Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in MAFLD-Related Acute-on-Chronic Liver Failure.

BACKGROUND: The prevalence of Metabolic dysfunction associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute on chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the AARC registry. The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease (CLD) as MAFLD (or previous nomenclature such as NAFLD, NASH, or NASH-cirrhosis). Patients with coexisting other etiologies of CLD (such as alcohol, HBV, HCV, etc.) were excluded. Data was randomly split into derivation (n=258) and validation (n=111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27%, and hypertension in 29%. The dominant precipitants included viral hepatitis (HAV and HEV, 32%), drug-induced injury (DILI, 29%) and sepsis (23%). MELD-Na and AARC scores upon admission averaged 32±6 and 10.4±1.9. At 90 days, 51% survived. Non-viral precipitant, diabetes, bilirubin, INR, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for non-viral precipitant) and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. CONCLUSION: Almost half of MAFLD-ACLF patients die within 90 days. Diabetes and non-viral precipitants such as DILI and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for MAFLD-ACLF patients.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Current perspectives on fecal microbiota transplantation in inflammatory bowel disease.

Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic modality within the domain of inflammatory bowel disease (IBD). While FMT has secured approval and demonstrated efficacy in addressing recurrent and refractory Clostridioides difficile infection, its application in IBD remains an area of active exploration and research. The current status of FMT in IBD reflects a nuanced landscape, with ongoing investigations delving into its effectiveness, safety and optimal implementation. Early-stage clinical trials and observational studies have provided insights into the potential of FMT to modulate the dysbiotic gut microbiota associated with IBD, aiming to mitigate inflammation and promote mucosal healing. However, considerable complexities persist, including variations in donor selection, treatment protocols and outcome assessments. Challenges in standardizing FMT protocols for IBD treatment are compounded by the dynamic nature of the gut microbiome and the heterogeneity of IBD itself. Despite these challenges, enthusiasm for FMT in IBD emanates from its capacity to address gut microbial dysbiosis, signifying a paradigm shift towards more comprehensive approaches in IBD management. As ongoing research progresses, an enhanced understanding of FMT's role in IBD therapy is anticipated. This article synthesizes the current status of FMT in IBD, elucidating the attendant challenges and aspiring towards the refinement of its application for improved patient outcomes.

Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Reduced expression of Ankyrin-G and E-cadherin in duodenal mucosal biopsy of subjects with celiac disease.

Confirmatory diagnosis of celiac disease (CD) include histopathology of duodenal biopsy and tissue trans-glutaminase-IgA. Identification of tissue-specific histological markers is warranted to improve the diagnosis. A genetic study in CD identified the association of ankyrin-G that connects E-cadherin with ß2-spectrin in epithelial cells of the duodenal tissue. We attempted to investigate the differential expression of ankyrin-G, E-cadherin and ß2-spectrin in duodenal biopsy of CD subjects compared to non-CD controls. Duodenal tissue was collected from 83 study participants, of which 50 were CD, and 33 were non-CD controls. Whole RNA was isolated from 32 CD and 23 non-CD controls from available tissues, and differential mRNA expression was measured using real-time PCR. Tissue sections from 18 CD cases and 10 non-CD controls were immunostained using monoclonal antibodies. Tissue immunohistochemistry were evaluated for differential expression and pattern of expression. RT-PCR revealed significantly reduced expression of ankyrin-G (fold change=0.63; p=0.03) and E-cadherin (fold change=0.50; p=0.02) among CD subjects compared to non-CD controls. Tissue immunohistochemistry confirmed the reduced expression of ankyrin-G and E-cadherin in CD. Differential expression is grossly limited within the outer columnar epithelial cell layer. Expression fold change of E-cadherin was seen to partially correlate with the serum tTG level (r=0.4; p=0.04). In CD, reduced expression of two key cytoskeletal proteins (ankyrin-G and E-cadherin) in duodenum mucosa was observed, which indicates its implication in disease biology and could be tested as a tissue-specific biomarker for CD. Functional studies may unravel the specific contribution of these proteins in CD pathophysiology.

