Phase transforming in situ gels for sustained and controlled transmucosal drug delivery via the intravaginal route.

Direct, reliable, controlled, and sustained drug delivery to female reproductive tract (FRT) remains elusive, with conventional dosage forms falling way short of the mark, leading to premature leakage, erratic drug delivery, and loss of compliance. Historically, the intravaginal route remains underserved by the pharmaceutical sector. To comprehensively address this, we turned our focus to phase-transforming sol-gels, using poloxamers, a thermosensitive polymer and, doxycycline (as hyclate salt, DOXH) as our model agent given its potential use in sexually transmitted infections (STIs). We further enhanced mucoadhesiveness through screening of differing viscosity grade hydroxypropyl methyl celluloses (HPMCs). The optimised sol-gels remained gelled at body temperature (<37 °C) and were prepared in buffer aligned to vaginal cavity pH and osmolality. Lead formulations were progressed based on their ability to retain key rheological properties, and acidic pH in the presence of simulated vaginal fluid (SVF). From a shelf-life perspective, DOXH stability, gelation temperature (Tsol-gel), and pH to three months (2-8 °C) was attained. In summary, the meticulously engineered, phase-transforming sol-gels provided sustained mucoretention despite dilution by vaginal fluid, paving the way for localised antimicrobial drug delivery at concentrations that potentially far exceed the minimum inhibitory concentration (MIC) for target STI-causing bacteria of the FRT.

Advances in body fluid identification: MiRNA markers as powerful tool.

Body fluids are one of the most encountered types of evidence in any crime and are commonly used for identifying a person's identity. In addition to these, they are also useful in ascertaining the nature of crime by determining the ty pe of fluid such as blood, semen, saliva, urine etc. Body fluids collected from crime scenes are mostly found in degraded, trace amounts and/or mixed with other fluids. However, the existing immunological and enzyme-based methods used for differentiating these fluids show limited specificity and sensitivity in such cases. To overcome these challenges, a new method utilizing microRNA expression of the body fluids has been proposed. This method is believed to be non-destructive as well as sensitive in nature and researches have shown promising results for highly degraded samples as well. This systematic review focuses on and explores the use and reliability of miRNAs in body fluid identification. It also summarizes the researches conducted on various aspects of miRNA in terms of body fluid examination in forensic investigations.

Most Monogenic Disorders Are Caused by Mutations Altering Protein Folding Free Energy.

Revealing the molecular effect that pathogenic missense mutations have on the corresponding protein is crucial for developing therapeutic solutions. This is especially important for monogenic diseases since, for most of them, there is no treatment available, while typically, the treatment should be provided in the early development stages. This requires fast targeted drug development at a low cost. Here, we report an updated database of monogenic disorders (MOGEDO), which includes 768 proteins and the corresponding 2559 pathogenic and 1763 benign mutations, along with the functional classification of the corresponding proteins. Using the database and various computational tools that predict folding free energy change (ΔΔG), we demonstrate that, on average, 70% of pathogenic cases result in decreased protein stability. Such a large fraction indicates that one should aim at in silico screening for small molecules stabilizing the structure of the mutant protein. We emphasize that knowledge of ΔΔG is essential because one wants to develop stabilizers that compensate for ΔΔG, but do not make protein over-stable, since over-stable protein may be dysfunctional. We demonstrate that, by using ΔΔG and predicted solvent exposure of the mutation site, one can develop a predictive method that distinguishes pathogenic from benign mutations with a success rate even better than some of the leading pathogenicity predictors. Furthermore, hydrophobic-hydrophobic mutations have stronger correlations between folding free energy change and pathogenicity compared with others. Also, mutations involving Cys, Gly, Arg, Trp, and Tyr amino acids being replaced by any other amino acid are more likely to be pathogenic. To facilitate further detection of pathogenic mutations, the wild type of amino acids in the 768 proteins mentioned above was mutated to other 19 residues (14,847,817 mutations), the ΔΔG was calculated with SAAFEC-SEQ, and 5,506,051 mutations were predicted to be pathogenic.

Opportunities for Bioactive Glass in Gastrointestinal Conditions: A Review of Production Methodologies, Morphology, Composition, and Performance.

Bioactive glasses (BGs) are widely used in orthopedic and dental applications for their ability to stimulate endogenous bone formation and regeneration. BG applications more recently broadened to include soft tissue conditions, based on their ability to stimulate angiogenesis, soft tissue regeneration, and wound healing. Sol-gel synthesis has helped facilitate this expansion, allowing formulators to tailor the morphological characteristics of the BG matrix. The effectiveness of BGs in skin wound healing is viewed as a gateway for their use as both a therapeutic and drug delivery platform in other soft tissue applications, notably gastrointestinal (GI) applications, which form the focus of this review. Recent changes in international guidelines for GI conditions shifted clinical objectives from symptom management to mucosal wound healing. The additional scrutiny of proton pump inhibitor (PPI) safety, increasing burden of disease, and financial costs associated with gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and inflammatory bowel disease (IBD) open new clinical possibilities for BG. This narrative literature review intersects materials engineering, formulation science, and clinical practice, setting it apart from prior literature. Broadly, current evidence for BG applications in GI conditions is sparse and under-developed, which this review directly addresses. It explores and synthesizes evidence that supports the potential use of sol-gel-derived BG for the efficacious treatment of soft tissue applications, with specific reference to GI conditions. An overview with comparative analysis of current BG synthesis techniques and associated challenges is presented, and influences of composition, biologically active ions, and morphological characteristics in soft tissue applications are explored. To contextualize this, sol-gel-derived BGs are proposed as a dual, tailorable therapeutic and drug delivery platform for upper and lower GI conditions. Future directions for this largely untapped area of translational research are also proposed, based on extant literature.

