Whole-body replacement of larval myofibers generates permanent adult myofibers in zebrafish.

Drastic increases in myofiber number and size are essential to support vertebrate post-embryonic growth. However, the collective cellular behaviors that enable these increases have remained elusive. Here, we created the palmuscle myofiber tagging and tracking system for in toto monitoring of the growth and fates of ~5000 fast myofibers in developing zebrafish larvae. Through live tracking of individual myofibers within the same individuals over extended periods, we found that many larval myofibers readily dissolved during development, enabling the on-site addition of new and more myofibers. Remarkably, whole-body surveillance of multicolor-barcoded myofibers further unveiled a gradual yet extensive elimination of larval myofiber populations, resulting in near-total replacement by late juvenile stages. The subsequently emerging adult myofibers are not only long-lasting, but also morphologically and functionally distinct from the larval populations. Furthermore, we determined that the elimination-replacement process is dependent on and driven by the autophagy pathway. Altogether, we propose that the whole-body replacement of larval myofibers is an inherent yet previously unnoticed process driving organismic muscle growth during vertebrate post-embryonic development.

Safety and efficacy revisited: a systematic review and meta-analysis of glue versus tack mesh fixation in laparoscopic inguinal herniorrhaphy.

Background: This analysis addresses the uncertainty surrounding the efficacy of glue mesh fixation (GMF) compared with tack mesh fixation (TMF) in laparoscopic herniorrhaphy. Our meta-analysis incorporates recently conducted randomized controlled trials (RCTs) to enhance the reference for assessing the efficacy and safety of GMF. Methods: PubMed Central, Google Scholar, Science Direct, and Cochrane Library were extensively reviewed for articles in the English language performed from inception to May 2023 using the keywords "Glue mesh repair," "Tack mesh repair," "Inguinal Hernia," "Herniorrhaphy," "Laparoscopic," "Mesh Fixation," and "Randomized controlled trials." Results: In this meta-analysis, we incorporated a total of 20 randomized controlled trials, evaluating each article individually using quality ratings. Compared with TMF, GMF demonstrated a significant reduction in the incidence of chronic pain [RR: 0.40, (0.23, 0.68)] and pain scores on postoperative day 1 [MD: -1.07, (-1.90, -0.25)]. We also used funnel plots and Egger's regression to test for publication bias. Conclusion: In summary, this meta-analysis establishes the significance of GMF in reducing chronic pain and postoperative day 1 pain compared with TMF. However, no statistically significant difference was noted between the GMF and TMF groups concerning hematoma, seroma, operation time, recurrence rate, and total complications. Nonetheless, given the small number of cases in this study, the findings must be validated in the future by multicenter, large-sample, high-quality RCTs.

Optimized Machine learning techniques Enable prediction of organic dyes photophysical Properties: Absorption Wavelengths, emission Wavelengths, and quantum yields.

Applications of organic dyes, ranging from basic research to industry, are functions of their photophysical properties. Two important aspects- (1) knowledge of the photophysical properties of existing dyes long before real applications and (2) discovery of new organic dyes with desired photophysical properties for either upgradation of existing or development of new applications-are needed to be addressed. These two cases are coupled together with the common goal of estimating photophysical properties with high accuracy at the minimum cost of time and money long before the hard-core laboratory experiment. For this purpose, machine learning-based techniques are the most suitable approach. In this study, we used optimized machine-learning techniques to assess a dataset of 3066 organic dyes, which were evaluated using three evaluation parameters: Root Mean Squared Error (RMSE), Mean Absolute Error (MAE), and the coefficient of determination (R2). The Quadratic Support Vector Machine (QSVM) was the best predictive model for RMSE-16.614, MAE-10.837, and R2-0.961 for absorption wavelengths and RMSE-23.636, MAE-16.278, and R2-0.929 for emission wavelengths. These R2 values are 0.7% and 0.4% greater than the Gradient Boost Regression Tree (GBRT) model's recently reported values of 0.954 and 0.925 for absorption and emission wavelengths, respectively. Furthermore, we estimated the quantum yield and found that the Coarse Gaussian Support Vector Machine (CGSVM) outperformed all examined models. For more validation of these models, we compared the predicted results with the experimental results of selective dyes. The proposed automated approach can be used for predicting photophysical properties without much computer programming knowledge.

