Early Life and Childhood Environmental Exposures, More Than Genetic Predisposition, Influence Age of Diagnosis in a Diverse Cohort of 2952 Patients With IBD.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) develops from a combination of genetic and environmental factors. The aim of this study was to determine the contribution of established environmental risk factors and genetic risk on age of IBD diagnosis in a diverse cohort. METHODS: IBD patients in clinic completed detailed questionnaires. Blood was drawn for genetic analysis. Environmental risk factors and age of diagnosis were analyzed by ethnicity (Hispanic/Latinx or non-Hispanic White [NHW] individuals) and IBD subtype (ulcerative colitis or Crohn's disease [CD]). Weighted genetic risk scores and environmental risk scores were developed. We examined the relationship between environmental risk scores, genetic risk scores, and age of diagnosis. RESULTS: A total of 2952 patients were included: 58.9% had CD. A total of 46.83% were of Hispanic background. Early life exposures like cesarean delivery and being born in a developed country were associated with a younger age of IBD diagnosis. Childhood exposures such as frequent plastic water bottle use and having more than 1 bathroom at home were associated with a younger age of IBD. Hispanic and NHW individuals shared similar susceptibilities to environmental exposures. Environmental factors explained 21% of the variance in age of CD diagnosis and 39% in ulcerative colitis. In models incorporating genetic risk score and environmental risk score, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups. CONCLUSIONS: Early life and childhood exposures impact IBD diagnosis and influence Hispanic and NHW individuals similarly. A cumulative environmental risk score contributes more to age of IBD diagnosis than genetic risk.

Social barriers influence inflammatory bowel disease (IBD) outcomes and disproportionally affect Hispanics and non-Hispanic Blacks with IBD.

Background: The impact of social determinants of health in inflammatory bowel disease (IBD) remains understudied. We evaluated the impact of social barriers on IBD outcomes within a diverse cohort of patients. Methods: We performed a cross-sectional study on adult IBD patients and assessed known social determinants of health. We calculated the total prevalence of these barriers in the sample as a whole and within each ethnic group. We summed the number of barriers present for each individual to create a cumulative social barrier score (SBS), and we evaluated the relationship of each barrier and of the cumulative SBS with IBD outcomes, including disease activity and depressive symptoms. Results: A total of 316 patients were included in the study. Disparities in the prevalence of social barriers emerged by ethnicity: non-Hispanic Blacks reported the greatest number of social barriers, followed by Hispanic patients. Prevalent social barriers included financial strains (38.4%), such as food insecurity, medical care delays (~30%), and low educational attainment (26.8%). Social barriers associated with poor IBD outcomes included low educational attainment, poor health literacy, and financial insecurity. High SBS was associated with greater depressive symptoms [odds ratio (OR) 1.94, 95% confidence interval (CI) 1.21-2.9, p = 0.001] and lower reported use of medications. Greater ulcerative colitis (UC) disease activity was observed in patients with greater SBS. No associations were identified between SBS and IBD surgeries, hospitalizations, or disease location. Conclusion: Our study identifies social barriers that may impact IBD care and are disproportionately higher in non-Hispanic Blacks and Hispanics in the United States. Future studies should focus on implementing interventions to reduce these barriers and improve delivery of care.

Rates of decompensation, hepatocellular carcinoma and mortality in AMA-negative primary biliary cholangitis cirrhosis.

