Metformin for sepsis-associated AKI: a protocol for the Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI).

INTRODUCTION: Acute kidney injury (AKI) is a common complication of sepsis associated with increased risk of death. Preclinical data and observational human studies suggest that activation of AMP-activated protein kinase, an ubiquitous master regulator of energy that can limit mitochondrial injury, with metformin may protect against sepsis-associated AKI (SA-AKI) and mortality. The Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) aims to evaluate the safety and feasibility of enteral metformin in patients with sepsis at risk of developing SA-AKI. METHODS AND ANALYSIS: Blind, randomised, placebo-controlled clinical trial in a single-centre, quaternary teaching hospital in the USA. We will enrol adult patients (18 years of age or older) within 48 hours of meeting Sepsis-3 criteria, admitted to intensive care unit, with oral or enteral access. Patients will be randomised 1:1:1 to low-dose metformin (500 mg two times per day), high-dose metformin (1000 mg two times per day) or placebo for 5 days. Primary safety outcome will be the proportion of metformin-associated serious adverse events. Feasibility assessment will be based on acceptability by patients and clinicians, and by enrolment rate. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board. All patients or surrogates will provide written consent prior to enrolment and any study intervention. Metformin is a widely available, inexpensive medication with a long track record for safety, which if effective would be accessible and easy to deploy. We describe the study methods using the Standard Protocol Items for Randomized Trials framework and discuss key design features and methodological decisions. LiMiT AKI will investigate the feasibility and safety of metformin in critically ill patients with sepsis at risk of SA-AKI, in preparation for a future large-scale efficacy study. Main results will be published as soon as available after final analysis. TRIAL REGISTRATION NUMBER: NCT05900284.

Laterality of lower extremity deep vein thrombosis after colectomy: A retrospective study using the national inpatient sample.

BACKGROUND AND AIMS: Deep venous thrombosis (DVT) is known to occur preferentially on the left lower extremity. The renowned surgeon Denis Burkitt advanced the theory that a heavy sigmoid colon would compress the left pelvic veins and predispose to DVT. Our study aimed to evaluate this hypothesis by comparing the laterality distributions with and without a prior colectomy. METHODS: We conducted a retrospective analysis of the 2016 National Inpatient Sample database by stratifying the patients at any age with acute DVT of lower extremity by history of prior colectomy, thereby eliminating local gut mechanical factors in the development of DVT. We compared the laterality distribution (i.e., left, right, bilateral, and unspecified) between the patients with and without a prior colectomy. We also conducted a subgroup analysis by the sex category to examine the difference in laterality distribution for male and female patients. Chi-square test for independence was used. P value ≤0.05 was considered statistically significant. RESULTS: We found an estimated total of 342,525 cases. Among patients without a prior colectomy, 136,605 (41.6%) were left-sided DVT versus 119,555 (36.4%) right-sided, with 55,555 bilateral and 16,865 unspecified. Among patients with a prior colectomy, 5,750 (41.2%) were left-sided, 5,000 (35.9%) were right-sided, 2,345 were bilateral and 850 were unspecified. The laterality distribution between the two groups was not significantly different (p = .167). The left-side predominance disappeared only in males with a prior colectomy (37.1% for left vs. 38.9% for right, p = .027). CONCLUSIONS: Our findings did not confirm the Burkitt's hypothesis. The left-side predominance of lower extremity DVT was attenuated only in male patients with a prior colectomy.

