Evaluation of the Crosstalk Between the Host Mycobiome and Bacteriome in Patients with Chronic Pancreatitis.

The human microbiome is a diverse consortium of microbial kingdoms that play pivotal roles in host health and diseases. We previously reported a dysbiotic bacteriome in chronic pancreatitis patients with diabetes (CPD) compared with patients with it's nondiabetic (CPND) phenotype. In this study, we extended our exploration to elucidate the intricate interactions between the mycobiome, bacteriome, and hosts' plasma metabolome with the disease phenotypes. A total of 25 participants (CPD, n = 7; CPND, n = 10; healthy control, n = 8) were recruited for the study. We observed elevated species richness in both the bacterial and fungal profiles within the CP diabetic cohort compared to the nondiabetic CP phenotype and healthy control cohorts. Notably, the CP group displayed heterogeneous fungal diversity, with only 40% of the CP nondiabetic patients and 20% of the CP diabetic patients exhibiting common core gut fungal profiles. Specific microbial taxa alterations were identified, including a reduction in Bifidobacterium adolescentis and an increase in the prevalence of Aspergillus penicilloides and Klebsiella sp. in the disease groups. In silico analysis revealed the enrichment of pathways related to lipopolysaccharide (LPS), apoptosis, and peptidase, as well as reduced counts of the genes responsible for carbohydrate metabolism in the CP groups. Additionally, distinct plasma metabolome signatures were observed, with CPD group exhibiting higher concentrations of sugars and glycerolipids, while the CPND cohort displayed elevated levels of amino acids in their blood. The fatty acid-binding protein (FABP) concentration was notably greater in the CPD group than in the HC group (4.220 vs. 1.10 ng/ml, p = 0.04). Furthermore, compared with healthy controls, disease groups exhibited fewer correlations between key fungal taxa (Aspergillus sp., Candida sp.) and bacterial taxa (Prevotella copri, Bifidobacteria sp., Rumminococcaceae). Our study unveils, for the first time, a dysbiotic mycobiome and emphasizes unique host bacterial-mycobial interactions in CP patient with diabetes, potentially influencing disease severity. These findings provide crucial insights for future mechanistic studies aiming to unravel the determinants of disease severity in this complex clinical context. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-024-01207-8.

Modulation of nuclear receptor 4A1 expression improves insulin secretion in a mouse model of chronic pancreatitis.

OBJECTIVES: Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to insulin secretory defects and associated metabolic alterations. Owing to lack of molecular understanding, no pharmacotherapies to treat insulin secretory defects have been approved to date. We aimed to delineate the molecular mechanism of ß-cell dysfunction in CP. METHODS: Transcriptomic analysis was conducted to identify endocrine specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis on NovaSeq 6000 of NR4A1 overexpressed (OE) MIN6 cells was performed to identify aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure. Downstream effect of NR4A1OE was examined by Fura2 AM based fluorometric and imaging studies of intracellular calcium. Mice with CP were treated with IFN-γ neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion. RESULTS: Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 µg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 µg/mg protein/minute, p = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold (p = 0.03), improved insulin secretion (4.4 ± 0.2-fold, p = 0.01), associated with increased Ca2+ levels (2.39 ± 0.06-fold, p = 0.009). CONCLUSIONS: Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP.

Biflanged metal stents versus plastic stents in the endoscopic ultrasound-guided drainage of walled-off necrosis: a randomized controlled trial.