Effectiveness of Tofacitinib in Ulcerative Proctitis Compared to Left Sided Colitis and Pancolitis.

BACKGROUND: Ulcerative proctitis (UP), though associated with high symptom burden and poor quality of life, is excluded from most of the randomized controlled trials in UC, including the OCTAVE trials. We aimed to analyse the effectiveness of tofacitinib in UP, and compare it to that in left sided colitis (LSC) and pancolitis (PC). METHODS: This was a prospective cohort study. Patients with either steroid-dependent or refractory ulcerative colitis, who received tofacitinib, were divided into three groups based on the disease extent [UP, LSC and PC]. The primary outcome was comparison of proportion of patients in clinical remission in the three groups, at weeks 8, 16 and 48. Safety outcomes were reported using incidence rate per patient year of exposure. RESULTS: Clinical remission was achieved in 47%(15/32), 24%(23/94), and 43%(23/54) of patients at week 8, 56%(18/32), 37%(35/94), and 56%(30/54) of patients at week 16, and 59%(19/32), 38%(36/94), and 24%(13/54) of patients at week 48 in groups UP, LSC and PC, respectively. Corticosteroid-free clinical remission rates were significantly higher in patients in groups UP at week 48. Five (15%) patients with UP were primary non-responders to tofacitinib at week 16, while three (9%) patients had secondary loss of response at week 48. The probability of sustained clinical response was highest in patients with UP. Patients with UP had the lowest incidence of adverse effects. CONCLUSION: The effectiveness of tofacitinib in inducing and maintaining clinical remission is greater in patients with UP compared to LSC and PC.

Burden of Anxiety, Depression and Perceived Stress in Patients with Inflammatory Bowel Disease: A Cohort Study from North India.

BACKGROUND: Patients with Inflammatory bowel disease (IBD) are susceptible to psychiatric co-morbidities. We aimed to ascertain the burden of anxiety, depression, and perceived stress in patients with IBD from north India. METHODS: Consenting adult patients with an established diagnosis of IBD were enrolled. The enrolled patients filled the Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS) questionnaires. The patient and disease characteristics were analyzed to determine the correlations and predictors of psychiatric comorbidities. RESULTS: A total of 318 patients (255 UC, 63 CD; mean age 40.13 ± 12.06 years, 168 [52.8%] males; mean partial Mayo score 2.10 ± 2.35; and mean HBI 2.77 ± 2.13) were enrolled. The prevalence of anxiety, depression and moderate to high perceived stress was 14%, 12%, and 41%, respectively. Females had higher mean perceived stress, anxiety and depression scores compared to males. The partial Mayo score (PMS) correlated poorly with anxiety (ρ = 0.083, p = 0.187), depression (ρ = 0.123, p = 0.49) and perceived stress (ρ = 0.169; p = 0.007). The Harvey Bradshaw index (HBI) correlated fairly with anxiety (ρ = 0.336, p = 0.007) and poorly with depression (ρ = 0.287, p = 0.022) and perceived stress (ρ = 0.20; p = 0.117). Younger age (OR 0.93, 95% CI 0.90-0.97; p = 0.001) and hand-grip strength (OR 4.63, 95% CI 1.88-11.42; p = 0.001) predicted anxiety in patients with UC while rural area of residence (OR 4.75, 95% CI 1.03-21.98; p = 0.046) and HBI (OR 1.60, 95% CI 1.12-2.29; p = 0.009) were significant predictors of anxiety in patients with CD. CONCLUSION: Psychiatric comorbidities are common in patients with IBD, with higher prevalence in females. Young adults with UC and sarcopenia; and individuals with active CD living in rural areas are at an increased risk of anxiety.

Tofacitinib Versus Oral Prednisolone for Induction of Remission in Moderately Active Ulcerative Colitis [ORCHID]: A Prospective, Open-Label, Randomized, Pilot Study.

