Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice.

PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease affecting 30% of the global population. In this article, we summarize current expert guidelines, review clinical practice implications, and provide insight into the utility of non-invasive tests (NITs). RECENT FINDINGS: The burden of MASLD is growing with the obesity epidemic, yet disease awareness and diagnosis is low. Patients can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), which can advance to liver fibrosis, cirrhosis, hepatic decompensation, and liver cancer. NITs help identify high-risk patients who may benefit from specialty referral and MASH-directed therapy. Global societies offer various recommendations for the screening and diagnosis of MASLD utilizing evidence-based, widely accessible methods such as serum indices, NITs, and liver biopsy. Several targeted steatotic liver disease (SLD) screening tools and novel therapies are under development.

Microangiopathic Hemolytic Anemia Is a Late and Fatal Complication of Gastric Signet Ring Cell Carcinoma: A Systematic Review and Case-Control Study.

BACKGROUND: Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome that has been reported in patients with gastric signet ring cell carcinoma (SRCC). Clinical and prognostic features of MAHA in this setting have been poorly described. MATERIALS AND METHODS: We conducted a systematic review in 8 databases of gastric SRCC complicated by MAHA and performed a case-control study assessing factors associated with survival in patients with gastric SRCC and MAHA in our pooled cohort compared with age-, sex-, and stage-matched cases of gastric SRCC from the Surveillance, Epidemiology, and End Results (SEER) database. Descriptive analyses were performed and multivariable Cox-proportional hazards regression modeling was used to determine factors associated with overall survival. RESULTS: All identified patients (n = 47) were symptomatic at index presentation, commonly with back/bone pain, and dyspnea. Microangiopathic hemolytic anemia was the first manifestation of gastric SRCC in 94% of patients. Laboratory studies were notable for anemia (median 7.7 g/dL), thrombocytopenia (median 45.5 × 103/µL), and hyperbilirubinemia (median 2.3 mg/dL). All patients with MAHA had metastatic disease at presentation, most often to the bone, bone marrow, and lymph nodes. Median survival in patients with gastric SRCC and MAHA was significantly shorter than a matched SEER-derived cohort with metastatic gastric SRCC (7 weeks vs 28 weeks, P < .01). In multivariate analysis, patients with MAHA were at significantly increased risk of mortality (HR 3.28, 95% CI 2.11-5.12). CONCLUSION: Microangiopathic hemolytic anemia is a rare, late-stage complication of metastatic gastric SRCC and is associated with significantly decreased survival compared with metastatic gastric SRCC alone.

Identifying Patient and Provider-specific Gaps in Care Among Patients With Hepatitis B.

GOALS: To examine patient, provider, and health system barriers to clinical follow-up among US veterans with chronic hepatitis B virus (HBV). BACKGROUND: Studies have demonstrated deficiencies in clinical care and follow-up in HBV; however, patient, provider, and health-system barriers in non-Asian populations are understudied. STUDY: A retrospective cohort of 517 US veterans with chronic HBV at 3 diverse Veterans Affairs sites from 1999 to 2015. Laboratory testing and completion of clinical appointments were collected for 2 years following initial presentation. RESULTS: Among HBV patients, 36% had drug abuse, 41% alcohol misuse, and 45% had psychiatric disorders. Patients had an average of 4.4 primary care visits within 2 years of the index hepatitis B surface antigen positive result, 38% had psychiatry visits, 21% had a psychiatric hospitalization; 26% saw gastroenterology/hepatology specialists. Within 1 year of the index hepatitis B surface antigen positive result, 75% had alanine aminotransferase testing, 14% had HBV entered into the problem list, and 8% had serologic confirmation. In multivariable analyses, cirrhosis [odds ratio (OR)=3.42; 95% confidence interval (CI), 1.84-6.36] was associated with higher odds of appropriate laboratory testing, alcohol misuse (OR=0.45; 95% CI, 0.29-0.80) was associated lower odds. Cirrhosis (OR=2.03; 95% CI, 1.11-3.72) and ≥2 primary care visits per year (OR=1.06; 95% CI, 1.01-1.11) were associated with higher odds of completing gastroenterology/hepatology consultation, whereas ≥1 psychiatric hospitalization in 2 years was associated with lower odds (OR=0.53; 95% CI, 0.34-0.82). CONCLUSIONS: In a diverse cohort of veterans with high psychiatric comorbidity and substance abuse, important patient and provider factors influence appropriate follow-up care. Future studies should evaluate the impact of provider education and care coordination strategies in HBV.

