A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern.

The emergence of new variants of SARS-CoV-2 necessitates unremitting efforts to discover novel therapeutic monoclonal antibodies (mAbs). Here, we report an extremely potent mAb named P4A2 that can neutralize all the circulating variants of concern (VOCs) with high efficiency, including the highly transmissible Omicron. The crystal structure of the P4A2 Fab:RBD complex revealed that the residues of the RBD that interact with P4A2 are a part of the ACE2-receptor-binding motif and are not mutated in any of the VOCs. The pan coronavirus pseudotyped neutralization assay confirmed that the P4A2 mAb is specific for SARS-CoV-2 and its VOCs. Passive administration of P4A2 to K18-hACE2 transgenic mice conferred protection, both prophylactically and therapeutically, against challenge with VOCs. Overall, our data shows that, the P4A2 mAb has immense therapeutic potential to neutralize the current circulating VOCs. Due to the overlap between the P4A2 epitope and ACE2 binding site on spike-RBD, P4A2 may also be highly effective against a number of future variants.

Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.

Trends of humoral immune responses to heterologous antigenic exposure due to vaccination & omicron SARS-CoV-2 infection: Implications for boosting.

Background & objectives: Vaccination and natural infection can both augment the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how omicron infection has affected the vaccine-induced and hybrid immunity is not well studied in Indian population. The present study was aimed to assess the durability and change in responses of humoral immunity with age, prior natural infection, vaccine type and duration with a minimum gap of six months post-two doses with either ChAdOx1 nCov-19 or BBV152 prior- and post-emergence of the omicron variant. Methods: A total of 1300 participants were included in this observational study between November 2021 and May 2022. Participants had completed at least six months after vaccination (2 doses) with either ChAdOx1 nCoV-19 or an inactivated whole virus vaccine BBV152. They were grouped according to their age (≤ or ≥60 yr) and prior exposure of SARS-CoV-2 infection. Five hundred and sixteen of these participants were followed up after emergence of the Omicron variant. The main outcome was durability and augmentation of the humoral immune response as determined by anti-receptor-binding domain (RBD) immunoglobulin G (IgG) concentrations, anti-nucleocapsid antibodies and anti-omicron RBD antibodies. Live virus neutralization assay was conducted for neutralizing antibodies against four variants - ancestral, delta and omicron and omicron sublineage BA.5. Results: Before the omicron surge, serum anti-RBD IgG antibodies were detected in 87 per cent participants after a median gap of eight months from the second vaccine dose, with a median titre of 114 [interquartile range (IQR) 32, 302] BAU/ml. The levels increased to 594 (252, 1230) BAU/ml post-omicron surge (P<0.001) with 97 per cent participants having detectable antibodies, although only 40 had symptomatic infection during the omicron surge irrespective of vaccine type and previous history of infection. Those with prior natural infection and vaccination had higher anti-RBD IgG titre at baseline, which increased further [352 (IQR 131, 869) to 816 (IQR 383, 2001) BAU/ml] (P<0.001). The antibody levels remained elevated after a mean time gap of 10 months, although there was a decline of 41 per cent. The geometric mean titre was 452.54, 172.80, 83.1 and 76.99 against the ancestral, delta, omicron and omicron BA.5 variants in the live virus neutralization assay. Interpretation & conclusions: Anti-RBD IgG antibodies were detected in 85 per cent of participants after a median gap of eight months following the second vaccine dose. Omicron infection probably resulted in a substantial proportion of asymptomatic infection in the first four months in our study population and boosted the vaccine-induced humoral immune response, which declined but still remained durable over 10 months.

Overlap and cumulative effects of pancreatic duct obstruction, abnormal pain processing and psychological distress on patient-reported outcomes in chronic pancreatitis.

