Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

Therapy-induced senescent cancer cells exhibit complement activation and increased complement regulatory protein expression.

Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated ß-galactosidase, p21Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.

Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.

OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass. DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow. SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU. PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index ( r = -0.225; ß = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; ß = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O 2 /s/10 6 cells; p = 0.002). CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

Cardiac implantable electronic devices in female patients: Esthetic, breast implant, and anatomic considerations.

INTRODUCTION: The implantation of a cardiac implantable electronic device (CIED) can have esthetic and psychological consequences on patients. We explore a heart team model for care coordination and discuss esthetic approaches for improved cosmetic outcomes in patients undergoing (CIED)-related procedures or de novo implantation. METHODS: Patients undergoing CIED surgery for approved indications between June 2015 and June 2022 were identified. Patients were included when surgical care was provided by a collaborative relationship between the primary electrophysiologist and the plastic surgeon. Patient demographics, details of the surgical procedure, information on breast implants, complications, and outcomes related to cosmesis were recorded. RESULTS: Twenty-two female patients were included in this study. The mean age was 50.2 ± 18.2 years. The mean follow-up duration was 2.2 ± 5.5 months. The top two indications for the procedure included CIED generator change (n = 9, 41%) and implantable cardioverter-defibrillator (ICD) implantation (n = 7, 32%). The most common reasons for involving plastic surgery in the procedure included surgery near breast implants (n = 10, 45%) and device displacement or discomfort (n = 8, 36%). CIED pocket position was prepectoral in 10 cases (45%), subpectoral in 11 patients (50%), and intramuscular in one patient (4.5%). The majority of the patients (20, 91%) had cosmetically acceptable results postprocedure. One patient (4.5%) had breast asymmetry on the CIED side, and another continued to have skin erosion over the CIED and leads. CONCLUSION: A heart team approach incorporating the expertize of cardiac electrophysiology and plastic surgery is essential for providing optimal care for patients with breast implants and patients requesting esthetic appeal.

Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity.

Lipid and cholinergic mediators are inflammatory regulators, but their role in the immunopathology of COVID-19 is still unclear. Here, we used human blood and tracheal aspirate (TA) to investigate whether acetylcholine (Ach), fatty acids (FAs), and their derived lipid mediators (LMs) are associated with COVID-19 severity. First, we analyzed the perturbation profile induced by SARS-CoV-2 infection in the transcriptional profile of genes related to the ACh and FA/LM pathways. Blood and TA were used for metabolomic and lipidomic analyses and for quantification of leukocytes, cytokines, and ACh. Differential expression and coexpression gene network data revealed a unique transcriptional profile associated with ACh and FA/LM production, release, and cellular signaling. Transcriptomic data were corroborated by laboratory findings: SARS-CoV-2 infection increased plasma and TA levels of arachidonic acid, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, 11-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid, and ACh. TA samples also exhibited high levels of PGE2, thromboxane B2, 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid, and 6-trans-leukotriene B4 Bioinformatics and experimental approaches demonstrated robust correlation between transcriptional profile in Ach and FA/LM pathways and parameters of severe COVID-19. As expected, the increased neutrophil-to-lymphocyte ratio, neutrophil counts, and cytokine levels (IL-6, IL-10, IL-1ß, and IL-8) correlated with worse clinical scores. Glucocorticoids protected severe and critical patients and correlated with reduced Ach levels in plasma and TA samples. We demonstrated that pulmonary and systemic hyperinflammation in severe COVID-19 are associated with high levels of Ach and FA/LM. Glucocorticoids favored the survival of patients with severe/critical disease, and this effect was associated with a reduction in ACh levels.

Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer.

Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

Genome-wide gene expression responses to experimental manipulation of Saccharomyces cerevisiae repressor activator protein 1 (Rap1) expression level.

