Segmental infralesional pathological spontaneous activity in subacute traumatic spinal cord injury.

INTRODUCTION/AIMS: There is a dearth of knowledge regarding the status of infralesional lower motor neurons (LMNs) in individuals with traumatic cervical spinal cord injury (SCI), yet there is a growing need to understand how the spinal lesion impacts LMNs caudal to the lesion epicenter, especially in the context of nerve transfer surgery to restore several key upper limb functions. Our objective was to determine the frequency of pathological spontaneous activity (PSA) at, and below, the level of spinal injury, to gain an understanding of LMN health below the spinal lesion. METHODS: Ninety-one limbs in 57 individuals (53 males, mean age = 44.4 ± 16.9 years, mean duration from injury = 3.4 ± 1.4 months, 32 with motor complete injuries), were analyzed. Analysis was stratified by injury level as (1) C4 and above, (2) C5, and (3) C6-7. Needle electromyography was performed on representative muscles innervated by the C5-6, C6-7, C7-8, and C8-T1 nerve roots. PSA was dichotomized as present or absent. Data were pooled for the most caudal infralesional segment (C8-T1). RESULTS: A high frequency of PSA was seen in all infralesional segments. The pooled frequency of PSA for all injury levels at C8-T1 was 68.7% of the limbs tested. There was also evidence of PSA at the rostral border of the neurological level of injury, with 58.3% of C5-6 muscles in those with C5-level injuries. DISCUSSION: These data support a high prevalence of infralesional LMN abnormalities following SCI, which has implications to nerve transfer candidacy, timing of the intervention, and donor nerve options.

Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides.

Delivery of nucleic acids can be hindered by multiple factors including nuclease susceptibility, endosome trapping, and clearance. Multiple nanotechnology scaffolds have offered promising solutions, and among these, lipid-based systems are advantageous because of their high biocompatibility and low toxicity. However, many lipid nanoparticle systems still have issues regarding stability, rapid clearance, and cargo leakage. Herein, we demonstrate the use of a synthetic nanodisc (ND) scaffold functionalized with an anti-HIF-1-α antisense oligonucleotide (ASO) to reduce HIF-1-α mRNA transcript levels. We prepared ND conjugates by using a mixture of phosphoglycerolipids with phosphocholine and phosphothioethanol headgroups that self-assemble into a ∼13 × 5 nm discoidal structure upon addition of a 22-amino-acid ApoA1 mimetic peptide. Optimized reaction conditions yield 15 copies of the anti-HIF-1-α ASO DNA covalently conjugated to the thiolated phospholipids using maleimide-thiol chemistry. We show that DNA-ND conjugates are active, nuclease resistant, and rapidly internalized into cells to regulate HIF-1-α mRNA levels without the use of transfection agents. DNA-ND uptake is partially mediated through Scavenger Receptor B1 and the ND conjugates show enhanced knockdown of HIF-1-α compared to that of the soluble ASOs in multiple cell lines. Our results demonstrate that covalently functionalized NDs may offer an improved platform for ASO therapeutics.

Andrographis paniculata mitigates first-line anti-tubercular drugs-induced nephrotoxicity in Wistar rats.

CONTEXT: Anti-tubercular drugs (ATDs) mediated adverse drug reactions are major concerns for clinicians to treat tuberculosis infection. This study aimed to investigate Andrographis paniculata extract-based phytotherapy to combat the nephrotoxic effects caused by ATDs therapy. METHODS: Reno-protective effect of A. paniculata extract in ATDs-induced rats was evaluated through LPO, GSH, CAT, SOD, GST, urea, creatinine, uric acid, and histopathological studies. Standardization of the extract was performed using RP-HPLC and FTIR analysis. Whereas, the effect of A. paniculata extract on ATDs induced genetic perturbation was analyzed using micronucleus assay. Moreover, the expression level of the xenometabolic gene was investigated using RT-PCR to explore the therapeutic mechanism. RESULTS: The nephrotoxic effect of ATDs was indicated by elevated levels of LPO and renal function markers along with the reduced activity of renal antioxidants. An up-regulated expression profile of NAT gene and histological alterations were observed in renal tissue however, micronucleated PCEs were observed in bone marrow cells. Concomitant treatment with A. paniculata extract revealed a noticeable amelioration of elevated oxidative stress markers, gene expression levels, genotoxic perturbation, and histological alterations in a dose-dependent manner. CONCLUSION: Hence, the present study using A. paniculata leaf extract confirmed to play effective phytotherapy against ATDs induced renal toxicity.