OBJECTIVE: Several factors have been suggested to mediate pain in patients with chronic pancreatitis. However, it is unknown whether these factors are overlapping and if they have cumulative effects on patient-reported outcomes (PROs). DESIGN: We performed a multicentre cross-sectional study of 201 prospectively enrolled subjects with definitive chronic pancreatitis. All subjects underwent evaluation for pancreatic duct obstruction, abnormalities in pain processing using quantitative sensory testing, and screening for psychological distress (anxiety, depression and pain catastrophising) based on validated questionnaires. Abnormality was defined by normal reference values. PROs included pain symptom severity (Brief Pain Inventory short form) and quality of life (EORTC-QLQ-C30 questionnaire). Associations between pain-related factors and PROs were investigated by linear trend analyses, multiple regression models and mediation analyses. RESULTS: Clinical evaluation suggestive of pancreatic duct obstruction was observed in 29%, abnormal pain processing in 23%, anxiety in 47%, depression in 39% and pain catastrophising in 28%; each of these factors was associated with severity of at least one PRO. Two or more factors were present in 51% of subjects. With an increasing number of factors, there was an increase in pain severity scores (p<0.001) and pain interference scores (p<0.001), and a reduction in quality of life (p<0.001). All factors had independent and direct effects on PROs, with the strongest effect size observed for psychological distress. CONCLUSION: Pain-related factors in chronic pancreatitis are often present in an overlapping manner and have a cumulative detrimental effect on PROs. These findings support a multidisciplinary strategy for pain management. TRIAL REGISTRATION NUMBER: The study was registered with ClinicalTrials.gov (NCT03434392).

Pancreatic hemorrhage contributes to late mortality in patients with acute necrotizing pancreatitis.

OBJECTIVES: The frequency, risk factors, and impact on survival of hemorrhage into (peri)pancreatic collections in patients with acute pancreatitis (AP) has not been well studied. The study was designed to evaluate the risk factors for hemorrhage, successful hemostasis and its effect on in-hospital mortality. METHODS: In a prospective cohort study for prediction of severity of AP, the incidence, risk factors, and outcomes of pancreatic hemorrhage were analyzed. Patients with significant hemorrhage were managed according to a predefined protocol including endovascular intervention. RESULTS: Out of 363 patients hospitalized during the study-period, 33(9%) patients developed hemorrhage. Median time from onset of AP to hemorrhage was 59(45-68) days. The cause of hemorrhage was arterial in 19(57.5%) patients and unlocalized in 14(42.5%) patients. Hemorrhage was managed by conservative approach in 7 (21.2%), radiographic angioembolisation in 16 (48.5%), radiographic angioembolisation followed by surgery in 3 (9.1%), and surgery in 7 (21.2%) patients. Persistent organ failure [aHR 2.3 (1.1-5.1), p = 0.03], use of large bore (>20 Fr) catheter for initial drainage [aHR 3.9 (1.7-9.1), p = 0.001] and extensive (>50%) necrosis [aHR 3.1 (1.4-6.9), p = 0.005] were significant risk factors for hemorrhage. Hemorrhage was an independent predictor of mortality [aHR 2.0 (1.2-3.4), p = 0.008] in addition to persistent organ failure (aHR 12.1 (5.7-25.8), p < 0.001). In-hospital mortality in patients with hemorrhage was 22/33 (66.7%) vs. 81/330 (25%) in no hemorrhage group [p <0.001]. CONCLUSION: Pancreatic hemorrhage occurs later in the course of acute pancreatitis in relatively sicker group of patients with organ failure and extensive necrosis, and is independently associated with a higher risk of in-hospital mortality.

Virus related acute pancreatitis and virus superinfection in the 'Dual disease' model of acute pancreatitis and SARS-Co-V2 infection: A multicentre prospective study.

