Autopsy-based all-cause unnatural mortality during pre-pandemic and pandemic of COVID-19 in Varanasi, India: a retrospective analysis.

The COVID-19 pandemic has led to significant disruptions in healthcare systems worldwide, with Varanasi, India, experiencing profound challenges in managing mortality rates. In order to inform public health initiatives, it is important to comprehend how the pandemic has affected all-cause unnatural death in comparison to pre-pandemic patterns. This retrospective study intended to investigate patterns of all-cause unnatural mortality employing autopsy records of cases from Varanasi's Institute of Medical Sciences, Banaras Hindu University during the pre-pandemic and pandemic period (First and Second wave) of COVID-19. The analysis included 2694 cases of unnatural mortality, such as road traffic accident (RTA), poisoning, hanging and other causes. Demographic, clinical, and circumstantial data were collected and compared between the two time periods, that revealed significant as well as non-significant shifts in all-cause unnatural mortality rates. Whilst certain types of unnatural deaths, such as RTAs, witnessed a non-significant 2.03% (p = 0.34722) decrease, others like hanging exhibited an unexpected significant 3.17% (p = 0.01732) rise, burning and poisoning witnessed a significant 4.18% (p = 0.00026) and 2.37% (p = 0.0271) decline respectively. RTA was the leading cause of mortality both during and before pandemic. Male deaths (79.18%) outweighed female deaths (20.82%) by a more substantial amount throughout research periods. Additionally, variations in demographic characteristics, circumstances surrounding deaths, and healthcare utilization were observed during the pandemic period. The majority of unnatural fatalities occur in the age group of 21-30 years old in both pre-pandemic (22.62%) and pandemic conditions (26.65%). This study provides important insights into the secondary effects of the pandemic on unnatural mortality and emphasizes the need for individualized public health. Furthermore, research is warranted to explore the long-term implications and address the associated challenges for healthcare systems and public health initiatives.

Shaping the Future of Antimicrobial Therapy: Harnessing the Power of Antimicrobial Peptides in Biomedical Applications.

Antimicrobial peptides (AMPs) have emerged as a promising class of bioactive molecules with the potential to combat infections associated with medical implants and biomaterials. This review article aims to provide a comprehensive analysis of the role of antimicrobial peptides in medical implants and biomaterials, along with their diverse clinical applications. The incorporation of AMPs into various medical implants and biomaterials has shown immense potential in mitigating biofilm formation and preventing implant-related infections. We review the latest advancements in biomedical sciences and discuss the AMPs that were immobilized successfully to enhance their efficacy and stability within the implant environment. We also highlight successful examples of AMP coatings for the treatment of surgical site infections (SSIs), contact lenses, dental applications, AMP-incorporated bone grafts, urinary tract infections (UTIs), medical implants, etc. Additionally, we discuss the potential challenges and prospects of AMPs in medical implants, such as effectiveness, instability and implant-related complications. We also discuss strategies that can be employed to overcome the limitations of AMP-coated biomaterials for prolonged longevity in clinical settings.

Intranasal (IN) COVID-19 vaccines - a breakthrough.

Emerging variants of COVID-19 have threatened the effectiveness of intramuscular (IM) vaccines since that are made to target only the spike protein. Development of Intranasal (IN) vaccination has been proven to provide both the mucosal and systemic immune responses for broader and long lasting protection. Many IN vaccine candidates (virus-vectored vaccines, recombinant subunit vaccines and live attenuated vaccines) are in different phases of clinical trials and in near future many companies would be releasing their vaccines into the drug market. Potential advantages of IN vaccination over IM vaccination makes them ideal to be administered in children and developing populations of the world. This paper focuses on the very recent developments in intranasal vaccination with a spotlight on their safety and efficacy concerns. IN vaccination can prove to be game-changer in handling COVID-19 and potential viral contagious diseases in future.

Insights into the role of Nup62 and Nup93 in assembling cytoplasmic ring and central transport channel of the nuclear pore complex.

