Efficacy and safety of chloroquine and hydroxychloroquine for COVID-19: A comprehensive evidence synthesis of clinical, animal, and in vitro studies.

Background: The world is facing a pandemic of COVID-19, a respiratory disease caused by a novel coronavirus which is now called SARS-CoV-2. Current treatment recommendations for the infection are mainly repurposed drugs based on experience with other clinically similar conditions and are not backed by direct evidence. Chloroquine (CQ) and its derivative Hydroxychloroquine (HCQ) are among the candidates. We aimed to synthesize current evidence systematically for in vitro, animal, and human studies on the efficacy and safety of chloroquine in patients with COVID-19. Methods: The Cochrane Library, Google Scholar, PubMed (via Medline), Embase, Scopus, and Web of Science, MedRxiv, clinical trial registries including clinicaltrials.gov, ChiCTR (Chinese Clinical Trial Registry), IRCT (Iranian Registry of Clinical Trials), and the EU Clinical Trials Register. We used the Cochrane tool for risk of bias assessment in randomized studies, the ROBINS tool for non-randomized studies, and the GRADE methodology to summarize the evidence and certainty in effect estimates. Results: The initial database searching retrieved 24,752 studies. Of these, 15,435 abstracts were screened and 115 were selected for full-text review. Finally, 20 human studies, 3 animal studies, and 4 in vitro studies were included in this systematic review. The risk of bias within studies was unclear to high and the overall certainty in evidence-based on GRADES- was very low. HCQ may be effective in clinical improvement in a subset of patients with COVID-19. However, the frequency of adverse events was higher in patients taking HCQ compared to standard of care alone. In contrast, animal studies, did not report any adverse effects. Furthermore, clear benefit of the drug in the survival of the animals has been reported. Most in vitro studies indicated a high selectivity index for the drug and one study that used a human coronavirus reported blockage of virus replication. Conclusion: Current evidence background is limited to six poorly conducted clinical studies with inconsistent findings which fail to show significant efficacy for HCQ. Safety data is also limited but the drug may increase adverse outcomes. Routine use of the drug is not recommended based on limited efficacy and concerns about the drug safety especially in high-risk populations.

Are cerebral veins hounsfield unit and H: H ratio calculating in unenhanced CT eligible to diagnosis of acute cerebral vein thrombosis?

BACKGROUND: For both the clinician and a radiologist, the diagnosis of cerebral venous sinus thrombosis (CVST), because of the variety of signs and symptoms, remains a challenge. In this study, the role of unenhanced brain computed tomography (CT) in the diagnosis of CVST was assessed. MATERIALS AND METHODS: In this case-control study, unenhanced CT of 35 patients with acute CVST was compared with 70 normal patients. Hematocrit (HCT), creatinine, and blood urea nitrogen were recorded in all patients. CT images were read, and the attenuation was measured by two independent experienced radiologists. The H:H ratio was calculated for all patients in both case and control groups to normalized densities regarding HCT. RESULTS: The mean of attenuation in patients was 66.95 ± 10.63 Hounsfield unit (HU) and in the controls was 52.51 ± 2.92 HU (P < 0.0001). The mean of H:H ratio in patients was 1.78 ± 0.40 and in controls was 1.46 ± 0.28 (P < 0.0001). Attenuation >60.4 HU was the best optimal cutoff with area under the curve of 0.918 (0.848-0.962) and had 71.4% sensitivity and 100% specificity. H:H ratio >1.42 as the optimal cutoff had 94.3% sensitivity and 54.3% specificity for identifying the CVST. CONCLUSION: Attenuation value >60.4 HU and H: H ratio >1.42 calculated based on unenhanced CT can be used as reliable methods to detect CVST in the absence of magnetic resonance imaging and magnetic resonance venography in the emergency setting.

Prevalence of stunting in Iranian children under five years of age: Systematic review and meta-analysis.

