Association between inpatient glycemic variability and COVID-19 mortality: a prospective study.

BACKGROUND: This study aimed to determine the association between glycemic variability (GV) and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: We prospectively analyzed data from inpatients (> 18 years old) with RT-PCR confirmed COVID-19 admitted between March 2020 and July 2021. All patients were hospitalized for more than 48 h and had at least six point-of-care capillary glucose tests obtained three times daily in the pre-prandial period during hospitalization. GV was measured using the glucose standard deviation (SD) and coefficient of variation (CV). ROC curve was adjusted to determine the SD and CV cutoff values associated with mortality (44.7 mg/dL and 27.5%, respectively); values above these were considered indicative of high GV. Logistic regression models were fitted to explore the association between GV and mortality in patients with and without diabetes. RESULTS: A total of 628 patients were stratified into SD < 44.7 mg/dL (n = 357) versus ≥ 44.7 mg/dL (n = 271) and CV < 27.5% (n = 318) versus ≥ 27.5% (n = 310) groups. After controlling for age, sex, presence of diabetes mellitus (DM) and cardiovascular disease, we found a significant association between high GV and mortality (odds ratio 2.99 [1.88-4.77] for SD and 2.43 [1.54-3.85] for CV; p values < 0.001). The mortality rate was higher with SD ≥ 44.7 mg/dL and CV ≥ 27.5% compared to that with SD < 44.7 mg/dL and CV < 27.5%, regardless of DM (p < 0.001 for all). CONCLUSION: High glycemic variability was independently associated with mortality in patients with and without DM, who were hospitalized with COVID-19.

Clinical characteristics and outcomes of hospitalized patients with COVID-19 in a city of South Brazil: Have they changed through the first year of the pandemic?

The Coronavirus Disease 2019 (COVID-19) pandemic posed various challenges to the healthcare system and disease management. This study aimed to describe changes in the clinical characteristics and outcomes of hospitalized patients during the first year of the COVID-19 pandemic in a city in southern Brazil. This prospective study was carried out in two tertiary care private hospitals in Curitiba. A total of 1151 patients hospitalized between March 2020 and March 2021 were included. We identified three epidemiological critical periods of the pandemic and compared patients' characteristics and the frequencies of oral intubation, intensive care unit (ICU) admission and mortality. Continuous variables were analyzed by variance analysis model (ANOVA) or the Kruskal-Wallis nonparametric test and categorical variables by the chi-square or Fisher's exact test. Models for univariate and multivariate logistic regression analysis were adjusted to identify the factors associated with mortality. All p-values were two-tailed and p<0.05 was considered statistically significant. The average age of the patients was 58 years and 60.9% (n = 701) were males. The most prevalent comorbidities were systemic arterial hypertension, diabetes and obesity. There were no significant variations in the demographic characteristics and previous comorbidities of the patients for the different periods of analysis. Mortality was positively associated with the age ≥65 years and the presence of one or more cardiometabolic comorbidities (p<0.001). March 2021 was the most important critical period of the pandemic since there were higher frequencies of patients admitted later in the course of the disease, with desaturation and more symptoms at hospital admission (p<0.001). There was also an increase in the duration of hospital stay (p<0.001) and the frequencies of all critical outcomes for this period: oral intubation (p<0.001), ICU admission (p = 0.606) and mortality (p = 0.001). Our key findings revealed that, although there were no statistically significant differences between the subgroups of hospitalized patients over time in terms of demographic characteristics and comorbidities, the course of COVID-19 was significantly more severe for patients admitted to the hospital at the end of the first year of the pandemic in Brazil.

Lung Inflammasome Activation in SARS-CoV-2 Post-Mortem Biopsies.

The inflammasome complex is a key part of chronic diseases and acute infections, being responsible for cytokine release and cell death mechanism regulation. The SARS-CoV-2 infection is characterized by a dysregulated cytokine release. In this context, the inflammasome complex analysis within SARS-CoV-2 infection may prove beneficial to understand the disease's mechanisms. Post-mortem minimally invasive autopsies were performed in patients who died from COVID-19 (n = 24), and lung samples were compared to a patient control group (n = 11) and an Influenza A virus H1N1 subtype group from the 2009 pandemics (n = 10). Histological analysis was performed using hematoxylin-eosin staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: ACE2, TLR4, NF-κB, NLRP-3 (or NALP), IL-1ß, IL-18, ASC, CASP1, CASP9, GSDMD, NOX4, TNF-α. Data obtained from digital analysis underwent appropriate statistical tests. IHC analysis showed biomarkers that indicate inflammasome activation (ACE2; NF-κB; NOX4; ASC) were significantly increased in the COVID-19 group (p < 0.05 for all) and biomarkers that indicate cell pyroptosis and inflammasome derived cytokines such as IL-18 (p < 0.005) and CASP1 were greatly increased (p < 0.0001) even when compared to the H1N1 group. We propose that the SARS-CoV-2 pathogenesis is connected to the inflammasome complex activation. Further studies are still warranted to elucidate the pathophysiology of the disease.

The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies.

Rationale: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Objective: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods and Results: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1ß, IL-4, IL-6, CD163, TNF-α, TGF-ß, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1ß, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-ß and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.

Deregulated miRNA expression is associated with endothelial dysfunction in post-mortem lung biopsies of COVID-19 patients.