Termite's potential in solid waste management in Himachal Pradesh: A mini review.

One of the major reasons for the degradation of Earth's setting is inappropriate disposal of solid waste. Mountains of solid waste are increasing in every country making solid waste management a challenge almost everywhere on Earth. It is vital to look for such municipal solid waste management solutions that are financially sustainable, technically possible, socially and legally acceptable and environmentally friendly. Currently vermicomposting is the only biological solid waste treatment process that uses multicellular organisms to biodegrade organic wastes. A few species of insects are capable of digesting lignin and cellulose. Of these, termites are the most numerous and play a decisive role as scavengers. Microflora which inhabit the termites' gut contribute to their waste degrading potential. Termites act as major soil ecosystem managers and are able to breakdown and recycle organic matter and composite. Although studies in the potential of termites to increase soil fertility are well-accounted for in the literature, the potential of termites for solid waste management still needs to be explored. This mini review presents the state of information on the use of termite species in solid waste degradation focused on the potential application in the Himachal Pradesh region, India. This review highlights different termite species found in Himachal Pradesh and the challenges that are needed to be conquered. The study also aims at encouraging competent authorities/researchers to work towards the improvement of the present system by further exploring the use of termites in solid waste management through suggestions and recommendations.

"Side effects--part of the package": a mixed methods approach to study adverse events among patients being programmatically treated for DR-TB in Gujarat, India.

BACKGROUND: High rates of Adverse Events (AEs) during treatment is one of the leading causes of unsuccessful treatment outcomes among patients with drug resistant tuberculosis (DR-TB). However, information related to AEs is not systematically collected and managed under programmatic setting. The present study assessed the a) incidence and pattern of adverse events in first three months of DR-TB treatment initiation; b) treatment seeking behaviour for AE management; and c) explore the challenges in seeking treatment and reporting AEs. METHODS: This mixed methods study included all patients diagnosed and initiated on treatment under RNTCP during July-September 2018 at Ahmedabad DR-TB centre. The patients were interviewed telephonically and assessed for all AEs experienced by them. In-depth interviews and key-informant interviews were conducted among patients, DOTS supervisors and programme staff (treatment supervisors, medical officer and district program managers). RESULTS: Total 207 AEs were reported by the 74 DR-TB patients. All patients experienced at least one AE during initial treatment period. Incidence rate of AEs (experienced) was 3.11 (1st month-4.6, 2nd month-2.7, 3rd month-2.02) per 100 person days. Of the 207 AEs, gastro-intestinal (59, 28.3%), ophthalmic (32, 15.4%) and otolaryngology (25, 11.9%) system related AEs were commonly experienced. Treatment was not sought in two-fifths of the AEs. Themes and sub-themes related to challenges in treatment seeking or reporting of AEs were 1) Patient related-Misconceptions, accessibility and affordability of management, lack of counselling support, stigma and discrimination, and past treatment experience; 2) Health system related- lack of guidelines and training for AE management, 3) Poor coordination between hospital and tuberculosis centre. CONCLUSION: The incidence of AEs was high among patients with DR-TB in the first three months of treatment and treatment seeking/reporting was low. Adequate health education and counselling of the patient and orientation of the health systems is the need of the hour. An efficient real-time reporting and management of AE should be developed and tested for effective DR-TB control.

Investigating the potential of carboxymethyl pullulan for protecting the rabbit eye from systematically induced precorneal tear film damage.