Background: Children in all countries, especially in developing countries, constitute a vulnerable group. Therefore, attention to their health issues is very important. The aim of this study was to determine the prevalence of stunting in Iranian children under-five years. Methods: All original studies were searched by complex search syntax from international databases including Medline (PubMed), Web of sciences, Google scholar, Scopus, CINHAL and the Iranian databases consist of SID (Scientific Information Database, www.sid.ir), Irandoc (Iranian Research Institute for Information Science and Technology, Irandoc.ac.ir), Iranmedex (www.iranmedex.com), and Magiran (www.magiran.com) from January 1989 to August 2017. Two independent reviewers identified relevant studies in several steps. We employed a random effect model to generate a pooled prevalence. The reported prevalence is presented as percent and 95% confidence interval (CI). Sources of heterogeneity among the studies were determined using subgroup analysis and meta-regression. Results: Finally, 16 studies from different settings remained for meta-analysis in order to have a pooled prevalence estimate, which prevalence of total stunting was 12% (95%CI: 10-14). Subgroup analysis for gender showed that the prevalence of stunting in both boys and girls children were equal to 10% (95%CI: 8-11) and 9% (CI 95% 8-10), respectively. Also pooled prevalence of stunting in southern provinces are higher than other provinces. Conclusion: The prevalence of stunting in some regions of Iran is higher than others. Although, in recent years much effort has been made to address deprivation such as economical, nutritional and social supporting, improvement of the quality of life, there are still nutritional problems in these areas of Iran.

Father-Son COVID-19-associated mucormycosis: Important role of genetic susceptibility in combination with environmental factors.

In this report, a father with a history of diabetes mellitus and his son without a remarkable past medical history, both got COVID-19- associated mucormycosis (CAM) as evidenced by their clinical and radiological findings. This suggests the possible role of genetics in combination with the environment in susceptibility to CAM.

Nonsteroidal anti-inflammatory drugs in acute viral respiratory tract infections: An updated systematic review.

In this systematic review, we aimed to assess the efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating respiratory tract infections in adults and children. PubMed, Scopus, Web of Science, Cochrane, and Embase databases were searched. A total of 34 randomized clinical trials were included in this systematic review. We assessed the risk of bias of all included studies using the Cochrane tool for risk of bias assessment. The evidence on ibuprofen, naproxen, aspirin, diclofenac, and other NSAIDs were rated for degree of uncertainty for each of the study outcomes and summarized using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Our findings suggest that high-quality evidence supports the use of NSAIDs to reduce fever in both adults and children. However, the evidence was uncertain for the use of NSAIDs to reduce cough. Most studies showed that NSAIDs significantly relieved sore throat. The evidence for mortality and oxygenation is limited. Regarding the adverse events, gastrointestinal discomfort was more frequently reported in children. For adults, our overall certainty in effect estimates was low and the increase in gastrointestinal adverse events was not clinically significant. In conclusion, NSAIDs seem to be beneficial in the outpatient management of fever and sore throat in adults and children. Although the evidence does not support their use to decrease mortality nor improve oxygenation in inpatient settings, the use of NSAIDs did not increase the rate of death or the need for ventilation in patients with respiratory tract infections. Further studies with a robust methodology and larger sample sizes are recommended.

From Bilateral Periorbital Necrotic Wound to Fungal Brain Abscess: A Complicated Case of COVID-19-Associated Mucormycosis.

COVID-19-associated mucormycosis (CAM) is categorized as rhinocerebral-orbital (RCOM), pulmonary, gastrointestinal, cutaneous, and disseminated mucormycosis. An alarming surge in morbidity and mortality attributed to mucormycosis concurrent with coronavirus disease 2019 (COVID-19) has emerged as a cause for concern during the current outbreak of COVID-19. The global incidence of CAM has been attributed to environmental, host, and iatrogenic factors. Further, Mucorales interacting with epithelial cells followed by endothelium invasion are pivotal in developing mucormycosis in patients with COVID-19. In essence, CAM is an emerging condition that requires increased vigilance in all COVID-19 patients, including those who have recovered. In this case report, we describe a rare case of CAM in a 33-year-old immunocompetent man who developed bilateral periocular pain and a small area of cutaneous necrosis in both medial canthi associated with impaired vision, which progressed into a fungal brain abscess formation in the post-COVID period. Furthermore, this case aims to illustrate the potential underlying risk factors of CAM other than known risk factors, especially in immunocompetent individuals.

Post-Translational Modification Networks of Contractile and Cellular Stress Response Proteins in Bladder Ischemia.

Molecular mechanisms underlying bladder dysfunction in ischemia, particularly at the protein and protein modification levels and downstream pathways, remain largely unknown. Here we describe a comparison of protein sequence variations in the ischemic and normal bladder tissues by measuring the mass differences of the coding amino acids and actual residues crossing the proteome. A large number of nonzero delta masses (11,056) were detected, spanning over 1295 protein residues. Clustering analysis identified 12 delta mass clusters that were significantly dysregulated, involving 30 upregulated (R2 > 0.5, ratio > 2, p < 0.05) and 33 downregulated (R2 > 0.5, ratio < -2, p < 0.05) proteins in bladder ischemia. These protein residues had different mass weights from those of the standard coding amino acids, suggesting the formation of non-coded amino acid (ncAA) residues in bladder ischemia. Pathway, gene ontology, and protein-protein interaction network analyses of these ischemia-associated delta-mass containing proteins indicated that ischemia provoked several amino acid variations, potentially post-translational modifications, in the contractile proteins and stress response molecules in the bladder. Accumulation of ncAAs may be a novel biomarker of smooth muscle dysfunction, with diagnostic potential for bladder dysfunction. Our data suggest that systematic assessment of global protein modifications may be crucial to the characterization of ischemic conditions in general and the pathomechanism of bladder dysfunction in ischemia.