MicroRNAs (miRNAs) are critical modulators of endothelial homeostasis, which highlights their involvement in vascular diseases, including those caused by virus infections. Our main objective was to identify miRNAs involved in the endothelial function and determine their expression in post-mortem lung biopsies of COVID-19 patients with severe respiratory injuries and thrombotic events. Based on functional enrichment analysis, miR-26a-5p, miR-29b-3p, and miR-34a-5p were identified as regulators of mRNA targets involved in endothelial and inflammatory signaling pathways, as well as viral diseases. A miRNA/mRNA network, constructed based on protein-protein interactions of the miRNA targets and the inflammatory biomarkers characterized in the patients, revealed a close interconnection of these miRNAs in association to the endothelial activation/dysfunction. Reduced expression levels of selected miRNAs were observed in the lung biopsies of COVID-19 patients (n = 9) compared to the Controls (n = 10) (P < 0.01-0.0001). MiR-26a-5p and miR-29b-3p presented the best power to discriminate these groups (area under the curve (AUC) = 0.8286, and AUC = 0.8125, respectively). The correlation analysis of the miRNAs with inflammatory biomarkers in the COVID-19 patients was significant for miR-26a-5p [IL-6 (r2 = 0.5414), and ICAM-1 (r2 = 0.5624)], and miR-29b-3p [IL-4 (r2 = 0.8332) and IL-8 (r2 = 0.2654)]. Altogether, these findings demonstrate the relevance and the non-random involvement of miR-26a-5p, miR-29b-3p, and miR-34a-5p in endothelial dysfunction and inflammatory response in patients with SARS-CoV-2 infection and the occurrence of severe lung injury and immunothrombosis.

Covid-19 cytokine storm in pulmonary tissue: Anatomopathological and immunohistochemical findings.

The COVID-19 pandemic is a worldwide threat, and information on physiopathological aspects of the disease is limited. Despite efforts in searching treatment options, a better understanding of the SARS-CoV-2 pathways can contribute to managing severe cases. In this study, we aim to describe pathological and immunopathogenic findings of two different cases, both in the high-risk group. Post-mortem lung biopsies were analyzed by traditional and immunohistochemical methods. Tissue expression of innate and adaptive immune response biomarkers was tested. We observed a higher innate response in case 1 with an abundance of mast cells, scarce CD8+ lymphocytes, high expression of TNF-alpha, and almost absent adaptative immune response. In case 2, the adaptative immune response was present, with numerous CD8+ lymphocytes and higher levels of IL-4 and TGF-beta. Both cases converged to a prothrombotic state expressing high IL-6, followed by ICAM-1 expression and endotheliites leading to systemic inflammatory response syndrome. In conclusion, differences in age and comorbidities and immune response described here may be related to the SARS-CoV-2 delay in the adaptative immune response, evolution stage of diffuse alveolar damage, and progression for systemic inflammatory response syndrome.

The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review.

BACKGROUND: The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial. OBJECTIVE AND RATIONALE: We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women. SEARCH METHODS: The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively. OUTCOMES: In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50 µg/day of estrogen combined with micronized progesterone appears to be the safer choice with respect to thrombotic and stroke risk. Also, vaginal HT administration may play a role in myocardial infarction and stroke risk prevention, but this is based on limited evidence and requires further investigation. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions such as coronary/carotid atherosclerosis, which are at risk of developing, and thus progressing to CVD. The quality of evidence was generally low or moderate and the findings were based mostly on observational data. WIDER IMPLICATIONS: Use of low-dose oral and transdermal HT appears to be safe with regard to CVD risk in women in menopausal transition and within the first years (e.g. 10 years) after menopause onset. In women with increased baseline thromboembolic risk, alternative non-hormonal medications are suggested as first-line treatment and transdermal estradiol alone or with micronized progesterone only should be considered when these options are not effective. When HT is initiated >10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health.

Migraine and cognitive function: Baseline findings from the Brazilian Longitudinal Study of Adult Health: ELSA-Brasil.

Background The association between migraine and cognitive performance is unclear. We analyzed whether migraine is associated with cognitive performance among participants of the Brazilian Longitudinal Study of Adult Health, ELSA-Brasil. Methods Cross-sectional analysis, including participants with complete information about migraine and aura at baseline. Headache status (no headaches, non-migraine headaches, migraine without aura and migraine with aura), based on the International Headache Society classification, was used as the dependent variable in the multilinear regression models, using the category "no headache" as reference. Cognitive performance was measured with the Consortium to Establish a Registry for Alzheimer's Disease word list memory test (CERAD-WLMT), the semantic fluency test (SFT), and the Trail Making Test version B (TMTB). Z-scores for each cognitive test and a composite global score were created and analyzed as dependent variables. Multivariate models were adjusted for age, gender, education, race, coronary heart disease, heart failure, hypertension, diabetes, dyslipidemia, body mass index, smoking, alcohol use, physical activity, depression, and anxiety. In women, the models were further adjusted for hormone replacement therapy. Results We analyzed 4208 participants. Of these, 19% presented migraine without aura and 10.3% presented migraine with aura. All migraine headaches were associated with poor cognitive performance (linear coefficient ß; 95% CI) at TMTB -0.083 (-0.160; -0.008) and poorer global z-score -0.077 (-0.152; -0.002). Also, migraine without aura was associated with poor cognitive performance at TMTB -0.084 (-0.160, -0.008 and global z-score -0.077 (-0.152; -0.002). Conclusion In participants of the ELSA-study, all migraine headaches and migraine without aura were significantly and independently associated with poorer cognitive performance.