Emotional Stress and Immune Response in Surgery: A Psychoneuroimmunological Perspective.

Psychoneuroimmunology (PNI) offers a deep dive into the nexus between emotional stress, immunity, and surgical outcomes. In this narrative review, we first trace PNI's historical roots, providing a foundational understanding of its evolution. We then dissect its significance across the surgical journey, from the preoperative phase through to postoperative recovery. It becomes evident through our exploration that emotional stress has profound implications for surgery, notably influencing wound healing rates, susceptibility to infections, and overall postoperative well-being. Among the arsenal to combat these challenges, interventions such as cognitive-behavioral therapy, mindfulness, and complementary practices such as meditation and yoga have emerged as potent tools. They not only mitigate stress but also play a pivotal role in enhancing immune function. However, the journey to optimizing surgical outcomes is not just about identifying effective interventions. A resounding theme is the importance of holistic care, ensuring that all patients have equitable access to these tools. As PNI continues to evolve, we stand at the precipice of a healthcare revolution, one that promises a blend of personalized care, anchored in a deep understanding of the mind-body connection in surgical contexts.

Schimmelpenning-Feuerstein-Mims syndrome with benign enlargement of subarachnoid space in infancy.

Schimmelpenning-Feuerstein-Mims syndrome is a rare disorder generally characterised by a craniofacial nevus with multisystemic presentations. Our patient, an infant, was brought to the emergency department in a postictal state following a first seizure episode. A physical examination showed a solitary dark brown, well-demarcated verrucous plaque extending from the patient's left temporal region to the left mandible without crossing the midline. Epibulbar choristomas were present on the ipsilateral side of the craniofacial lesion. Neuroimaging showed benign enlargement of the subarachnoid space. Due to the known risk of seizures associated with this condition, the patient was started on levetiracetam and showed adequate compliance. We present this as the first reported case of Schimmelpenning-Feuerstein-Mims syndrome with benign enlargement of the subarachnoid space in an infant presenting with seizures to emphasise the value of collaboration among multidisciplinary professionals to improve the quality of care for such patients.

The Role of Matrix Metalloproteinase 13 and Vitamin D in Osteoarthritis: A Hospital-Based Observational Study.

Introduction Osteoarthritis (OA) is the most common form of degenerative joint disease characterized by the progressive degeneration of articular cartilage, osteophyte formation, and joint space narrowing. Matrix metalloproteinases (MMPs) are potential biomarkers for osteoarthritis. Aims and objective The study's aim is the estimation of serum and synovial fluid matrix metalloproteinase (MMP) 13 and serum vitamin D levels in the grade 3 and grade 4 stages of osteoarthritis according to the Kellgren and Lawrence (KL) system of classification. Materials and methods A total of 100 subjects were included; of them, 25 patients with grade 3 and 25 patients with grade 4 knee osteoarthritis diagnosed clinically and radiologically according to the Kellgren and Lawrence criteria have been enrolled in the study, and 50 patients with knee pain having a diagnosis other than degenerative OA of the knee were taken as controls. Venous blood and synovial fluid have been collected from all of them for the estimation of MMP-13 and vitamin D. The enzyme-linked immunosorbent assay (ELISA) and chemiluminescent microparticle immunoassay (CMIA) methods were used for the estimation of MMP-13 and vitamin D, respectively. Results The mean value of synovial fluid MMP-13 was found to be elevated in grade 4 as compared to grade 3 and the control group, whereas the mean value of serum MMP-13 was found to be elevated in grade 3 as compared to grade 4 and control. The level of serum vitamin D was found deficient in OA patients as compared to control. The Kruskal-Wallis test was performed to compare these groups, and there was a significant difference between these groups (p-value of <0.05). Summary and conclusion High synovial and serum MMP-13 is associated with knee structural abnormalities in patients with knee OA as compared to the control group suggesting that MMP-13 can be a biomarker in knee OA, whereas the decreased level of vitamin D may be associated with an increased risk for the progression of OA; hence, serum vitamin D may be a good indicator for the prediction of the initiation of OA.