OBJECTIVE: Endoscopic ultrasound(EUS) guided drainage of walled off necrosis(WON) with either plastic stents or metal stents is the mainstay of WON management. This is a single center randomized controlled study evaluating the efficacy of bi-flanged metal stent(BFMS) and plastic stents for WON drainage. DESIGN: Patients with symptomatic WON amenable for EUS guided drainage were randomized to either BFMS or plastic stents. Primary outcome was reintervention free clinical success at 4 weeks. Secondary outcomes were overall clinical success(complete resolution of symptoms and significant reduction in size of WON (<50% of original size and <5 cm largest diameter size at 4-week follow-up)), number of re-interventions, adverse events, hospital stay for first admission and medium term outcomes at 6 months (recurrence, disconnected pancreatic duct, chronic pancreatitis and new onset diabetes mellitus). RESULTS: 92 patients were randomized - 46 in each arm. The reintervention free clinical success was significantly higher in BFMS group(67.4% vs 43.5%; P: 0.021; ITT analysis). Overall clinical success at one month was similar in both groups. There were significantly lower number of reinterventions (median 0(IQR 0-1) vs 1(0-2) P:0.028)and hospital stay duration in BFMS group(7.04 ± 3.36 days vs 9.09 ± 5.53 days; P:0.035). There was no difference in procedure-related adverse events, mortality and medium-term outcomes. CONCLUSIONS: The BFMS provides higher reintervention free clinical success at 4 weeks with shorter hospital stay without increased risk of adverse events compared to plastic stents for EUS-guided drainage of WON. Medium term outcomes are however similar in both BFMS, and plastics stents.

Extracorporeal Shock-Wave Lithotripsy and Endoscopy for the Treatment of Pain in Chronic Pancreatitis : A Sham-Controlled, Randomized Trial.

BACKGROUND: No randomized controlled trials have substantiated endoscopic decompression of the pancreatic duct in patients with painful chronic pancreatitis. OBJECTIVE: To investigate the pain-relieving effect of pancreatic duct decompression in patients with chronic pancreatitis and intraductal stones. DESIGN: 24-week, parallel-group, randomized controlled trial (ClinicalTrials.gov: NCT03966781). SETTING: Asian Institute of Gastroenterology in India from February 2021 to July 2022. PARTICIPANTS: 106 patients with chronic pancreatitis. INTERVENTION: Combined extracorporeal shock-wave lithotripsy (ESWL) and endoscopic retrograde pancreatography (ERP) compared with sham procedures. MEASUREMENTS: The primary end point was pain relief on a 0- to 10-point visual analog scale (VAS) at 12 weeks. Secondary outcomes were assessed after 12 and 24 weeks and included 30% pain relief, opioid use, pain-free days, questionaries, and complications to interventions. RESULTS: 52 patients in the ESWL/ERP group and 54 in the sham group were included. At 12 weeks, the ESWL/ERP group showed better pain relief compared with the sham group (mean difference in change, -0.7 [95% CI, -1.3 to 0] on the VAS; P = 0.039). The difference between groups was not sustained at the 24-week follow-up, and no differences were seen for 30% pain relief at 12- or 24-week follow-up. The number of pain-free days was increased (median difference, 16.2 days [CI, 3.9 to 28.5 days]), and the number of days using opioids was reduced (median difference, -5.4 days [CI, -9.9 to -0.9 days]) in the ESWL/ERP group compared with the sham group at 12-week follow-up. Safety outcomes were similar between groups. LIMITATION: Single-center study and limited duration of follow-up. CONCLUSION: In patients with chronic pancreatitis and intraductal stones, ESWL with ERP provided modest short-term pain relief. PRIMARY FUNDING SOURCE: Asian Institute of Gastroenterology and Aalborg University Hospital.

Development of a novel CT-based index for predicting the number of extracorporeal shockwave lithotripsy (ESWL) sessions required for successful fragmentation of obstructing pancreatic duct stones.

BACKGROUND & AIM: Extracorporeal shock wave lithotripsy (ESWL) is used for the treatment of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). We aimed to develop a CT based index to predict the required number of ESWL sessions for technical success. METHODS: We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL. Technical success was defined as the complete fragmentation of stones to <3 mm. CT features including PDS size, number, location, and density in Hounsfield units (HU) were noted. We analyzed the relationship between PDS characteristics and the number of ESWL sessions required for technical success. A multiple linear regression model was used to combine size and density into the pancreatic duct stone (PDS) index that was translated into a web-based calculator. RESULTS: There were 206 subjects (mean age 38.6 ± 13.7 years, 59.2% male) who underwent ESWL. PDS size showed a moderate correlation with the number of ESWL sessions (r = 0.42, p < 0.01). PDS in the head required a fewer number of sessions in comparison to those in the body (1.4 ± 0.6 vs. 1.6 ± 0.7, p = 0.01). There was a strong correlation between PDS density and the number of ESWL sessions (r = 0.617, p-value <0.01). The PDS index {0.3793 + [0.0009755 x PDS density (HU)] + [0.02549 x PDS size (mm)]} could accurately predict the required number of ESWL sessions with an AUC of 0.872 (p < 0.01). CONCLUSION: The PDS index is a useful predictor of the number of ESWL sessions needed for technical success that can help in planning and patient counseling.