BACKGROUND: Oral corticosteroids are first-line agents to induce remission in moderately active ulcerative colitis [UC], but are associated with adverse effects. We compared the efficacy and safety of tofacitinib and prednisolone for induction of remission in moderately active UC. METHODS: This was a single-centre, prospective, open-label, randomized, active-controlled pilot study. Eligible patients [aged ≥18 years] had moderately active UC. Participants were randomly assigned to receive either prednisolone [40 mg daily, tapered by 5 mg every week] or tofacitinib [10 mg twice daily] for 8 weeks. The primary endpoint was composite remission [defined as total Mayo clinic score ≤2, with endoscopic sub-score of 0 and faecal calprotectin <100 µg/g] at 8 weeks. RESULTS: Seventy-eight patients were randomly assigned to either of the treatment groups. At week 8, the proportion of patients achieving composite remission in the tofacitinib [7/43, 16.28%] and prednisolone groups [3/35, 8.57%] were not significantly different (odds ratio [OR] 2.07, 95% confidence interval [CI] 0.49-8.70; p = 0.31). The time to achieve symptomatic remission [normal stool frequency with absence of rectal bleeding] was similar (10 days, interquartile range [IQR 7-18.75] and 10 days [IQR 5-12.5] for tofacitinib and prednisolone, respectively; p = 0.25) in the two groups. One patient each in the tofacitinib and prednisolone group discontinued treatment due to development of pulmonary tuberculosis and pustular acne, respectively. One patient receiving tofacitinib developed herpes zoster, but did not require cessation of therapy. No serious adverse events or major adverse cardiovascular events were observed. CONCLUSION: In patients with moderately active UC, there was no difference in the efficacy and safety of tofacitinib and oral prednisolone for induction of remission at 8 weeks. TRAIL REGISTRATION: Clinical Trials Registry of India [CTRI/2021/10/037641].

Trends of inflammatory bowel disease from the Global Burden of Disease Study (1990-2019).

BACKGROUND: The global burden of inflammatory bowel disease (IBD) is reportedly increasing. Methodologies and datasets are routinely updated, allowing for more accurate estimates to guide healthcare policy. METHODS: The Global Burden of Diseases, Injuries and Risk Factors Study (GBD) dataset was accessed and the trends in IBD at the global and regional levels from 1990 to 2019 were estimated for incidence, prevalence, deaths, years of life lost (YLL), years lived with disability (YLD) and disability-adjusted life-years (DALYs) per 100,000 population. The three decadal trends of the disease measures were calculated. RESULTS: In 2019, there were 4.9 million (95% Uncertainty Interval [UI] 4.3-5.5) cases of IBD globally. The age-standardized prevalence and incidence rates decreased from 73.23 (95% UI 63.8-83.6) and 6.1 (95% UI 5.3-6.9) in 1990 to 59.2 (95% UI 52.7-66.4) and 4.9 (95% UI 4.4-5.6) in 2019, respectively. Like prior estimates, the highest age-standardized prevalence and incidence rates occurred in North America, but the lowest rates were reported in Oceania (209.5 [195.4-224.4] and 24.5 [22.6-26.7] and 3.87 [3.1-4.7] and 0.5 [0.5-0.7], respectively) and not the Caribbean, as previously reported. High socio-demographic index (SDI) locations had the highest age-standardized prevalence rate, though the rates declined in 2019 compared to 1990. The age-standardized prevalence and incidence rates increased in middle, low middle and low SDI quintiles over the three decades. The age-standardized rates for deaths, DALYs, YLD and YLL decreased globally from 1990 to 2019. Between 1990 and 2019 the total number of patients with IBD in India doubled from 0.13 million (95% UI 0.10-0.16) to 0.27 million (95% UI 0.21-0.33) with age-standardized incidence rate increasing from 2.23 (95% UI 1.85-2.73) to 2.34 (95% UI 1.95-2.86). CONCLUSION: This analysis of the GBD 2019 database demonstrates that the overall global burden of IBD is lower than previously estimated, but an increasing disease burden is observed in the middle and low-SDI locations.

A duodenal mucosa transcriptome study identified reduced expression of a novel gene CDH18 in celiac disease.

