Improving 30-day mortality after PEG tube placement in England from 2007 to 2019: a retrospective national cohort analysis of 87,862 patients.

BACKGROUND AND AIMS: PEG has been associated with poor case selection and high mortality. We examined indications, 30-day mortality, and 7-day adverse events in a national cohort undergoing PEG tube insertion. METHODS: Adult patients undergoing their first PEG tube insertion from 2007 to 2019 were identified in the Hospital Episode Statistics database. Indications and adverse events were identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes. Multivariable logistic regression modeling examined factors associated with mortality. RESULTS: Of 87,682 patients identified, 58% were men and median age was 69 years (interquartile range, 57-79). The number of patients with dementia or stroke as the indication for PEG fell from 2007 to 2019 (dementia, from 147 to 28 [P < .001]; stroke, from 2851 to 1781 [P < .001]). The median interval from stroke admission to PEG tube insertion increased from 21 (interquartile range, 12-36) to 28 (interquartile range, 13-45) days (P < .001). Aspiration pneumonia within 7 days of PEG fell from 10.2% to 8.6% (P = .04). Thirty-day mortality fell from 13.2% to 5.3% (P < .001), with associated factors of increasing age (≥82 years quintile odds ratio [OR], 4.44; 95% confidence interval [CI], 4.01-4.92), PEG tube insertion during emergency admission (OR, 2.10; 95% CI, 1.97-2.25), Charlson comorbidity score ≥5 (OR, 1.67; 95% CI, 1.53-1.82), and dementia (OR, 1.46; 95% CI, 1.26-1.71). Female sex (OR, .81; 95% CI, .77-.85), least-deprived quintile (OR, .88; 95% CI, .81-.95), and more recent years of PEG tube insertion (2019; OR, .44; 95% CI, .39-.51) were negatively associated with mortality. CONCLUSIONS: Thirty-day mortality after PEG tube insertion has fallen 60% over 13 years. Dementia or stroke as an indication for PEG fell, and the time interval from stroke to PEG tube insertion increased. These findings may be attributable to improved patient selection and timing for PEG tube insertion.

The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF).

Macrophage migration inhibitory factor (MIF) is a key innate immune mediator with chemokine- and cytokine-like properties in the inflammatory pathway. While its actions on macrophages are well-studied, its effects on other cell types are less understood. Here we report that MIF is required for expansion of intestinal tuft cells during infection with the helminth Nippostrongylus brasiliensis. MIF-deficient mice show defective innate responses following infection, lacking intestinal epithelial tuft cell hyperplasia or upregulation of goblet cell RELMß, and fail to expand eosinophil, type 2 innate lymphoid cell (ILC2) and macrophage (M2) populations. Similar effects were observed in MIF-sufficient wild-type mice given the MIF inhibitor 4-IPP. MIF had no direct effect on epithelial cells in organoid cultures, and MIF-deficient intestinal stem cells could generate tuft cells in vitro in the presence of type 2 cytokines. In vivo the lack of MIF could be fully compensated by administration of IL-25, restoring tuft cell differentiation and goblet cell expression of RELM-ß, demonstrating its requirement upstream of the ILC2-tuft cell circuit. Both ILC2s and macrophages expressed the MIF receptor CXCR4, indicating that MIF may act as an essential co-factor on both cell types to activate responses to IL-25 in helminth infection.

Profile of Tofacitinib in the Treatment of Ulcerative Colitis: An Evidence-Based Review of Recent Data.

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.

Macrophage Migration Inhibitory Factor (MIF) Is Essential for Type 2 Effector Cell Immunity to an Intestinal Helminth Parasite.

Immunity to intestinal helminths is known to require both innate and adaptive components of the immune system activated along the Type 2 IL-4R/STAT6-dependent pathway. We have found that macrophage migration inhibitory factor (MIF) is essential for the development of effective immunity to the intestinal helminth Heligmosomoides polygyrus, even following vaccination which induces sterile immunity in wild-type mice. A chemical inhibitor of MIF, 4-IPP, was similarly found to compromise anti-parasite immunity. Cellular analyses found that the adaptive arm of the immune response, including IgG1 antibody responses and Th2-derived cytokines, was intact and that Foxp3+ T regulatory cell responses were unaltered in the absence of MIF. However, MIF was found to be an essential cytokine for innate cells, with ablated eosinophilia and ILC2 responses, and delayed recruitment and activation of macrophages to the M2 phenotype (expressing Arginase 1, Chil3, and RELM-α) upon infection of MIF-deficient mice; a macrophage deficit was also seen in wild-type BALB/c mice exposed to 4-IPP. Gene expression analysis of intestinal and lymph node tissues from MIF-deficient and -sufficient infected mice indicated significantly reduced levels of Arl2bp, encoding a factor involved in nuclear localization of STAT3. We further found that STAT3-deficient macrophages expressed less Arginase-1, and that mice lacking STAT3 in the myeloid compartment (LysMCrexSTAT3fl/fl) were unable to reject a secondary infection with H. polygyrus. We thus conclude that in the context of a Type 2 infection, MIF plays a critical role in polarizing macrophages into the protective alternatively-activated phenotype, and that STAT3 signaling may make a previously unrecognized contribution to immunity to helminths.