Continuous renal replacement therapy in critically ill patients with acute on chronic liver failure and acute kidney injury: A retrospective cohort study
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BACKGROUND: Incident acute kidney injury (AKI) in critically ill patients with acute on chronic liver failure (ACLF) is associated with poor prognosis. The role of continuous renal replacement therapy (CRRT) is not well established for patients with ACLF and AKI. MATERIALS AND METHODS: We conducted a retrospective cohort study to examine clinical outcomes in 66 patients with ACLF and AKI requiring CRRT. RESULTS: All-cause hospital mortality was 89.4%. Five (7.6%) patients were listed for liver transplantation, of whom 1 (1.5%) was eventually subjected to transplantation. Etiology of AKI included type 1 hepatorenal syndrome (HRS) with or without some degree of acute tubular necrosis (ATN) in 20 (30.3%) patients, and primarily ATN in 46 (69.7%) patients. When evaluated at the time of CRRT initiation, Child-Pugh-Turcotte (CPT) and Model for End-stage Liver Disease (MELD) (area under the receiver operating characteristics curve (AUROC) 0.67 for both) had fair performance for prediction of mortality, whereas Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure (CLIF)-SOFA performed better for the prediction of mortality (AUROC 0.87 for both). SOFA and CLIF-SOFA also performed well when determined at the time of ICU admission (AUROC 0.86 and 0.85, respectively). Etiology of liver disease or AKI did not influence prognosis. CONCLUSION: Critically ill patients with ACLF and AKI requiring CRRT have poor hospital survival, even with provision of extracorporeal support therapy. SOFA and CLIF-SOFA are good prognostic tools of mortality in this susceptible population.

Higher number of Helicobacter pylori CagA EPIYA C phosphorylation sites increases the risk of gastric cancer, but not duodenal ulcer.

BACKGROUND: Helicobacter pylori infection is one of the most common infections worldwide and is associated with gastric cancer and peptic ulcer. Bacterial virulence factors such as CagA have been shown to increase the risk of both diseases. Studies have suggested a causal role for CagA EPIYA polymorphisms in gastric carcinogenesis, and it has been shown to be geographically diverse. We studied associations between H. pylori CagA EPIYA patterns and gastric cancer and duodenal ulcer, in an ethnically admixed Western population from Brazil. CagA EPIYA was determined by PCR and confirmed by sequencing. A total of 436 patients were included, being 188 with gastric cancer, 112 with duodenal ulcer and 136 with gastritis. RESULTS: The number of EPIYA C segments was significantly associated with the increased risk of gastric carcinoma (OR=3.08, 95% CI=1.74 to 5.45, p<10-3) even after adjustment for age and gender. Higher number of EPIYA C segments was also associated with gastric atrophy (p=0.04) and intestinal metaplasia (p=0.007). Furthermore, patients infected by cagA strains possessing more than one EPIYA C segment showed decreased serum levels of pepsinogen I in comparison with those infected by strains containing one or less EPIYA C repeat. Otherwise, the number of EPIYA C segments did not associate with duodenal ulcer. CONCLUSIONS: Our results demonstrate that infection with H. pylori strains harbouring more than one CagA EPIYA C motif was clearly associated with gastric cancer, but not with duodenal ulcer.Higher number of EPIYA C segments was also associated with gastric precancerous lesions as demonstrated by histological gastric atrophic and metaplastic changes and decreased serum levels of pepsinogen I.

dupA polymorphisms and risk of Helicobacter pylori-associated diseases.

The dupA of Helicobacter pylori has been suggested as a virulence marker associated with the development of duodenal ulcer disease. However, the studies performed in different geographical areas have shown that there are variations in the prevalence of dupA and its association with H. pylori clinical outcomes. Our group did not observe associations between the presence of dupA and H. pylori clinical outcomes in Brazil. On the other hand, we observed 2 mutations in the sequence of dupA that lead to stop codons: a deletion of an adenine at position 1311 and an insertion of an adenine at position 1426 of the gene. Our aim was to evaluate associations of the presence of dupA with duodenal ulcer and gastric cancer, considering dupA-positive only those H. pylori strains that do not have the mutations in the gene sequence. We also evaluated the effect of infection with a strain carrying an intact dupA on the gastric mucosa histology and IL-8 gastric levels. Colonization with strains that had the intact dupA was negatively associated with gastric carcinoma (p=0.001, OR=0.32, 95% CI=0.16-0.66). The presence of dupA was also associated with an increased degree of antral mucosa inflammation (p=0.01) and with decreased corpus atrophy (p<0.01) as well as with increased gastric mucosa IL-8 levels (p=0.04). In conclusion, the infection with a H. pylori strain containing the dupA without the stop codon polymorphisms is associated with a lower risk of development of gastric carcinoma in Brazilian subjects.