Precise regulation of transcription in gene expression is critical for all aspects of normal organism form, fitness, and function and even minor alterations in the level, location, and timing of gene expression can result in phenotypic variation within and between species including evolutionary innovations and human disease states. Eukaryotic transcription is regulated by a complex interplay of multiple factors working both at a physical and molecular levels influencing this process. In Saccharomyces cerevisiae, the TF with the greatest number of putative regulatory targets is the essential gene Repressor Activator Protein 1 (RAP1). While much is known about the roles of Rap1 in gene regulation and numerous cellular processes, the response of Rap1 target genes to systematic titration of RAP1 expression level remains unknown. To fill this knowledge gap, we used a strain with a tetracycline-titratable promoter replacing wild-type regulatory sequences of RAP1 to systematically reduce the expression level of RAP1 and followed this with RNA sequencing (RNA-seq) to measure genome-wide gene expression responses. Previous research indicated that Rap1 plays a significant regulatory role in particular groups of genes including telomere-proximal genes, homothallic mating (HM) loci, glycolytic genes, DNA repair genes, and ribosomal protein genes; therefore, we focused our analyses on these groups and downstream targets to determine how they respond to reductions in RAP1 expression level. Overall, despite being known as both an activator and as a repressor of its target genes, we found that Rap1 acts as an activator for more target genes than as a repressor. Additionally, we found that Rap1 functions as an activator of ribosomal protein genes and a repressor for HM loci genes consistent with predictions from the literature. Unexpectedly, we found that Rap1 functions as a repressor of glycolytic enzyme genes contrary to prior reports of it having the opposite effect. We also compared the expression of RAP1 to five different genes related to DNA repair pathway and found that decreasing RAP1 downregulated four of those five genes. Finally, we found no effect of RAP1 depletion on telomere-proximal genes despite its functioning to silence telomeric repeat-containing RNAs. Together our results enrich our understanding of this important transcriptional regulator.

Metabolomics and Proteomics in Prostate Cancer Research: Overview, Analytical Techniques, Data Analysis, and Recent Clinical Applications.

Prostate cancer (PCa) is a significant global contributor to mortality, predominantly affecting males aged 65 and above. The field of omics has recently gained traction due to its capacity to provide profound insights into the biochemical mechanisms underlying conditions like prostate cancer. This involves the identification and quantification of low-molecular-weight metabolites and proteins acting as crucial biochemical signals for early detection, therapy assessment, and target identification. A spectrum of analytical methods is employed to discern and measure these molecules, revealing their altered biological pathways within diseased contexts. Metabolomics and proteomics generate refined data subjected to detailed statistical analysis through sophisticated software, yielding substantive insights. This review aims to underscore the major contributions of multi-omics to PCa research, covering its core principles, its role in tumor biology characterization, biomarker discovery, prognostic studies, various analytical technologies such as mass spectrometry and Nuclear Magnetic Resonance, data processing, and recent clinical applications made possible by an integrative "omics" approach. This approach seeks to address the challenges associated with current PCa treatments. Hence, our research endeavors to demonstrate the valuable applications of these potent tools in investigations, offering significant potential for understanding the complex biochemical environment of prostate cancer and advancing tailored therapeutic approaches for further development.

The turning point of COVID-19 severity is associated with a unique circulating neutrophil gene signature.

COVID-19 has a broad spectrum of clinical manifestations associated with the host immune response heterogeneity. Despite the advances in COVID-19 research, it is still crucial to seek a panel of molecular markers that enable accurate stratification of COVID-19 patients. Here, we performed a study that combined analysis of blood transcriptome, demographic data, clinical aspects and laboratory findings from 66 participants classified into different degrees of COVID-19 severity and healthy subjects. We identified a perturbation in blood-leukocyte transcriptional profile associated with COVID-19 aggravation, which was mainly related to processes that disfavoured lymphocyte activation and favoured neutrophil activation. This transcriptional profile stratified patients according to COVID-19 severity. Hence, it enabled identification of a turning point in transcriptional dynamics that distinguished disease outcomes and non-hospitalized from hospitalized moderate patients. Central genes of this unique neutrophil signature were S100A9, ANXA3, CEACAM6, VNN1, OLFM4, IL1R2, TCN1 and CD177. Our study indicates the molecular changes that are linked with the differing clinical aspects presented by humans when suffering from COVID-19, which involve neutrophil activation.