The nuclear pore complex (NPC) is a highly modular assembly of 34 distinct nucleoporins (Nups) to form a versatile transport channel between the nucleus and the cytoplasm. Among them, Nup62 is known as an essential component for nuclear transport, Nup93 for proper nuclear envelope assembly. These Nups constitute various NPC subcomplexes such as the central transport channel (CTC), the cytoplasmic ring (CR), and the inner ring (IR). However, how they play their roles in NPC assembly and transport activity is not clear. Here we delineated the interacting regions and conducted biochemical reconstitution and structural characterization of the mammalian CR complex to reveal its intrinsic dynamic behavior and a distinct "4"-shaped architecture resembling the CTC complex. Our in vitro reconstitution data demonstrate that the Nup62 coiled-coil domain is critical to form both Nup62322-525 •Nup88517-742 and Nup62322-525•Nup88517-742•Nup214693-926 heterotrimers and both can bind to Nup931-150. We therefore propose that Nup93 acts as a "sensor" to bind to Nup62 shared heterotrimers including the Nup62•Nup54 heterotrimer of the CTC, which was not shown previously to be an interacting partner. Altogether, our biochemical study suggests that Nup62 via its coiled-coil domain is central to form compositionally distinct yet structurally similar heterotrimers and Nup93 binds these diverse heterotrimers nonselectively.

Treatment of gingival class I or class II recession using subepithelial connective tissue graft and acellular dermal matrix allograft.

The present randomized control was conducted clinically to evaluate the effectiveness of Acellular Dermal Matrix Allograft (ADMA) and Subepithelial Connective Tissue Graft (SCTG) in combination with Coronally Positioned Flap (CPF) in the treatment of Miller's class I and II multiple gingival recession in aesthetic areas. A total of 20 patients aged between 18 to 40 years were selected for this study, meeting all the criteria for inclusion. 10 patients were treated with ADMA and 10 patients with SCTG in combination with CPF. Various clinical parameters were assessed viz. probing pocket depth (PPD), clinical attachment level (CAL), gingival recession height (RH) and width of keratinized gingiva (WKG) at baseline and 6 months after surgery. The mean RH at baseline in the control and test groups was 3.05 ±0 .55(mean± SD) and 2.60 ±.99 respectively. At 3 months the mean RH was found to be 1.60±0.74 and 1.05 ± .60 in the control and test group respectively. The mean percentage of root coverage (MRC%) at 6 months in the control and test group was 65.69 ±26.52 (mean± SD) and 65.54 ±.9.16 respectively but no statistically significant difference was seen between the two groups. The results of the study suggest that the combination of both subepithelial connective tissue graft and acellular dermal matrix graft with a coronally positioned flap can produce an equivalent amount of esthetic root coverage.

Tyrosine-Derived Novel Benzoxazine Active in a Rat Syngenic Mammary Tumor Model of Breast Cancer.

In continuing efforts of improving benzoxazepine derivatives as an anti-breast cancer agent, a new chemical entity, benzoxazine, was designed from scaffold morphing. Structure-activity relationship studies revealed that H, -OMe, -CF3, and -F were well tolerated on R1 and R2 positions of ring A, and R2 as -CH2CH2N(CH2)4 (N-ethyl pyrrolidine) and -CH2CH2N(CH2)5 (N-ethyl piperidine) chains on ring D increased activities (Series B, Figure 3). 13d selected as a lead compound (IC50: 0.20 to 0.65 µM) induces apoptosis, cell cycle arrest, and loss of mitochondrial membrane potential in breast cancer cells. Compound 13d was formulated into 13d-f using cyclodextrin to improve its solubility for a pharmacokinetic, in vivo efficacy study. Both 13d and 13d-f regressed tumor growth at concentrations of 5 and 20 mg/kg better than tamoxifen without any mortality in a rat syngenic mammary tumor model. Collectively, our data suggest that tyrosine-derived novel benzoxazine 13d could be a potential lead for the treatment of breast cancer and hence deserve further in-depth studies.

Platelet-rich plasma as an effective biological therapy in early-stage knee osteoarthritis: One year follow up.