BACKGROUND: Celiac disease (CD) a complex immune disease that affects duodenal mucosa. Identification of tissue specific biomarkers is expected to improve the existing biopsy based CD diagnosis. AIMS: To investigate the differentially expressed genes (DEGs) in duodenal mucosa tissue to identify clinically relevant gene expression pattern in CD. METHODS: Whole RNA extracted from the duodenal biopsies of three CD patients and four non-CD controls were sequenced. Significant DEGs were identified. Prioritized DEGs were validated using qRT-PCR in an independent group (CD=23; Control=26). Enriched pathways were analyzed, protein-protein interaction networks were evaluated. RESULTS: 923 DEGs comprising of 135 up-regulated, and 788 down-regulated genes, with p-value≤0.05; log2FC>2 or <-2 were identified. A novel down-regulated gene CDH18 (p = 0.03; log2FC=-0.74) was identified. Previously known CXCL9 was replicated. CDH18, a trans-membrane protein was found to interact with other CDH proteins, α/ß catenins, and other membrane transporters such as SLC and ABCB. Pathways and protein networks contributing in channel activity (p = 2.15E-12), membrane transporters (p = 2.15E-12), and cellular adhesion (p = 8.05E-6) were identified. CONCLUSIONS: CDH18, a novel DEG identified in the present study is a pivotal gene involved in maintaining epithelial membrane organization and integrity. The functional significance of lower expression of CDH18 in pathogenesis of CD warranted to be investigated. CDH18 expression could be tested for its effectiveness in diagnostic, prognostic and therapeutic purposes.

Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial.

INTRODUCTION: Intravenous corticosteroids are the mainstay of treatment of patients hospitalized with acute severe ulcerative colitis (ASUC). However, 30%-40% of the patients are refractory to corticosteroids. We investigated whether addition of tofacitinib to corticosteroids improved the treatment responsiveness in patients with ASUC. METHODS: This single-center, double-blind, placebo-controlled trial randomized adult patients with ASUC (defined by the Truelove Witts severity criteria) to receive either tofacitinib (10 mg thrice daily) or a matching placebo for 7 days while continuing intravenous corticosteroids (hydrocortisone 100 mg every 6 hours). The primary end point was response to treatment (decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy) by day 7. The key secondary outcome was the cumulative probability of requiring initiation of infliximab or undergoing colectomy within 90 days following randomization. All analyses were performed in the intention-to-treat population. RESULTS: A total of 104 patients were randomly assigned to a treatment group (53 to tofacitinib and 51 to placebo). At day 7, response to treatment was achieved in 44/53 (83.01%) patients receiving tofacitinib vs 30/51 (58.82%) patients receiving placebo (odds ratio 3.42, 95% confidence interval 1.37-8.48, P = 0.007). The need for rescue therapy by day 7 was lower in the tofacitinib arm (odds ratio 0.27, 95% confidence interval 0.09-0.78, P = 0.01). The cumulative probability of need for rescue therapy at day 90 was 0.13 in patients who received tofacitinib vs 0.38 in patients receiving placebo (log-rank P = 0.003). Most of the treatment-related adverse effects were mild. One patient, receiving tofacitinib, developed dural venous sinus thrombosis. DISCUSSION: In patients with ASUC, combination of tofacitinib and corticosteroids improved treatment responsiveness and decreased the need for rescue therapy.

Colonic Lipoma: A Rare Cause of Intussusception.

The most common and challenging chief complaint in the emergency department is abdominal pain. Intussusception, although rare in adults, is an important etiology to consider. The diagnosis is often delayed because of the nonspecific symptoms, especially in adults. This case highlights a rare case of intussusception in a middle-aged male with a colonic lipoma as a leading point. Endo-loop was applied to the colonic lipoma, leading to the resolution of intussusception. Therefore, this can be an effective alternative to surgery in select cases.

Cardiovascular implications of inflammatory bowel disease: An updated review.

