Targeting PKCα alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin.

ABSTRACT: Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By using diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKCα was required to sustain baseline Fpn expression and diabetes-induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKCα abolished diabetes-associated iron overload. Mechanistically, activation of PKCα increased the exocytotic trafficking of Fpn and decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKCα also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKCα, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKCα and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis-associated iron overload. Our study has highlighted, to our knowledge, for the first time, that PKCα is an important positive regulator of Fpn and a new target in the control of iron homeostasis.

The Role of High-Resolution Manometry Prior to and Following Antireflux Surgery: The Padova Consensus.

BACKGROUND: In the last two decades the development of high-resolution manometry (HRM) has changed and revolutionized the diagnostic assessment of patients complain foregut symptoms. The role of HRM before and after antireflux procedure remains unclear, especially in surgical practice, where a clear understanding of esophageal physiology and hiatus anatomy is essential for optimal outcome of antireflux surgery (ARS). Surgeons and gastroenterologists (GIs) agree that assessing patients following antireflux procedures can be challenging. Although endoscopy and barium-swallow can reveal anatomic abnormalities, physiologic information on HRM allowing insight into the cause of eventually recurrent symptoms could be key to clinical decision making. METHOD: A multi-disciplinary international working group (14 surgeons and 15 GIs) collaborated to develop consensus on the role of HRM pre- and post- ARS, and to develop a postoperative classification to interpret HRM findings. The method utilized was detailed literature review to develop statements, and the RAND/University of California, Los Angeles Appropriateness Methodology (RAM) to assess agreement with the statements. Only statements with an approval rate >80% or a final ranking with a median score of 7 were accepted in the consensus. The working groups evaluated the role of HRM prior to ARS and the role of HRM following ARS. CONCLUSION: This international initiative developed by surgeons and GIs together, summarizes the state of our knowledge of the use of HRM pre- and post-ARS. The Padova Classification was developed to facilitate the interpretation of HRM studies of patients underwent ARS.

Metagenomic insights into novel microbial lineages with distinct ecological functions in the Arctic glacier foreland ecosystems.

Land-terminating glaciers are retreating globally, resulting in the expansion of the ice-free glacier forelands (GFs). These GFs act as a natural laboratory to study microbial community succession, soil formation, and ecosystem development. Here, we have employed gene-centric and genome-resolved metagenomic approaches to disseminate microbial diversity, community structure, and their associated biogeochemical processes involved in the carbon, nitrogen, and sulfur cycling across three GF ecosystems. Here, we present a compendium of draft Metagenome Assembled Genomes (MAGs) belonging to bacterial (n = 899) and archaeal (n = 4) domains. These MAGs were reconstructed using a total of 27 shotgun metagenomic datasets obtained from three different GFs, including Midtre Lovénbreen glacier (Svalbard), Russell glacier (Greenland), and Storglaciaren (Sweden). The taxonomic classification revealed that 98% of MAGs remained unclassified at species levels, suggesting the presence of novel microbial lineages. The abundance of metabolic genes associated with carbon, nitrogen, and sulfur cycling pathways varied between and within the samples collected across the three GF ecosystems. Our findings indicate that MAGs from different GFs share close phylogenetic relationships but exhibit significant differences in abundance, distribution patterns, and metabolic functions. This compendium of novel MAGs, encompassing autotrophic, phototrophic, and chemolithoautotrophic microbial groups reconstructed from GF ecosystems, represents a valuable resource for further studies.

Functional lumen imaging probe topography identifies patients with normal acid exposure and esophageal hypervigilance amongst proton-pump inhibitor non-responders.