The present investigation was aimed to develop a rabbit model for protecting the rabbit eye from systematically induced precorneal tear film (PTF) damage, evaluation of carboxymethyl pullulan for its protective action against PTF damage and its curative potential. For the same, pullulan was modified by carboxymethylation and structural modification was confirmed by spectral attributes. Further, the carboxymethyl pullulan (CMP) solutions (0.1-2.0%, w/v) were evaluated for their physical properties and its concentration 1.5% (w/v) was found to fit the criterion to prepare an eye solution. The safety and non-toxicity of CMP (1.5%, w/v) eye solution was confirmed by HET-CAM method and rabbit eye irritation test. Further, a systematic rabbit eye model was developed that mimic PTF damage in day to day life. Therefore, three levels of PTF damage were developed equating symptoms of damage due to high temperature (level I) or long term mobile use (level II) or heavy air pollution (level III). Thus, a representative model with benzalkonium chloride (BAC, 0.1% v/v, 0.2% v/v and 0.3% v/v), administered two drops twice a day for two days to develop level I, level II and level III eye damage. The CMP (1.5%, w/v) eye solution possessed a protective potential against level I and II PTF damage. The rabbit eyes remained unharmed and comparable with the normal control during the complete experimental period. Additionally, CMP (1.5%, w/v) eye solution has shown early fast recovery (8 days) from PTF damage induced by instillation of PTF damage agent (BAC). Carboxymethyl pullulan eye protective solution has normalized the tear film stability in rabbit eye model. It is established from the present work that, carboxymethyl pullulan has protective action against precorneal tear film damage and it potentiates the early recovery too.

Expression profile of markers of oxidative stress, injury and apoptosis in anti-tuberculosis drugs induced nephrotoxicity.

AIM: Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA) are part of first-line anti-tuberculosis therapy used against infection caused by Mycobacterium tuberculosis. However, these drugs are known to be potentially harmful as these are associated with numerous side effects and when taken together their harmful outcomes are elevated in a synergistic manner. Identification of possible mechanism underlying RIF + INH + PZA induced nephrotoxicity may be advantageous in developing strategies to prevent their toxic implications. METHODS: In this study rats were distributed in two groups of six each: Control (tap water) and Toxicant (INH + RIF + PZA) in dosage derived through extrapolation from human dosage for 28 days once in a day. Antioxidant activity and histology of kidney were examined. In addition, apoptosis was also studied using pro and anti-apoptotic markers and TUNEL staining to check nephrotoxicity. RESULTS: Findings indicated that combined (INH, RIF and PZA) 28 day exposure in Wistar rats caused increase in number of free radicals/ reactive oxygen species which further cause changes in levels of enzymatic antioxidants such as glutathione, Superoxide dismutase, Catalase, and Glutathione-s-transferase. Altered content of pro (BAD&BAX) and anti-apoptotic genes (BCL-2&BCL2L1) genes, TUNEL positive cells and DNA fragmentation emphasized involvement of apoptosis. CONCLUSION: This study concluded that nephrotoxicity is accompanied during combinational anti-tuberculosis drug therapy.

Kinetic Control of Graphene Localization in Co-continuous Polymer Blends via Melt Compounding.

Selective localization of graphene in co-continuous polymer blends is an attractive method for preparing conductive polymer composites. Localization of graphene at the interface between the two polymer phases produces good conductivity at ultra-low concentrations. Although graphene localization is ultimately dependent on thermodynamic factors such as the surface energy of graphene and the two polymer components, kinetics also strongly affects the migration and localization of graphene in polymer blends during melt compounding. However, few studies have systemically investigated the important role of kinetics on graphene localization. Here, we introduced graphene nanoplatelets (GNPs) in polylactic acid (PLA)/polystyrene (PS) co-continuous polymer blends. Although GNPs in thermal equilibrium prefer the PS phase, we were able to kinetically trap GNPs at the interface of polymer blends via control of melt-compounding sequences, mixing times and shear rates. Utilizing morphological, rheological, and electrical measurements, we verified graphene localization and the suppression of coarsening in co-continuous polymer blends during annealing. When GNPs were premixed with the thermodynamically less-favorable PLA phase before mixing with the PS phase, GNPs can be kinetically trapped at the interface during melt compounding. Moreover, we show that a shorter melt-compounding time gives rise to a higher GNP interfacial coverage and a more effective morphology stabilization effect. Blends with as low as 0.5 wt % GNPs with only 30 s of melt compounding have a room-temperature conductivity of ∼10-6 S/cm, which is larger than blends with longer melt-compounding times and potentially useful for antistatic materials. The in-depth study on the kinetics of graphene localization in our work provides a general guideline for the kinetic control of the localization of platelike nanofillers in polymer blends. Our study also demonstrates a facile method for manufacturing conductive polymer blends with low percolation thresholds.