BACKGROUND: SARS-CoV-2 can cause acute pancreatitis (AP) and SARS-CoV-2 superinfection can occur in patients with AP during prolonged hospitalisation. Our objective was to characterize SARS-CoV-2 related AP and study the impact of SARS-CoV-2 superinfection on outcomes in AP. METHODS: In this multicentre prospective study, all patients with AP and SARS-CoV-2 infection between August 2020 and February 2021 were divided into two groups: SARS-CoV-2-related AP and superadded SARS-CoV-2 infection in patients with AP. The two groups were compared with each other and the whole cohort was compared with a non-COVID AP cohort. RESULTS: A total of 85 patients with SARS-CoV-2 and AP (SARS-CoV-2-related AP; n = 18 and AP with SARS-CoV-2 superadded infection; n = 67) were included during the study period. They had a higher mortality [28 (32.9%) vs. 44 (19.1%), aOR 2.8 (95% CI, 1.5-5.3)] than 230 propensity matched non-COVID AP patients. Mortality in SARS-CoV-2 and AP patients was due to critical COVID. SARS-CoV-2-related- AP (n = 18) had a higher but statistically insignificant mortality than SARS-CoV-2 superinfection in AP [8/18 (44.4%) vs 20/67 (29.8%), p = 0.24]. On multivariable analysis, infection with SARS-CoV-2 (aHR 2.3; 95% CI, 1.43.7) was a predictor of in-hospital mortality in addition to organ failure (OF) in patients with AP. CONCLUSION: Patients with AP and SARS-CoV-2 infection had a higher mortality than matched non-COVID AP patients which was largely attributable to the severity of COVID-19. SARS-CoV-2 related AP had higher OF and in-hospital mortality.

Early infection is an independent risk factor for increased mortality in patients with culture-confirmed infected pancreatic necrosis.

BACKGROUND: Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined. OBJECTIVES: To determine the association between mortality and the development of early IPN. METHODS: International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses. RESULTS: A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05). CONCLUSION: Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality.

Early Versus Delayed Cholecystectomy for Acute Biliary Pancreatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Recommendations regarding the timing of cholecystectomy for acute biliary pancreatitis (ABP) require a systematic summary of current evidence to guide clinical practice. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing early cholecystectomy (EC) versus delayed cholecystectomy (DC) in patients with ABP. METHODS: We searched databases Medline, Embase, SCOPUS, Web of Science and Cochrane CENTRAL for randomized controlled trials addressing this question. Pairs of reviewers abstracted data and assessed the risk of bias in included studies. A random-effects meta-analysis was done to study the effect of the timing of cholecystectomy on outcomes of interest in patients with ABP. GRADE methodology was used to rate the quality in the body of evidence for each outcome as high, moderate, low, or very low. RESULTS: 11 randomized trials (1176 participants) were included. High-quality evidence from seven RCTs (867 participants) showed a statistically significant reduction in the risk for recurrent biliary events in favour of early cholecystectomy (RR 0.10, 95% CI 0.05 to 0.19, I2 = 0%). High-quality evidence from five trials was in favour of early cholecystectomy with a significant reduction in the risk 7of recurrent pancreatitis (RAP) in comparison to delayed cholecystectomy (RR 0.21, 95% CI 0.09 to 0.51, I2 = 0%). CONCLUSION: This review showed that EC has definite advantages over DC in terms of reducing recurrent pancreaticobiliary events and LOS following mild ABP. However, more RCTs are required to study the role of EC in patients with moderately-severe and severe ABP. Trial Registration Protocol registered on Prospero (CRD42020192823).

Clinical Course of Chronic Pancreatitis During Pregnancy and its Effect on Maternal and Fetal Outcomes.

INTRODUCTION: There are limited data on the effect of chronic pancreatitis (CP) on pregnancy outcomes and vice versa. Our aim was to evaluate the clinical trajectory of CP during pregnancy and its effect on pregnancy outcomes. METHODS: All female patients of child-bearing age (≥15 years) diagnosed with CP were studied from January 2004 to July 2019. The change in frequency of painful episodes was assessed before, during, and after pregnancy. Maternal and fetal outcomes were compared between pregnant women (early onset) and women presenting with CP after completion of all pregnancies (late onset). RESULTS: Of 187 women with CP, pregnancy outcomes and clinical course were assessed in 99 patients. The frequency of painful exacerbations was significantly lower during pregnancy compared with prepregnancy and postpregnancy periods (P < 0.001). The median pain score decreased significantly to 0 (0-2) during pregnancy from 3 (0-6) before conception and increased to 4 (0-8) after pregnancy (P = 0.002). Women with early onset CP (n = 57) had their first child later and had fewer pregnancies compared with those with late onset CP (n = 42). There was no difference in maternal outcomes such as gestational diabetes, hypertension, and preterm delivery, and fetal outcomes such as abortion, low birth weight, and still birth between the groups. There was no reported congenital anomaly. DISCUSSION: Younger patients with CP had later and fewer pregnancies, but there was no increased risk of adverse maternal and fetal outcomes. The clinical course of CP was usually benign during pregnancy with decreased frequency and severity of pain.