Opioid analgesia and severity of acute pancreatitis: An international multicentre cohort study on pain management in acute pancreatitis.

BACKGROUND: The effect of analgesic modalities on short-term outcomes in acute pancreatitis remains unknown. However, preclinical models have raised safety concerns regarding opioid use in patients with acute pancreatitis. OBJECTIVE: This study aimed to assess the association between analgesics, particularly opioids, and severity and mortality in hospitalised patients with acute pancreatitis. METHODS: This prospective multicentre cohort study recruited consecutive patients admitted with a first episode of acute pancreatitis between April 1 and 30 June 2022, with a 1-month follow-up. Data on aetiology, clinical course, and analgesic treatment were collected. The primary outcome was the association between opioid analgesia and acute pancreatitis severity, which was analysed using univariate and multivariate analyses. RESULTS: Among a total of 1768 patients, included from 118 centres across 27 countries, 1036 (59%) had opioids administered on admission day, and 167 (9%) received opioids after admission day. On univariate analysis, moderately severe or severe acute pancreatitis was associated with male sex, Asian ethnicity, alcohol aetiology, comorbidity, predicted severe acute pancreatitis, higher pain scores, longer pain duration and opioid treatment (all p < 0.001). On multivariate analysis, comorbidity, alcohol aetiology, longer pain duration and higher pain scores increased the risk of moderately severe or severe acute pancreatitis (all p < 0.001). Furthermore, opioids administered after admission day (but not on admission day) doubled the risk of moderately severe or severe disease (OR 2.07 (95% CI, 1.29-3.33); p = 0.003). Opioid treatment for 6 days or more was an independent risk factor for moderately severe or severe acute pancreatitis (OR 3.21 (95% CI, 2.16-4.79; p < 0.001). On univariate analysis, longer opioid duration was associated with mortality. CONCLUSION: Opioid treatment increased the risk of more severe acute pancreatitis only when administered after admission day or for 6 days or more. Future randomised studies should re-evaluate whether opioids might be safe in acute pancreatitis.

Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitis.

BACKGROUND: Extracorporeal shockwave lithotripsy (ESWL) and/or endoscopic retrograde cholangiopancreatography (ERCP) are recommended as first-line therapy for painful uncomplicated chronic pancreatitis with obstructed main pancreatic duct (MPD) in the pancreas head/body. However, predictors of pain relief after ESWL are unknown. We evaluated independent predictors of persistent pain in patients who underwent ESWL for chronic pancreatitis. METHODS: 640 consecutive adult patients with chronic pancreatitis, who underwent successful ESWL with ERCP and pancreatic duct (PD) stent placement, were followed for 12 months. The pain was assessed at baseline and at 12 months using the Izbicki Pain Score, with a score decrease of >50% considered pain relief. Independent predictors of pain relief were derived from logistic regression analysis. RESULTS: Of 640 patients (mean age 36.71 [SD 12.19] years; 60.5% men), 436 (68.1%) had pain relief and 204 (31.9%) had persistent pain. On univariate analysis, older age, male sex, alcohol and tobacco intake, longer duration of symptoms, dilated MPD and MPD stricture were associated with persistent pain at 12 months (P<0.05). Consumption of alcohol (odds ratio [OR] 1.93, 95%CI 1.26-2.97), tobacco (OR 4.09, 95%CI 2.43-6.90), duration of symptoms (OR 1.02, 95%CI 1.01-1.04), MPD size (OR 1.22, 95%CI 1.11-1.33), and MPD stricture (OR 8.50, 95%CI 5.01-14.42) were independent predictors of persistent pain. CONCLUSIONS: Alcohol, tobacco, duration of symptoms, MPD size and stricture were independent predictors of persistent pain after successful ESWL. A multidisciplinary team approach that includes behavioral therapy and surgical options should be considered for such patients.