Tuberculosis screening for pediatric household contacts in India: Time to adapt newer strategies under the National TB Elimination Programme!

INTRODUCTION: The study aimed to evaluate the effectiveness of screening pediatric household contacts (under the age of 15 years) for tuberculosis (TB) in India through verbal screening, tuberculin skin testing, and chest radiography at intervals of 0, 3, 6, 9, and 12 months. The study also aimed to determine the proportion of contacts who tested positive for TB and to describe the challenges in implementing regular follow-up. Current National TB Elimination Programme (NTEP) guidelines only require verbal screening for contacts under 6 years old at TB treatment initiation. The study aimed to fill this knowledge gap and provide valuable insights for improving TB screening in pediatric household contacts in India. METHODS: The study was conducted in two districts of Karnataka, India from 2021 to 2022, and utilized a cohort study design to enroll contacts of index tuberculosis (TB) cases diagnosed under the National TB Elimination Programme (NTEP). Participants were followed up at regular intervals for one year to evaluate the effectiveness of TB screening in pediatric household contacts. RESULTS: In this study, 686 pediatric household contacts were enrolled and screened for tuberculosis (TB) using verbal symptom screening, tuberculin skin testing (TST), and chest radiography. Projected figures estimated that 0.8%, 42%, and 4% of contacts would test positive for symptomatic screening, TST, and chest radiography, respectively. TB cases were detected in 2.91% (1.84-4.38) of contacts, with females above 6 years of age having a 22% higher risk of contracting the infection than males above 6 to < 15 years. However, not all cases were subjected to TST and chest radiography. The primary reason for not investigating child contact for TB was their reported healthy or asymptomatic status. CONCLUSION: The implementation of regular screening intervals for tuberculin skin test (TST) and chest radiography, along with verbal screening, among pediatric household contacts under the age of 15 years seems to be beneficial for the National TB Elimination Programme (NTEP), despite the challenges faced during implementation. Innovative strategies should be explored by NTEP to ensure effective implementation.

Surface-Engineered Extracellular Vesicles in Cancer Immunotherapy.

Extracellular vesicles (EVs) are lipid bilayer-enclosed bodies secreted by all cell types. EVs carry bioactive materials, such as proteins, lipids, metabolites, and nucleic acids, to communicate and elicit functional alterations and phenotypic changes in the counterpart stromal cells. In cancer, cells secrete EVs to shape a tumor-promoting niche. Tumor-secreted EVs mediate communications with immune cells that determine the fate of anti-tumor therapeutic effectiveness. Surface engineering of EVs has emerged as a promising tool for the modulation of tumor microenvironments for cancer immunotherapy. Modification of EVs' surface with various molecules, such as antibodies, peptides, and proteins, can enhance their targeting specificity, immunogenicity, biodistribution, and pharmacokinetics. The diverse approaches sought for engineering EV surfaces can be categorized as physical, chemical, and genetic engineering strategies. The choice of method depends on the specific application and desired outcome. Each has its advantages and disadvantages. This review lends a bird's-eye view of the recent progress in these approaches with respect to their rational implications in the immunomodulation of tumor microenvironments (TME) from pro-tumorigenic to anti-tumorigenic ones. The strategies for modulating TME using targeted EVs, their advantages, current limitations, and future directions are discussed.

Efficacy and Safety of Stempeucel in Osteoarthritis of the Knee: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled Study.