Helicobacter pylori transiently in the mouth may participate in the transmission of infection.

Helicobacter pylori infection is associated with peptic ulcer and gastric carcinoma. The oral cavity may be a reservoir for H. pylori; however, the results of studies on this subject are controversial. We employed single-step and nested polymerase chain reactions (PCR) to detect the presence of the vacA, ureA and 16S rDNA genes of H. pylori in the stomach, saliva and dental plaque of 30 subjects. The results were confirmed by sequencing. Nested 16S rDNA and ureA amplification was achieved in 80% of gastric, 30% of saliva and 20% of dental plaque specimens. Sequencing of 10, seven and four 16S rDNA products from stomach, saliva and dental plaque, respectively, showed > 99% identity with H. pylori. Sequencing of the other four oral cavity PCR products showed similarity with Campylobacter and Wolinella species. Additionally, the vacA genotype identified in the samples of different sites was the same within a given subject.H. pylori may be found in the oral cavity of patients with gastric infection, thus it could be a source of transmission. However, results obtained with detection methods based only on PCR should be interpreted with caution because other microorganisms that are phylogenetically very close to H. pylori are also present in the mouth.

Helicobacter pylori transiently in the mouth may participate in the transmission of infection

Helicobacter pylori infection is associated with peptic ulcer and gastric carcinoma. The oral cavity may be a reservoir for H. pylori; however, the results of studies on this subject are controversial. We employed single-step and nested polymerase chain reactions (PCR) to detect the presence of the vacA, ureA and 16S rDNA genes of H. pylori in the stomach, saliva and dental plaque of 30 subjects. The results were confirmed by sequencing. Nested 16S rDNA and ureA amplification was achieved in 80 percent of gastric, 30 percent of saliva and 20 percent of dental plaque specimens. Sequencing of 10, seven and four 16S rDNA products from stomach, saliva and dental plaque, respectively, showed > 99 percent identity with H. pylori. Sequencing of the other four oral cavity PCR products showed similarity with Campylobacter and Wolinella species. Additionally, the vacA genotype identified in the samples of different sites was the same within a given subject.H. pylori may be found in the oral cavity of patients with gastric infection, thus it could be a source of transmission. However, results obtained with detection methods based only on PCR should be interpreted with caution because other microorganisms that are phylogenetically very close to H. pylori are also present in the mouth.

IL2-330G polymorphic allele is associated with decreased risk of Helicobacter pylori infection in adulthood.

We evaluated whether polymorphisms in genes coding molecules linked to the innate and adaptive immune response are associated with susceptibility to Helicobacter pylori infection. IL1B-511C-->T, IL1B-31T-->C, IL1RN allele 2, IL2-330T-->G, TNFA-307G-->A, TLR2Arg677Trp, TLR2Arg753Gln, TLR4Asp299Gly, and TLR5(392STOP) polymorphisms were determined in 541 blood donors. IL2-330T-->G allele carriers had a decreased H. pylori infection risk (OR=0.63, 95% CI=0.43-0.93) after adjustment for demographic and environmental factors. Hence, we investigated whether the polymorphism is functional by evaluating IL-2 serum concentration in 150 blood donors and 100 children. IL-2 pro-inflammatory and anti-inflammatory properties were indirectly investigated by determining serum IFN-gamma and IL-10/TGF-beta levels. The polymorphism was associated with increased mean IL-2 levels in H. pylori-positive adults (2.65 pg/mL vs. 7.78 pg/mL) and children (4.19 pg/mL vs. 8.03 pg/mL). Increased IL-2 was associated with pro-inflammatory activity in adults (IFN-gamma=18.61 pg/mL vs. 25.71 pg/mL), and with anti-inflammatory activity in children (IL-10=6.99 vs. 14.17 pg/mL, TGF-beta=45.88 vs. 93.44 pg/mL) (p<10(-3) for all). In conclusion, in the context of H. pylori infection, IL2-330 T-->G polymorphism is functional and is associated with decreased risk of infection in adults.