Is There a Relationship between Abdominal Aortic Aneurysms and Alpha1-antitrypsin Deficiency (PiZ)?

AbstractObjective:to determine if the frequency of α1AT deficiency (PiZ) is increased in patients with abdominal aortic aneurysm (AAA), and, to investigate whether aneurysmal stiffness and other clinical characteristics differ in AAA patients with and without α1AT deficiency.Methods:we identified α1AT-deficient individuals by a monoclonal-antibody ELISA technique, in 102 consecutive patients with AAA. Positive ELISA samples were further phenotyped by isoelectric focusing to differentiate between the heterozygosity (PiZ) and homozygosity (PiZZ) state. Aneurysmal diameter and stiffness was measured using echotracking sonography and blood pressure measurements.Results:the frequency of heterozygous α1AT deficiency (PiZ) in patients with AAA was similar to that in the general population (6.8% and 4.7%, respectively,p>0.3). The frequency of popliteal and femoral aneurysm was similar in male PiZ-carriers and non-carriers with AAA, as were age at diagnosis of AAA, aneurysmal diameter, aneurysmal stiffness, and presence of factors that may be associated with AAA (i.e. smoking, hypertension, diabetes mellitus, and family history of AAA). Occurrence of ischaemic heart disease was more frequent in male non-PiZ-carriers than in male PiZ-carriers with AAA (p=0.03).Conclusions:the frequency of α1AT deficiency (PiZ) was not increased in our series of patients with AAA and patients in whom the two disorders coexisted did not appear to have different clinical characteristics except for the lower occurrence of ischaemic heart disease among the PiZ-carriers

Kikuchi–Fujimoto Disease: Review of 11 Cases Diagnosed Over 10 Years at a Tertiary Care Hospital in Doha, Qatar

Introduction: Kikuchi-Fujimoto (KF) disease is a rare and self-limiting disorder of unknown aetiology characterized by cervical lymphadenopathy (CLN) and fever. The pathophysiology remains unclear and may be triggered by an infectious agent leading to a self-limiting autoimmune process. There are no confirmatory laboratory tests and lymph node biopsy is required to differentiate KF disease from other serious conditions. Materials and methods: We report 11 cases of KF disease diagnosed at Hamad General Hospital, Qatar, between 2006 to 2016. The diagnosis is based on clinical presentation, investigations and histopathological examination of lymph nodes. Results: All patients had painful neck swelling (average duration of 2.9 weeks) and 10 had fever (average duration of 3.2 weeks). Five patients developed mild leucopenia which resolved completely. HIV and tuberculosis (TB) screening including sputum for AFB, a PPD skin test and chest x-ray was done for all patients and came back negative. Autoimmune screening was done for all patients and excluded any rheumatological disease. Ultrasound and CT of the neck confirmed cervical lymphadenopathy. Except for hepatomegaly in one patient, CT scans of the chest and abdomen were negative for any lymphadenopathy or organomegaly (performed in seven patients). Diagnosis was confirmed on lymph node excision biopsy. Histopathological examination showed findings consistent with the diagnosis of histiocytic necrotizing lymphadenitis (KF disease).Conclusion: KF disease should be kept in mind for patients presenting with fever and CLN. Lymphoma, TB and autoimmune diseases like systemic lupus erythematosus should be excluded in such patients

Update on hepatorenal Syndrome: Definition, Pathogenesis, and management

Hepatorenal syndrome (HRS) is acute kidney injury (AKI) that occurs without evidence of structural abnormalities in the kidneys in patients with liver disease. It is thought to be due to splanchnic vasculature dilatation that is associated with intense increase of renal arteries’ tone, leading to renal cortex ischemia and AKI. Nitric oxide, endotoxins, neurohormonal changes, bacterial infection, high serum bilirubin and bile acids are examples for factors contributing to HRS development. Nevertheless, other unknown factors may have role in HRS pathophysiology. Hence, further discussion and research are needed to clearly understand HRS. Plasma volume restoration and vasoconstrictors are the cornerstone of HRS treatment. Others such as octreotide, noradrenaline, infection control, systemic inflammatory response prevention, shunting, and renal replacement therapy are currently used to manage HRS. Liver or combined liver and kidney transplantation is currently the ultimate cure for HRS. This review was written to help in better understanding the pathogenesis, diagnosis, and treatment options for HRS