BACKGROUND: Osteoarthritis is a chronic, progressive, and degenerative condition with limited therapy options. Recently, biologic therapies have been an evolving option for the management of osteoarthritis. PURPOSE: To assess whether allogenic mesenchymal stromal cells (MSCs) have the potential to improve functional parameters and induce cartilage regeneration in patients with osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 146 patients with grade 2 and 3 osteoarthritis were randomized to either an MSC group or placebo group with a ratio of 1:1. There were 73 patients per group who received either a single intra-articular injection of bone marrow-derived MSCs (BMMSCs; 25 million cells) or placebo, followed by 20 mg per 2 mL of hyaluronic acid under ultrasound guidance. The primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. The secondary endpoints were WOMAC subscores for pain, stiffness, and physical function; the visual analog scale score for pain; and magnetic resonance imaging findings using T2 mapping and cartilage volume. RESULTS: Overall, 65 patients from the BMMSC group and 68 patients from the placebo group completed 12-month follow-up. The BMMSC group showed significant improvements in the WOMAC total score compared with the placebo group at 6 and 12 months (percentage change: -23.64% [95% CI, -32.88 to -14.40] at 6 months and -45.60% [95% CI, -55.97 to -35.23] at 12 months P < .001; percentage change, -44.3%). BMMSCs significantly improved WOMAC pain, stiffness, and physical function subscores as well as visual analog scale scores at 6 and 12 months (P < .001). T2 mapping showed that there was no worsening of deep cartilage in the medial femorotibial compartment of the knee in the BMMSC group at 12-month follow-up, whereas in the placebo group, there was significant and gradual worsening of cartilage (P < .001). Cartilage volume did not change significantly in the BMMSC group. There were 5 adverse events that were possibly/probably related to the study drug and consisted of injection-site swelling and pain, which improved within a few days. CONCLUSION: In this small randomized trial, BMMSCs proved to be safe and effective for the treatment of grade 2 and 3 osteoarthritis. The intervention was simple and easy to administer, provided sustained relief of pain and stiffness, improved physical function, and prevented worsening of cartilage quality for ≥12 months. REGISTRATION: CTRI/2018/09/015785 (National Institutes of Health and Clinical Trials Registry-India).

Diagnostic and prognostic value of circulating tumor cells in Indian women with suspected ovarian cancer.

Background: "Liquid biopsy," where body fluids are screened for biomarkers, is gathering substantial research. We aimed to examine women with suspected ovarian cancer for the presence of circulating tumor cells (CTCs) and study its role in prediction of chemoresistance and survival. Methods: Magnetic powder labeled monoclonal antibodies for epithelial cell adhesion molecule (EpCAM), mucin 1 cell surface associated, mucin 16 cell surface associated, or carbohydrate antigen 125 (CA125), were prepared according to the manufacturer's protocol. Expression of three ovarian cancer related genes was detected in CTCs using multiplex reverse transcriptase-polymerase chain reaction. CTCs and serum CA125 were measured in 100 patients with suspected ovarian cancer. Correlations with clinicopathological parameters and treatment were analyzed. Results: CTCs were detected in 18/70 (25.7%) of women with malignancy compared to 0/30 (0.0%) in those with benign gynecologic diseases (P = 0.001). The sensitivity and specificity of the CTC test for predicting a malignant histology in pelvic masses were 27.7% (95% CI: 16.3%, 37.7%) and 100% (95% CI: 85.8%, 100%), respectively. The number of CTCs correlated with stage of ovarian cancer (P = 0.030). The presence of EpCAM + CTC at primary diagnosis in ovarian cancer was found to be an independent predictor of a poor progression free survival (HR, 3.3; 95% CI, 1.3-8.4; P = 0.010), overall survival (HR, 2.6; 95% CI,1.1-5.6; P = 0.019), and resistance to chemotherapy (OR 8.6; 95% CI, 1.8-43.7; P = 0.009). Conclusion: Expression of EpCAM + CTC in ovarian cancer predicts platinum resistance and poor prognosis. This information could be further used in investigating anti-EpCAM-targeted therapies in ovarian cancer.

A comparative study of conventional FRET and light harvesting properties of Rh-110/Rh-6G and Rh-19/Rh-B organic dye pairs impregnated in sol-gel glasses.