Low postoperative perfused vessel density is associated with increased soluble endothelial cell adhesion molecules during circulatory shock after cardiac surgery.

INTRODUCTION: Microcirculatory dysfunction after cardiovascular surgery is associated with significant morbidity and worse clinical outcomes. Abnormal capillary blood flow can occur from multiple causes, including cytokine-mediated vascular endothelial injury, microthrombosis, and an inadequate balance between vasoconstriction and vasodilation. In response to proinflammatory cytokines, endothelial cells produce cellular adhesion molecules (CAMs) which regulate leukocyte adhesion, vascular permeability, and thus can mediate tissue injury. The relationship between changes in microcirculatory flow during circulatory shock and circulating adhesion molecules is unclear. The objective of this study was to compare changes in plasma soluble endothelial cell adhesion molecules (VCAM-1, ICAM-1, and E-Selectin) in patients with functional derangements in microcirculatory blood flow after cardiovascular surgery. METHODS: Adult patients undergoing elective cardiac surgery requiring cardiopulmonary bypass who exhibited postoperative shock were enrolled in the study. Sublingual microcirculation imaging was performed prior to surgery and within 2 h of ICU admission. Blood samples were taken at the time of microcirculation imaging for biomarker analysis. Plasma soluble VCAM-1, ICAM-1, and E-selectin in addition to plasma cytokines (IL-6, IL-8, and IL-10) were measured by commercially available enzyme-linked immunoassay. RESULTS: Of 83 patients with postoperative shock who were evaluated, 40 patients with clinical shock had a postoperative perfused vessel density (PVD) >1 SD above (High PVD group = 28.5 ± 2.3 mm/mm2, n = 20) or below (Low PVD = 15.5 ± 2.0 mm/mm2, n = 20) the mean postoperative PVD and were included in the final analysis. Patient groups were well matched for comorbidities, surgical, and postoperative details. Overall, there was an increase in postoperative plasma VCAM-1 and E-Selectin compared to preoperative levels, but there was no difference between circulating ICAM-1. When grouped by postoperative microcirculation, patients with poor microcirculation were found to have increased circulating VCAM-1 (2413 ± 1144 vs. 844 ± 786 ng/mL; p < 0.0001) and E-Selectin (242 ± 119 vs. 87 ± 86 ng/mL; p < 0.0001) compared to patients with increased microcirculatory blood flow. Microcirculatory flow was not associated with a difference in plasma soluble ICAM-1 (394 ± 190 vs. 441 ± 256; p = 0.52). CONCLUSIONS: Poor postoperative microcirculatory blood flow in patients with circulatory shock after cardiac surgery is associated with increased plasma soluble VCAM-1 and E-Selectin, indicating increased endothelial injury and activation compared to patients with a high postoperative microcirculatory blood flow. Circulating endothelial cell adhesion molecules may be a useful plasma biomarker to identify abnormal microcirculatory blood flow in patients with shock.

Divergent androgenic modulation of SARS-CoV-2 infection cooperates with dysregulated immune response to dictate worse COVID-19 outcomes in men.

BACKGROUND: Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients. METHODS: A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome. RESULTS: There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings. CONCLUSIONS: These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.