BACKGROUND: Multiple factors contribute to symptom generation and treatment response in proton-pump inhibitor non-responders (PPI-NRs). We aimed to test whether PPI-NRs with normal acid exposure have a higher degree of esophageal hypersensitivity and hypervigilance and can be identified using functional lumen imaging probe (FLIP) topography at the time of endoscopy. METHODS: Data from PPI-NRs whom underwent endoscopy, FLIP and wireless 96-h pH-metry were retrospectively analyzed. Patients were grouped according to acid exposure time (AET) as (a) 0 days abnormal (AET > 6%), (b) 1-2 days abnormal, or (c) 3-4 days abnormal. The esophageal hypervigilance and anxiety scale (EHAS) score and other symptom scores were compared between groups. The discriminatory ability of the esophagogastric junction (EGJ) distensibility index (DI) and max EGJ diameter in identifying patients with 0 days abnormal AET was tested via receiver-operating-characteristic (ROC) curve analysis. RESULTS: EHAS score was 38.6 in the 0 days abnormal AET group, 30.4 in the 1-2 days abnormal AET group (p = 0.073 when compared to 0 days abnormal) and 28.2 in the 3-4 days abnormal AET group (p = 0.031 when compared to 0 days abnormal). Area-under-the-curve (AUC) for the DI in association with 0 days AET > 6% was 0.629. A DI of < 2.8 mm2/mmHg had a sensitivity of 83.3%, and negative predictive value of 88% in classifying patients with 0 days abnormal acid exposure (p = 0.004). CONCLUSIONS: FLIP complements prolonged wireless pH-metry in distinguishing the subset of PPI-NRs with completely normal acid exposure and a higher burden of esophageal hypervigilance. Proper identification of patients along the functional heartburn spectrum can improve overall surgical outcomes.

Insights and Opinions of Critical Care Healthcare Professionals in the Management of Carbapenem-resistant Enterobacteriaceae Cases and Antibiotic-Resistant Infections in the Intensive Care Unit Setting: A Survey-Based Approach.

INTRODUCTION: A survey-based approach to managing antibiotic-resistant infections in the intensive care unit (ICU) setting, with a focus on carbapenem-resistant Enterobacteriaceae (CRE) cases, was conducted. Among CRE, New Delhi metallo-ß-lactamase 1 (NDM-1) is a carbapenemase that is resistant to ß-lactam antibiotics and has a broader spectrum of antimicrobial resistance than other carbapenemase types. The article explains that healthcare-associated infections (HAIs) are a significant problem, particularly in low- and middle-income countries, and that carbapenem in combination with other antibiotics are the most potent class of antimicrobial agents effective in treating life-threatening bacterial infections, including those caused by resistant strains. AIM: The survey aimed to gather critical care healthcare professionals (HCPs') opinions on their current practices in managing infections acquired in the hospital and ICU settings, with a focus on CRE cases, specifically NDM-1 and other antibiotic-resistant infections. METHODS: Responses from critical care healthcare professionals, including online surveys and in-person interviews, to gain insights into the management of infections caused by multidrug-resistant bacteria. The findings related to the insights on the prevalence of bacterial flora, clinical experiences on efficacy and safety of meropenem sulbactam ethylenediaminetetraacetic acid (EDTA) (MSE) in CRE cases, and various combination therapies of antibiotics used to treat antibiotic-resistant infections in ICU setting were evaluated. RESULTS: Klebsiella pneumoniae bacteria were the most common bacteria in cultures, followed by Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. NDM-1 was the type of carbapenemase found in around 50% of CRE patients. MSE is among the most preferred antibiotics besides colistin, polymyxin B, and ceftazidime avibactum for CRE cases and specifically for NDM-1 cases due to its high rate of efficacy and safety. CONCLUSION: The article concludes with a discussion on the antibiotics used in response to CRE cases, reporting that critical care HCP considers MSE with high efficacy and safe antibiotic combination and was used as both monotherapy and in combination with other antibiotics. The survey highlights the need for exploring and better understanding the role of MSE in the management of CRE infections, especially in NDM-1.

Interrater Reliability of Functional Lumen Imaging Probe Panometry and High-Resolution Manometry for the Assessment of Esophageal Motility Disorders.

