Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis.

BACKGROUND: Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms. METHODS: We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort. RESULTS: Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm. CONCLUSIONS: Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.

Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

Bronchial carcinoid misdiagnosed as COVID pneumonia: a case report.

Bronchial carcinoid tumours are rare, slow-growing, malignant, Low-grade neuroendocrine tumours that arise from Enterochromaffin (Kulchitsky) cells and are usually detected typically as indolent and solitary tumours. Approximately 2% of all lung tumours are bronchial carcinoid tumours. Case presentation: The authors report a case of 55-years-old man who presented with a history of cough for 1 month and was initially diagnosed with a case of COVID-19. Then he was treated as a case of pneumonia as seen on high-resolution computed tomography. Later, contrast-enhanced computed tomography and bronchoscopy-guided biopsy were done which revealed a right lower lobe neuroendocrine tumour (carcinoid), which was successfully resected. Clinical discussion: The majority of typical carcinoids are located in the central airways leading to bronchial obstruction with recurrent pneumonia, chest pain, and wheezing. During the COVID-19 pandemic, lung cancer patients were at higher risk of being affected by COVID-19. This study emphasizes that early identification and differential diagnosis are extremely difficult in the absence of comprehensive study and workup as the clinical and imaging findings of COVID-19 may resemble lung cancer. Although hilar and mediastinal lymph nodes are the most common metastatic sites for typical carcinoids, most lymphadenopathies are caused by a reactive inflammatory reaction. Conclusion: Bronchial carcinoids are uncommon, malignant neuroendocrine tumours for which the only curative management is complete surgical resection. With full resection, the result of typical carcinoids with lymph node metastases is favourable.

Biomolecular map of albumin identifies signatures of severity and early mortality in acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. METHODS: Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n = 40; survivors, n = 8; non-survivors, n = 32; and HC, n = 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n = 160; survivors, n = 53; non-survivors, n = 107; and HC, n = 20). RESULTS: In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95-1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. CONCLUSIONS: In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. IMPACTS AND IMPLICATIONS: Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF.

Efficacy of Direct Renin Inhibitors in Slowing Down the Progression of Diabetic Kidney Disease: A Meta-Analysis.

Albuminuria is a risk factor for chronic kidney disease and cardiovascular events in diabetic people. The pathogenic processes in these circumstances have been documented to be significantly influenced by enhanced renin-angiotensin system activity. The current meta-analysis was carried out to assess the efficacy of direct renin inhibitors in preventing the progression of diabetic kidney disease. This meta-analysis was conducted as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched the relevant medical literature through PubMed, Cochrane library and EMBASE. The primary efficacy outcome was a percentage change in urine albumin-creatinine ratio (UACR) (in mg/g) level. Other primary efficacy outcomes included remission from microalbuminuria to normal albuminuria and progression from microalbuminuria to macroalbuminuria. Four randomized control studies were identified and included in the current meta-analysis involving 9,609 participants. The use of direct renin inhibitors was superior in reducing mean UACR compared to angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. The pooled mean difference in UACR between direct renin inhibitors and the control group was 9.42% (95% CI: -15.70 to -3.15: p-value=0.003). The odds of progression from microalbuminuria to normal albuminuria are 1.26 times higher in patients receiving direct renin inhibitors compared to patients in the control group (OR: 1.26, 95% CI: 1.08-1.46, p-value=0.002). The odds of remission from microalbuminuria to macroalbuminuria were 20% lower in patients receiving direct renin inhibitors compared to patients in the control group (OR: 0.80, 95% CI: 0.69-0.93, p-value=0.003). The use of aliskiren is associated with a significant reduction in UACR, increased remission from microalbuminuria to normal albuminuria and decreased progression from microalbuminuria to macroalbuminuria.

A Regional Pooling Intervention in a High-Throughput COVID-19 Diagnostic Laboratory to Enhance Throughput, Save Resources and Time Over a Period of 6 Months.

An effective and rapid diagnosis has great importance in tackling the ongoing COVID-19 pandemic through isolation of the infected individuals to curb the transmission and initiation of specialized treatment for the disease. It has been proven that enhanced testing capacities contribute to efficiently curbing SARS-CoV-2 transmission during the initial phases of the outbreaks. RT-qPCR is considered a gold standard for the diagnosis of COVID-19. However, in resource-limited countries expenses for molecular diagnosis limits the diagnostic capacities. Here, we present interventions of two pooling strategies as 5 sample pooling (P-5) and 10 sample pooling (P-10) in a high-throughput COVID-19 diagnostic laboratory to enhance throughput and save resources and time over a period of 6 months. The diagnostic capacity was scaled-up 2.15-folds in P-5 and 1.8-fold in P-10, reagents (toward RNA extraction and RT-qPCR) were preserved at 75.24% in P-5 and 86.21% in P-10, and time saved was 6,290.93 h in P-5 and 3147.3 h in P-10.