nutritional quality of the diet. We estimated the association between FSAm-NPS-DI score, and CD and UC risks using Cox models stratified by centre, sex and age; and adjusted for smoking status, BMI, physical activity, energy intake, educational level and alcohol intake. RESULTS: We included 394,255 participants (68.1% women; mean age at recruitment 52.1 years). After a mean follow-up of 13.6 years, there were 184 incident cases of CD and 459 incident cases of UC. Risk of CD was higher in those with a lower nutritional quality, that is higher FSAm-NPS-DI Score (fourth vs. first quartile: aHR: 2.04, 95% CI: 1.24-3.36; p-trend: <0.01). Among items of the FSAm-NPS-DI Score, low intakes of dietary fibre and fruits/vegetables/legumes/nuts were associated with higher risk of CD. Nutritional quality was not associated with risk of UC (fourth vs. first quartile of the FSAm-NPS-DI Score: aHR: 0.91, 95% CI: 0.69-1.21; p-trend: 0.76). CONCLUSIONS: A diet with low nutritional quality as measured by the FSAm-NPS-DI Score is associated with a higher risk of CD but not UC.

Prolonged venom-induced consumptive coagulopathy following Mangshan pit viper (Protobothrops mangshanensis) envenomation despite Hemato Polyvalent antivenom administration.

This case report summarizes an envenomation by the Mangshan pit viper (Protobothrops mangshanensis), a rare, endangered, venomous snake endemic to Mount Mang of China, and the first reported use of Hemato Polyvalent antivenom (HPAV) for this species. The snakebite occurred in a United States zoo to a 46-year-old male zookeeper. He presented via emergency medical services to a tertiary center after sustaining a single P. mangshanensis bite to the abdomen and was transported with antivenom from the zoo. Within 2 hours of envenomation, he developed oozing of sanguineous fluid and ecchymosis at the puncture site, and about 4 hours post-bite, was treated with HPAV. His coagulation profile fluctuated with the following pertinent peak/nadir laboratory values and corresponding hospital day (HD): undetectable fibrinogen levels, d-dimer 8.89 mg/L and 7.43 mg/L, and INR 2.97 and 1.46 on HD zero and three, respectively. Other peak/nadir values included hemoglobin 9.7 g/dL and creatinine phosphokinase 2410 U/L on HD four and platelets 81 × 109/L on HD seven. The patient received a total of 30 vials of HPAV over 5 days and 1 unit of cryoprecipitate on HD six. Upon discharge on HD eight, laboratory studies were normalizing, except for platelets, and edema stabilized. This case describes an acute, recurrent, and prolonged venom-induced consumptive coagulopathy despite prompt administration and repeated doses of HPAV.

Food Processing and Risk of Crohn's Disease and Ulcerative Colitis: A European Prospective Cohort Study.

BACKGROUND & AIMS: Industrial foods have been associated with increased risks of several chronic conditions. We investigated the relationship between the degree of food processing and risks of Crohn's disease (CD) and ulcerative colitis (UC) in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Analyses included 413,590 participants (68.6% women; mean baseline age, 51.7 y) from 8 European countries. Dietary data were collected at baseline from validated country-specific dietary questionnaires. Associations between proportions of unprocessed/minimally processed and ultraprocessed food intake and CD and UC risks were estimated using Cox models to obtain hazard ratios (HRs) and 95% CIs. Models were stratified by center, age, and sex, and adjusted for smoking status, body mass index, physical activity, energy intake, educational level, and alcohol consumption. RESULTS: During a mean follow-up period of 13.2 years, 179 incident cases of CD and 431 incident cases of UC were identified. The risk of CD was lower in people consuming high proportions of unprocessed/minimally processed foods (adjusted HR for the highest vs lowest quartile: 0.57; 95% CI, 0.35-0.93; P trend < .01), particularly fruits and vegetables (adjusted HRs, 0.54; 95% CI, 0.34-0.87 and 0.55; 95% CI, 0.34-0.91, respectively). There was no association between unprocessed/minimally processed food intake and the risk of UC. No association was detected between ultraprocessed food consumption and CD or UC risks. CONCLUSIONS: In the European Prospective Investigation into Cancer and Nutrition cohort, consumption of unprocessed/minimally processed foods was associated with a lower risk of CD. No association between UC risk and food processing was found.

Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study.

BACKGROUND: Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS: We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS: Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS: COMBIO can be effective and safe in patients with refractory/overlapping IMIDs.

Severe colitis in patients with melanoma treated with BRAF/MEK inhibitors.