"Can Magnetic Resonance Enterography (MRE) replace ileo-colonoscopy for evaluating disease activity in Crohn's disease?"

Crohn's disease is a form of chronic inflammatory bowel disease that can lead to structural bowel damage due to transmural inflammation. Ileo-colonosocopy is currently essential for initial diagnosis. Reassessment of disease burden is frequently needed during episodes of active disease and when evaluating treatment efficacy. This review compares the role of Magnetic Resonance Enterography (MRE) and ileocolonoscopy in Crohn's disease management and whether cross-sectional imaging can replace invasive endoscopic tests. MRE can give information on the small bowel not visible at ileo-colonoscopy, and on extra-luminal complications. Evaluation of the bowel by MRE allows assessment of the submucosa and serosa, and thus transmural healing. MRE offers a well tolerated investigation and additional information on disease activity to better manage patients with Crohn's disease. Increasingly, there are a range of newer techniques such as diffusion weighted imaging, magnetisation transfer and motility MRI which provide greater information on fibrosis and predictors to treatment response which has been lacking despite the use of ileo-colonoscopy for several decades.

Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion.

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14-17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

Helminths in the gastrointestinal tract as modulators of immunity and pathology.

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract.

The communication of a secondary care diagnosis of autoimmune hepatitis to primary care practitioners: a population-based study.

BACKGROUND: Autoimmune Hepatitis is a chronic liver disease which affects young people and can result in liver failure leading to death or transplantation yet there is a lack of information on the incidence and prevalence of this disease and its natural history in the UK. A means of obtaining this information is via the use of clinical databases formed of electronic primary care records. How reliably the diagnosis is coded in such records is however unknown. The aim of this study therefore was to assess the proportion of consultant hepatologist diagnoses of Autoimmune Hepatitis which were accurately recorded in General Practice computerised records. METHODS: Our study population were patients with Autoimmune Hepatitis diagnosed by consultant hepatologists in the Queens Medical Centre, Nottingham University Hospitals (UK) between 2004 and 2009. We wrote to the general practitioners of these patients to obtain the percentage of patients who had a valid READ code specific for Autoimmune Hepatitis. RESULTS: We examined the electronic records of 51 patients who had biopsy evidence and a possible diagnosis of Autoimmune Hepatitis. Forty two of these patients had a confirmed clinical diagnosis of Autoimmune Hepatitis by a consultant hepatologist: we contacted the General Practitioners of these patients obtaining a response rate of 90.5% (39/42 GPs). 37/39 of these GPs responded with coding information and 89% of these patients (33/37) used Read code J638.00 (Autoimmune Hepatitis) to record a diagnosis. CONCLUSIONS: The diagnosis of Autoimmune Hepatitis made by a Consultant Hepatologist is accurately communicated to and electronically recorded by primary care in the UK. As a large proportion of cases of Autoimmune Hepatitis are recorded in primary care, this minimises the risk of introducing selection bias and therefore selecting cases using these data will be a valid method of conducting population based studies on Autoimmune Hepatitis.

Primary biliary cirrhosis does not increase the risk of UTIs following diagnosis compared to other chronic liver diseases?