Approach to preventive care in the elderly.

OBJECTIVE: To guide family physicians in creating preventive screening and treatment plans for their elderly patients. SOURCES OF INFORMATION: The MEDLINE database was searched for Canadian guidelines on primary health care and the elderly; guidelines or meta-analyses or practice guidelines or systematic reviews related to mass screening in those aged 80 and older and the frail elderly, limited to between 2006 and July 2016; and articles on preventive health services for the elderly related to family practice or family physicians, limited to English-language publications between 2012 and July 2016. MAIN MESSAGE: Estimating life expectancy is not an easy or precise science, but frailty is an emerging concept that can help with this. The Canadian Task Force on Preventive Health Care offers cancer screening guidelines, but they are less clear for patients older than 74 years and management plans need to be individualized. Estimating remaining years of life helps guide your recommendations for preventive screening and treatment plans. Risks often increase along with an increase in frailty and comorbidity. Conversely, benefits often diminish as life expectancy decreases. Preventive management plans should take into account the patient's perspective and be mutually agreed upon. A mnemonic device for key primary care preventive areas-CCFP, short for cancer, cardiovascular disease, falls and osteoporosis, and preventive immunizations-might be useful. CONCLUSION: Family physicians might find addressing the following areas helpful when considering a preventive health intervention: age, life expectancy (including concept of frailty), comorbidities and functional status, risks and benefits of screening or treatment, and values and preferences of the patient.

[Aborder les soins préventifs chez les aînés].

OBJECTIF: Guider les médecins de famille dans l'élaboration de plans de dépistage et de traitements préventifs à l'intention de leurs patients âgés. SOURCES DE L'INFORMATION: Une recension a été effectuée dans la base de données MEDLINE pour trouver des lignes directrices canadiennes sur les soins de santé primaires et les personnes âgées; des lignes directrices, des méta-analyses, des guides de pratique clinique ou des révisions systématiques portant sur le dépistage de masse chez les 80 ans et plus et les aînés fragiles, se limitant à ceux publiés entre 2006 et juillet 2016; et des articles sur les services de santé préventifs à l'intention des aînés et présentant un intérêt pour la pratique familiale ou les médecins de famille, limités à ceux publiés en anglais entre 2012 et juillet 2016. MESSAGE PRINCIPAL: L'estimation de l'espérance de vie n'est pas une science facile ou précise, mais la fragilité est un concept émergent susceptible d'être utile à cet égard. Le Groupe d'étude canadien sur les soins de santé préventifs propose des lignes directrices sur le dépistage du cancer, mais elles sont moins précises en ce qui concerne les patients de plus de 74 ans et il faut donc individualiser les plans de prise en charge. L'estimation des années de vie qui restent aide à orienter vos recommandations concernant les plans de dépistage et de traitements préventifs. Les risques augmentent souvent proportionnellement avec la fragilité et la comorbidité. D'autre part, les bienfaits diminuent souvent à mesure que l'espérance de vie raccourcit. Les plans de prise en charge préventive devraient tenir compte des points de vue du patient et être convenus d'un commun accord. Un moyen mnémonique pour se rappeler des principaux domaines de prévention en soins primaires - CCMF, abréviation pour cancer, cardiovasculaire, mauvais équilibre, chute et ostéoporose, fiche de vaccinations préventives - pourrait se révéler utile. CONCLUSION: Les médecins de famille pourraient trouver utile de tenir compte des éléments suivants lorsqu'ils envisagent une intervention en soins préventifs : l'âge, l'espérance de vie (incluant le concept de la fragilité), la comorbidité et l'état fonctionnel, les risques et les bienfaits du dépistage ou du traitement, de même que les valeurs et les préférences du patient.

Depression and Outcome of Fear of Falling in a Falls Prevention Program.