Pancreatic duct pressure: A review of technical aspects and clinical significance.

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP.

Kynurenine pathway alteration in acute pancreatitis and its role as a biomarker of infected necrosis.

INTRODUCTION: Infected pancreatic necrosis (IPN) is a major cause of mortality in acute pancreatitis (AP). Currently, no specific strategies are available to predict the development of IPN. Earlier we reported that persistent down-regulation of HLA-DR increases risk of developing IPN. Altered kynurenine pathway (KP) metabolites showed poor prognosis in sepsis. Here we evaluated the role of HLA-DR and KP in IPN. METHODS: Patients with ANP and healthy controls were enrolled. Demographic and clinical parameters were recorded. Circulating interleukin (IL)-8, 6, 1ß, 10, Tumor necrosis factor-α were quantified using flowcytometry. Plasma procalcitonin, endotoxin, and KP (tryptophan, kynurenine) concentrations were estimated using ELISA. qRT-PCR was conducted to evaluate mRNA expression of HLA-DR, IL-10, Toll like receptor-4 (TLR-4), and kynurenine-3-monooxygenase (KMO) genes on peripheral blood mononuclear cells. Plasma metabolites were quantified using gas chromatography mass spectrometry (GC-MS/MS). Standard statistical methods were used to compare study groups. Metaboanalyst was used to analyse/visualize the metabolomics data. RESULTS: We recruited 56 patients in Cohort-1 (IPN:26,Non-IPN:30), 78 in Cohort-2 (IPN:57,Non-IPN:21), 26 healthy controls. Increased cytokines, endotoxin, and procalcitonin were observed in patients with IPN compared to Non-IPN. HLA-DR and KMO gene expressions were significantly down-regulated in IPN groups, showed positive correlation with one another but negatively correlated with IL-6 and endotoxin concentrations. Increased IDO and decreased plasma tryptophan were observed in IPN patients. Metabolome analysis showed significant reduction in several essential amino acids including tryptophan in IPN patients. Tryptophan, at a concentration of 9 mg/ml showed an AUC of 91.9 (95%CI 86.5-97.4) in discriminating IPN. CONCLUSION: HLA-DR downregulation and KP alteration are related to IPN. The KP metabolite plasma tryptophan can act as a potential biomarker for IPN.

Frequent guidewire passage into the pancreatic duct is an independent risk factor for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) among high-risk individuals: A post-hoc analysis of a randomized controlled trial data.

OBJECTIVES: To systematically evaluate the patient and procedural risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) among patients receiving rectal indomethacin. METHODS: Data from a randomized controlled trial (RCT) of high-risk patients undergoing ERCP who received rectal indomethacin with or without topical epinephrine was evaluated. PEP was defined based on the consensus criteria. Pancreatic stenting was excluded to avoid confounding results with the role of epinephrine spray. Multivariable logistic regression analysis was used to identify patient and procedural risk factors for PEP. RESULTS: Among 960 patients enrolled in the RCT, the PEP incidence was 6.4%. An increased risk of PEP was seen with age <50 years and female gender (odds ratio [OR] 2.40, 95% confidence interval [CI] 1.35-4.26), malignant biliary stricture(s) (OR 3.51, 95% CI 1.52-8.10), >2 guidewire passes into the pancreatic duct (PD) (OR 2.84, 95% CI 1.43-5.64), and pancreatic brush cytology (OR 6.37, 95% CI 1.10-36.90), whereas a decreased risk of PEP was seen with contrast- over guidewire-assisted cannulation (OR 0.14, 95% CI 0.02-0.99) and the use of lactated Ringer's (LR) over other fluid types (OR 0.52, 95% CI 0.27-0.98). There was a significant trend between the number of guidewire passes into the PD and PEP risk (P = 0.002). CONCLUSIONS: More than two guidewire passes into the PD and pancreatic brush cytology increased while the use of LR decreased the risk of PEP among high-risk patients receiving rectal indomethacin. Pancreatic stent placement and/or LR should be considered in patients with >2 guidewire passes into the PD.