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss' κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95-0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90-0.94], 0.92 [0.89-0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%-84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%-81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.

Expanding the role of pneumatic dilation for nonachalasia patients: a comparative study.

BACKGROUND AND AIMS: Treatment options for nonachalasia obstructive disorders of the esophagogastric junction (EGJ) are limited. The aim of this study was to assess the treatment efficacy of pneumatic dilation (PD) for the disorders of EGJ outflow obstruction (EGJOO) and postfundoplication EGJ obstruction (PF-EGJO) and to assess attitudes regarding training in PD. METHODS: This was a 2-part study. The main study was a prospective, single-center study comparing treatment outcomes after PD in patients with EGJOO and PF-EGJO, defined using manometry criteria, versus achalasia. Treatment success was defined as a post-PD Eckardt score (ES) of ≤2 at the longest duration of follow-up available. In a substudy, a 2-question survey was sent to 78 advanced endoscopy fellowship sites in the United States regarding training in PD. RESULTS: Of the 58% of respondents to the advanced endoscopy program director survey, two-thirds reported no training in PD at their program. The primary rationale cited was lack of a clinical need for PD. Sixty-one patients (15 achalasia, 32 EGJOO, and 14 PF-EGJO) were included in the main study with outcomes available at a mean follow-up of 8.8 months. Overall, mean ES decreased from 6.30 to 2.89 (P < .0001), and a mean percentage of improvement in symptoms reported by patients was 55.3%. ES ≤2 was achieved by 33 of 61 patients (54.1%). CONCLUSIONS: PD is an effective treatment for the nonachalasia obstructive disorders of the EGJ. There may be a current gap in training and technical expertise in PD.

Vertical segregation and phylogenetic characterization of archaea and archaeal ammonia monooxygenase gene in the water column of the western Arctic Ocean.

Archaea constitute a substantial fraction of marine microbial biomass and play critical roles in the biogeochemistry of oceans. However, studies on their distribution and ecology in the Arctic Ocean are relatively scarce. Here, we studied the distributions of archaea and archaeal ammonia monooxygenase (amoA) gene in the western Arctic Ocean, using the amplicon sequencing approach from the sea surface to deep waters up to 3040 m depth. A total of five archaeal phyla, Nitrososphaerota, "Euryarchaeota", "Halobacteriota," "Nanoarchaeota", and Candidatus Thermoplasmatota, were detected. We observed a clear, depth-dependent vertical segregation among archaeal communities. Ca. Thermoplasmatota (66.8%) was the most dominant phylum in the surface waters. At the same time, Nitrososphaerota (55.9%) was dominant in the deep waters. Most of the amoA gene OTUs (99%) belonged to the Nitrosopumilales and were further clustered into five subclades ("NP-Alpha", "NP-Delta", "NP-Epsilon", "NP-Gamma", and "NP-Theta"). "NP-Epsilon" was the most dominant clade throughout the water column and "NP_Alpha" showed higher abundance only in the deeper water. Salinity and inorganic nutrient concentrations were the major factors that determined the vertical segregation of archaea. We anticipate that the observed differences in the vertical distribution of archaea might contribute to the compartmentalization of dark carbon fixation and nitrification in deeper water and organic matter degradation in surface waters of the Arctic Ocean.

Stochastic Processes Dominate in the Water Mass-Based Segregation of Diazotrophs in a High Arctic Fjord (Svalbard).