OBJECTIVE: To examine whether depression predicts less improvement in fear of falling and falls efficacy in older adults attending a falls prevention program (FPP). METHODS: Using a prospective observational design in an academic medical center, the authors studied 69 nondemented adults aged 55 years or older (mean age: 77.8±8.9 years) who had experienced at least one fall in the previous year and who attended the FPP. The primary outcome variable was change in severity of fear of falling during the FPP. Secondary outcome variables were change in falls efficacy and fear-related restriction of activities during the FPP. Independent variables were baseline depressive disorders and depressive symptom severity. RESULTS: Twenty-one of 69 study participants (30.4%) had a depressive disorder at baseline. Depressive disorder and depressive symptoms were not associated with change in severity of fear of falling or restriction of activity. On the other hand, depressive disorder was associated with improvement in falls efficacy, although this finding was not significant in multivariate analysis. Among participants with a depressive disorder, improvement in falls efficacy was significantly correlated with improvement in depressive symptoms. CONCLUSION: There was no association between baseline depression and change in fear of falling in this FPP. The correlation between improvement in depressive symptoms and improvement in falls efficacy raises the question as to whether a cognitive-behavioral intervention that simultaneously targets both depression and falls efficacy would be a useful component of a FPP.

Five-weekend care of the elderly certificate course: continuing professional development activity for family physicians.

PROBLEM ADDRESSED: Primary care practitioners have unique clinical challenges in caring for elderly patients and require educational courses that are specifically designed for their needs in caring for this patient population. OBJECTIVE OF PROGRAM: To improve family physicians' knowledge of and confidence in managing common geriatric problems. PROGRAM DESCRIPTION: The accredited course curriculum is delivered on 5 weekends over approximately 6 months.Each weekend focuses on a different theme including cognitive impairment, gait disorders, mental health and pain management, geriatric medical problems, and failure to thrive. Participants complete written assignments between weekend sessions, which involve self-reflection on how the new knowledge and skills gained through the course will be incorporated in the management of elderly patients in their practices. CONCLUSION: The 5-Weekend Care of the Elderly Certificate Course is an accredited continuing professional development program for primary care practitioners. Preliminary evaluation suggests improvement in participants' self-rated knowledge of and confidence in managing geriatric problems. Qualitative data show positive changes in clinical practice.

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated ß-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

A validation study of administrative data algorithms to identify patients with Parkinsonism with prevalence and incidence trends.

BACKGROUND: Epidemiological studies for identifying patients with Parkinson's disease (PD) or Parkinsonism (PKM) have been limited by their nonrandom sampling techniques and mainly veteran populations. This reduces their use for health services planning. The purpose of this study was to validate algorithms for the case ascertainment of PKM from administrative databases using primary care patients as the reference standard. METHODS: We conducted a retrospective chart abstraction using a random sample of 73,003 adults aged ≥ 20 years from a primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Physician diagnosis in the EMR was used as the reference standard and population-based administrative databases were used to identify patients with PKM from the derivation of algorithms. We calculated algorithm performance using sensitivity, specificity, and predictive values and then determined the population-level prevalence and incidence trends with the most accurate algorithms. RESULTS: We selected, '2 physician billing codes in 1 year' as the optimal administrative data algorithm in adults and seniors (≥ 65 years) due to its sensitivity (70.6-72.3%), specificity (99.9-99.8%), positive predictive value (79.5-82.8%), negative predictive value (99.9-99.7%), and prevalence (0.28-1.20%), respectively. CONCLUSIONS: Algorithms using administrative databases can reliably identify patients with PKM with a high degree of accuracy.

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents.

Chronic hepatitis B virus (HBV) infection affects over 295 million people globally and an estimated 1.6 million people in the United States. It is associated with significant morbidity and mortality due to cirrhosis, liver failure, and liver cancer. Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression, which in turn has been associated with a decreased risk of liver complications. However, current antiviral regimens are limited by concerns with adverse effects, adherence, resistance, long-term treatment, and ongoing risk for liver events. Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core/capsid inhibitors, entry inhibitors, RNA interference (siRNA/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.

Structural basis for recognition of arginine methylated Piwi proteins by the extended Tudor domain.

