Browsing by Author "Serrano, Jose"
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Item A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes(The Endocrine Society, 2023) Hart, Phil A.; Kudva, Yogish C.; Yadav, Dhiraj; Andersen, Dana K.; Li, Yisheng; Toledo, Frederico G. S.; Wang, Fuchenchu; Bellin, Melena D.; Bradley, David; Brand, Randall E.; Cusi, Kenneth; Fisher, William; Mather, Kieren; Park, Walter G.; Saeed, Zeb; Considine, Robert V.; Graham, Sarah C.; Rinaudo, Jo Ann; Serrano, Jose; Goodarzi, Mark O.; Medicine, School of MedicinePurpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases.Item Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children with Acute Recurrent or Chronic Pancreatitis(Wiley, 2022-11) Uc, Aliye; Cress, Gretchen A.; Wang, Fuchenchu; Abu-El-Haija, Maisam; Ellery, Kate M.; Fishman, Douglas S.; Gariepy, Cheryl E.; Gonska, Tanja; Lin, Tom K.; Liu, Quin Y.; Mehta, Megha; Maqbool, Asim; McFerron, Brian A.; Morinville, Veronique D.; Ooi, Chee Y.; Perito, Emily R.; Schwarzenberg, Sarah Jane; Sellers, Zachary M.; Serrano, Jose; Shah, Uzma; Troendle, David M.; Wilschanski, Michael; Zheng, Yuhua; Yuan, Ying; Lowe, Mark E.; Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer; Pediatrics, School of MedicineObjectives: To investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. Results: Of 689 children, 365 had ARP (53%), 324 CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. Conclusions: Children with family history of CP, constant pain or obstructive risk factors should raise suspicion for CP.Item Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children with Acute Recurrent or Chronic Pancreatitis(Wiley, 2022) Uc, Aliye; Cress, Gretchen A.; Wang, Fuchenchu; Abu-El-Haija, Maisam; Ellery, Kate M.; Fishman, Douglas S.; Gariepy, Cheryl E.; Gonska, Tanja; Lin, Tom K.; Liu, Quin Y.; Mehta, Megha; Maqbool, Asim; McFerron, Brian A.; Morinville, Veronique D.; Ooi, Chee Y.; Perito, Emily R.; Schwarzenberg, Sarah Jane; Sellers, Zachary M.; Serrano, Jose; Shah, Uzma; Troendle, David M.; Wilschanski, Michael; Zheng, Yuhua; Yuan, Ying; Lowe, Mark E.; Pediatrics, School of MedicineObjectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.Item Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms (DREAM) Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)(Wolters Kluwer, 2022) Dungan, Kathleen M.; Hart, Phil A.; Andersen, Dana K.; Basina, Marina; Chinchilli, Vernon M.; Danielson, Kirstie K.; Evans-Molina, Carmella; Goodarzi, Mark O.; Greenbaum, Carla J.; Kalyani, Rita R.; Laughlin, Maren R.; Pichardo-Lowden, Ariana; Pratley, Richard E.; Serrano, Jose; Sims, Emily K.; Speake, Cate; Yadav, Dhiraj; Bellin, Melena D.; Toledo, Frederico G. S.; Type 1 Diabetes in Acute Pancreatitis Consortium; Medicine, School of MedicineObjectives: The metabolic abnormalities that lead to diabetes mellitus (DM) following an episode of acute pancreatitis (AP) have not been extensively studied. This manuscript describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) Study. Methods: Three months after an index episode of AP, participants without pre-existing DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three sub-cohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently-sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. Conclusions: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.Item Association of Chronic Pancreatitis Pain Features With Physical, Mental, and Social Health(Elsevier, 2023) Yadav, Dhiraj; Askew, Robert L.; Palermo, Tonya; Li, Liang; Andersen, Dana K.; Chen, Minxing; Fisher, William E.; Fogel, Evan L.; Forsmark, Christopher E.; Hart, Phil A.; Othman, Mohamed O.; Pandol, Stephen J.; Park, Walter G.; Topazian, Mark D.; Van Den Eeden, Stephen K.; Swaroop Vege, Santhi; Yang, Yunlong; Serrano, Jose; Conwell, Darwin L.; Consortium for the Study of Chronic Pancreatitis; Diabetes, and Pancreatic Cancer (CPDPC); Medicine, School of MedicineBackground and aims: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities. Methods: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants completed the PROMIS-Global Health, which captures global physical and mental health, and the PROMIS-29 profile, which captures 7 symptom domains. Self-reported pain was categorized by severity (none, mild-moderate, severe) and temporal nature (none, intermittent, constant). Demographic and clinical data were obtained from the PROCEED database. Results: Pain was significantly associated with impairments in physical