Nitrogen-fixing or diazotrophic microbes fix atmospheric nitrogen (N2) to ammonia (NH3+) using nitrogenase enzyme and play a crucial role in regulating marine primary productivity and carbon dioxide sequestration. However, there is a lack of information about the diversity, structure, and environmental regulations of the diazotrophic communities in the high Arctic fjords, such as Kongsfjorden. Here, we employed nifH gene sequencing to clarify variations in composition, community structure, and assembly mechanism among the diazotrophs of the salinity-driven stratified waters of Kongsfjorden. The principal environmental and ecological drivers of the observed variations were identified. The majority of the nifH gene sequences obtained in the present study belonged to cluster I and cluster III nifH phylotypes, accounting for 65% and 25% of the total nifH gene sequences. The nifH gene diversity and composition, irrespective of the size fractions (free-living and particle attached), showed a clear separation among water mass types, i.e., Atlantic-influenced versus glacier-influenced water mass. Higher nifH gene diversity and relative abundances of non-cyanobacterial nifH OTUs, affiliated with uncultured Rhizobiales, Burkholderiales, Alteromonadaceae, Gallionellaceae (cluster I) and uncultured Deltaproteobacteria including Desulfuromonadaceae (cluster III), were prevalent in GIW while uncultured Gammaproteobacteria and Desulfobulbaceae were abundant in AIW. The diazotrophic community assembly was dominated by stochastic processes, principally ecological drift, and to lesser degrees dispersal limitation and homogeneous dispersal. Differences in the salinity and dissolved oxygen content lead to the vertical segregation of diazotrophs among water mass types. These findings suggest that water column stratification affects the composition and assembly mechanism of diazotrophic communities and thus could affect nitrogen fixation in the Arctic fjord.

Assessment of genetic diversity of the fat-tailed Dumba sheep of India by mitochondrial and microsatellite markers.

India has a centuries-old tradition of sheep production and breeding that accomplish economic, agricultural, and religious roles. In addition to the 44 registered sheep breeds, there is a fat-tailed sheep population referred to as Dumba. This study evaluated genetic variation in Dumba sheep and its differentiation from other Indian sheep breeds using mitochondrial DNA and genomic microsatellite loci. Haplotype and nucleotide diversity based on mitochondrial DNA analysis revealed substantially high maternal genetic diversity in Dumba sheep. Major ovine haplogroups A and B observed in sheep populations across the globe registered their presence in the Dumba sheep. The molecular genetic analysis using microsatellite markers also showed high measures of allele (10.125 ± 0.762) and gene diversity (0.749 ± 0.029). Results correspond to the non-bottleneck population that is near mutation-drift equilibrium despite some deficiency in the number of heterozygotes (FIS = 0.043 ± 0.059). Phylogenetic clustering confirmed Dumba to be a distinct population. Results of this study endow authorities with critical information imperative for sustainable utilization and conservation of Indian fat-tailed sheep, which is considered to be an untapped genetic resource contributing to the food security, livelihood, and economic sustainability of rural households in marginal areas of the country.

Optimization of test day for milk yield recording and sire evaluation in Murrah buffaloes.

In the present study, random regression models (RRM) were used to estimate genetic parameters for test-day milk yield in Murrah buffaloes using Legendre polynomial function (LP), with the objective to find the best combination of "minimum test-day model," which would be essential and sufficient to evaluate the trait successfully. Data included for analysis were 10,615 first lactation monthly test-day milk yield records (5th, 35th, 65th, …, 305th) from 965 Murrah buffaloes for the period 1975-2018. Cubic to octic-order orthogonal polynomials with homogeneous residual variances were used for the estimation of genetic parameters. Random regression models with sixth-order were selected based on goodness of fit criteria like lower AIC, BIC and residual variance. Heritability estimates ranged from 0.079 (TD6) to 0.21(TD10). For both ends of lactation, the additive genetic and environmental variances were higher and ranged from 0.21 ± 0.12 (TD6) to 0.85 ± 0.35 kg2 (TD1) and 3.74 ± 0.36 (TD11) to 1.36 ± 0.14 kg2 (TD9), respectively. Between adjacent test-day records, genetic correlation estimates ranged from 0.09 ± 0.31 (TD1 and TD2) to 0.97 ± 0.03 (TD3 and TD4; TD4 and TD5), but values gradually declined as the distance between test days increased. Negative genetic correlations were also obtained between TD1 with TD3 to TD9, TD2 with TD9 and TD10, and TD3 with TD10. On the basis of genetic correlations, models with 5 and/or 6 test-days combination were able to account for 86.1%-98.7% of variation along the lactation. Models with fourth and fifth-order LP functions were considered to account for variance with combinations of 5 and/or 6 test-day milk yields. The model with 6 test-day combinations had a higher rank correlation (0.93) with model using 11 monthly test-day milk yield records. On the basis of relative efficiency, the model with 6 monthly test day combinations with fifth-order was more efficient (maximum 99%) than the model using 11 monthly test-day milk yield records. Looking into the similar accuracy with the 11TD model, and the low resources requirement, we recommend the use of the "6 test-day combination model" for sire evaluation. These models may help in reducing the cost and time for data recording of milk yield.