Arginine methylation modulates diverse cellular processes and represents a molecular signature of germ-line-specific Piwi family proteins. A subset of Tudor domains recognize arginine methylation modifications, but the binding mechanism has been lacking. Here we establish that, like other germ-line Tudor proteins, the ancestral staphylococcal nuclease domain-containing 1 (SND1) polypeptide is expressed and associates with PIWIL1/Miwi in germ cells. We find that human SND1 binds PIWIL1 in an arginine methylation-dependent manner with a preference for symmetrically dimethylated arginine. The entire Tudor domain and a bifurcated SN domain are required for this binding activity, whereas the canonical Tudor domain alone is insufficient for methylarginine ligand binding. Crystal structures show that the intact SND1 extended Tudor domain forms a wide and negatively charged binding groove, which can accommodate distinct symmetrically dimethylated arginine peptides from PIWIL1 in different orientations. This analysis explains how SND1 preferentially recognizes symmetrical dimethylarginine via an aromatic cage and conserved hydrogen bonds, and provides a general paradigm for the binding mechanisms of methylarginine-containing peptides by extended Tudor domains.

Concurrent PANK2 and OCA2 variants in a patient with retinal dystrophy, hypopigmented irides and neurodegeneration.

PURPOSE: To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese patient who presented with early-onset reduced vision, nyctalopia, and neurological symptoms. MATERIALS AND METHODS: Based on the ocular phenotype and provisional diagnosis of rod-cone dystrophy, genetic testing was pursued. Peripheral blood DNA extraction was carried out with the next-generation sequencing technique, which involved a population-specific medical exome virtual panel. Pre- and post-test counseling were carried out by clinical geneticists. RESULT: Homozygous missense variants in PANK2 {NM_153638.3}:c.655 G>A (p.(Gly219Ser)) and OCA2{NM_025160.6}:c.1327 G>A(p.(Val443Ile)) were identified. The molecular diagnoses of pantothenate kinase associated neurodegeneration (OMIM#234200) and albinism, oculocutaneous, type II (OMIM#203200) were supported by clinical findings. CONCLUSION: Two rare autosomal recessive diseases, pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) were detected in our patient. Ocular and systemic manifestations, as well as neuroimaging findings were compatible with the diseases identified. Genetic analysis is imperative in making an accurate molecular diagnosis in these rare conditions to allow timely counseling, disease prognostication and management.

Signal transfer in human protein tyrosine phosphatase PTP1B from allosteric inhibitor P00058.

Protein tyrosine phosphatases constitute a family of cytosolic and receptor-like signal transducing enzymes that catalyze the hydrolysis of phospho-tyrosine residues of phosphorylated proteins. PTP1B, encoded by PTPN1, is a key negative regulator of insulin and leptin receptor signaling, linking it to two widespread diseases: type 2 diabetes mellitus and obesity. Here, we present crystal structures of the PTP1B apo-enzyme and a complex with a newly identified allosteric inhibitor, 2-(2,5-dimethyl-pyrrol-1-yl)-5-hydroxy-benzoic acid, designated as P00058. The inhibitor binding site is located about 18 Å away from the active center. However, the inhibitor causes significant re-arrangements in the active center of enzyme: residues 45-50 of catalytic Tyr-loop are shifted at their Cα-atom positions by 2.6 to 5.8 Å. We have identified an event of allosteric signal transfer from the inhibitor to the catalytic area using molecular dynamic simulation. Analyzing change of complex structure along the fluctuation trajectory we have found the large Cα-atom shifts in external strand, residues 25-40, which occur at the same time with the shifts in adjacent catalytic p-Tyr-loop. Coming of the signal to this loop arises due to dynamic fluctuation of protein structure at about 4.0 nanoseconds after the inhibitor takes up its space. Communicated by Ramaswamy H. Sarma.

X-CHIP: an integrated platform for high-throughput protein crystallization and on-the-chip X-ray diffraction data collection.

The X-CHIP (X-ray Crystallization High-throughput Integrated Platform) is a novel microchip that has been developed to combine multiple steps of the crystallographic pipeline from crystallization to diffraction data collection on a single device to streamline the entire process. The system has been designed for crystallization condition screening, visual crystal inspection, initial X-ray screening and data collection in a high-throughput fashion. X-ray diffraction data acquisition can be performed directly on-the-chip at room temperature using an in situ approach. The capabilities of the chip eliminate the necessity for manual crystal handling and cryoprotection of crystal samples, while allowing data collection from multiple crystals in the same drop. This technology would be especially beneficial for projects with large volumes of data, such as protein-complex studies and fragment-based screening. The platform employs hydrophilic and hydrophobic concentric ring surfaces on a miniature plate transparent to visible light and X-rays to create a well defined and stable microbatch crystallization environment. The results of crystallization and data-collection experiments demonstrate that high-quality well diffracting crystals can be grown and high-resolution diffraction data sets can be collected using this technology. Furthermore, the quality of a single-wavelength anomalous dispersion data set collected with the X-CHIP at room temperature was sufficient to generate interpretable electron-density maps. This technology is highly resource-efficient owing to the use of nanolitre-scale drop volumes. It does not require any modification for most in-house and synchrotron beamline systems and offers a promising opportunity for full automation of the X-ray structure-determination process.