Two different pairs of laser dyes, Rhodamine-110 (Rh-110)/Rhodamine-6G (Rh-6G) and Rhodamine-19 (Rh-19)/Rhodamine-B (Rh-B) (the first dye in each pair as a donor and the second as an acceptor) were impregnated in silica samples prepared by the sol-gel method and spectroscopically studied using absorption and steady-state fluorescence techniques. The critical transfer distance (R0), actual distance (r) between the donor and acceptor, overlap integral [J(υ¯)], FRET (fluorescence resonance energy transfer) efficiency (E), and antenna effect efficiency (AE) were investigated in detail based on the variation in acceptor concentration. The FRET efficiency, antenna effect efficiency, and actual donor-acceptor distance for Rh-110/Rh-6G and Rh-19/Rh-B dye pairs corresponding to acceptor concentration ranges (3.83 to 7.65) × 10-5M l-1and (3.71 to 8.34) × 10-5M l-1, respectively, were found to be in the ranges of 57.38% to 74.89%, 36.97% to 24.13%, 5.44 nm to 4.77 nm, and 77.01%. Furthermore, maximum FRET efficiencies of 85.68% and 87.63% and antenna effect efficiencies of 36.97% and 40.95% for Rh-110/Rh-6G and Rh-19/Rh-B, respectively, were also reported. Our results demonstrate the superior FRET efficiency of Rh-19/Rh-B over Rh-110/Rh-6G dye pair in sol-gel glasses, while the antenna effect efficiency of Rh-110/Rh-6G is higher than that of Rh-19/Rh-B for the same donor to acceptor (D/A) ratio. Finally, Rh-110/Rh-6G is a better energy harvester than the Rh-19/Rh-B dye pair at the common D/A ratio. These results are explained in terms of molecular structure similarity, polarity, and rigidity of donor and acceptor.

Mastering the Art of Dermatosurgery: Aesthetic Alchemy in Medical Excellence.

Dermatosurgery, a specialized branch within dermatology, has traversed an extraordinary journey through time, shaped by ancient practices, technological leaps, and shifting societal perceptions. This review explores the evolution of dermatosurgery, highlighting its profound transformation from addressing solely medical concerns to seamlessly integrating aesthetics. From its roots in ancient civilizations, where cultural traditions laid the foundation for modern techniques, to the twentieth-century technological renaissance, marked by innovative tools and enhanced understanding of skin anatomy, dermatosurgery has emerged as a dynamic field. Societal notions of beauty and health have significantly influenced dermatosurgery, blurring the lines between medical necessity and elective aesthetic procedures. The delicate balance between satisfying aesthetic desires and upholding medical ethics is a central challenge that dermatosurgeons face today. Open dialogue between practitioners and patients as well as psychological support plays a pivotal role in navigating this terrain. The training and ethics associated with dermatosurgery have evolved to meet the increasing demand for specialized procedures. Maintaining a focus on patient safety and satisfaction remains paramount as commercial pressures and disparities in access to care loom. Upholding best practices and standards in the field is essential for ensuring consistent, high-quality care for all patients. Looking ahead, dermatosurgery stands on the brink of a transformative era, marked by non-invasive techniques, artificial intelligence (AI) integration, and personalized medicine. The field's ability to harmonize medical science with aesthetic artistry is evident in various case studies, showcasing the intricate balance dermatosurgeons strike between addressing medical concerns and fulfilling aesthetic desires. As dermatosurgery continues to evolve, it promises to provide patients with even more precise, tailored treatments that enhance both their physical well-being and aesthetic satisfaction.

Hepatitis B in hepatocellular carcinoma patients and its correlation with alpha-fetoprotein and liver enzymes.