BACKGROUND: The natural history of patients with anti-mitochondrial antibody (AMA)-negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant results. Furthermore, most studies of AMA-negative PBC have limited numbers of patients with cirrhosis and liver-related outcomes. METHODS: We investigated the association of AMA-negative PBC and the development of death, liver-related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. RESULTS: In a cohort of 521 patients with PBC cirrhosis (65 AMA-negative) with a total follow-up of 2504.3 person-years (PY) from cirrhosis diagnosis, patients with AMA-negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA-negative PBC cirrhosis was associated with similar unadjusted rates of liver-related death (4.6 vs 5.9 per 100 PY, P = .44), overall death (7.7 vs 9.6 per 100 PY, P = .31), decompensation (7.3 vs 5.1 per 100 PY, P = .12) and HCC (0.6 vs 1.0 per 100 PY, P = .63) to AMA-positive PBC. After adjusting for confounders, AMA-negative PBC cirrhosis was associated with similar rates of liver-related death (sub-Hazard Ratio [sHR] 1.27, 95% CI 0.71-2.28, P = .42, death [sHR] 1.24, 95% CI 0.81-1.90, P = .32), decompensation (sHR 1.05, 95% CI 0.56-1.98, P = .87) and HCC (sHR 0.48, 95% CI 0.11-2.10, P = .33) to AMA-positive patients. CONCLUSION: In a cohort of predominantly male patients, AMA-negative PBC cirrhosis was associated with similar rates of overall or liver-related death, HCC or decompensation compared with AMA-positive disease.

Ursodeoxycholic Acid Response Is Associated With Reduced Mortality in Primary Biliary Cholangitis With Compensated Cirrhosis.

INTRODUCTION: Patients with cirrhosis and men have been under-represented in most studies examining the clinical benefit of response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC). The aim of this study was to study the association of UDCA response and liver-related death or transplantation, hepatic decompensation, and hepatocellular carcinoma (HCC) in patients with PBC cirrhosis. METHODS: We conducted a retrospective cohort study of veterans, predominantly men, with PBC and compensated cirrhosis to assess the association of UDCA response with the development of all-cause and liver-related mortality or transplantation, hepatic decompensation, and HCC using competing risk time-updating Cox proportional hazards models. RESULTS: We identified 501 subjects with PBC and compensated cirrhosis, including 287 UDCA responders (1,692.8 patient-years [PY] of follow-up) and 214 partial responders (838.9 PY of follow-up). The unadjusted rates of hepatic decompensation (3.8 vs 7.9 per 100 PY, P < 0.0001) and liver-related death or transplantation (3.7 vs 6.2 per 100 PY, P < 0.0001) were lower in UDCA responders compared with partial responders. UDCA response was associated with a lower risk of hepatic decompensation (subhazard ratio [sHR] 0.54, 95% confidence interval [CI] 0.31-0.95, P = 0.03), death from any cause or transplantation (adjusted hazard ratio 0.49, 95% CI 0.33-0.72, P = 0.0002), and liver-related death or transplantation (sHR 0.40, 95% CI 0.24-0.67, P = 0.0004), but not HCC (sHR 0.39, 95% CI 0.60-2.55, P = 0.32). In a sensitivity analysis, the presence of portal hypertension was associated with the highest UDCA-associated effect. DISCUSSION: UDCA response is associated with a reduction in decompensation, all-cause, and liver-related death or transplantation in a cohort of predominantly male patients with cirrhosis, with the highest benefit in patients with portal hypertension.

Male Sex Is Associated With Higher Rates of Liver-Related Mortality in Primary Biliary Cholangitis and Cirrhosis.

BACKGROUND AND AIMS: The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. APPROACH AND RESULTS: We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings. CONCLUSIONS: In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation.

Negative regulators of TGF-ß1 signaling in renal fibrosis; pathological mechanisms and novel therapeutic opportunities.

Elevated expression of the multifunctional cytokine transforming growth factor ß1 (TGF-ß1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-ß1 pathway (e.g., neutralizing antibodies against TGF-ß1), however, remain elusive in humans. TGF-ß1 signaling is subjected to extensive negative control at the level of TGF-ß1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-ß1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-ß1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-ß1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-ß1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-ß1 hyperactivation during chronic kidney disease (CKD) progression.

Patient Adherence to Fecal Calprotectin Testing Is Low Compared to Other Commonly Ordered Tests in Patients With Inflammatory Bowel Disease.

Background: Limited data exist on adherence to fecal calprotectin (FCP) testing in patients with inflammatory bowel disease. Methods: Completion rates for patients who had at least one FCP test ordered (n = 3082) and a subgroup with C-reactive protein, complete blood count, and Clostridium difficile tests also ordered (n = 1563) were analyzed. Results: More patients completed blood than stool tests, with FCP having the poorest adherence of all tests analyzed. Older patients had higher FCP completion rates. No differences were noted in completion rates across age, gender, or ethnicity for blood tests. Conclusions: Further studies are needed to develop strategies that improve the uptake of FCP.