OBJECTIVE: PRP is produced by centrifugation of whole blood containing highly concentrated platelets, associated growth factors, and other bioactive agents which has been shown to provide some symptomatic relief in early knee osteoarthritis (OA). The principal objective of our study was to evaluate the effectiveness and safety of standardized intra-articular injection of autologous PRP in early osteoarthritis knee. METHODS: A total of 98 eligible symptomatic patients received two injections of standardized PRP 3 weeks apart. Clinical outcomes were evaluated using the VAS and Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire before treatment and at 6 weeks, 3 months, 6 months, and 1 year after treatment. Secondary objectives were safety (side effects), and the effect of PRP on the different grades of knee degeneration. RESULTS: There was a statistically significant improvement in mean VAS and WOMAC scores at 6 weeks, 3 months, 6 months, and slight loss of improvement at 1 year follow-up. There was also a correlation between the degree of degeneration and improvement in the mean scores. The decrease in mean pain score is more in grades 1 and 2 (early OA) than in grade 3. The intraarticular injection is safe, with no major complications. CONCLUSION: PRP is a safe and effective biological regenerative therapy for early OA Knees. It provides a significant clinical improvement in patients with some loss of improvement with time. More studies will be needed to confirm our findings.

Molecular and structural analysis of central transport channel in complex with Nup93 of nuclear pore complex.

The central transport channel (CTC) of nuclear pore complexes (NPCs) is made up of three nucleoporins Nup62, Nup58 and Nup54. In which manner and capacity, these nucleoporins form the CTC, is not yet clear. We explored the CTC Nups from various species and observed that distinct biochemical characteristics of CTC Nups are evolutionarily conserved. Moreover, comparative biochemical analysis of CTC complexes showed various stoichiometric combinations of Nup62, Nup54 and Nup58 coexisting together. We observed the conserved amino-terminal domain of mammalian Nup93 is crucial for the anchorage of CTC and its localization to NPCs. We could reconstitute and purify mammalian CTC·Nup93 quaternary complex by co-expressing full length or N-terminal domain of Nup93 along with CTC complex. Further, we characterized CTC·Nup93 complex using small angle X-ray scattering and electron microscopy that revealed a "V" shape of CTC·Nup93 complex. Overall, this study demonstrated for the first time evolutionarily conserved plasticity and stoichiometric diversity in CTC Nups.

CFTR constrains the differentiation from mouse embryonic stem cells to intestine lineage cells.

Cystic fibrosis transmembrane conductance regulator (CFTR) is a transmembrane Cl- and HCO3- transporter and its malfunction leads to cystic fibrosis (CF) and multiple congenital diseases. The most common mutation in CF patient is DF508 and the patients have increased risk in developing gastrointestinal tumors. To explore the etiology of high cancer risk in DF508-CF patients, we have derived mouse DF508-CFTR embryonic stem (ES) cells and use it as a novel in vitro model to study the role of CFTR from developmental angle. We found the self-renewal properties are intact in DF508-CFTR ES cells. Nevertheless, the differentiation of intestine lineage, the expression of intestine progenitor and major intestine differentiated cell markers is significantly upregulated in DF508-CFTR ES cell differentiated cells. Therefore, CFTR plays an important role in intestine lineage differentiation. Besides, DF508-CFTR ES cells formed teratomas demonstrated enhanced expressions of cell proliferation, migration and epithelial-mesenchymal transition associated marker genes, indicating the tumor suppressive role of CFTR. Taken together, our derived DF508-CFTR ES cells can serve as a new model to study the etiology of CF disease in vitro and malignant teratoma formation in vivo.

Diversity oriented synthesis of chromene-xanthene hybrids as anti-breast cancer agents.

A diverse library of chromene-xanthene hybrids were synthesized through intramolecular Friedel-Crafts reaction of the arenoxy carbinols. Examples include first incorporation of amino acid tyrosine into xanthene skeletons with polar functionalities. A careful structural evaluation revealed that tyrosine crafted chromene-xanthene hybrids exhibited good activities against breast cancer cell lines MCF-7, MDA-MB-231. The lead compound 16 displays significant cell cycle arrest at G1 phase and induces apoptosis in MDA-MB-231 cells.

Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids.

Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.

Serotype distribution and antimicrobial susceptibility pattern in children≤5years with invasive pneumococcal disease in India - A systematic review.