Salinity-controlled distribution of prokaryotic communities in the Arctic sea-ice melt ponds.

The thawing of snow and sea ice produces distinctive melt ponds on the surface of the Arctic sea ice, which covers a significant portion of the surface sea ice during summer. Melt-pond salinity impacts heat transfer to the ice below and the melting rate. It is widely known that melt ponds play a significant role in heat fluxes, ice-albedo feedback, and sea-ice energy balance. However, not much attention has been given to the fact that melt ponds also serve as a unique microbial ecosystem where microbial production begins as soon as they are formed. Here, we investigated the role of melt pond salinity in controlling the diversity and distribution of prokaryotic communities using culture-dependent and -independent approaches. The 16 S rRNA gene amplicon based next generation sequencing analysis retrieved a total of 14 bacterial phyla, consisting of 146 genera, in addition to two archaeal phyla. Further, the culture-dependent approaches of the study allowed for the isolation and identification of twenty-four bacterial genera in pure culture. Flavobacterium, Candidatus_Aquiluna, SAR11 clade, Polaribacter, Glaciecola, and Nonlabens were the dominant genera observed in the amplicon analysis. Whereas Actimicrobium, Rhodoglobus, Flavobacterium, and Pseudomonas were dominated in the culturable fraction. Our results also demonstrated that salinity, chlorophyll a, and dissolved organic carbon were the significant environmental variables controlling the prokaryotic community distribution in melt ponds. A significant community shift was observed in melt ponds when the salinity changed with the progression of melting and deepening of ponds. Different communities were found to be dominant in melt ponds with different salinity ranges. It was also observed that melt pond prokaryotic communities significantly differed from the surface ocean microbial community. Our observations suggest that complex prokaryotic communities develop in melt ponds immediately after its formation using dissolved organic carbon generated through primary production in the oligotrophic water.

Ambulatory Reflux Monitoring Guides Proton Pump Inhibitor Discontinuation in Patients With Gastroesophageal Reflux Symptoms: A Clinical Trial.

BACKGROUND AND AIMS: Proton pump inhibitor (PPI) therapy fails to provide adequate symptom control in up to 50% of patients with gastroesophageal reflux symptoms. Although a proportion do not require ongoing PPI therapy, a diagnostic approach to identify candidates appropriate for PPI cessation is not available. This study aimed to examine the clinical utility of prolonged wireless reflux monitoring to predict the ability to discontinue PPIs. METHODS: This double-blinded clinical trial performed over 3 years at 2 centers enrolled adults with troublesome esophageal symptoms of heartburn, regurgitation, and/or chest pain and inadequate PPI response. Participants underwent prolonged wireless reflux monitoring (off PPIs for ≥7 days) and a 3-week PPI cessation intervention. Primary outcome was tolerance of PPI cessation (discontinued or resumed PPIs). Symptom burden was quantified using the Reflux Symptom Questionnaire electronic Diary (RESQ-eD). RESULTS: Of 128 enrolled, 100 participants met inclusion criteria (mean age, 48.6 years; 41 men). Thirty-four participants (34%) discontinued PPIs. The strongest predictor of PPI discontinuation was number of days with acid exposure time (AET) > 4.0% (odds ratio, 1.82; P < .001). Participants with 0 days of AET > 4.0% had a 10 times increased odds of discontinuing PPI than participants with 4 days of AET > 4.0%. Reduction in symptom burden was greater among the discontinued versus resumed PPI group (RESQ-eD, -43.7% vs -5.3%; P = .04). CONCLUSIONS: Among patients with typical reflux symptoms, inadequate PPI response, and absence of severe esophagitis, acid exposure on reflux monitoring predicted the ability to discontinue PPIs without symptom escalation. Upfront reflux monitoring off acid suppression can limit unnecessary PPI use and guide personalized management. (ClinicalTrials.gov, Number: NCT03202537).