Lactated Ringers Use in the First 24 Hours of Hospitalization Is Associated With Improved Outcomes in 999 Patients With Acute Pancreatitis.

INTRODUCTION: Recent pilot trials in acute pancreatitis (AP) found that lactated ringers (LR) usage may result in decreased risk of moderately severe/severe AP compared with normal saline, but their small sample sizes limit statistical power. We investigated whether LR usage is associated with improved outcomes in AP in an international multicenter prospective study. METHODS: Patients directly admitted with the diagnosis of AP were prospectively enrolled at 22 international sites between 2015 and 2018. Demographics, fluid administration, and AP severity data were collected in a standardized prospective manner to examine the association between LR and AP severity outcomes. Mixed-effects logistic regression analysis was performed to determine the direction and magnitude of the relationship between the type of fluid administered during the first 24 hours and the development of moderately severe/severe AP. RESULTS: Data from 999 patients were analyzed (mean age 51 years, female 52%, moderately severe/severe AP 24%). Usage of LR during the first 24 hours was associated with reduced odds of moderately severe/severe AP (adjusted odds ratio 0.52; P = 0.014) compared with normal saline after adjusting for region of enrollment, etiology, body mass index, and fluid volume and accounting for the variation across centers. Similar results were observed in sensitivity analyses eliminating the effects of admission organ failure, etiology, and excessive total fluid volume. DISCUSSION: LR administration in the first 24 hours of hospitalization was associated with improved AP severity. A large-scale randomized clinical trial is needed to confirm these findings.

Multi-Omics Analysis Demonstrates the Critical Role of Non-Ethanolic Components of Alcoholic Beverages in the Host Microbiome and Metabolome: A Human- and Animal-Based Study.

It is known that alcoholic beverages alter the human gut microbiome. This study focused on the potential impact of non-ethanolic ingredients in whisky on the gut bacteriome. A pilot study was carried out on 15 whisky drinkers, 5 rice beer drinkers, and 9 non-drinkers to determine the effect of alcoholic beverages on the host microbiome and metabolome. Additionally, a mouse model was used to assess the differential impact of three whisky brands (each with an equal ethanol concentration). The results indicate that the non-ethanolic components have an impact on the gut microbiome, as well as on the metabolites in blood and feces. The amount of Prevotella copri, a typical core Indian gut bacterium, decreased in both the human and mouse groups of whisky type 1, but an increase in abundance of Helicobacteriaceae (p = 0.01) was noticed in both groups. Additionally, the alcohol-treated cohorts had lower levels of short-chain fatty acids (SCFAs), specifically butyric acid, and higher amounts of lipids and stress marker IL1-ß than the untreated groups (p = 0.04-0.01). Furthermore, two compounds, ethanal/acetaldehyde (found in all the whisky samples) and arabitol (unique to whisky type 1), were tested in the mice. Similar to the human subjects, the whisky type 1 treated mouse cohort and the arabitol-treated group showed decreased levels of Prevotella copri (p = 0.01) in their gut. The results showed that non-ethanolic compounds have a significant impact on host gut bacterial diversity and metabolite composition, which has a further vital impact on host health. Our work further emphasizes the need to study the impact of non-ethanolic ingredients of alcoholic beverages on host health.

The Pattern of Alcohol Use in Alcohol-Related Cirrhosis in Indian Patients: AUDIT Indian Liver Study.