BACKGROUND: Streptococcus pneumoniae is a leading cause of childhood diseases that result in significant morbidity and mortality in India. Commercially licensed and available pneumococcal conjugate vaccines (PCVs) include ten (PCV-10) and 13 (PCV-13) pneumococcal serotypes. Vaccines with other serotype combinations are under development. Reviewing and reporting trends and distribution of pneumococcal serotypes causing invasive pneumococcal disease in India will be useful for policy making as PCV is being introduced into India's universal immunization program. METHODS: We conducted a systematic literature review of hospital based observational studies (both peer reviewed and gray literature published in English) from India available from January 1990 to December 2016. Studies that documented data on the prevalence of serotype distribution and the antimicrobial resistance pattern of S. pneumoniae in children≤5years of age were included. RESULT: We screened a total number of 116 studies, of which 109 studies were excluded. Final analysis included seven studies. The most frequent pneumococcal serotypes causing invasive disease among children≤5years were 14, 1, 19F, 6B, 5, 6A, 9V and 23F. Serotype 14 and 19A were represented in most of the geographical regions studied in the reviewed articles. Currently available PCV formulations included 67.3-78.4% of all serotypes contributing to IPD among Indian children≤5years. Pneumococcal resistance to trimethoprim/sulfamethoxazole, erythromycin, penicillin, chloramphenicol, levofloxacin and cefotaxime was seen in 81%, 37%, 10%, 8%, 6% and 4% of all pneumococcal isolates respectively, while vancomycin resistance was not reported. CONCLUSION: The present review demonstrates that up to 78.4% of reported invasive pneumococcal disease in children≤5years in India are currently caused by serotypes that are included in the available licensed PCVs. However, sentinel surveillance must be continued in representative parts of the country to assess the changing trends in distribution of pneumococcal serotypes and their implication for vaccine selection and rollout in India.

Chemometric Based Identification and Validation of Specific Chemical Markers for Geographical, Seasonal and Gender Variations in Tinospora cordifolia Stem using HPLC-ESI-QTOF-MS Analysis.

INTRODUCTION: Tinospora cordifolia is a widely distributed medicinal plant used in various traditional and commercial Ayurvedic formulations. Due to the wide use of this plant it is important to know the extent of variability in the metabolite profile resulting from geographical location, season and gender. OBJECTIVE: To develop a statistical approach based on phytochemical markers for confident prediction of variations in metabolic profile and cytotoxicity due to geographical, seasonal and gender difference in T. cordifolia stem. METHODS: A HPLC-ESI-QTOF-MS method was used for the metabolite profiling of T. cordifolia stem. The data were analysed using chemometric methods including Student's t-test, ANOVA, FA/PCA and ROC curve analysis and validated for the identification of chemical variations. The bioactivity of selected samples was also tested using a cell cytotoxicity assay to assess the functional aspect of the phytochemical variability. RESULTS: The chemometric approach applied here identified marker ions for geographical locations (m/z 294.1139 and 445.2136), seasons (m/z 344.1482, 359.1501, and 373.1305) and gender (m/z 257.1380) with 100% statistical sensitivity and specificity. An in vitro cytotoxicity evaluation revealed that male T. cordifolia stem was the most effective in inhibiting the growth of cancerous cell lines. CONCLUSIONS: The developed and validated chemometric approach identified the analytical markers for phytochemical variations in unknown T. cordifolia stem samples from male or female plants and samples collected from different geographical locations and seasons. The results are supported by comparative cytotoxic activity data. Copyright © 2017 John Wiley & Sons, Ltd.

Laser Induced breakdown spectroscopy: A rapid tool for the identification and quantification of minerals in cucurbit seeds.

Laser-induced breakdown spectroscopy (LIBS) was investigated to estimate the viability as a simple and rapid method for analysis of nutrient elements in seed kernels of cucurbits. LIBS spectra were recorded in the range of 200-975nm by using Q-switched Nd:YAG laser at 532nm (4ns, 10Hz) attached to echelle spectrometer with intensified charged coupled device (ICCD). The spectral analysis revealed the presence of several elements like C, O, N, Mg, Ca, Na and K in seeds. The quantification of elements (Mg, Ca, Na and K) through LIBS was done using calibration curve method in which all calibration curve shows good linearity (r>0.95). The result obtained through LIBS was in reasonable agreement with that obtained through atomic absorption spectroscopy (AAS). Principal Component Analysis (PCA) was also applied to the LIBS data for rapid categorization of seed samples belonging to same species although samples have similar nutrient elements.