Reclassifying Pseudopolyps in Inflammatory Bowel Disease: Histologic and Endoscopic Description in the New Era of Mucosal Healing.

INTRODUCTION: In this study, we identify the frequency of pseudopolyps (PPs) with normal histology and their association to surrounding tissue. METHODS: Patients were enrolled in a study identifying endoscopic characteristics of PPs (n = 29) or were collected as part of our IBD biobank (n = 16). Statistical analysis included Stata v.15.0. chi-square and Student t-test. RESULTS: A total of 45 patients with 117 PP biopsies were identified. More patients with healed PP were in endoscopic remission compared with those with inflammatory PP (82.6% vs 17.4%, respectively). CONCLUSION: This is the first study to find mucosal healing of PPs and its association with deep remission.

Predicting Postoperative Complications after Acute Care Surgery: How Accurate Is the ACS NSQIP Surgical Risk Calculator?

The ACS NSQIP Surgical Risk Calculator (SRC) is an evidence-based clinical tool commonly used for evaluating postoperative risk. The goal of this study was to validate SRC-predicted complications by comparing them with observed outcomes in the acute care surgical setting. In this study, pre- and postoperative data from 1693 acute care surgeries (hernia repair, enterolysis, intestinal incision/excision and enterectomy, gastrectomy, debridement, colectomy, appendectomy, cholecystectomy, gastrorrhaphy, and incision and drainage of soft tissue, breast abscesses, and removal of foreign bodies) performed at a Level I trauma center over a five-year time period were abstracted. Predictions for any and serious complications were based on SRC were compared with observed outcomes using various measures of diagnostic. When evaluated as one group, the SRC had good discriminative power for predicting any and serious complications after acute care surgeries (Area Under the Curve (AUC) 0.79, 0.81). In addition, the SRC met Brier score requirements for an informative model overall. However, the predictive accuracy of the SRC varied for various procedures within the acute care patient population. For serious complications, the diagnostic measures ranged from an AUC of 0.61 and negative likelihood ratio of 0.716 for incision & drainage soft tissue to AUC of 0.91 and negative likelihood ratio of 0.064 for gastrorrhaphy. Length of stay was significantly underestimated by the SRC overall (8.56 days, P < 0.01) and for individual procedures. The SRC performs well at predicting complications after acute care surgeries overall; however, there is great variability in performance between procedure types. Further refinements in risk stratification may improve SRC predictions.

Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.

Protein phosphatase magnesium-dependent-1A (PPM1A) dephosphorylates SMAD2/3, which suppresses TGF-ß signaling in keratinocytes and during Xenopus development; however, potential involvement of PPM1A in chronic kidney disease is unknown. PPM1A expression was dramatically decreased in the tubulointerstitium in obstructive and aristolochic acid nephropathy, which correlates with progression of fibrotic disease. Stable silencing of PPM1A in human kidney-2 human renal epithelial cells increased SMAD3 phosphorylation, stimulated expression of fibrotic genes, induced dedifferentiation, and orchestrated epithelial cell-cycle arrest via SMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 up-regulation. PPM1A stable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted a SMAD3-dependent connective tissue growth factor and plasminogen activator inhibitor-1-induced proliferative response. Paracrine factors secreted by PPM1A-depleted epithelial cells augmented fibroblast proliferation (>50%) compared with controls. PPM1A suppression in renal cells further enhanced TGF-ß1-induced SMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3-mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression. Thus, phosphate tensin homolog on chromosome 10 is an upstream regulator of renal PPM1A deregulation. These findings establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.-Samarakoon, R., Rehfuss, A., Khakoo, N. S., Falke, L. L., Dobberfuhl, A. D., Helo, S., Overstreet, J. M., Goldschmeding, R., Higgins, P. J. Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.

Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.

Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFß1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFß1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFß1 to induce the expression of profibrotic genes and tubular apoptosis.