and mental health. Compared with participants with no pain, CP participants with severe pain (but not mild-moderate pain) had more decrements in each PROMIS domain in multivariable models (effect sizes, 2.54-7.03) and had a higher prevalence of clinically significant depression, anxiety, sleep disturbance, and physical disability (odds ratios, 2.11-4.74). Similar results were noted for constant pain (but not intermittent pain) for PROMIS domains (effect sizes, 4.08-10.37) and clinically significant depression, anxiety, sleep disturbance and physical disability (odds ratios, 2.80-5.38). Conclusions: Severe and constant pain are major drivers for poor psychological and physical health in CP. Systematic evaluation and management of psychiatric comorbidities and sleep disturbance should be incorporated into routine management of patients with CP.Item Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study(Elsevier, 2017-04) Nicoletti, Paola; Aithal, Guruprasad P.; Bjornsson, Einar S.; Andrade, Raul J.; Sawle, Ashley; Arrese, Marco; Barnhart, Huiman X.; Bondon-Guitton, Emmanuelle; Hayashi, Paul H.; Bessone, Fernando; Carvajal, Alfonso; Cascorbi, Ingolf; Cirulli, Elizabeth T.; Chalasani, Naga; Conforti, Anita; Coulthard, Sally A.; Daly, Mark J.; Day, Christopher P.; Dillon, John F.; Fontana, Robert J.; Grove, Jane I.; Hallberg, Pär; Hernández, Nelia; Ibáñez, Luisa; Kullak-Ublick, Gerd A.; Laitinen, Tarja; Larrey, Dominique; Lucena, M. Isabel; Maitland-van der Zee, Anke H.; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Powell, Elizabeth E.; Qin, Shengying; Serrano, Jose; Stephens, Camilla; Stolz, Andrew; Wadelius, Mia; Watkins, Paul B.; Floratos, Aris; Shen, Yufeng; Nelson, Matthew R.; Urban, Thomas J.; Daly, Ann K.; International Drug-Induced Liver Injury Consortium; Drug-Induced Liver Injury Network Investigators; International Serious Adverse Events Consortium; Medicine, School of MedicineBACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.Item Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies(Wolters Kluwer, 2023) Saloman, Jami L.; Conwell, Darwin L.; Fogel, Evan; Vege, Santhi Swaroop; Li, Liang; Li, Shuang; Andersen, Dana K.; Fisher, William E.; Forsmark, Christopher E.; Hart, Phil A.; Pandol, Stephen J.; Park, Walter G.; Evans Phillips, Anna; Topazian, Mark; Van Den Eeden, Stephen K.; Serrano, Jose; Yadav, Dhiraj; Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer; Medicine, School of MedicinePain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.Item Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group(Public Library of Science, 2018-10-25) Bonkovsky, Herbert L.; Barnhart, Huiman X.; Foureau, David M.; Steuerwald, Nury; Lee, William M.; Gu, Jiezhun; Fontana, Robert J.; Hayashi, Paul J.; Chalasani, Naga; Navarro, Victor M.; Odin, Joseph; Stolz, Andrew; Watkins, Paul B.; Serrano, Jose; US Drug-Induced Liver Injury Network; Acute Liver Failure Study Group; Medicine, School of MedicineChanges in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.8 g/dL) and lower levels of only four analytes, namely, IL-9, IL-17, PDGF-bb, and RANTES, were highly predictive of early death [accuracy = 96%]. The goals of this study were to assess levels of the same 27 immune analytes in larger numbers of subjects to learn whether the earlier findings would be confirmed in new and larger cohorts of subjects, compared with a new cohort of healthy controls. We studied 127 subjects with acute DILI enrolled into the US DILIN. We also studied 118 subjects with severe acute liver injury of diverse etiologies, enrolled into the ALF SG registry of subjects. Controls comprised 63 de-identified subjects with no history of liver disease and normal liver tests. Analytes associated with poor outcomes [death before 6 months, n = 32 of the total of 232 non-acetaminophen (Apap) subjects], were lower serum albumin [2.6 vs 3.0 g/dL] and RANTES [6,458 vs 8,999 pg/mL] but higher levels of IL-6 [41 vs 18], IL-8 [78 vs 48], and MELD scores [30 vs 24]. Similar patterns were observed for outcome of death/liver transplant within 6 months. A model that included only serum albumin < 2.8 g/dL and RANTES below its median value of 11,349 had 83% (or 81%) accuracy for predicting early death (or early death/liver transplant) in 127 subjects from DILIN. No patterns of serum immune analytes were reflective of the etiologies of acute liver failure, but there were cytokine patterns that predicted prognosis in both acute DILI and ALF.Item Design and Rationale for the