Bilateral Adrenal PNET: A Rare Presentation.

Primitive neuroectodermal tumours or PNET's are rare, malignant tumours with aggressive course and extremely poor prognosis. They have no sex preference. They arise mostly in the second decade of life. They are believed to be of neural crest origin and carry the name primitive because majority of the neuronal cells in these tumours appear undifferentiated. Solid organ origin is very rare and tumours arising from the adrenals are very infrequent. We report a case of metastatic bilateral adrenal PNET in a 45-year-old man. We believe this to be the first such case reported in the urological literature.

Vitamin B6 Tethered Endosomal pH Responsive Lipid Nanoparticles for Triggered Intracellular Release of Doxorubicin.

This study reports the development of Vitamin B6 (VitB6) modified pH sensitive charge reversal nanoparticles for efficient intracellular delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic acid, and the nanoparticles of the lipid were formulated by solvent injection method (DOX-B6-SA-NP). Because of the pKa (5.6) of VitB6, DOX-B6-SA-NP showed positive charge and enhanced release of DOX at pH 5. Confocal microscopy illustrated that DOX-B6-SA-NP treatment kept higher DOX accumulation inside the cells than conventional pH insensitive lipid nanoparticles (DOX-SA-NP). The cationic charge of nanoparticles subsequently facilitated the endosomal escape and promoted the nuclear accumulation of DOX. Furthermore, in vitro cytotoxicity, apoptosis, cell cycle arrest, and mitochondrial membrane depolarization studies supported the enhanced efficacy of DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous pharmacokinetics and biodistribution investigations indicated that pH sensitive nanoparticles can significantly prolong the blood circulation time of DOX in biological system and increase the drug accumulation to tumor site. Consequent to this, DOX-B6-SA-NP also exhibited much enhanced therapeutic efficacy and lower toxicity in tumor-bearing rats compared to free DOX. The reduction in toxicity was confirmed by histological and survival analysis. In conclusion, these results suggest that the VitB6 modified charge reversal nanoparticles can be a novel platform for the successful delivery of anticancer drugs.

Development of acetazolamide-loaded, pH-triggered polymeric nanoparticulate in situ gel for sustained ocular delivery: in vitro. ex vivo evaluation and pharmacodynamic study.

The objective of research was to develop a novel pH-triggered polymeric nanoparticulate in situ gel (NP-ISG) for ophthalmic delivery of acetazolamide (ACZ) to enhance the conjunctival permeation and precorneal residence time of the formulation by overcoming the limitations of protective ocular barriers. Nanoparticles (NP1--NP12) were developed by nanoprecipitation method and evaluated for pharmacotechnical characteristics including transmission electron microscopy. The optimized formulation, NP10 was dispersed in carbopol 934 P to form nanoparticulate in situ gels (NP-ISG1--NP-ISG5). NP-ISG5 was selected as optimized formulation on the basis of gelation ability and residence time. Ex vivo transcorneal permeation study exhibited significantly higher ACZ permeation from NP-ISG5 (74.50 ± 2.20 mg/cm(2)) and NP10 (93.5 ± 2.25 mg/cm(2)) than eye drops (20.08 ± 3.12 mg/cm(2)) and ACZ suspension (16.03 ± 2.14). Modified Draize test with zero score indicated nonirritant property of NP-ISG5. Corneal toxicity study revealed no visual signs of tissue damage. Further, NP-ISG5 when tested for hypotensive effect on intraocular pressure (IOP) in rabbits revealed that NP-ISG5 caused significant decrease in IOP (p < 0.05) in comparison to eye drops. Conclusively, NP-ISG5 may offer intensive management of glaucoma via higher permeation, prolonged precorneal residence time and sustained drug release along with higher in vitro efficacy, safety and patient compliance.