BACKGROUND AND AIMS: Dual blockade of BRAF and MEK kinases is a standard of care for metastatic V600E/K BRAF mutant melanoma. This study reports the first systematic description of colitis due to BRAF and MEK inhibitors. METHODS: We studied consecutive patients with melanoma, treated with BRAF and MEK inhibitors, who had colitis requiring hospitalisation. Electronic files were studied; endoscopic biopsies and colectomy specimens were read centrally. RESULTS: Between January 2021 and March 2022, nine women and one man, aged 50-90 years, were studied. Nine patients received encorafenib and binimetinib; one patient received dabrafenib and trametinib. The main symptoms were diarrhoea, haematochezia, abdominal pain and intestinal obstruction. Blood tests showed anaemia, increased CRP and low serum albumin levels in most patients. All patients had ulcerations of the right colon with (2/10) or without (8/10) stenosis of the ileocecal valve, and 4/10 patients also had ulcerations distal to the right colon. Histopathological findings were suggestive of ischaemia and mild inflammation. Nine of the 10 patients discontinued BRAF/MEK inhibitors. Drugs were reintroduced in four patients, three of whom had a severe relapse of diarrhoea. Two patients required surgery and underwent intestinal resection. One patient died of enterocolitis. CONCLUSION: BRAF/MEK inhibitors can induce severe colitis characterised by ulcerations of the right colon.

A BCB4 variant is associated with hepatobiliary MR abnormalities in people with low-phospholipid-associated cholelithiasis syndrome.

Background & Aims: The low-phospholipid-associated cholelithiasis (LPAC) syndrome is a recently described peculiar form of cholelithiasis associated with the ATP-binding-cassette subfamily B, member 4 (ABCB4) gene deficiency. The purpose of our study was to analyse the relationship between magnetic resonance (MR) features and the genetic status of ABCB4 in people with LPAC syndrome. Methods: A total of 233 individuals with proven LPAC syndrome were enrolled between January 2003 and June 2018 in a retrospective single-centre study. Inclusion criteria included availability of clinical files, MR images, and genetic data. MR images were analysed by consensus among 3 senior radiologists blinded to the status of ABCB4 gene mutation. Results: A total of 125 individuals (mean age at first MR imaging 40.8 years; 66% females; 48% ABCB4 variant) were included. MR abnormalities were found in 61 (49%) of the 125 individuals. Forty (67%) of the 60 individuals with an ABCB4 gene variant had MR abnormalities as compared with 21 (33%) of the 65 individuals without an ABCB4 gene variant (odds ratio [OR] 4.1, 95% CI 1.9-9.5, p = 0.0001). Compared to individuals with no variant, individuals with an ABCB4 variant were more likely to show intrahepatic macrolithiasis (56 vs. 17%; OR 6.3, 95% CI 2.6-16.2, p <0.0001), bile duct dilatation (60 vs. 18%; OR 6.5, 95% CI 2.7-16.3, p <0.0001), and at least 1 MR feature of complication (35 vs. 15%; OR 2.9, 95% CI 1.1-7.8, p <0.05). Conclusions: ABCB4-related LPAC syndrome is associated with more frequent and severe hepatobiliary MR abnormalities. This finding strongly supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome and highlights a genotype-phenotype association in this inherited disease with genetic heterogeneity. Lay summary: ABCB4-related LPAC syndrome associated with an ABCB4 gene variant demonstrates more frequent and severe hepatobiliary MR abnormalities. This finding supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome.

Meat Intake Is Associated with a Higher Risk of Ulcerative Colitis in a Large European Prospective Cohort Studyø.

BACKGROUND AND AIMS: We aimed to investigate the association between protein intake and risk of inflammatory bowel disease [IBD] in the European Prospective Investigation into Cancer and Nutrition. METHODS: A total of 413 593 participants from eight European countries were included. Dietary data were collected at baseline from validated food frequency questionnaires. Dietary data were calibrated to correct errors in measures related to each country-specific questionnaire. Associations between proteins [total, animal, and vegetable] or food sources of animal proteins, and IBD risk were estimated by Cox proportional hazard models. RESULTS: After a mean follow-up of 16 years, 177 patients with Crohn's disease [CD] and 418 with ulcerative colitis [UC], were identified. There was no association between total protein, animal protein, or vegetable protein intakes and CD or UC risks. Total meat and red meat intakes were associated with UC risk (hazard ratio [HR] for the 4th vs 1st quartile = 1.40, 95% confidence interval [CI] = 0.99-1.98, p-trend = 0.01; and 1.61, 95% CI = 1.10-2.36, p-trend = 0.007, respectively]. There was no association between other food sources of animal protein [processed meat, fish, shellfish, eggs, poultry] and UC. We found no association between food sources of animal proteins and CD risk. CONCLUSIONS: Meat and red meat consumptions are associated with higher risks of UC. These results support dietary counselling of low meat intake in people at high-risk of IBD.

Systematic review with meta-analysis: the effectiveness of either ustekinumab or vedolizumab in patients with Crohn's disease refractory to anti-tumour necrosis factor.