Deleterious effects of 28-day oral co-administration of first-line anti-TB drugs on spleen, blood and bone marrow chromosomes in normal rat.

CONTEXT: Isoniazid, rifampicin and pyrazinamide are most reliable and cost-effective remedy for tuberculosis treatment and prophylaxis among first-line anti-tuberculosis (TB) drugs and have a pronounced tendency to cause adverse drug reactions. Hepatotoxicity is well-studied side effect of these drugs but their effects on other organs like spleen and blood are still needed to be explored. OBJECTIVE: To explore the probable outcome of co-administration these three major antitubercular drugs (ATDs), rifampicin, isoniazid and pyrazinamide on spleen, blood and bone marrow. MATERIALS AND METHODS: Different parameters were evaluated like lipid peroxidation, glutathione (GSH) and protein content in spleen by spectrophotometric evaluation, hematological evaluation by determining total hemoglobin, total leukocyte count, differential leukocyte count and scanning electron microscopy studies in blood, genotoxicity studied by bone marrow chromosomal analysis and DNA fragmentation. The female rats n = 12 (150-200 g) were grouped as control group orally given saline and toxicant group given INH (30.85 mg/kg b.wt.) + RIF (61.7 mg/kg b.wt.) + PZA (132.65 mg/kg b.wt.) dosage extrapolated from dose that is used in human for 28 d once daily. RESULTS: After 28 d-oral co-administration of anti-TB drugs (INH (30.85 mg/kg b.wt.) + RIF (61.7 mg/kg b.wt.) + PZA (132.65 mg/kg b.wt.)), it was revealed that there were an increase thiobarbituric acid reactive substances, decrease in GSH and protein contents in spleen. Marked changes in hematological parameters, DNA fragmentation and chromosomes were also observed. CONCLUSION: This can be concluded from this work that co-administration of first-line ATDs is toxic to spleen and blood also these drugs can cause damage at genetic level.

Human health risk assessment and uncertainty analysis of silver nanoparticles in water.

Despite frequent detection in environmental waters, literature which quantifies the health risk of silver nanoparticles (Ag NPs) through oral ingestion is scarce. This study compiled literature data to find the removal of Ag NPs from different treatment schemes (i.e., natural, engineered, or hybrid). Ag NP concentrations were found either in surface water or in groundwater based on where the effluent of treatment schemes was discharged, i.e., either in surface water or in groundwater. Monte-Carlo simulation was carried out for probabilistic assessment of health risks for children for two hypothetical exposure scenarios: (a) ingesting river water while swimming and (b) drinking groundwater. Bio-accessible fraction, dietary metal adsorption factor, and concentrations of silver ions were incorporated to simulate realistic situations. Different treatment schemes were ranked for their nanoparticles' removal efficiency with respect to (i) exceedance probability from guideline value and (ii) health risk to children. Hybrid treatment combinations, i.e., conventional primary and secondary treatment units followed by nature-based units (constructed wetlands and soil aquifer treatment), were ranked the best. The health risk value was found to be less than 1, with the 99th percentile value less than 10-3 in all cases. The maximum allowable concentration of Ag NPs was found to be as low as 1.43 mg/L for groundwater, suggesting probable potential for risk. Uncertainty analysis revealed that the uncertainty of the influent NPs concentration in raw wastewater contributes > 99% to the variance of the hazard index. The results of this work indicate that the use of natural treatment technologies with existing engineered treatments provides higher nanoparticle removal from wastewater without the requirement of any tertiary treatment unit.

Counseling intervention improves treatment adherence among newly diagnosed drug sensitive Tuberculosis patients of Ahmedabad city - A mixed methods approach.