Regulation of Cellular Stress Signaling in Bladder Ischemia.

INTRODUCTION: The etiology of lower urinary tract symptoms in patients with non-obstructed non-neurogenic bladder remains largely unknown. Clinical studies divulged a significant correlation between reduced bladder blood flow and low bladder compliance. Animal models of bladder ischemia displayed structural modifications, characterized by loss of smooth muscle cells and accumulation of connective tissue in the bladder wall. The underlying mechanisms contributing to structural damage in bladder ischemia remain largely elusive. We previously reported that structural modifications in bladder ischemia correlate with upregulated stress proteins and cell survival signaling, suggesting the potential role of cellular stress in ischemic damage. However, stress response molecules and downstream pathways eliciting bladder damage in ischemia remain largely undetermined. METHODS: Using a rat model of bladder ischemia along with a cell culture hypoxia model, we investigated stress signaling molecules in the ischemic bladder tissues and hypoxic bladder smooth muscle cells. RESULTS: Our data suggest simultaneous upregulation of two major cellular stress-sensing molecules, namely apoptosis signal-regulating kinase 1 (ASK1) and caspase-3, implying degenerative insult via stress signaling pathway in bladder ischemia. Consistent with bladder ischemia, incubation of cultured human bladder smooth muscle cells at low oxygen tension increased both ASK1 and caspase-3 expression, insinuating hypoxia as an essential factor in ASK1 and caspase-3 upregulation. Gene deletion of ASK1 by ASK1 siRNA in cultured smooth muscle cells prevented caspase-3 upregulation by hypoxia, suggesting caspase-3 regulation by ASK1 under the ischemic/hypoxic conditions. Upregulation of ASK1 and caspase-3 in rat bladder ischemia and human bladder smooth muscle cell hypoxia was associated with subcellular structural modifications consistent with the initial stages of apoptotic insult. CONCLUSION: Our data suggest that stress sensing by ASK1 and caspase-3 may contribute to subcellular structural damage and low bladder compliance. The ASK1/caspase-3 pathway may provide therapeutic targets against cellular stress and degenerative responses in bladder ischemia.

Medicinal plants in the adjunctive treatment of patients with type-1 diabetes: a systematic review of randomized clinical trials.

PROPOSE: This study aims to systematically review the randomized controlled trials that address the effectiveness and safety of herbal medicine in patients with type 1 diabetes. METHODS: The Cochrane Library (latest issue); MEDLINE (until recent); EMBASE (until recent); AMED (Allied and Complementary Medicine Database) (until recent); and CINHAL (until recent) were searched electronically for the identification of trials until October 2019. Articles were initially screened based on title and abstract and then by full text by two independent authors. References of retrieved studies were hand-searched for further studies. Risk of bias was assessed according to the Cochrane handbook of systematic reviews of interventions. The results were summarized into GRADE (grading of recommendations, assessment, development and evaluation) tables. No meta-analysis was applicable as only one study was found for each intervention. RESULTS: Four RCTs were finally included in the systematic review with an overall moderate quality of conduct and low quality of reporting. The sample sizes were very small. The results of these RCTs show that cinnamon pills and Berberine/Silymarine compound capsules may decrease blood glucose indices from baseline, while fenugreek seeds and fig leaf decoction do not show any statistically significant effect. CONCLUSIONS: The evidence is scarce and no recommendations can be made based on current evidence. Further trials with more rigorous methodology and stronger quality of reporting are needed to make conclusions.

Relationship between renal volume calculated by using multislice computed tomography and glomerular filtration rate calculated by using the Cockcroft-Gault and modification of diet in renal disease equations in living kidney donors.