Background: Alcohol is one of the most common causes of liver cirrhosis. Yet, the pattern of alcohol consumption in cirrhosis is rarely studied. This study aims to study the drinking patterns along with the educational, socioeconomic, and mental health in a cohort of patients with and without liver cirrhosis. Methods: This prospective observational study was conducted at a tertiary-care hospital and included patients with harmful drinking. Demographic, alcohol intake history, assessment of socioeconomic and psychological status by modified Kuppuswamy scale and Beckwith Inventory, respectively, were recorded and analyzed. Results: Cirrhosis was present in 38.31% of patients with heavy drinking (64%). Cirrhosis was more among illiterates (51.76%) with early onset (22.4. ± 7.30 yrs P = 0.0001) and longer duration of alcohol (12.5 ± 6.5 vs. 6.8 ± 3.4 P = 0.001). Higher education qualification was associated with lower cirrhosis (P < 0.0001). With the same employment and education qualifications, net income in cirrhosis was lower [USD 298 (175-435) vs. USD 386 (119-739) P = 0.0001]. Whiskey (86.8%) was the commonest drink consumed. Similar median alcoholic drinks per week were consumed by both groups [34 (22-41) vs. 30 (24-40), P = 0.625], while indigenous alcohol was more consumed in cirrhosis [105 (98.5-109.75) vs. 89.5.0 (69.25-110.0) P = 0.0001]. Loss of jobs (12.36%) and partner violence were more in cirrhotic (9.89% vs. 5.80%) with similar borderline depression. Conclusion: Alcohol use disorder-related cirrhosis is present in a quarter of patients with harmful early onset and longer duration of drinking and is inversely related to the education status and affects the socioeconomic, physical, and family health of patients.

Obesity and alcoholic etiology as risk factors for multisystem organ failure in acute pancreatitis: Multinational study.

BACKGROUND: Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF. OBJECTIVE: We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP. METHODS: A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex. RESULTS: Among 1544 AP subjects, there was a sex-dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04-1.15) but not in females (OR 0.98, 95% CI 0.90-1.1). Male subjects with AP, whose BMIs were 30-34 and >35 kg/m2 , had odds ratios of 3.78 (95% CI 1.62-8.83) and 3.44 (95% CI 1.08-9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non-alcohol etiologies (OR 4.17, 95% CI 2.16-8.05). CONCLUSION: Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP.

Ethambutol optic neuropathy in the extended anti-tubercular therapy regime: A systematic review.

The extended use of ethambutol beyond 2 months for treating tuberculosis has increased risk of optic neuropathy. We performed a systematic review of studies evaluating optic neuropathy in extended ethambutol use since 2010 and compared the outcome with a similar systematic review (1965-2010) by Ezer et al. Literature search was conducted in PubMed, Medline, EMBASE, and Cochrane databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Main outcome measures were visual acuity, color vision, visual field defects, optical coherence tomography (OCT), and visual evoked potential (VEP). The JBI Critical Appraisal Checklists were used for quality assessment. Twelve studies were selected (out of 639 studies) for analysis of ethambutol optic neuropathy. Visual acuity improvement after stopping ethambutol was statistically significant. Similar improvement was not noted for other outcome measures. On comparing the results of this review with those by Ezer et al., significant improvement was noted in visual acuity, color vision, and visual field defects. Moreover, more patients reported increased optic nerve toxicity, color vision defects, and visual field defects in the present review. Hence, we conclude that the extended use of ethambutol beyond 2 months results in significant optic nerve toxicity. Further randomized controlled trials with different populations are needed to understand the magnitude of this issue.

Electrocardiography Assessment of Sympatico-Vagal Balance during Resting and Pain Using the Texas Instruments ADS1299.

Sympatico-vagal balance is essential for regulating cardiac electrophysiology and plays an important role in arrhythmogenic conditions. Various noninvasive methods, including electrocardiography (ECG), have been used for clinical assessment of the sympatico-vagal balance. This study aimed to use a custom-designed wearable device to record ECG and ECG-based cardiac function biomarkers to assess sympatico-vagal balance during tonic pain in healthy controls. Nineteen healthy volunteers were included for the ECG measurements using the custom-designed amplifier based on the Texas Instruments ADS1299. The ECG-based biomarkers of the sympatico-vagal balance, (including heart rate variability, deceleration capacity of the heart rate, and periodic repolarization dynamic), were calculated and compared between resting and pain conditions (tonic pain). The custom-designed device provided technically satisfactory ECG recordings. During exposure to tonic pain, the periodic repolarization dynamics increased significantly (p = 0.02), indicating enhancement of sympathetic nervous activity. This study showed that custom-designed wearable devices can potentially be useful in healthcare as a new telemetry technology. The ECG-based novel biomarkers, including periodic repolarization dynamic and deceleration capacity of heart rate, can be used to identify the cold pressor-induced activation of sympathetic and parasympathetic systems, making it useful for future studies on pain-evoked biomarkers.