Role of dual-point 18F-FDG-PET/CT in the diagnosis of pancreatic adenocarcinoma, in patients with and without concomitant chronic pancreatitis: Comparison with CECT and EUS.

PURPOSE: The aim of this study was to evaluate the diagnostic performance of dual-time-point-PET/CT, CECT and EUS + FNA in diagnosing pancreatic-ductal-adenocarcinomas (PDAC), in context of concomitant Chronic Pancreatitis (CP). METHODS: 18F-FDG-PET/CTs were prospectively acquired in 22 confirmed CP and 23 confirmed PDAC patients (calculated for 90% power); and cut-offs of 2.2 for early-SUV(∼1hr), 2.4 for delayed-SUV(∼3hr) and 1.36 for Retention-index (RI), were derived. These cut-offs were validated in PET/CTs of 75 patients (51.9 ± 13.3years; 54 men) with pancreatic masses of unknown nature. Comparisons were made with triple-phase-CECT (73 patients) and EUS + FNA (54 patients). Histopathology was obtained in 68 patients (including all PDACs) and 7 were followed up for minimum of 2 years. RESULTS: In patients without concomitant CP, sensitivity, specificity and accuracy for diagnosing malignancy in standard-acquisition-PET/CT, dual-time-point-PET/CT, CECT and EUS + FNA were 97.4%, 83.3%, 94.0%; 97.4%, 75.0%, 92%; 94.6%, 66.7%, 87.8% and 92.6%, 88.9%, 91.7% respectively. Corresponding values in patients with concomitant CP were 88.9%, 57.1%, 80.0%; 100%, 57.1%, 88%; 82.4%, 57.1%, 75% and 100%, 100%, 100% respectively. In lesions ≤2 cm (AJCC-T1), dual-time-point-PET/CT was the most sensitive (95.8%). ROC-analysis revealed significantly higher area-under-the-curve for RI over early-SUV (p = 0.002) in cases with concomitant CP only. In patients with confirmed liver-metastases, PET/CT and CECT identified 15/16 and 13/16 lesions. PET/CT identified additional lung-metastases in 3 and bone-metastasis in one patient. CONCLUSION: In patients without concomitant CP and with larger lesions, PET/CT and CECT are equivocal as screening modalities, with no benefit of dual-time-point-PET/CT acquisitions. However, in patients with concomitant CP and smaller lesions, dual-time-point PET/CT is better; with sensitivity comparable to EUS + FNA.

Endoscopic transmural drainage tailored to quantity of necrotic debris versus laparoscopic transmural internal drainage for walled-off necrosis in acute pancreatitis: A randomized controlled trial.