Optimal Wireless Reflux Monitoring Metrics to Predict Discontinuation of Proton Pump Inhibitor Therapy.

INTRODUCTION: Ambulatory reflux monitoring performed off proton pump inhibitor (PPI) is the gold standard diagnostic test for nonerosive gastroesophageal reflux disease (GERD). However, the diagnostic metrics and optimal duration of monitoring are not well defined. This study evaluated the performance of multiple metrics across distinct durations of wireless reflux monitoring off PPI against the ability to discontinue PPI therapy in patients with suboptimal PPI response. METHODS: This single-arm clinical trial performed over 4 years at 2 centers enrolled adults with troublesome GERD symptoms and inadequate response to > 8 weeks of PPI. Participants underwent 96-hour wireless pH monitoring off PPI. Primary outcome was whether the subject successfully discontinued PPI or resumed PPI within 3 weeks. RESULTS: Of 132 participants, 30% discontinued PPI. Among multiple metrics assessed, total acid exposure time (AET) of 4.0% performed best in predicting PPI discontinuation (odds ratio 2.9 [95% confidence interval 1.4, 6.4]; P = 0.006), with other thresholds of AET and DeMeester score performing comparably. AET was significantly higher on day 1 of monitoring compared with other days, and prognostic performance significantly declined when only assessing the first 48 hours of monitoring (area under the curve for 96 hours 0.63 vs area under the curve for 48 hours 0.57; P = 0.01). DISCUSSION: This clinical trial highlights the AET threshold of 4.0% as a high-performing prognostic marker of PPI discontinuation. 96 hours of monitoring performed better than 48 hours, in predicting ability to discontinue PPI. These data can inform current diagnostic approaches for patients with GERD symptoms who are unresponsive to PPI therapy.

Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19.

Purpose: End-organ damage in coronavirus disease-2019 (COVID-19) is linked to "cytokine storm" and excessive release of inflammatory mediators. Various novel therapies have been used in COVID-19 including urinary trypsin inhibitor therapy. This study explores the efficacy of ulinastatin in COVID-19. Materials and methods: We retrieved the medical records of patients admitted during one month and did a propensity score analysis to create matched treatment and control groups. We analyzed these groups and the outcomes were presented with appropriate statistics. Survival curve was prepared to compare the survival effect of ulinastatin therapy at the end of hospitalization, among both the groups. Results: A total of 736 patients were admitted, and after adjusting the data with propensity score matching, 55 cases were selected by the system. On the final outcome analysis, we found that intensive care unit (ICU) length of stay [median (interquartile range) days 3 (3.5-7.8) vs 2 (0-4); p-value 0.28] in control vs intervention groups, and in hospital mortality (odds ratio: 0.491, CI 95%: 0.099-2.44, p-value 0.435) were not statistically different among the groups. In survival plot analysis also, there was no statistical difference (p-value 0.414) among both the groups.Conclusion: In this retrospective study, we conclude that the final outcome of the ICU length of stay, and overall, in hospital mortality were not different among both the groups. Hence, adequately powered randomized control trials are urgently required to confirm any benefit of ulinastatin therapy in COVID-19 treatment. How to cite this article: Jain A, Kasliwal R, Jain SS, Jain R, Gupta D, Gupta P, et al. Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19. Indian J Crit Care Med 2022;26(6):696-703.