Long-term Outcome of Peroral Endoscopic Myotomy in Esophageal Motility Disorders: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Peroral endoscopic myotomy (POEM) is an established treatment for achalasia. In this systematic review and meta-analysis, we aimed to analyze the mid and long-term outcomes of POEM in esophageal motility disorders. METHODS: Literature search was performed in databases including PubMed, Embase, Cochrane databases, and Google scholar from January 2010 to May 2021. The primary objective of the study was the clinical success (Eckardt score ≤3 or <4) at mid-term (30 to 60 mo) and long-term (>60 mo) follow-up after POEM. Secondary objectives included post-POEM gastroesophageal reflux (GER) as evaluated by symptoms, increased esophageal acid exposure, and reflux esophagitis. RESULTS: Seventeen studies with 3591 patients were included in the review. Subtypes of motility disorders were type I (27%), type II (54.5%), type III (10.7%), distal esophageal spasm/Jackhammer esophagus (2%), and esophagogastric junction outflow obstruction (17.5%). Pooled mean follow-up duration was 48.9 months (95% CI, 40.02-57.75). Pooled rate of clinical success at mid-term follow-up was 87% (95% CI, 81-91; I2 , 86%) and long-term was 84% (95% CI, 76-89; I2 , 47%). In nonachalasia motility disorders (esophagogastric junction outflow obstruction, distal esophageal spasm, and Jackhammer esophagus), pooled rate of clinical success was 77% (95% CI, 65-85; I2 , 0%). GER as estimated by symptoms was 23% (95% CI, 19-27; I2 , 74%), erosive esophagitis was 27% (95% CI, 18-38%; I2 , 91%), and increased esophageal acid exposure was 41% (95% CI, 30-52; I2 , 88%). CONCLUSION: POEM is a durable treatment option in cases with achalasia. One-fourth of patients suffer from erosive GER in the long-term and success rates are lower in nonachalasia esophageal motility disorders.

New-onset prediabetes, diabetes after acute pancreatitis: A prospective cohort study with 12-month follow-up.

BACKGROUND: Acute pancreatitis (AP) is known to result in endocrine dysfunction (prediabetes, diabetes). The objective of this study was to determine the temporal incidence of endocrine dysfunction after onset of AP and determine the risk factors in Indian patients. METHODS: In this prospective study, enrolled patients diagnosed with AP between February 2019 and May 2019 were followed at 3, 6, and 12 months until May 2020. Patients with recurrent AP, chronic pancreatitis, and pre-existing endocrine dysfunction were excluded. Demographic and disease severity (clinical, laboratory, and radiological) data were recorded. Mann-Whitney U and Chi-square tests were used to compare groups. Temporal trend for development of endocrine dysfunction was evaluated using the Extended Mantel Haenszel Chi-square test for trend. Logistic regression was used to identify independent risk factors. RESULTS: Eighty-six patients (males 66, median [IQR] age 33.0 [26.0-44.2] years) who fulfilled enrolment criteria were finally analyzed. The most common etiology was alcohol (n=31 [36%]) followed by gallstones (n=17 [19.8%]). The proportion of patients with moderately severe acute pancreatitis and severe AP were 59.3% and 15.1%, respectively. Overall, the frequency of prediabetes and diabetes increased temporally across the follow-up period. These were 2 (2.33%) and 1 (1.16%) at 3 months, 11 (12.8%) and 5 (5.81%) at 6 months, and 20 (23.2%) and 9 (10.5%) at 1 year, respectively. On multivariable logistic regression, intervention for walled-off necrosis (WON) emerged as the single independent risk factor for endocrine dysfunction (odds ratio 9.01 [2.3-35.5]; p=0.002). CONCLUSIONS: Endocrine dysfunction is frequent after an episode of AP. Intervention for WON is an independent risk factor for endocrine dysfunction.