BACKGROUND AND AIMS: Both endoscopic and laparoscopic transmural internal drainage are practiced for drainage of walled-off necrosis (WON) following acute pancreatitis (AP) but the superiority of either is not established. Our aim was to compare transperitoneal laparoscopic drainage with endoscopic drainage using either lumen apposing metal stents (LAMS) or plastic stents tailored to the amount of necrotic debris in WON. METHODS: In a randomized controlled trial, adequately powered to exclude the null hypothesis, patients with symptomatic WON were randomized to either endoscopic or laparoscopic drainage. In the endoscopy group, two plastic stents were placed if the WON contained <1/3rd necrotic debris and a LAMS was placed if it was >1/3rd. Primary outcome was resolution of WON within 4 weeks without re-intervention for secondary infection. Secondary outcome was overall success (resolution of WON at 6 months) and adverse events. RESULTS: Forty patients were randomized: 20 to each group. Baseline characteristics were comparable between the groups. Primary outcome was similar between the groups [16 (80%) in laparoscopy and 15 (75%) in endoscopy group; p = 0.89]. The overall success was similar [18 (90%) in laparoscopy vs. 17 (85%) in endoscopy; p = 0.9]. Median duration of hospital stay was shorter in endoscopy group [4 (4-8) vs. 6 days (5-9); p = 0.03]. Adverse events were comparable between the groups. CONCLUSION: Laparoscopic drainage was not superior to endoscopic transmural drainage with placement of multiple plastic stent or LAMS depending on the amount of necrotic debris for symptomatic WON in AP. The hospital stay was shorter with the endoscopic approach.

Immediate and Long-Term Outcomes of Percutaneous Radiological Interventions for Hemorrhagic Complications in Acute and Chronic Pancreatitis.

PURPOSE: To evaluate and compare the immediate and long-term outcomes of radiological interventions for hemorrhagic complications in patients with acute and chronic pancreatitis. MATERIALS AND METHODS: This retrospective study, conducted between January 2014 and June 2020, included all patients with acute and chronic pancreatitis presenting with hemorrhagic complications who underwent angiography and/or embolization. Their clinical, angiographic, and embolization details were evaluated and correlated with procedure success, complications, recurrence, and mortality. The patients were subgrouped into groups A (acute pancreatitis) and C (chronic pancreatitis), and comparisons were made. RESULTS: The study included 141 patients (mean age, 36.3 ± 11.2 years; 124 men), of whom 106 patients had abnormal angiography findings and underwent embolization. Of them, group A had 50 patients (56 lesions) and group C had 56 patients (61 lesions). All the patients in group A had severe acute pancreatitis, with a mean computed tomography severity index of 7.6. The technical and clinical success rates of embolization, complications, recurrence, and long-term outcomes were not significantly different between the groups. Group A had significantly higher mortality due to sepsis and organ failure. Embolic agents did not have any significant association with complications, recurrence, and mortality. After a mean follow-up of 2 years, 72.5% of the patients were asymptomatic, and none had symptoms attributable to embolization. CONCLUSIONS: Success, complications, and recurrence after embolization for hemorrhagic complications were comparable between acute and chronic pancreatitis. Acute pancreatitis was associated with significantly higher mortality. Embolic agents did not significantly influence the outcomes. None had long-term adverse effects attributable to embolization.

Organ Failure Due to Systemic Injury in Acute Pancreatitis.

Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.

Chloroquine and Hydroxychloroquine for the Treatment of COVID-19: a Systematic Review and Meta-analysis.

BACKGROUND: There is no effective therapy for COVID-19. Hydroxychloroquine (HCQ) and chloroquine (CQ) have been used for its treatment but their safety and efficacy remain uncertain. OBJECTIVE: We performed a systematic review to synthesize the available data on the efficacy and safety of CQ and HCQ for the treatment of COVID-19. METHODS: Two reviewers searched for published and pre-published relevant articles between December 2019 and 8 June 2020. The data from the selected studies were abstracted and analyzed for efficacy and safety outcomes. Critical appraisal of the evidence was done by Cochrane risk of bias tool and Newcastle Ottawa Scale. The quality of evidence was graded as per the GRADE approach. RESULTS: We reviewed 12 observational and 3 randomized trials which included 10,659 patients of whom 5713 received CQ/HCQ and 4966 received only standard of care. The efficacy of CQ/HCQ for COVID-19 was inconsistent across the studies. Meta-analysis of included studies revealed no significant reduction in mortality with HCQ use [RR 0.98 95% CI 0.66-1.46], time to fever resolution (mean difference - 0.54 days (- 1.19-011)) or clinical deterioration/development of ARDS with HCQ [RR 0.90 95% CI 0.47-1.71]. There was a higher risk of ECG abnormalities/arrhythmia with HCQ/CQ [RR 1.46 95% CI 1.04 to 2.06]. The quality of evidence was graded as very low for these outcomes. AUTHORS' CONCLUSION: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19. Well-designed randomized trials are required for assessing the efficacy and safety of HCQ and CQ for COVID-19.