INTRODUCTION: Counselling sessions based on the health behaviour module for patients on TB treatment may help improve the level of understanding of tuberculosis and its treatment, importance of adherence to therapy, possible side effects, dietary habits and to address any misconceptions; leading to better adherence and improved outcome. Hence, study attempted to assess the impact of brief counselling intervention through treatment adherence supportive activist (TASA) in improving adherence to treatment among drug sensitive TB patients. METHODS: An explanatory mixed methods design (QUAN-Qual) was carried out. Out of 23 Tuberculosis units (TUs) in Ahmedabad Municipal Corporation (AMC) two were selected, one interventional group where trained counsellor was recruited while other was the control group. All drug sensitive TB patients diagnosed at both selected TUs during January to March 2020 were included in the study. Among all patients who were non-adherent in both the TUs, 14 were selected to explore factors contributing to non-adherence to treatment. RESULTS: At the end of intensive phase, drug adherence in the study TU was 85.71% while it was 67.5% in the control TU. At the end of one month of treatment, the proportion of patients having better level adherence was more among counselled patients as compared to non-counselled patients. Marital status, religion, gender did not affect the level of adherence. Reasons for non-adherence as well as perceived barriers to adherence to TB treatment were treatment related, patient related and social barriers. CONCLUSION: Dedicated NTEP counsellor (TASA) can help improve the treatment adherence and impact of physical counselling.

DNA mechanocapsules for programmable piconewton responsive drug delivery.

The mechanical dysregulation of cells is associated with a number of disease states, that spans from fibrosis to tumorigenesis. Hence, it is highly desirable to develop strategies to deliver drugs based on the "mechanical phenotype" of a cell. To achieve this goal, we report the development of DNA mechanocapsules (DMC) comprised of DNA tetrahedrons that are force responsive. Modeling shows the trajectory of force-induced DMC rupture and predicts how applied force spatial position and orientation tunes the force-response threshold. DMCs functionalized with adhesion ligands mechanically denature in vitro as a result of cell receptor forces. DMCs are designed to encapsulate macromolecular cargos such as dextran and oligonucleotide drugs with minimal cargo leakage and high nuclease resistance. Force-induced release and uptake of DMC cargo is validated using flow cytometry. Finally, we demonstrate force-induced mRNA knockdown of HIF-1α in a manner that is dependent on the magnitude of cellular traction forces. These results show that DMCs can be effectively used to target biophysical phenotypes which may find useful applications in immunology and cancer biology.

Integrated analytical hierarchy process-grey relational analysis approach for mechanical recycling scenarios of plastics waste in India.

Mechanical recycling is an indispensable tool for plastic waste (PW) recycling and has the highest share in the PW recycling sector in India. The transition to the circular economy of plastics (CEoP) needs a systemic perspective on the mechanical recycling processes. Nevertheless, the assessment of multiple parameters influencing the mechanical recycling of PW is a complex decision-making problem for the development of triple-bottom-line mechanical recycling. A systemic perspective of various mechanical recycling scenarios was performed by employing a multi-criteria decision-making approach to examine the complexity of interlinked factors in the present investigation. Analytical hierarchy process (AHP) integrated with grey relational analysis (GRA) was used to evaluate the criteria that directly influence quality-oriented mechanical recycling. Data were collected by conducting semi-structured interviews using a framed questionnaire in stakeholder engagement with mechanical recyclers of PW. The first level hierarchy included economy, technical, resource consumption and environmental criteria. These criteria were further categorized into various significant indices such as quality of recyclate, recyclability, water and energy consumption during recycling. The results of the integrated grey relational analysis indicated that the technical parameters including quality of recyclate, resource efficiency, PW processing rate and recyclability have a significant influence on mechanical recycling. Based on AHP-GRA, scenario MR6, i.e. manufacturing of PET strap from recycled PET flakes, was ranked the optimal mechanical process amongst the various scenarios. MR6 was followed by Straps and Films at the second and third rank. The lowest ranking was observed for polymer blend recycling. These processes with higher ranks produced good quality recyclate with better efficiency and recyclability. Moreover, these processes consumed optimal resources during manufacturing. These processes also exhibited less maintenance cost, high production rate, low chemical consumption and waste generation as well as implemented pollution control practices.

Impression Disinfection and Its Effect on Dimensional Accuracy and Surface Detail in the Times of COVID-19: An In Vitro Study.