Atomistic simulation and measurement of pH dependent cancer therapeutic interactions with nanodiamond carrier.

In this work, we have combined constant-pH molecular dynamics simulations and experiments to provide a quantitative analysis of pH dependent interactions between doxorubicin hydrochloride (DOX) cancer therapeutic and faceted nanodiamond (ND) nanoparticle carriers. Our study suggests that when a mixture of faceted ND and DOX is dissolved in a solvent, the pH of this solvent plays a controlling role in the adsorption of DOX molecules on the ND. We find that the binding of DOX molecules on ND occurs only at high pH and requires at least ∼10% of ND surface area to be fully titrated for binding to occur. As such, this study reveals important mechanistic insight underlying an ND-based pH-controlled therapeutic platform.

Structure of Francisella tularensis peptidyl-tRNA hydrolase.

The rational design of novel antibiotics for bacteria involves the identification of inhibitors for enzymes involved in essential biochemical pathways in cells. In this study, the cloning, expression, purification, crystallization and structure of the enzyme peptidyl-tRNA hydrolase from Francisella tularensis, the causative agent of tularemia, was performed. The structure of F. tularensis peptidyl-tRNA hydrolase is comparable to those of other bacterial peptidyl-tRNA hydrolases, with most residues in the active site conserved amongst the family. The resultant reagents, structural data and analyses provide essential information for the structure-based design of novel inhibitors for this class of proteins.

Office management of gait disorders in the elderly.

OBJECTIVE: To provide family physicians with an approach to office management of gait disorders in the elderly. SOURCES OF INFORMATION: Ovid MEDLINE was searched from 1950 to July 2010 using subject headings for gait or neurologic gait disorders combined with physical examination. Articles specific to family practice or family physicians were selected. Relevant review articles and original research were used when appropriate and applicable to the elderly. MAIN MESSAGE: Gait and balance disorders in the elderly are difficult to recognize and diagnose in the family practice setting because they initially present with subtle undifferentiated manifestations, and because causes are usually multifactorial, with multiple diseases developing simultaneously. To further complicate the issue, these manifestations can be camouflaged in elderly patients by the physiologic changes associated with normal aging. A classification of gait disorders based on sensorimotor levels can be useful in the approach to management of this problem. Gait disorders in patients presenting to family physicians in the primary care setting are often related to joint and skeletal problems (lowest-level disturbances), as opposed to patients referred to neurology specialty clinics with sensory ataxia, myelopathy, multiple strokes, and parkinsonism (lowest-, middle-, and highest-level disturbances). The difficulty in diagnosing gait disorders stems from the challenge of addressing early undifferentiated disease caused by multiple disease processes involving all sensorimotor levels. Patients might present with a nonspecific "cautious" gait that is simply an adaptation of the body to disease limitations. This cautious gait has a mildly flexed posture with reduced arm swing and a broadening of the base of support. This article reviews the focused history (including medication review), practical physical examination, investigations, and treatments that are key to office management of gait disorders. CONCLUSION: Family physicians will find it helpful to classify gait disorders based on sensorimotor level as part of their approach to office management of elderly patients. Managing gait disorders at early stages can help prevent further deconditioning and mobility impairment.

Fully covered metal biliary stents: A review of the literature.

Fully covered self-expandable metal stents (FCSEMS) represent the latest advancement of metal biliary stents used to endoscopically treat a variety of obstructive biliary pathology. A large stent diameter and synthetic covering over the tubular mesh prolong stent patency and reduce risk for tissue hyperplasia and tumor ingrowth. Additionally, FCSEMS can be easily removed. All these features address issues faced by plastic and uncovered metal stents. The purpose of this paper is to comprehensively review the application of FCSEMS in benign and malignant biliary strictures, biliary leak, and post-sphincterotomy bleeding.