Catheter ablation of atrial fibrillation in patients with and without hypertrophic cardiomyopathy: systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). There is limited data regarding the outcomes of AF catheter ablation in HCM patients. In this study, we aimed to synthesize all available evidence on the effectiveness of ablation of AF in patients with HCM compared to those without HCM. METHODS AND RESULTS: We systematically reviewed bibliographic databases to identify studies published through February 2023. We included cohort studies with available quantitative information on rates of recurrent atrial arrhythmias, anti-arrhythmic drug (AAD) therapy, and repeat ablation procedures after initial AF ablation in patients with vs without HCM. Estimates were combined using random-effects meta-analysis models and reported as risk ratios (RR) and 95% confidence intervals (CI). Eight studies were included in quantitative synthesis (262 HCM and 642 non-HCM patients). During median follow-up 13-54 months across studies, AF recurrence rates ranged from 13.3% to 92.9% in HCM and 7.6% to 58.8% in non-HCM patients. The pooled RR for recurrent atrial arrhythmia after the first AF ablation in HCM patients compared to non-HCM controls was 1.498 (95% CI = 1.305-1.720; P < 0.001). During follow-up, HCM patients more often required AAD therapy (RR = 2.844; 95% CI = 1.713-4.856; P < 0.001) and repeat AF ablation (RR = 1.544; 95% CI = 1.070-2.228; P = 0.02). The pooled RR for recurrent atrial arrhythmias after the last AF ablation was higher in patients with HCM than those without HCM (RR = 1.607; 95% CI = 1.235-2.090; P < 0.001). CONCLUSIONS: Compared to non-HCM patients, those with HCM had higher rates of recurrent atrial arrhythmias, AAD use, and need for repeat AF ablation after initial ablation of AF.

Biotechnological approaches for the production of gymnemic acid from Gymnema sylvestre R. Br.

Diabetes is a chronic disease that affects several organs and can be treated using phytochemicals found in medicinal plants. Gymnema sylvestre (Asclepiadaceae) is one such medicinal plant rich in anti-diabetic properties. The plant is commonly known as madhunashini in Sanskrit because of its ability to cure diabetes (sugar). Gymnemic acid (GA) is a phytochemical (a triterpenoid saponin) responsible for the herb's main pharmacological activity. This secondary metabolite has a lot of potential as a phytochemical with pharmacological properties including nephroprotection, hypoglycemia, antioxidant, antimicrobial, and anti-inflammatory. Gymnema has acquired a lot of popularity in recent years due to its low side effects and high efficacy in healing diabetes, which has led to overexploitation by pharmaceutical enterprises for its biomass in the wild for the purification of gymnemic acid. Modern biotechnological techniques involving the establishment of cell and organ cultures from G. sylvestre will assist us in fulfilling the need for gymnemic acid production. The present review provides insights on the establishment of cell and organ cultures for the production of a potent antidiabetic molecule gymnemic acid. Further, the review also delves into the intricacies of the different strategies for improved production of gymnemic acid using various elicitors. There is huge potential for sustainable production of gymnemic acid which could be met by establishment of bioreactor scale production. Understanding and engineering the biosynthetic pathway could also lead to improved GA production. KEY POINTS: • Gymnemic acid is one of the potential anti-diabetic molecules from madhunashini • Cell and organ culture offers potential approach for gymnemic acid production • Elicitation strategies have improved the gymnemic acid production.

Omphalocele: clinical and epidemiological profile of patients born in a tertiary care center in Rio de Janeiro.

BACKGROUND: The objective of this paper is to describe the clinical and epidemiological profile and the early outcomes of patients with omphalocele born in a fetal medicine, pediatric surgery, and genetics reference hospital in Rio de Janeiro - Brazil. To determine its prevalence, describe the presence of genetic syndromes, and congenital malformations, emphasizing the characteristics of congenital heart diseases and their most common types. METHODS: Using Latin-American Collaborative Study of Congenital Malformations (ECLAMC) database and records review, a retrospective cross-sectional study was performed, including all patients born with omphalocele between January 1st, 2016, and December 31st, 2019. RESULTS: During the period of the study, our unity registered 4,260 births, 4,064 were live births and 196 stillbirths. There were 737 diagnoses of any congenital malformation, among them 38 cases of omphalocele, 27 were live born, but one was excluded for missing data. 62.2% were male, 62.2% of the women were multiparous and 51.3% of the babies were preterm. There was an associated malformation in 89.1% of the cases. Heart disease was the most common (45.9%) of which tetralogy of Fallot was the most frequent (23.5%). Mortality rate was 61.5%. CONCLUSIONS: Our data showed a good correspondence with the existing literature. Most patients with omphalocele had other malformations, especially congenital heart disease. No pregnancy was interrupted. The presence of concurrent defects showed a huge impact on prognosis, since, even if most survived birth, few remained alive and received hospital discharge. Based on these data, fetal medicine and neonatal teams must be able to adjust parents counseling about fetal and neonatal risks, especially when other congenital diseases are present.