BACKGROUND: Ustekinumab and vedolizumab are commonly used after anti-tumour necrosis factor (TNF) failure in patients with Crohn's disease (CD). No randomised controlled trial has compared these drugs. AIMS: To compare the effectiveness of ustekinumab and vedolizumab in CD patients refractory to anti-TNF. METHODS: From PubMed, EMBASE and the Cochrane Library, through March 27, 2021, we identified studies that compared ustekinumab and vedolizumab in patients with CD refractory to anti-TNF. The main outcomes were clinical remission and steroid-free clinical remission at weeks 14 and 52. Secondary outcomes were biological remission and treatment persistence. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) using random effects meta-analysis. RESULTS: We identified 1513 reports. Among them, 38 studies were assessed for eligibility and five studies were included. All studies included were of high quality: four were retrospective and one was prospective. Among 1026 patients, 659 received ustekinumab and 367 received vedolizumab. At week 14, clinical remission (OR 1.36; 95%CI: 0.74-2.47; I2  = 50%), steroid-free clinical remission (OR 1.24; 95%CI: 0.79-1.92; I2  = 52%) and biological remission (OR 0.80; 95%CI: 0.50-1.28; I2  = 0%) rates were similar between the two treatments. At week 52, ustekinumab was associated with higher rates of clinical remission (OR 1.87; 95% CI: 1.18-2.98; I2  = 0%), steroid-free clinical remission (OR 1.56; 95% CI: 1.23-1.97; I2  = 0%), biological remission (OR 1.86; 95% CI: 1.03-3.37; I2  = 29%) and treatment persistence (OR 2.37; 95% CI: 1.56-3.62; I2  = 0%). CONCLUSION: In patients with CD refractory to anti-TNF, ustekinumab and vedolizumab are similarly effective in induction, but as maintenance treatment, ustekinumab appears to be more effective than vedolizumab.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

[Hypophosphatemia following the administration of intravenous iron formulations: A case report and literature review]. / Hypophosphatémie et fer injectable : à propos d'un cas et revue de la littérature.

Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.

Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities.

BACKGROUND & AIMS: Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease. METHODS: We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease. RESULTS: In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5-1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer. CONCLUSIONS: In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer. LAY SUMMARY: In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.

Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease.

BACKGROUND: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear. AIM: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models. RESULTS: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale. CONCLUSIONS: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.

Antibody Responses to Helicobacter pylori and Risk of Developing Colorectal Cancer in a European Cohort.

BACKGROUND: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. RESULTS: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00-1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99-1.82), the latter being nonstatistically significant only in the fully adjusted model. CONCLUSIONS: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. IMPACT: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence.

Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders.

BACKGROUND AND AIMS: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. METHODS: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. RESULTS: Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. CONCLUSIONS: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.

Systematic review with meta-analysis: mortality in acute severe ulcerative colitis.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a life-threatening condition. Mortality in ASUC decreased in published series but there is uncertainty as to whether this also applies to the real-life setting. AIM: To perform a systematic review and meta-analysis of mortality in ASUC in studies from referral centres and in population-based studies, separately and combined. A second aim was to identify risk factors of mortality in ASUC. METHODS: We searched pubmed and embase from 1998 to 2016, to identify studies that reported 3-month or 12-month mortalities of acute UC in adult patients treated in referral centres, and in population-based studies. RESULTS: Six population-based studies with 741 743 patients and 47 referral centre-based studies with 2556 patients were included. The pooled 3-month and 12-month mortalities were respectively 0.84% and 1.01%. Advanced age was significantly associated with both 3 month and 12 month mortalities (OR = 1.15 per year, 95% CI: 1.10-1.20 and OR = 1.19 per year, 95% CI: 1.15-1.23 respectively). The pooled 3-month and 12-month mortalities were 0.78% and 0.85% in studies with median age of less than 50 and 2.81% and 4.17% in studies with median age of 50 or more, respectively. After adjustment for age, 3-month and 12-month mortalities did not differ between population-based and referral centre-based studies. CONCLUSIONS: Mortality in acute severe ulcerative colitis is approximately 1%; it is higher in older patients. Efforts should be made to improve the care of elderly patients with severe UC.

Cannabinoid exposure during pregnancy and its impact on immune function.

Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis can be beneficial for certain heath conditions, abuse of potent synthetic cannabinoids has been on the rise. Exposure to cannabinoids is also prevalent in women of child-bearing age and pregnant women. These compounds can cross the placental barrier and directly affect the fetus. They mediate their effects primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In addition to significant neurological effects, cannabinoids can trigger robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells and inducing suppressor cells of the immune system. Profound effects of cannabinoids on the immune system as discussed in this review, suggest that maternal exposure during pregnancy could lead to dysregulation of innate and adaptive immune system of developing fetus and offspring potentially leading to weakening of immune defenses against infections and cancer later in life. Emerging evidence also indicates the underlying role of epigenetic mechanisms causing long-lasting impact following cannabinoid exposure in utero.

Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients.

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.