Background: Hepatocellular carcinoma (HCC) in India ranges from 0.7 to 7.5 for men and 0.2 to 2.2 for women, per 100,000 population per year. The major risk factors for the development of HCC are infection with hepatitis B virus (HBV), hepatitis C virus, and cirrhosis of liver. Alpha-fetoprotein (AFP) and liver enzymes are widely used by clinicians for diagnostic purpose in HCC. Aims and Objective: This study was conducted in HCC patients related to HBV infection and to assess the significance of AFP and liver enzymes in it. Materials and Methods: Blood samples of 68 patients were taken. The samples were analyzed for AFP and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]). Liver enzymes were estimated by auto analyzer OLYMPUS AU400. AFP was analyzed by chemiluminescence immunoassay. Results: The mean values of AFP in serum hepatitis B surface antigen (HBsAg) negative and positive patients ranges from 22745.4 to 23269.3 ng/ml with P = 0.921. The mean value of ALP in HbsAg-negative patients was 418 U/ml, whereas in positive patients, it was 310 U/ml. Both the groups did not show any significant changes in AFP levels. The ALP showed slight rise in negative group. The other parameters did not show significant rise in all patients. Conclusion: These values suggest that there was no significant influence of viral etiology on AFP and liver enzymes level in HCC patients.

Assessment of Maternal Serum Biochemical Attributes and Fetal Ultrasound Scans in First-Trimester Low-Risk Noninvasive Prenatal-Tested Pregnant Women.

INTRODUCTION: The first trimester of pregnancy is marked by several important disrupting changes as a result of complex biological upshot of events required for the development of the fetus. These changes in the biological events result in changes in the maternal serum biomarkers that are associated with fetal growth. The aim of the present study was to evaluate the correlation between the maternal blood biochemical determinants such as pregnancy-associated plasma protein-A (PAPP-A) and alpha fetoprotein (AFP) with ultrasound scans during early pregnancy in the first trimester. METHODS: The study included 139 women whose fetus was alive between 11±1 weeks of gestation. The risk of fetal chromosomal abnormalities at first trimester was analyzed by the VeriSeq NIPT Solution v2 platform (Illumina, San Diego, CA, USA) for noninvasive prenatal testing (NIPT) assay. The PAPP-A and AFP levels were evaluated by chemiluminescent immunoassays. The levels of PAPP-A and AFP were correlated with the fetal heart rate (HR), crown rump length (CRL), and nuchal translucency (NT) by Pearson's correlation analysis. RESULTS: The mean age of the participants was 28.35±3.87 years (minimum=21, maximum=35). The mean AFP and PAPP-A levels in the maternal plasma were 14.76±1.04 ng/mL and 4.37±0.86 mIU/ml respectively. The mean FHR, CRL, and NT were 138±7.62 bpm, 59±3.24 mm, and 2.3±0.61 mm respectively. PAPP-A and AFP significantly (p<0.05) correlated with fetal HR, CRL, and NT at 11±1 weeks of gestation. The mean ratio of AFP:PAPP-A in low-risk pregnancies was 3.37. CONCLUSIONS: The maternal serum biochemical attributes correlated well with the fetal ultrasound scans. The findings of the present study can prove to be clinically useful for clinical research, obstetrics, and gynaecology, especially for examinations of first-trimester pregnancies.

FN3 linked nanobubbles as a targeted contrast agent for US imaging of cancer-associated human PD-L1.

PD-L1 (programmed death-ligand 1) targeted therapies may be useful for several cancers. The use of non-invasive diagnostic and prognostic molecular imaging platforms could improve clinical assessment of PD-L1 tumor status during these therapies. Contrast enhanced ultrasound molecular imaging (CE-USMI) techniques may offer versatile and cost-effective ways to detect and quantify the expression levels of cellular targets in vivo. However, conventional use of microbubbles as a blood pool contrast agent for CE-USMI is limited to accessing intravascular biomarkers rather than reflecting the tumor molecular status. Using a microfluidic based reconstruction process we therefore developed ultra-stable nanobubbles (NBs) as a contrast agent for molecular imaging of vascular and extravascular cell surface markers. We then functionalized these NBs by covalently linking to nanobody (FN3hPD-L1) targeting human (h)PD-L1 to measure the expression of human PD-L1 in the tumor microenvironment (TME) in vivo. We showed the specific binding of hPD-L1 targeted NBs in cell culture, and in xenografted mouse models of hPD-L1 expressing CT26 tumors. CE-USMI of hPD-L1 in the TME in vivo showed ~3-fold increase in contrast signal compared to non-targeted NBs. Overall, in vivo use of CE-USMI with hPD-L1 targeted NBs has the potential for clinical translation and imaging of human cancers during immunotherapy, and for prognostic evaluation of patient response to PD-L1 targeted immunotherapy.