Introduction The disinfection of impressions is crucial to eliminate the viral and other microbial loads to prevent the cross contamination of diseases. The aim of this study was to compare the effect of different virucidal disinfecting methods on the dimensional accuracy and surface detail reproduction (SDR) of impression materials. Methods A total of 160 samples were fabricated with different impression materials using zinc oxide eugenol (Group 1), alginate (Group 2), polyether (Group 3), and addition silicone (Group 4) impression materials, each containing 40 samples (n=40). These groups were further divided into Subgroups A, B, C, and D (n=10) based on the disinfecting method used. Disinfection was carried out using 0.2% peracetic acid (A), a natural polymer of glucosamine (B), ultraviolet (UV) radiation (C), and ozonated water (D). The disinfected impressions were poured in type IV gypsum, and the obtained casts were checked for dimensional accuracy and surface detail reproduction (SDR). For dimensional accuracy, a one-way analysis of variance (ANOVA) test and, for surface detail reproduction, the chi-square test were used to compare the different subgroups of each impression material separately. Results Zinc oxide eugenol samples showed the lowest mean dimensional change when disinfected with 0.2% peracetic acid (1A=154.1 µm), and alginate showed the lowest mean dimensional change when disinfected using ozonated water (2D=134.9 µm). On the other hand, the lowest mean dimensional change observed in polyether and addition silicone samples was those which were disinfected using UV radiation (3C=100.9 µm and 4C=113.5 µm). Surface detail was reproduced adequately in most of the samples. Conclusion A 0.2% peracetic acid could be used to disinfect zinc oxide eugenol impressions, ozonated water for alginate impressions, and UV radiation for polyether and addition silicone impressions.

Environmental contamination with carbapenem resistant Acinetobacter baumannii in healthcare settings in Fiji: a potential source of infection.

Introduction: There are multiple ongoing outbreaks of carbapenem resistant Acinetobacter baumannii (CRAb) infection in Fiji's hospitals. CRAb is able to colonize and persist on various hospital surfaces for extended periods. We conducted a study to understand the extent of hospital environmental contamination and phylogenetic links with clinical isolates. Methods: Swabs were collected from high-touch surfaces at Colonial War Memorial Hospital (CWMH) September 2021 and December 2022; Lautoka Hospital (LTKH) August 2022; and Labasa Hospital (LBSH) November 2022. All bacterial isolates were identified, and antimicrobial susceptibility testing (AST) performed; isolates resistant to carbapenems and producing a carbapenemase underwent whole genome sequencing. Comparison was made to clinical isolates obtained from CWMH in 2016-2017 and 2019-2021 and from LTKH and LBSH from 2020-2021. Results: From the 180 environmental samples collected, ten (5.6%) CRAb were isolated; no other carbapenem-resistant gram-negative organisms were isolated. Seven (70%) of the CRAb were isolated from CWMH and three (30%) from LTKH; no CRAb were isolated from LBSH. Of the seven CWMH CRAb, two were sequence type 2 (ST2), three ST25, and two ST499. All LTKH isolates were ST499. The two environmental CRAb ST2 isolates were closely genetically linked to isolates obtained from patients in CWMH, LTKH, and LBSH 2020-2021. Similarly, the three environmental CRAb ST25 isolates were closely genetically linked to isolates obtained from patients admitted to CWMH in 2019-2021 and LBSH in 2020. The environmental CRAb ST499 isolates represented two distinct clones, with clone 1 comprising two genetically identical isolates from CWMH and clone 2 the three isolates from LTKH. Although no genetic linkages were observed when comparing environmental ST499 isolates to those from CWMH patients in 2020-2021, both clone 1 isolates were genetically identical to an isolate obtained from a patient admitted during the sampling period. Conclusion: Our study highlights the contamination of high-touch surfaces within Fiji hospitals with CRAb, suggesting that these may serve as important sources for CRAb. Phylogenetic linkages to CRAb isolated from patients since 2019 underscores the persistence of this resistant pathogen in hospital settings and the ongoing risk for hospital-acquired infections.