Emerging data highlights the heightened risk of atherosclerotic cardiovascular diseases (ASCVD) in patients with chronic inflammatory disorders, particularly those afflicted with inflammatory bowel disease (IBD). This review delves into the epidemiological connections between IBD and ASCVD, elucidating potential underlying mechanisms. Furthermore, it discusses the impact of current IBD treatments on cardiovascular risk. Additionally, the cardiovascular adverse effects of novel small molecule drugs used in moderate-to-severe IBD are investigated, drawing parallels with observations in patients with rheumatoid arthritis. This article aims to comprehensively evaluate the existing evidence supporting these associations. To achieve this, we conducted a meticulous search of PubMed, spanning from inception to August 2023, using a carefully selected set of keywords. The search encompassed topics related to IBD, such as Crohn's disease and ulcerative colitis, as well as ASCVD, including coronary artery disease, cardiovascular disease, atrial fibrillation, heart failure, conduction abnormalities, heart blocks, and premature coronary artery disease. This review encompasses various types of literature, including retrospective and prospective cohort studies, clinical trials, meta-analyses, and relevant guidelines, with the objective of providing a comprehensive overview of this critical intersection of inflammatory bowel disease and cardiovascular health.

Inflammatory Bowel Disease and X (Formerly Twitter) Influencers: Who Are They and What Do They Say?

Background and objective More than half of the population suffering from inflammatory bowel disease (IBD) use the internet as a primary source of information on their condition. X (formerly Twitter) has been increasingly used to disseminate healthcare-related information. In this study, we aimed to identify top influencers on the topic of IBD on X and correlate the relevance of their social media engagements with their professional expertise or academic productivity. Methods X (formerly Twitter) influence scores for the search topic IBD were obtained using Cronycle API, a proprietary software employing multiple algorithms to rank influencers. Data regarding gender, profession, location, and research productivity represented as h-index was collected. Results We collected information on the top 100 IBD influencers on X. The majority of influencers were gastroenterologists, followed by IBD advocates. Of note, 62% of the IBD influencers were from the US followed by the UK and Canada. A positive correlation was observed between the X topic score and the h-index of the influencer (r=+0.488, p<0.001) Conclusions The strong correlation observed between the X topic score and h-index suggests that social media is a viable platform for gaining information regarding IBD. Further research aimed at counteracting misleading information by providing facts and data in a succinct manner about IBD on social media is required to improve disease awareness.

Analysis of Clinical Trial Screen Failures in Inflammatory Bowel Diseases (IBD): Real World Results from the International Organization for the study of IBD.

BACKGROUND: Recruitment for randomized controlled trials (RCTs) in IBD have substantially dropped over time. This study aimed to assess reasons why IBD patients are not included in sponsored multicenter phase IIb-III RCTs. METHODS: All IOIBD members (n=58) were invited to participate. We divided barriers to participation as follow: 1) reasons patients with active IBD were not deemed appropriate for a RCT; 2) reasons qualified patients did not wish to participate; 3) reasons for screen failure (SF) in patients agreeing to participate. We assess those in a 4-week prospective study including, consecutively, all patients with symptomatic disease for whom a treatment change was required. In addition, we performed a 6-month retrospective study to further evaluate reasons for SF. RESULTS: A total of 106 patients (60 male (56.6%), 63 Crohn's disease [CD] (59.4%)), from 10 centers across the world, were included in the prospective study. A RCT has not been proposed to 65 of them (mainly due to eligibility criteria). Of the 41 patients to whom a RCT was offered, 8 refused (mainly due to reluctance to receive placebo) and 28 agreed to participate. Among these 28 patients, 5 failed their screening and 23 were finally included in a RCT. A total of 107 patients (61 male (57%), 67 CD (62.6%)), from 13 centers worldwide, were included in our retrospective study of SFs. The main reason was insufficient disease activity. CONCLUSION: This first multicenter study analyzing reasons for non-enrollment in IBD RCTs shown that we lose patients at each step. Eligibility criteria, the risk of placebo assignment and insufficient disease activity were part of the main barriers.

Management of Perianal Fistulizing Crohn's Disease.

Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.

With advances in the therapeutic armamentarium, revisiting the strategies employed to treat the perianal fistulizing Crohn's disease is essential. In the current review, we discuss the pathophysiology, classification, and management of the perianal fistulizing Crohn's disease.