Polypharmacy and drug interactions amongst cirrhotic patients discharged from a tertiary center: Results from a national quality improvement audit

Background and Study AimsAuditing of polypharmacy is particularly essential in patients with cirrhosis because of the crucial role of liver in drug metabolism. The aim of this study was to audit the drug prescribed in this group of patients and analyzed the quantity and severity of potential drug-drug interaction. Patients and MethodsIn this cross-sectional study we analyzed the last prescription as recorded in the Electronic Medical Record at the time of discharge for cirrhotic patients who were hospitalized during 24-months study period. Data were also collected for age, gender, and diagnoses. The drugs were analyzed for cross interactions using the Lexicomp-online e-formulary. The drug interactions are classified as: class A: no known interaction, class B: no action needed, Class C: monitor therapy, class D: consider therapy modification, and Class X: the drug should be avoided. ResultsA total of 333 patients with cirrhosis were audited, whereas complete and relevant data were available for 181 patients (134 males, 74%) with a mean age ± SD 59.7 ± 10.1. Out of these, 168 (92.8%) patients were using at least one medicine and the total number of medications used was 808 drugs. The observed average of utilization was 7.8 ± 3.1 drugs (range = 1–17) and 102 (56.3%) patients used polypharmacy. A total of 198 (24.5%) consumed drugs were related to cirrhosis and its complications. Six (3.3%), 30 (16.6%) and 65 (35.9%) patients had Class-X, Class D, and Class C, respectively. Utilization of polypharmacy was statistical significant in patients with class X (83.3%, p = 0.03), class D (16.6%, p = 0.01), and class C (35.9%, p = 0.02). ConclusionThe findings highlight the importance of auditing for polypharmacy to recognize and prevent potential drug-related problems in patients with cirrhosis. Implementation of strategies to optimize medication use in patients with cirrhosis should be considered necessary as it can have a bearing on length of stay and morbidity

SnoRNAs and miRNAs networks underlying COVID-19 disease severity

There is a lack of predictive markers for early and rapid identification of disease progression in COVID-19 patients. Our study aims at identifying microRNAs (miRNAs)/small nucleolar RNAs (snoRNAs) as potential biomarkers of COVID-19 severity. Using differential expression analysis of microarray data (n = 29), we identified hsa-miR-1246, ACA40, hsa-miR-4532, hsa-miR-145-5p, and ACA18 as the top five differentially expressed transcripts in severe versus asymptomatic, and ACA40, hsa-miR-3609, ENSG00000212378 (SNORD78), hsa-miR-1231, hsa-miR-885-3p as the most significant five in severe versus mild cases. Moreover, we found that white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil (%), lymphocyte (%), red blood cell (RBC) count, hemoglobin, hematocrit, D-Dimer, and albumin are significantly correlated with the identified differentially expressed miRNAs and snoRNAs. We report a unique miRNA and snoRNA profile that is associated with a higher risk of severity in a cohort of SARS-CoV-2 infected patients. Altogether, we present a differential expression analysis of COVID-19-associated microRNA (miRNA)/small nucleolar RNA (snoRNA) signature, highlighting their importance in SARS-CoV-2 infection

Alpha-1-antitrypsin phenotypes in adult liver disease patients

Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of AAT phenotypes from Hardy-Weinberg equilibrium (chi-square = 34.77, df 11, P = 0.000) in the patient group was caused by a higher than expected frequency of Pi ZZ homozygotes (f = 0.0143 and f = 0.0005, respectively, P = 0.000). In addition, Pi M homozygotes were more frequent in patients than in controls (63% and 46%, respectively, P = 0.025). Our study results show that Pi ZZ homozygosity in adults could be associated with severe liver disease. Presence of Pi M homozygosity could be associated with liver disease via some mechanism different from Z allele-induced liver damage through accumulation of AAT polymers