Preparation and Characterization of Clopidogrel Bisulfate-hydroxypropyl-ß-Cyclodextrin Mixed Inclusion Complex for Improved Intestinal Solubility and Anti-Thrombotic Efficacy.

The study aimed to increase the intestinal solubility and absorption of orally bioavailable clopidogrel-bisulfate (CPB) by complexing with hydroxypropyl-ß-cyclodextrin (HCD) to form a binary inclusion complex that was stabilized by Tween 80 (T80) resulting into mixed inclusion complex. The results of phase solubility studies and molecular docking of CPB with ß-cyclodextrin (ß-CD) and HCD suggested higher solubility and binding energy of the stable CPB: HCD complex in the presence of T80 as compared to the CPB: ß-CD complex. The D-Optimal mixture design was used to optimize the formulation containing the CPB: HCD: T80 mixed inclusion complex. The results suggest the enhanced stability of the CPB: HCD inclusion complex in the presence of T80. The spectral attributes confirmed the inclusion complexation and pointed out the central position of CPB in a hydrophilic cavity of HCD. Further, the prepared soft gelatin capsule successfully confirmed the importance of obliterating the intestinal precipitation associated problem of CPB through an in-vitro release study. The anticoagulant activity in rabbits confirmed that soft gelatin capsules showed 1.2 folds and 1.3 folds increase in clotting time, 1.2 fold and 1.5 folds increase in bleeding time when compared to marketed formulation and pure drug, respectively. Conclusively, soft gelatin capsules exhibit the potential to enhance the oral bioavailability of CPB, leading to reduction of the dose and dose-related side effects.

Nanodiscoidal Nucleic Acids for Gene Regulation.

Therapeutic nucleic acids represent a powerful class of drug molecules to control gene expression and protein synthesis. A major challenge in this field is that soluble oligonucleotides have limited serum stability, and the majority of nucleic acids that enter the cells are trapped within endosomes. Delivery efficiency can be improved using lipid scaffolds. One such example is the nanodisc (ND), a self-assembled nanostructure composed of phospholipids and peptides and modeled after high density lipoproteins (HDLs). Herein, we describe the development of the nanodiscoidal nucleic acid (NNA) which is a ND covalently modified with nucleic acids on the top and bottom lipid faces as well as the lateral peptide belt. The 13 nm ND was doped with thiolated phospholipids and thiol-containing peptides and coupled in a one-pot reaction with oligonucleotides to achieve ∼30 DNA/NNA nucleic acid density. NNAs showed superior nuclease resistance and enhanced cellular uptake that was mediated through the scavenger receptor B1. Time-dependent Förster resonance energy transfer (FRET) analysis of internalized NNA confirmed that NNAs display increased stability. NNAs modified with clinically validated antisense oligonucleotides (ASOs) that target hypoxia inducible factor 1-α (HIF-1-α) mRNA showed enhanced activity compared with that of the soluble DNA across multiple cell lines as well as a 3D cancer spheroid model. Lastly, in vivo experiments show that ASO-modified NNAs are primarily localized into livers and kidneys, and NNAs were potent in downregulating HIF-1-α using 5-fold lower doses than previously reported. Collectively, our results highlight the therapeutic potential for NNAs.

School Health Services in India: Status, Challenges and the Way Forward.

Schools provide a crucial platform for health and well-being interventions targeting children and adolescents. Early promotive and preventive initiatives are vital for enabling children and adolescents to reach their optimal potential, thereby adding to the country's social return-on-investment, creating a favourable demographic dividend. This review analyses the evolution of school health initiatives in India, including the current curriculum proposed under the Ayushman Bharat program. The manuscript highlights the challenges, and gaps in implementation of the current school health programs and proposes potential pathways for bridging these gaps for promotion of adolescent well-being. The review also discusses the concept of Health Promoting Schools and suggests adaptations and key recommendations to Indian context regarding 'how' to translate it into on-field reality based on the appraisal of successful case studies from other countries. Though India started school health services more than 100 y ago, the school health programmes in most Indian states are weak and fragmented, with piecemeal health screening with minimal focus on health promotion and well-being. The recently launched School Health and Wellness initiative under the Ayushman Bharat program has lots of promise. However, it needs to be translated into effective implementation to prevent it from meeting the fate of its forerunner programs. The school health program needs to move beyond the screening centric approach and be aspirational and holistic in nature focusing upon the overall well-being of the adolescents. Concerted efforts through intersectoral convergence are needed to optimally utilise the platforms of schools for promotion of adolescent well-being.