BACKGROUND: Urinary Tract Infections (UTIs) occur more frequently in patients with Primary Biliary Cirrhosis (PBC). Previous studies have compared UTI occurrence in PBC and general population controls, however, it remains unclear if UTI is a feature of all chronic liver diseases (CLD)s, or is specific to PBC, or if this is a cause or consequence of PBC. AIMS: We aimed to determine if UTIs are more common after a diagnosis of PBC compared to general population and CLD controls. METHODS: A cohort study was conducted using the General Practice Research Database. We selected all cases of PBC plus 10 age- and sex-matched general population controls, and an unmatched group with other CLDs. We formed a Cox-proportional hazard model of time to first UTI following diagnosis. RESULTS: Two hundred and forty-eight (24.6%) of PBC cases had a UTI event compared with 2127 (21.1%) of matched and 2131 (11.7%) of the unmatched CLD controls. Comparing PBC with matched controls showed an approximately 30% increased risk of UTI [hazard ratio (HR) 1.33 confidence interval (CI) 1.17-1.52]. Adjusting for diabetes, smoking and previous UTI reduced this (HR 1.25 CI 1.09-1.42). The Hazard Ratio comparing PBC with unmatched CLD controls was 2.00 (CI 1.76-2.28), but this became non-significant when adjusting for age, sex, diabetes, smoking and previous UTI 0.98 (0.86-1.12). CONCLUSIONS: There is increased risk of UTI in PBC patients compared to general population controls, but not compared to CLD controls suggesting that this association is not specific to PBC after diagnosis.

An increased risk of urinary tract infection precedes development of primary biliary cirrhosis.

BACKGROUND: Primary Biliary Cirrhosis is known to be associated with Urinary Tract Infections (UTIs), but whether these precede or follow the liver disease is unclear. We have therefore attempted to determine whether UTIs are more common in people with Primary Biliary Cirrhosis (PBC) prior to their diagnosis. METHODS: We conducted a case control study in the General Practice Research Database. All cases of PBC first recorded at least one year after entry to the dataset were selected along with up to 10 controls matched for age, sex. A second unmatched control group who had Chronic Liver Diseases but not PBC were chosen. The main exposures studied were the occurrence of Urinary tract infections and pyelonephritis at least one or at least five years before diagnosis. We also performed an analysis restricted to those younger than 55 at diagnosis, as we hypothesized the relationship to be stronger in the younger age group. RESULTS: PBC is associated with UTI prior to diagnosis, OR 1.50 (CI 1.26-1.78), which was similar 5 years prior to diagnosis and after adjusting for smoking. The strongest relationships were observed in pyelonephritis exposures five years before diagnosis in cases under 55 years: adjusted odds ratios were 2.60 (1.02-6.63) in comparison with matched general population controls and adjusted odds ratios were OR 2.45 (1.02-5.59) in the comparison with chronic liver disease controls. CONCLUSIONS: We found that the association between urosepsis and PBC is specific to this disease and precedes the diagnosis of PBC in a manner not previously observed in human data. This is consistent with a causal relationship.

Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme.

AIMS: To determine whether the risk of adverse cardiovascular (CV) outcomes associated with diabetes differs in patients with low and preserved ejection fraction (EF) heart failure (HF). METHODS AND RESULTS: We analysed outcomes in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme which randomized 7599 patients with symptomatic HF and a broad range of EF. The prevalence of diabetes was 28.3% in patients with preserved EF (>40%) and 28.5% in those with low EF (

Discordant short- and long-term outcomes associated with diabetes in patients with heart failure: importance of age and sex: a population study of 5.1 million people in Scotland.

BACKGROUND: Diabetes and heart failure frequently coexist. Our aim was to assess the association between diabetes and short- and long-term outcomes in all patients admitted to the hospital for the first time with heart failure in Scotland between 1986 and 2003. METHODS AND RESULTS: A total of 116 556 patients were studied, of whom 13% (n=15 161) had a diagnosis of diabetes. At 30 days, diabetes was associated with a lower case fatality. By 1 year, the association between diabetes and better outcome was reversed, and diabetes was a significant independent predictor of higher case fatality. The longer term risk of death associated with diabetes was greatest in younger patients. In patients aged 65 years or younger, the hazard ratio for mortality at 5 years associated with diabetes was 1.41 (95% CI, 1.31 to 1.52) for men and 1.64 (1.50 to 1.79) for women. The risk associated with diabetes was less in patients aged 75 years or older: a hazard ratio in men 1.16 (1.10 to 1.22) and in women 1.15 (1.10 to 1.20). In the younger age group the risk associated with diabetes was significantly greater in women than in men (P=0.005 for diabetes-sex interaction). Diabetes was also a significant independent predictor of heart failure readmission, and again the risk was greatest in younger women. CONCLUSIONS: Although diabetes was associated with a lower case fatality at 30 days, by 1 year it was a significant independent predictor of higher case fatality. The risk associated with diabetes was greatest in young patients, and in young patients the risk was greatest in women.