Essential Oil from Coriandrum sativum: A review on Its Phytochemistry and Biological Activity.

Essential oils are hydrophobic liquids produced as secondary metabolites by specialized secretory tissues in the leaves, seeds, flowers, bark and wood of the plant, and they play an important ecological role in plants. Essential oils have been used in various traditional healing systems due to their pharmaceutical properties, and are reported to be a suitable replacement for chemical and synthetic drugs that come with adverse side effects. Thus, currently, various plant sources for essential oil production have been explored. Coriander essential oil, obtained from the leaf and seed oil of Coriandrum sativum, has been reported to have various biological activities. Apart from its application in food preservation, the oil has many pharmacological properties, including allelopathic properties. The present review discusses the phytochemical composition of the seed and leaf oil of coriander and the variation of the essential oil across various germplasms, accessions, at different growth stages and across various regions. Furthermore, the study explores various extraction and quantification methods for coriander essential oils. The study also provides detailed information on various pharmacological properties of essential oils, such as antimicrobial, anthelmintic, insecticidal, allelopathic, antioxidant, antidiabetic, anticonvulsive, antidepressant, and hepatoprotective properties, as well as playing a major role in maintaining good digestive health. Coriander essential oil is one of the most promising alternatives in the food and pharmaceutical industries.

Perception of Minimum Interventional Dentistry among Dental Undergraduate Students and Interns.

Background: The philosophy of minimum interventional dentistry (MID) is to integrate prevention, remineralization, and minimal intervention for the placement and replacement of restorations. All branches of dentistry play an important role in practicing MID, and their primary goal is to realize that any restoration is of less biological significance than the healthy original tissue Objectives: The objective of this study was to assess the perception of MID among dental undergraduate students and interns in terms of knowledge, attitude, and practice at the College of Dentistry. Materials and Methods: This cross-sectional study was conducted among undergraduate students and interns at the College of Dentistry, Qassim University, Saudi Arabia. A self-administered questionnaire was distributed, which included basic demographic profiles and questions about the knowledge, attitude, and practices toward MID. The data were tabulated in MS Excel, and all statistical analyses were performed using SPSS version 21. Results: A total of 163 dental students were recruited, with senior students comprising 73% and interns comprising 27%. Male students were slightly more prevalent (50.9%) than female students (49.1%). About 37.6% of participants received training about MID during educational courses, while 10.3% received it during their internship. A statistical test revealed that the prevalence of interns who were trained in performing MID was significantly higher (p < 0.001). Conclusions: The majority of the participants demonstrated proper knowledge, attitude, and practice in different aspects of MID. Interns reported a higher rate of knowledge, attitude, and practice in MID compared to undergraduate students. However, more education and hands-on training about MID concepts during the college curriculum are necessary to attain better knowledge, attitude, and practices that could be useful for more conservative clinical practice.

Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.

BACKGROUND: A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396). FINDINGS: Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6-95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. INTERPRETATION: This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort. FUNDING: Moscow City Health Department, Russian Direct Investment Fund, and Sberbank.

Adverse effect of vaccination in xenogeneic animals.