Acute pancreatitis and nosocomial COVID-19: Cause specific host responses may determine lung injury.

BACKGROUND: Coronavirus disease 2019 (COVID-19) presents with myriad extra-pulmonary manifestation and a high mortality in patients with comorbidities. Its effect on patients with pre-existing acute pancreatitis is not known. METHODS: We hereby, present 3 cases with severe acute pancreatitis with persistent respiratory failure who acquired nosocomial COVID-19 during their hospital stay after recovery from respiratory failure. Their clinical course is highlighted which reflects on pathophysiology of organ dysfunction in these 2 disease states. RESULTS: None of the 3 patients with severe acute pancreatitis who developed nosocomial COVID-19 redeveloped respiratory failure due to COVID-19 despite having recently recovered from pancreatitis induced acute hypoxemic respiratory failure. Only one patient developed SARS-CoV2 induced moderate pneumonia. CONCLUSION: These cases highlight that host responses and mechanisms of lung injury might be different in severe acute pancreatitis and COVID-19.

International consensus guidelines on the role of diagnostic endoscopic ultrasound in the management of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with variable presentations and outcomes. This statement is part of the international consensus guidelines on CP, specifically on the diagnostic role of endoscopic ultrasound (EUS). METHODS: An international working group with experts on the role of diagnostic EUS in the management of CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated two key statements generated from evidence on two questions deemed to be the most clinically relevant. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus was obtained for both of the following statements [1]. The ideal threshold number of EUS criteria necessary to diagnose CP has not been firmly established, but the presence of 5 or more and 2 or less strongly suggests or refutes the diagnosis, respectively. The Rosemont scoring system standardizes the reporting of EUS signs indicative of chronic pancreatitis, but further studies are needed to demonstrate an overall improvement of its diagnostic accuracy over conventional scoring [2]. Specificity, inter- and intra-observer variability and pre-test probability limit the reliability and utility of EUS to help diagnose CP especially early stages of the disease. CONCLUSIONS: The presence of 5 or more and 2 or less EUS criteria strongly suggests or refutes the diagnosis of CP, respectively. Intra-observer variability still limits the role of EUS in diagnosing CP especially early stage disease.

International consensus guidelines on interventional endoscopy in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND/OBJECTIVES: This paper is part of the international consensus guidelines on chronic pancreatitis, presenting for interventional endoscopy. METHODS: An international working group with experts on interventional endoscopy evaluated 26 statements generated from evidence on 9 clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the level of evidence. To determine the level of agreement, a nine-point Likert scale was used for voting on the statements. RESULTS: Strong consensus was obtained for 15 statements relating to nine questions including the recommendation that endoscopic intervention should be offered to patients with persistent severe pain but not to those without pain. Endoscopic decompression of the pancreatic duct could be used for immediate pain relief, and then offered surgery if this fails or needs repeated endoscopy. Endoscopic drainage is preferred for portal-splenic vein thrombosis and pancreatic fistula. A plastic stent should be placed and replaced 2-3 months later after insertion. Endoscopic extraction is indicated for stone fragments remaining after ESWL. Interventional treatment should be performed for symptomatic/complicated pancreatic pseudocysts. Endoscopic treatment is recommended for bile duct obstruction and afterwards surgery if this fails or needs repeated endoscopy. Surgery may be offered if there is significant calcification and/or mass of the pancreatic head. Percutaneous endovascular treatment is preferred for hemosuccus pancreaticus. Surgical treatment is recommended for duodenal stenosis due to chronic pancreatitis. CONCLUSIONS: This international expert consensus guideline provides evidenced-based statements concerning indications and key aspects for interventional endoscopy in the management of patients with chronic pancreatitis.