Prospective arrhythmia surveillance after a COVID-19 diagnosis.

BACKGROUND: Cardiac arrhythmias have been observed among patients hospitalised with acute COVID-19 infection, and palpitations remain a common symptom among the much larger outpatient population of COVID-19 survivors in the convalescent stage of the disease. OBJECTIVE: To determine arrhythmia prevalence among outpatients after a COVID-19 diagnosis. METHODS: Adults with a positive COVID-19 test and without a history of arrhythmia were prospectively evaluated with 14-day ambulatory electrocardiographic monitoring. Participants were instructed to trigger the monitor for palpitations. RESULTS: A total of 51 individuals (mean age 42±11 years, 65% women) underwent monitoring at a median 75 (IQR 34-126) days after a positive COVID-19 test. Median monitoring duration was 13.2 (IQR 10.5-13.8) days. No participant demonstrated atrial fibrillation, atrial flutter, sustained supraventricular tachycardia (SVT), sustained ventricular tachycardia or infranodal atrioventricular block. Nearly all participants (96%) had an ectopic burden of <1%; one participant had a 2.8% supraventricular ectopic burden and one had a 15.4% ventricular ectopic burden. While 47 (92%) participants triggered their monitor for palpitation symptoms, 78% of these triggers were for either sinus rhythm or sinus tachycardia. CONCLUSIONS: We did not find evidence of malignant or sustained arrhythmias in outpatients after a positive COVID-19 diagnosis. While palpitations were common, symptoms frequently corresponded to sinus rhythm/sinus tachycardia or non-malignant arrhythmias such as isolated ectopy or non-sustained SVT. While these findings cannot exclude the possibility of serious arrhythmias in select individuals, they do not support a strong or widespread proarrhythmic effect of COVID-19 infection after resolution of acute illness.

Engineered Cell-Derived Vesicles Displaying Targeting Peptide and Functionalized with Nanocarriers for Therapeutic microRNA Delivery to Triple-Negative Breast Cancer in Mice.

Polymeric nanocarriers (PNCs) can be used to deliver therapeutic microRNAs (miRNAs) to solid cancers. However, the ability of these nanocarriers to specifically target tumors remains a challenge. Alternatively, extracellular vesicles (EVs) derived from tumor cells show homotypic affinity to parent cells, but loading sufficient amounts of miRNAs into EVs is difficult. Here, it is investigated whether uPAR-targeted delivery of nanococktails containing PNCs loaded with therapeutic antimiRNAs, and coated with uPA engineered extracellular vesicles (uPA-eEVs) can elicit synergistic antitumor responses. The uPA-eEVs coating on PNCs increases natural tumor targeting affinities, thereby enhancing the antitumor activity of antimiRNA nanococktails. The systemic administration of uPA-eEV-PNCs nanococktail shows a robust tumor tropism, which significantly enhances the combinational antitumor effects of antimiRNA-21 and antimiRNA-10b, and leads to significant tumor regression and extension of progression free survival for syngeneic 4T1 tumor-bearing mice. In addition, the uPA-eEV-PNCs-antimiRNAs nanococktail plus low dose doxorubicin results in a synergistic antitumor effect as evidenced by inhibition of tumor growth, reduction of lung metastases, and extension of survival of 4T1 tumor-bearing mice. The targeted combinational nanococktail strategy could be readily translated to the clinical setting by using autologous cancer cells that have flexibility for ex vivo expansion and genetic engineering.

MTHFR C677T and MTR A2756G Gene Polymorphism in Neural Tube Defect Patients and Its Association with Red Blood Cell Folate Level in Eastern Indian Population.