Lumpy skin disease (LSD) is a devastating, emerging viral disease of cattle. It causes significant economic losses due to trade restrictions that are placed on infected animals and the biological effects of the disease: infertility, dramatic loss in milk production, induction of abortion and mortality. It is caused by lumpy skin disease virus (LSDV), which belongs to the Poxviridae family. Vaccination has been determined to be the most effective way to control LSD infection among livestock. However, some adverse effects have been reported in animals vaccinated with live vaccines. To the best of our knowledge, this is the first study to report the systemic lesions that are associated with LSD vaccination in xenogeneic animals. The aim of our study was to compare the immunogenicity and pathogenicity of a live attenuated vaccine of Romanian strain of sheeppox virus (SPPV) through study of two different routes of administration in xenogeneic animals (mice). Swiss male mice were inoculated with two doses of SPPV vaccine by two different routes intranasal (IN, through nebulisation), and intraperitoneal (IP) injection) and the levels of immunoglobulins and histopathological findings were reported. Our results showed marked increases in levels of immunoglobulins (Ig) dependent on the administration route: IgG in IP-inoculated mice and IgA in IN-vaccinated mice. IgM levels became markedly high after vaccination via both routes. Histologically, nebulisation of mice with SPPV vaccine caused more pulmonary lesions than did IP injection and promoted the proliferation of megakaryocytes in splenic tissues. In contrast, IP injection had less effect on pulmonary tissues and induced activation of extramedullary haematopoiesis (EH) in the hepatic tissues. LSD vaccination in xenogeneic animals caused serious systemic complications and the severity of the lesions caused to tissue depended on the route of administration.

Differing Bilateral Benefits for Spatial Release From Masking and Sound Localization Accuracy Using Bone Conduction Devices.

OBJECTIVES: Normal binaural hearing facilitates spatial hearing and therefore many everyday listening tasks, such as understanding speech against a backdrop of competing sounds originating from various locations, and localization of sounds. For stimulation with bone conduction hearing devices (BCD), used to alleviate conductive hearing losses, limited transcranial attenuation results in cross-stimulation so that both cochleae are stimulated from the position of the bone conduction transducer. As such, interaural time and level differences, hallmarks of binaural hearing, are unpredictable at the level of the inner ears. The aim of this study was to compare spatial hearing by unilateral and bilateral BCD stimulation in normal-hearing listeners with simulated bilateral conductive hearing loss. DESIGN: Bilateral conductive hearing loss was reversibly induced in 25 subjects (mean age = 28.5 years) with air conduction and bone conduction (BC) pure-tone averages across 0.5, 1, 2, and 4 kHz (PTA 4 ) <5 dB HL. The mean (SD) PTA 4 for the simulated conductive hearing loss was 48.2 dB (3.8 dB). Subjects participated in a speech-in-speech task and a horizontal sound localization task in a within-subject repeated measures design (unilateral and bilateral bone conduction stimulation) using Baha 5 clinical sound processors on a softband. For the speech-in-speech task, the main outcome measure was the threshold for 40% correct speech recognition when masking speech and target speech were both colocated (0°) and spatially and symmetrically separated (target 0°, maskers ±30° and ±150°). Spatial release from masking was quantified as the difference between colocated and separated masking and target speech thresholds. For the localization task, the main outcome measure was the overall variance in localization accuracy quantified as an error index (0.0 = perfect performance; 1.0 = random performance). Four stimuli providing various spatial cues were used in the sound localization task. RESULTS: The bilateral BCD benefit for recognition thresholds of speech in competing speech was statistically significant but small regardless if the masking speech signals were colocated with, or spatially and symmetrically separated from, the target speech. Spatial release from masking was identical for unilateral and bilateral conditions, and significantly different from zero. A distinct bilateral BCD sound localization benefit existed but varied in magnitude across stimuli. The smallest benefit occurred for a low-frequency stimulus (octave-filtered noise, CF = 0.5 kHz), and the largest benefit occurred for unmodulated broadband and narrowband (octave-filtered noise, CF = 4.0 kHz) stimuli. Sound localization by unilateral BCD was poor across stimuli. CONCLUSIONS: Results suggest that the well-known transcranial transmission of BC sound affects bilateral BCD benefits for spatial processing of sound in differing ways. Results further suggest that patients with bilateral conductive hearing loss and BC thresholds within the normal range may benefit from a bilateral fitting of BCD, particularly for horizontal localization of sounds.