Classifying Esophageal Motility by FLIP Panometry: A Study of 722 Subjects With Manometry.

INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers ("controls") and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.

Blown-out myotomy: an adverse event of laparoscopic Heller myotomy and peroral endoscopic myotomy for achalasia.

BACKGROUND AND AIMS: Although laparoscopic Heller myotomy (LHM) or peroral endoscopic myotomy (POEM) is highly effective, 10% to 20% of patients with achalasia remain symptomatic after treatment. In evaluating such patients, we have observed a pattern of failure associated with a pseudodiverticulum, or blown-out myotomy (BOM), in the distal esophagus. We aimed to assess risk factors and patient-reported outcomes associated with a BOM. METHODS: We reviewed our manometry database for patients with achalasia previously treated with LHM or POEM. We included patients who had a post-treatment esophagram within 1 year of their follow-up manometry. A BOM was defined radiographically as a wide-mouthed outpouching (>50% increase in esophageal diameter) in the area of the myotomy. RESULTS: One hundred twenty-nine patients with achalasia who underwent treatment were included; 23 (17.8%) had a BOM. Comparing patients with a BOM with those without, post-treatment Eckardt scores were significantly greater (5 vs 2, P = .002), type III achalasia was more common (39.1% vs 14.2%, P = .005), and LHM was more common than POEM (73.9% vs 26.1%, P = .013). The integrated relaxation pressure was also significantly greater in the BOM group (15.0 mm Hg vs 11.0 mm Hg, P = .025). CONCLUSIONS: BOM is a common adverse event after myotomy for achalasia but is not seen after pneumatic dilation. Pretreatment type III achalasia, LHM as opposed to POEM, and a greater post-treatment integrated relaxation pressure were risk factors for developing a BOM. We speculate that esophageal wall strain in the area weakened by myotomy, whether from residual spastic contractility or continued esophageal outflow obstruction, may be the underlying mechanism of BOM development.

Utilizing functional lumen imaging probe in directing treatment for post-fundoplication dysphagia.

BACKGROUND: Esophagogastric junction obstruction (EGJO) post-fundoplication (PF) is difficult to identify with currently available tests. We aimed to assess the diagnostic accuracy of EGJ opening on functional lumen imaging probe (FLIP) and dilation outcome in FLIP-detected EGJO in PF dysphagia. METHODS: We prospectively collected data on PF patients referred to Esophageal Clinic over 18 months. EGJO diagnosis was made by (a) endoscopist's description of a narrow EGJ/wrap area, (b) appearance of wrap obstruction or contrast/tablet retention on esophagram, or (c) EGJ-distensibility index (DI) < 2.8 mm2/mmHg on real-time FLIP. In patients with EGJO and dysphagia, EGJ dilation was performed to 20 mm, 30 mm, or 35 mm in a stepwise fashion. Outcome was assessed as % dysphagia improvement during phone call or on brief esophageal dysphagia questionnaire (BEDQ) score. RESULTS: Twenty-six patients were included, of whom 17 (65%) had a low EGJ-DI. No patients had a hiatal hernia greater than 3 cm. Dysphagia was the primary symptom in 17/26 (65%). In 85% (κ = 0.677) of cases, EGJ assessment (tight vs. open) was congruent between the combination of endoscopy (n = 26) and esophagram (n = 21) vs. EGJ-DI (n = 26) on FLIP. Follow-up data were available in 11 patients who had dilation based on a low EGJ-DI (4 with 20 mm balloon and 7 with ≥ 30 mm balloon). Overall, the mean % improvement in dysphagia was 60% (95% CI 37.7-82.3%, p = 0.0001). Nine out of 11 patients, including 6 out of 7 undergoing pneumatic dilation, had improvement ≥ 50% in dysphagia (mean % improvement 72.2%; 95% CI 56.1-88.4%, p = 0.0001). CONCLUSIONS AND INFERENCES: Functional lumen imaging probe is an accurate modality for evaluating for EGJ obstruction PF. FLIP may be used to select patients who may benefit from larger diameter dilation.

