Comparison of the effects of etomidate, ketamine, sodium thiopental, and midazolam on the mortality of patients with COVID-19 requiring intubation.

Background: Among the medications administered for the management of COVID-19 patients, the induction drugs used for intubation have received little attention. The aim of this study was to compare the effect of induction drugs on the mortality of patients with COVID-19 requiring intubation. Methods: In this retrospective study, all patients who were admitted to Shahid Sadoughi and Shahid Rahnemoun hospitals in Yazd from February to March 2020 with definitive diagnosis of COVID-19 and needed intubation were enrolled. Patients were divided into 4 groups based on the type of drugs used in intubation, and mortality rate was assessed at the end of the first, second, fourth, and seventh days of the study. Statistical analyses were performed using SPSS 20 and P values <.05 was considered significant. Results: In this study, 76 patients were examined. Patients were divided into 4 groups, of which 21 were in etomidate group, 8 in ketamine group, 21 in sodium thiopental group, and 35 in midazolam group. Mortality rate in these 4 groups was 25%, 12.5%, 14.3%, and 14.3% (p=0.822), respectively at the end of the first day after intubation; it was 83.3%, 12.5%, 28.6%, and 25.7% (p=0.001), respectively, at the end of the second day; it was 83.3%, 12.5%, 42.9%, and 42.9% (p=0.015), respectively, until the end of the fourth day; it was 100%, 25%, 61.9%, and 65.7% (p=0.007), respectively, until the end of the seventh day. Admission to intubation time interval was 0.91±0.99, 3.12±1.95, 4.09±2.44, and 4.74±2.62 days, respectively (p<0.001). Conclusion: The results of this study suggest that the use of etomidate may be associated with higher mortality in COVID-19 patients. Further studies are needed to verify the results of this study.

Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells?

Chemotherapeutic drugs kill cancer cells or control their progression all over the patient's body, while radiation- and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresistance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conventional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.

Resveratrol: A "miracle" drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis.

BACKGROUND: Over the last decade resveratrol has been trialled for the prevention and treatment of cognitive decline; however, the results have shown a conflict between human studies compared with animal studies, especially on cognition, blood pressure, neuroimaging, and mood. METHODS: Human clinical trials and animal studies published prior to January 2020, were identified searching across major electronic databases. PRISMA guidelines were used for data extraction, which was independently performed by two authors. Pooled standard mean difference (SMD, random effect model) and odds ratios (ORs) were calculated. RESULTS: Most publications on animal models reported positive outcomes on cognition and brain function following exposure to resveratrol or grape seed extracts. By contrast, 11 meta-analyses of data from human placebo vs resveratrol, grape or wine treatment trials identified no statistically significant effect on a variety of measures, including cognitive and mood assessments, grey matter volume and blood pressure. CONCLUSIONS: Based on currently available data, the promising effects of resveratrol in animal models is not replicated in human clinical trials. The effects, if any, of resveratrol on human cognition are likely to be small. This work may be useful for the design and implementation of future pre-clinical and clinical studies using resveratrol in a neurological setting.

Innate immune response in systemic autoimmune diseases: a potential target of therapy.

Innate immunity refers to defense mechanisms that are always present, ready to combat microbes and other offending agents. Innate immunity acts as a first-line defense and activates the conventional immune responses; however, it has been speculated that the importance of innate immunity in initiation and development of some disorders is more than just the "first line of defense". Autoimmune diseases, caused by immune system overactivation, are among the most challenging scientific and clinical problems, and there is still much to be learned about their pathogenesis. We aimed to provide a comprehensive overview of available documents about the role of innate immunity in systemic autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, polymyositis, and systemic sclerosis. This study highlights the innate immunity pathways or molecules that are under investigation for therapy of these diseases.

Determining the association of thrombophilic gene polymorphisms with recurrent pregnancy loss in Iranian women.

OBJECTIVE: Thrombophilia is known to be associated with poor pregnancy outcomes. In this study, three thrombophilic gene polymorphisms, including EPCR (Ser219Gly), F11 (rs4253417) and F7 (323 Ins10) were investigated in an Iranian population of women in order to determine the correlation between thrombophilia and recurrent pregnancy loss (RPL). METHODS: Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to evaluate the frequency of three candidate thrombophilic risk factors for recurrent pregnancy loss. The frequencies of the polymorphisms were compared between the case (144 patients with a history of at least two miscarriages) and the control (150 healthy women with no abortion) group. RESULTS: Our results show that EPCR and FVII polymorphisms of the patient and control group have the same genotype frequency, and the difference is not statistically significant (p-value > .05). Regarding FXI polymorphism, TT genotype frequency was higher in the patient group than the control group (p-value < .05); however, CT heterozygote form was higher in the control group compared to the patient group (p-value < .05). CONCLUSION: In FXI polymorphism, T allele is possibly an RPL risk factor and C allele has a protective role. Thus, wild type FXI could be related to RPL, but EPCR and FVII polymorphism have no such correlation.

Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes.

Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases.

Coexistence of KRAS and BRAF Mutations in Colorectal Cancer: A Case Report Supporting The Concept of Tumoral Heterogeneity.

The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor (EGFR)-targeted therapy resistance of colorectal carcinomas. The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers (CRCs) with the prevalence of less than 0.001% of the cases. In patients with KRAS-mutant tumors, BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor. The current report demonstrates a case with advanced adenocarcinoma of the colon showing the coexistence of KRAS and BRAF mutations and may have profound clinical implications for disease progression and therapeutic responses.

The prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/ COX2) rs5277 polymorphism does not influence risk of colorectal cancer in an Iranian population.

BACKGROUND: The prostaglandin-endoperoxide synthase 2 [PTGS2, commonly known as cyclooxygenase-2 (COX-2)] is an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue and involved in the synthesis of prostaglandins and thromboxanes, regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether a functional genetic polymorphism, rs5277, in COX-2 may have a risk-modifying effect on sporadic colorectal cancer in an Iranian population. MATERIALS AND METHODS: We conducted a case-control study on 167 patients with colorectal cancer and 197 cancer-free controls in Taleghani Hospital in Tehran, Iran, between 2007 and 2011. Peripheral blood samples of both groups were processed for DNA extraction and genotyping of the COX-2 gene polymorphism (rs5277) using PCR-RFLP. RFLP results were confirmed by direct sequencing. Logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: There was no significant difference in the distribution of COX-2 gene rs5277 polymorphism genotype and the allelic form, among CRC patients compared with the healthy control group (p: 0.867). CONCLUSIONS: Our results suggest that rs5277 polymorphism in COX2 could not be a good prognostic indicator for patients with CRC.