Introduction: Single-nucleotide polymorphism (SNP) is a single-nucleotide change in a deoxyribose nucleic acid (DNA) sequence that occurs in >1% of population. Methylene tetra hydro folate reductase (MTHFR) C677T (rs1801133) and methionine synthase enzyme (MTR) A2756G (rs1805087) are two such SNPs occurring in coding sequence of the respective genes, which are frequently seen with neural tube defects (NTDs). MTHFR and MTR genes are involved in folate metabolism. The folate level in the course of pregnancy is treated as vital in the etiopathogenesis of NTDs. This study aims to explore the association of SNPs of both genes and red blood cell (RBC) folate levels in the predisposition to NTDs. Aims and Objective: The purpose of this investigation was to determine the relationship of NTDs with polymorphisms in MTHFR and MTR genotype and to estimate and compare the RBC folate levels in NTD patients and controls. Materials and Methods: A total of 397 individuals were enrolled (163 patients and 234 controls) for this observational study. Genotyping to find out MTHFR C677T and MTR A2756G was performed by polymerase chain reaction-restriction fragment length polymorphism technique from DNA extracted from the subject's blood. RBC folate level was estimated by chemiluminescence immunoassay method with the same blood sample. Results: The total RBC folate levels were significantly less among cases compared to controls (P = 0.020). A significant difference for RBC folate was observed between case and control groups of various genotypes of MTHFR C677T, except heterozygote CT (P = 0.459). Among MTR A2756G, genotypes with only homozygous AA have significant difference (P = 0.003) for RBC folate levels. Among different types of NTDs, there were no significant differences for RBC folate levels. Among MTHFR C677T, T allele possessed 1.9 times risk compared to C allele for the occurrence of NTDs. In MTR A2756G polymorphism, the odds of developing NTDs were 1.6 times in heterozygous AG compared to homozygous AA. Similarly, the risk for NTDs was three times higher in subjects with both heterozygous AG and CT genotypes compared to wild-type homozygous AA and CC genotypes. Conclusion: The total RBC folate levels were significantly less among cases compared to controls, and the genotypes had no such effect in decrease in RBC folate levels. The presence of mutant allele in homozygous or heterozygous condition for both SNPs had increased risk associated with NTDs.

A Microfluidics-Based Scalable Approach to Generate Extracellular Vesicles with Enhanced Therapeutic MicroRNA Loading for Intranasal Delivery to Mouse Glioblastomas.

Extracellular vesicles (EVs), including exosomes and microvesicles derived from different cell sources, are used as promising nanovesicles for delivering therapeutic microRNAs (miRNAs) and drugs in cancer therapy. However, their clinical translation is limited by the quantity, size heterogeneity, and drug or small RNA loading efficiency. Herein, we developed a scalable microfluidic platform that can load therapeutic miRNAs (antimiRNA-21 and miRNA-100) and drugs while controlling the size of microfluidically processed EVs (mpEVs) using a pressure-based disruption and reconstitution process. We prepared mpEVs of optimal size using microvesicles isolated from neural stem cells engineered to overexpress CXCR4 receptor and characterized them for charge and miRNA loading efficiency. Since the delivery of therapeutic miRNAs to brain cancer is limited by the blood-brain barrier (BBB), we adopted intranasal administration of miRNA-loaded CXCR4-engineered mpEVs in orthotopic GBM mouse models and observed a consistent pattern of mpEVs trafficking across the nasal epithelia, bypassing the BBB into the intracranial compartment. In addition, the CXCR4-engineered mpEVs manifested selective tropism toward GBMs by stromal-derived factor-1 chemotaxis to deliver their miRNA cargo. The delivered miRNAs sensitized GBM cells to temozolomide, resulting in prominent tumor regression, and improved the overall survival of mice. A simple and efficient approach of packaging miRNAs in mpEVs using microfluidics, combined with a noninvasive nose-to-brain delivery route presents far-reaching potential opportunities to improve GBM therapy in clinical practice.