Marine Group-II archaea dominate particle-attached as well as free-living archaeal assemblages in the surface waters of Kongsfjorden, Svalbard, Arctic Ocean.

Marine archaea are a significant component of the global oceanic ecosystems, including the polar oceans. However, only a few attempts have been made to study archaea in the high Arctic fjords. Given the importance of Archaea in carbon and nitrogen cycling, it is imperative to explore their diversity and community composition in the high Arctic fjords, such as Kongsfjorden (Svalbard). In the present study, we evaluated archaeal diversity and community composition in the size-fractionated microbial population, viz-a-viz free-living (FL; 0.2-3 µm) and particle-attached (PA; > 3 µm) using archaeal V3-V4 16S rRNA gene amplicon sequencing. Our results indicate that the overall archaeal community in the surface water of Kongsfjorden was dominated by the members of the marine group-II (MGII) archaea, followed by the MGI group members, including Nitrosopumilaceae and Nitrososphaeraceae. Although a clear niche partitioning between PA and FL archaeal communities was not observed, 2 OTUs among 682 OTUs, and 3 ASVs out of 1932 ASVs were differentially abundant among the fractions. OTU001/ASV0002, classified as MGIIa, was differentially abundant in the PA fraction. OTU006/ASV0006/ASV0010 affiliated with MGIIb were differentially abundant in the FL fraction. Particulate organic nitrogen and C:N ratio were the most significant variables (P < 0.05) explaining the observed variation in the FL and PA archaeal communities, respectively. These results indicate an exchange between archaeal communities or a generalist lifestyle switching between FL and PA fractions. Besides, the particles' elemental composition (carbon and nitrogen) seems to play an essential role in shaping the PA archaeal communities in the surface waters of Kongsfjorden.

Comparison of Predictive Ability of Epidemiological Factors, Inflammatory Biomarkers, and CT Severity Score for Mortality in COVID-19.

INTRODUCTION: COVID-19 patients are categorized as per their clinical severity and their level of care is decided based on the clinical severity. Apart from clinical severity of patients, a need for robust predictors was also felt for early categorization and accurate prediction of final fatal outcome in hospitalized patients. MATERIAL AND METHOD: In this retrospective observational cohort study all the adult patients admitted during November month were included. Available data for epidemiological factors, inflammatory biomarkers and CT severity score were collected and analyzed by univariate and multivariate logistic regression analysis to know predictive ability of each variable. A Receiver operating characteristic analysis was done to compare the predictive ability of each factor for final outcome of death. RESULTS: We analyzed records of 735 total patients. Most of them were male (72.38%), have a median (IQR) age of 60 years (50-69). Diabetes (42.85%), and hypertension (39.86%) were the most common co-morbidities. After univariate and multivariate regression analysis we could find that CRP, D-Dimer and CT severity score levels only can predict final outcome of death. During multivariate regression and receiver operative characteristic (ROC) analysis also, age and Charlson's co-morbidity index failed to predict in hospital mortality. CRP and D-Dimer on admission positively predicts final outcome of in hospital mortality with AUROC of 0.749(p=0.007, CI 0.61-0.88), and 0.864(p= 0.000, CI 0.74-0.99) respectively. Whereas, CT severity score had AUROC 0.73 (p= 0.014, CI 0.575-0.83). Cut off for CRP was 45 mg/L (Sn 0.8, Sp 0.56), D-dimer was 1000 µg/L (Sn:0.8, Sp: 0.9), and CT severity score was 15 (Sn 0.8, Sp 0.58). CONCLUSION: CRP level of 45 mg/l, D-dimer level of 1000 µg/L and CT severity level of >15 at the time of admission can be added to conventional clinical severity algorithm to more accurately predicting final outcome and stratifying the level of care offered at the time of admission, and hence may improve odds off survival.