Complement C5a and clinical markers as predictors of COVID-19 disease severity and mortality in a multi-ethnic population

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly

Prevalence and global trends of polypharmacy among people living with HIV: a systematic review and meta-analysis

Background: There has been a rising prevalence of polypharmacy among people living with HIV (PLWH). Uncertainty however remains regarding the exact estimates of polypharmacy among these cohorts of patients. Methods: We conducted a systematic search of PubMed; EMBASE, CROI, Cochrane Database of Systematic Reviews; Science Citation Index and Database of Abstracts of Reviews of Effects for studies between 1 January 2000 and 30 June 2021 that reported on the prevalence of polypharmacy (ingestion of > 5 non-ART medications) among PLWH on antiretroviral therapy regimen (ART). Prevalence of polypharmacy among HIV-positive patients on ART with Clopper–Pearson 95% confidence intervals were presented. The heterogeneity between studies was evaluated using (Formula presented.) and (Formula presented.) statistics. Results: One hundred ninety-seven studies were initially identified, 23 met the inclusion criteria enrolling 55,988 PLWH, of which 76.7% [95% confidence interval (CI): 76.4–77.1] were male. The overall pooled prevalence of polypharmacy among PLWH was 33% (95% CI: 25–42%) (I2 = 100%, τ2 = 0.9170, p < 0.0001). Prevalence of polypharmacy is higher in the Americas (44%, 95% CI: 27–63%) (I2 = 100%, τ2 = 1.0886, p < 0.01) than Europe (29%, 95% CI: 20–40%) (I2 = 100%, τ2 = 0.7944, p < 0.01). Conclusion: The pooled prevalence estimates from this synthesis established that polypharmacy is a significant and rising problem among PLWH. The exact interventions that are likely to significantly mitigate its effect remain uncertain and will need exploration by future prospective and systematic studies. Registration: PROSPERO: CRD42020170071 Plain Language Summary: Background: In people living with HIV (PLWH), what is the prevalence of polypharmacy and is this influenced by sociodemographic factors? Methods and Results: In this systematic review and meta-analysis of 23 studies comprising 55,988 participants, we have for the first time found an estimated polypharmacy pooled prevalence of 33% among PLWH. There was a relatively higher pooled prevalence of polypharmacy among the America’s compared with European cohorts of PLWH. Conclusion: Polypharmacy among PLWH is a rising morbidity that needs urgent intervention both at policy and patient levels of care.This research was supported by the Qatar National Library

Validation of a risk prediction model for COVID-19: the PERIL prospective cohort study.

This study aims to perform an external validation of a recently developed prognostic model for early prediction of the risk of progression to severe COVID-19. Patients were recruited at their initial diagnosis at two facilities within Hamad Medical Corporation in Qatar. 356 adults were included for analysis. Predictors for progression of COVID-19 were all measured at disease onset and first contact with the health system. The C statistic was 83% (95% CI: 78%-87%) and the calibration plot showed that the model was well-calibrated. The published prognostic model for the progression of COVID-19 infection showed satisfactory discrimination and calibration and the model is easy to apply in clinical practice.d.This study was approved by the medical ethics committee of Qatar University and Hamad Medical Corporation (protocol nuos. QU-IEB 1434-E/20 and MRC 05-137, respectively) and written informed consent was obtained from all participants

Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

<p>Abstract</p> <p>Background</p> <p>Hereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y <it>HFE </it>associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER). In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH.</p> <p>Results</p> <p>Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR), as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR), as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency) expression on ER stress responses acted as potential disease modifiers with respect to each other.</p> <p>Conclusion</p> <p>Our novel observations suggest that both the ER overload response (EOR) and the unfolded protein response (UPR) are activated by mutant C282Y HFE protein.</p