It is essential to ascertain the state of health and renal function of potential kidney donors before organ removal. In this regard, one of the primary steps is to estimate the donor's glomerular filtration rate (GFR). For this purpose, the modification of diet in renal disease (MDRD) and the Cockcroft-Gault (CG) formulas has been used. However, these two formulas produce different results and finding new techniques with greater accuracy is required. Measuring the renal volume from computed tomography (CT) scan may be a valuable index to assess the renal function. This study was conducted to investigate the correlation between renal volume and the GFR values in potential living kidney donors referred to the multislice imaging center at Alzahra Hospital during 2014. The study comprised 66 subjects whose GFR was calculated using the two aforementioned formulas. Their kidney volumes were measured by using 64-slice CT angiography and the correlation between renal volume and GFR values were analyzed using the Statistical Package for the Social Science software. There was no correlation between the volume of the left and right kidneys and the MDRD-based estimates of GFR (P = 0.772, r = 0.036, P = 0.251, r = 0.143, respectively). A direct linear correlation was found between the volume of the left and right kidneys and the CG-based GFR values (P = 0.001, r = 0.397, P <0.001, r = 0.465, respectively). The kidney volume derived from multislice CT scan can help predict the GFR value in kidney donors with normal renal function. The limitations of our study include the small sample size and the medium resolution of 64-slice multislice scanners. Further studies with larger sample size and using higher resolution scanners are warranted to determine the accuracy of this method in potential kidney donors.

Progressive changes in detrusor function and micturition patterns with chronic bladder ischemia.

PURPOSE: Lower urinary tract symptoms (LUTS) are bothersome constellation of voiding symptoms in men and women as they age. Multiple factors and comorbidities are attributed to this problem but underlying mechanisms of nonobstructive nonneurogenic detrusor overactivity, detrusor underactivity and LUTS remain largely unknown. Our goal was to characterize detrusor function and voiding patterns in relation to muscarinic receptors expression, nerve fiber density, and neural ultrastructure in chronic bladder ischemia. MATERIALS AND METHODS: Iliac artery atherosclerosis and bladder ischemia were produced in male Sprague-Dawley rats. At 8 and 16 weeks after ischemia, micturition patterns and cystometrograms were recorded in conscious rats then bladder blood flow and nonvoiding spontaneous contractions were measured under general anesthesia. Bladder tissues were processed for Western blotting, immunostaining, and transmission electron microscopy. RESULTS: Bladder responses to ischemic insult depended on the duration of ischemia. Micturition patterns and cystometric changes at 8-week ischemia suggested detrusor overactivity, while voiding behavior and cystometrograms at 16-week ischemia implied abnormal detrusor function resembling underactivity. Upregulation of muscarinic M2 receptor was found after 8- and 16 weeks of ischemia. Downregulation of M3 and upregulation of M1 were detected at 16-week ischemia. Neural structural damage and marked neurodegeneration were found after 8 and 16 weeks of ischemia, respectively. CONCLUSIONS: Prolonged ischemia may be a mediating variable in progression of overactive bladder to dysfunctional patterns similar to detrusor underactivity. The mechanism appears to involve differential expression of M1, M2, and M3 receptors, neural structural injury, and progressive loss of nerve fibers.

Corrigendum: Correction of title spelling. Progressive changes in detrusor function and micturition patterns with chronic bladder ischemia.

[This corrects the article on p. 249 in vol. 57.].

Anti-Hepatitis E Antibody in Hemodialysis Patients in Isfahan, Iran: Prevalence and Risk Factors.

BACKGROUND: Many studies have been performed regarding the prevalence of hepatitis E in the general population, but there is controversial evidence for an increased risk of the infection in patients on maintenance hemodialysis (HD). OBJECTIVES: The primary end point of the present study was to determine if the prevalence of anti-hepatitis E virus IgG (anti-HEV IgG) is higher in patients on maintenance HD than in the normal population in Isfahan. PATIENTS AND METHODS: In a case-control study performed in Isfahan in June 2012, we compared the seroprevalence of HEV among 274 patients on maintenance HD and 275 otherwise healthy individuals. The patients were recruited from 3 HD centers in Isfahan. Anti-HEV IgG was detected using a Dia Pro Diagnostic HEV enzyme immunoassay (ELISA) kit. Demographic and clinical data (sex, age, blood transfusion history, HD duration, age at HD initiation, and evidence of hepatitis B and hepatitis C infections) were obtained from the medical records of the HD patients. RESULTS: Anti-HEV IgG was detected in 27 (9.9%) controls and 78 (28.3%) patients, with the difference being statistically significant (P < 0.05). Furthermore, there was a significant association between positive anti-HEV antibody, HD duration, and blood transfusion history in the HD patients. CONCLUSIONS: Considering the results, it seems necessary to conduct prospective studies in order to identify factors responsible for the high seroprevalence of HEV in Isfahan HD units.