Use of Magnetic Resonance Imaging Biomarkers to Predict Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium(Wolters Kluwer, 2022) Tirkes, Temel; Chinchilli, Vernon M.; Bagci, Ulas; Parker, Jason G.; Zhao, Xuandong; Dasyam, Anil K.; Feranec, Nicholas; Grajo, Joseph R.; Shah, Zarine K.; Poullos, Peter D.; Spilseth, Benjamin; Zaheer, Atif; Xie, Karen L.; Wachsman, Ashley M.; Campbell-Thompson, Martha; Conwell, Darwin L.; Fogel, Evan L.; Forsmark, Christopher E.; Hart, Phil A.; Pandol, Stephen J.; Park, Walter G.; Pratley, Richard E.; Yazici, Cemal; Laughlin, Maren R.; Andersen, Dana K.; Serrano, Jose; Bellin, Melena D.; Yadav, Dhiraj; Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC); Radiology and Imaging Sciences, School of MedicineThis core component of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study will examine the hypothesis that advanced magnetic resonance imaging (MRI) techniques can reflect underlying pathophysiologic changes and provide imaging biomarkers that predict diabetes mellitus (DM) following acute pancreatitis (AP). A subset of participants in the DREAM study will enroll and undergo serial MRI examinations using a specific research protocol. We aim to differentiate at-risk individuals from those who remain euglycemic by identifying parenchymal features following AP. Performing longitudinal MRI will enable us to observe and understand the natural history of post-AP DM. We will compare MRI parameters obtained by interrogating tissue properties in euglycemic, prediabetic and incident diabetes subjects and correlate them with metabolic, genetic, and immunological phenotypes. Differentiating imaging parameters will be combined to develop a quantitative composite risk score. This composite risk score will potentially have the ability to monitor the risk of DM in clinical practice or trials. We will use artificial intelligence, specifically deep learning, algorithms to optimize the predictive ability of MRI. In addition to the research MRI, the DREAM study will also correlate clinical computerized tomography and MRI scans with DM development.Item Development and initial validation of an instrument for video-based assessment of technical skill in ERCP(Elsevier, 2021) Elmunzer, B. Joseph; Walsh, Catharine M.; Guiton, Gretchen; Serrano, Jose; Chak, Amitabh; Edmundowicz, Steven; Kwon, Richard S.; Mullady, Daniel; Papachristou, Georgios I.; Elta, Grace; Baron, Todd H.; Yachimski, Patrick; Fogel, Evan L.; Draganov, Peter V.; Taylor, Jason R.; Scheiman, James; Singh, Vikesh K.; Varadarajulu, Shyam; Willingham, Field F.; Cote, Gregory A.; Cotton, Peter B.; Simon, Violette; Spitzer, Rebecca; Keswani, Rajesh; Wani, Sachin; SVI study group; U.S. Cooperative for Outcomes Research in Endoscopy; Medicine, School of MedicineBackground and aims: The accurate measurement of technical skill in ERCP is essential for endoscopic training, quality assurance, and coaching of this procedure. Hypothesizing that technical skill can be measured by analysis of ERCP videos, we aimed to develop and validate a video-based ERCP skill assessment tool. Methods: Based on review of procedural videos, the task of ERCP was deconstructed into its basic components by an expert panel that developed an initial version of the Bethesda ERCP Skill Assessment Tool (BESAT). Subsequently, 2 modified Delphi panels and 3 validation exercises were conducted with the goal of iteratively refining the tool. Fully crossed generalizability studies investigated the contributions of assessors, ERCP performance, and technical elements to reliability. Results: Twenty-nine technical elements were initially generated from task deconstruction. Ultimately, after iterative refinement, the tool comprised 6 technical elements and 11 subelements. The developmental process achieved consistent improvements in the performance characteristics of the tool with every iteration. For the most recent version of the tool, BESAT-v4, the generalizability coefficient (a reliability index) was .67. Most variance in BESAT scores (43.55%) was attributed to differences in endoscopists' skill, indicating that the tool can reliably differentiate between endoscopists based on video analysis. Conclusions: Video-based assessment of ERCP skill appears to be feasible with a novel instrument that demonstrates favorable validity evidence. Future steps include determining whether the tool can discriminate between endoscopists of varying experience levels and predict important outcomes in clinical practice.