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP. METHODS: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP. CONCLUSIONS: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.

Thromboelastography-guided Blood Product Transfusion in Cirrhosis Patients With Variceal Bleeding: A Randomized Controlled Trial.

GOALS: The aim of this study was to assess the use of thromboelastography (TEG)-directed blood product transfusion in cirrhotic patients with acute variceal bleeding compared with conventional transfusion for correction of coagulopathy. BACKGROUND: Coagulopathy is common in patients with cirrhosis. Recommendations for correction of conventional parameters of coagulation-platelets and the international normalized ratio before endoscopy in patients with acute variceal bleeding-need more validation. STUDY: In this randomized controlled trial, cirrhotic patients with severe coagulopathy and acute variceal bleeding were randomized to either TEG-guided blood product transfusion or conventional transfusion from March 2017 to December 2017. The primary outcome was the difference in the amount of fresh frozen plasma and platelet units transfused between the groups. Secondary outcomes were rebleeding at 5 days and 42 days, and 6-week mortality. RESULTS: Of the 60 recruited patients, 30 each were randomized to the TEG and conventional transfusion groups. There were no differences in baseline characteristic and endoscopic findings between the 2 groups. Four subjects in the TEG group received blood product transfusions versus all in the conventional transfusion group (13.3% vs. 100%; P<0.001). The control of bleeding on initial endoscopy was similar in the 2 groups. Rebleeding in the TEG and conventional transfusion groups at 5 days was similar [1 (3.3%) vs. 4 (13.3%), P=0.167], whereas it was significantly less in the TEG group at 42 days [3 (10%) vs. 11 (36.7%), P=0.012]. Mortality at 6 weeks was seen in 4 (13.3%) in the TEG group and in 8 (26.7%) patients in the conventional transfusion group (P=0.176). CONCLUSIONS: TEG-guided strategy was associated with reduced blood product transfusion to correct coagulopathy without compromising hemostasis in cirrhotic patients (Clinical trial ID: CTRI/2017/02/007864).

Outcomes following laparoscopic internal drainage of walled off necrosis of pancreas: experience of 134 cases from a tertiary care centre.

INTRODUCTION: Internal drainage of walled of necrosis of pancreas has been considered as the standard of care. For symptomatic walled off necrosis (WON) of pancreas with the advent of laparoscopy and refinement of techniques and instrumentation, laparoscopic internal drainage is becoming the standard surgical drainage procedure for these patients. However, there is a dearth of literature regarding outcomes following laparoscopic drainage. Most of the studies have small number of patients with limited follow-up. We in this study describe our experience of laparoscopic internal drainage of walled off necrosis over the last 13 years. MATERIALS AND METHODS: This is a retrospective analysis of a prospectively maintained database. All patients with WON undergoing laparoscopic internal drainage between January 2005 and December 2018 were included. Primary outcome measure was successful drainage. Secondary outcome measures included morbidity, hospital stay, re-intervention rate and mortality. Patients were followed up post-operatively at 1 week, 4 weeks, 3 months and then annually thereafter. Ultrasonography was done periodically for the assessment of cyst resolution. RESULTS: Between 2005 and 2018, 154 surgical drainage procedures were performed for symptomatic pseudocyst/walled off necrosis. Out of these, 134 underwent laparoscopic drainage; 129 patients (96.3%) underwent laparoscopic cystogastrostomy and 5 (3.7%) underwent laparoscopic cystojejunostomy. Majority of the patients were male (male:female = 6:1) with a mean age of 36 ± 12.9 years (range 15-58 years). The mean operative time was 94 min (range 64-144 min). There were three conversions because of intra-operative bleeding. The overall post-operative morbidity was 8.9%. The average hospital stay was 4.4 days (2-19 days). The mean duration of follow-up was 5.5 years (range 6 months-13 years). Complete cyst resolution was achieved in 95.5% (n = 128) patients. There has been no mortality till date. CONCLUSION: In conclusion, laparoscopic internal drainage is a very effective technique for drainage of WON with an excellent success rate.