"We are everyone's ASHAs but who's there for us?" a qualitative exploration of perceptions of work stress and coping among rural frontline workers in Madhya Pradesh, India.

OBJECTIVE: More than a million female village-level lay providers called 'Accredited Social Health Activists (ASHAs)', who deliver primary care, face high levels of stress due to work demands and low compensation, within the context of poverty and gender inequality. Evidence on ASHAs has focused on workplace challenges from a system perspective, without sufficient probing into individual-level stress. This study aims to gain perspectives into the experiences of work stress, the related health symptoms, and the responses to stress among ASHAs in India. METHODS: Focus group discussions (FGDs) conducted with ASHAs in Sehore district, Madhya Pradesh, were audio-recorded and transcribed. Grounded theory was used to generate themes under the various domains of ASHAs' work and domestic life. We identified pathways between the conditions that trigger stressful events, experiences of these events, resulting perceptions, effects on health and wellbeing, and approaches used by ASHAs to respond to stress. RESULTS: Six FGDs with 59 ASHAs generated the following themes: (a) Facility: Workload, undue pressures, unstructured work; ASHAs' relationships with seniors (e.g., feelings of being disrespected, blamed, or targeted), and low access to physical and administrative resources; (b) Home: Feelings of guilt for putting less time for family/child care; disrespect by the elderly for a poorly incentivised job; (c) Community: Low acceptance by the villagers; caste- and gender-bias; difficult community-level relationships (emotional labour, fear/stigma towards her services); (d) Somatic and psychological symptoms: headache, exhaustion, depressive symptoms (to cite a few); and (e) Responses to stress: Motivation (support from peers, family, a sense of identity/pride, incentives), Individual strengths (e.g., social responsibility), and spiritual recourse mechanisms. CONCLUSIONS: This study will inform the development of a strengths-based coaching intervention to address work stress among ASHAs. The findings are relevant to building the evidence on alleviation of work stress among female frontline cadres in low-resource settings globally.

SLC20a1/PiT-1 is required for chorioallantoic placental morphogenesis.

The placenta mediates the transport of nutrients, such as inorganic phosphate (Pi), between the maternal and fetal circulatory systems. The placenta itself also requires high levels of nutrient uptake as it develops to provide critical support for fetal development. This study aimed to determine placental Pi transport mechanisms using in vitro and in vivo models. We observed that Pi (P33) uptake in BeWo cells is sodium dependent and that SLC20A1/Slc20a1 is the most highly expressed placental sodium-dependent transporter in mouse (microarray), human cell line (RT-PCR) and term placenta (RNA-seq), supporting that normal growth and maintenance of the mouse and human placenta requires SLC20A1/Slc20a1. Slc20a1 wild-type (Slc20a1+/+) and knockout (Slc20a1-/-) mice were produced through timed intercrosses and displayed yolk sac angiogenesis failure as expected at E10.5. E9.5 tissues were analyzed to test whether placental morphogenesis requires Slc20a1. At E9.5, the developing placenta was reduced in size in Slc20a1-/-. Multiple structural abnormalities were also observed in the Slc20a1-/-chorioallantois. We determined that monocarboxylate transporter 1 protein (MCT1+) cells were reduced in developing Slc20a1-/-placenta, confirming that Slc20a1 loss reduced trophoblast syncytiotrophoblast 1 (SynT-I) coverage. Next, we examined the cell type-specific Slc20a1 expression and SynT molecular pathways in silico and identified Notch/Wnt as a pathway of interest that regulates trophoblast differentiation. We further observed that specific trophoblast lineages express Notch/Wnt genes that associate with endothelial cell tip-and-stalk cell markers. In conclusion, our findings support that Slc20a1 mediates the symport of Pi into SynT cells, providing critical support for their differentiation and angiogenic mimicry function at the developing maternal-fetal interface.