Most monogenic disorders are caused by mutations altering protein folding free energy.

Revealing the molecular effect that pathogenic missense mutations cause on the corresponding protein is crucial for developing therapeutic solutions. This is especially important for monogenic diseases since, for most of them, there is no treatment available, while typically, the treatment should be provided in the early development stages. This requires fast, targeted drug development at a low cost. Here, we report a database of monogenic disorders (MOGEDO), which includes 768 proteins, the corresponding 2559 pathogenic and 1763 benign mutations, along with the functional classification of the corresponding proteins. Using the database and various computational tools that predict folding free energy change (ΔΔG), we demonstrate that, on average, 70% of pathogenic cases result in decreased protein stability. Such a large fraction indicates that one should aim at in-silico screening for small molecules stabilizing the structure of the mutant protein. We emphasize that knowledge of ΔΔG is essential because one wants to develop stabilizers that compensate for ΔΔG but not to make protein over-stable since over-stable protein may be dysfunctional. We demonstrate that using ΔΔG and predicted solvent exposure of the mutation site; one can develop a predictive method that distinguishes pathogenic from benign mutation with a success rate even better than some of the leading pathogenicity predictors. Furthermore, hydrophobic-hydrophobic mutations have stronger correlations between folding free energy change and pathogenicity compared with others. Also, mutations involving Cys, Gly, Arg, Trp and Tyr amino acids being replaced by any other amino acid are more likely to be pathogenic. To facilitate further detection of pathogenic mutations, the wild type of amino acids in the 768 proteins mentioned above was mutated to other 19 residues (14,847,817 mutations), and the ΔΔG was calculated with SAAFEC-SEQ, and 5,506,051 mutations were predicted to be pathogenic.

Porous silicon embedded in a thermoresponsive hydrogel for intranasal delivery of lipophilic drugs to treat rhinosinusitis.

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 µg of MF/g of tissue vs. <10 µg of MF/g of tissue, respectively).

Predicting the Effect of Single Mutations on Protein Stability and Binding with Respect to Types of Mutations.

The development of methods and algorithms to predict the effect of mutations on protein stability, protein-protein interaction, and protein-DNA/RNA binding is necessitated by the needs of protein engineering and for understanding the molecular mechanism of disease-causing variants. The vast majority of the leading methods require a database of experimentally measured folding and binding free energy changes for training. These databases are collections of experimental data taken from scientific investigations typically aimed at probing the role of particular residues on the above-mentioned thermodynamic characteristics, i.e., the mutations are not introduced at random and do not necessarily represent mutations originating from single nucleotide variants (SNV). Thus, the reported performance of the leading algorithms assessed on these databases or other limited cases may not be applicable for predicting the effect of SNVs seen in the human population. Indeed, we demonstrate that the SNVs and non-SNVs are not equally presented in the corresponding databases, and the distribution of the free energy changes is not the same. It is shown that the Pearson correlation coefficients (PCCs) of folding and binding free energy changes obtained in cases involving SNVs are smaller than for non-SNVs, indicating that caution should be used in applying them to reveal the effect of human SNVs. Furthermore, it is demonstrated that some methods are sensitive to the chemical nature of the mutations, resulting in PCCs that differ by a factor of four across chemically different mutations. All methods are found to underestimate the energy changes by roughly a factor of 2.

Self reported benefits of participating in group prayer in a hospital outpatient setting: A cross-sectional observational study.

BACKGROUND: Prayer had long been used as a tool to bring hope among patients suffering with intractable diseases. Most clinical researches conducted so far on prayer were done upon indoor patients. Effects of prayer involving patients and health care providers in a hospital outpatient setting have never been explored. OBJECTIVES: This cross sectional study aimed to observe the self-perceived changes post prayer among patients and hospital staff involved in the health care delivery and who actually have participated in the prayer sessions. MATERIAL AND METHOD: Survey was conducted with the help of a structured questionnaire on routine OP days at Ayurveda -Arthritis Treatment and Advanced Research Center, Lucknow. Patients visiting the center for OP based consultation and hospital staff who has participated in any prayer session were eligible to participate in the survey. RESULTS: 49 hospital staff and 85 patients have participated in the survey. Among most important self-reported attributes following the prayer sessions in patients were Positive Attitude (84.70%), Optimism about cure (92.90%), Feeling of well-being (95.30%), Optimism about future (95.30%) and Changes in energy level (89.40%). Among hospital staff the important attributes were related to change in energy level (93.90%), increased empathy (93.90%), feeling of universal good (96.00%), less fatigue post prayer (69.40%), sustained effects (81.60%) and healthier feeling (81.60%). CONCLUSION: This observational study suggests that a simple prayer session in outpatient department may be helpful in inculcating hope and building self-esteem among patients and can bring a better self-image, efficiency and connectedness in the hospital staff. Eventually, this may help in improving the outcomes and quality of care being provided at outpatient setting at any hospital.

'Obesity and arthritis' as the morbid duo: Designing and experimenting a novel strategy for weight reduction at a secondary care ayurveda -arthritis center.

Obesity has been a critical confounding factor in arthritis. Its impacts are seemingly more apparent in conditions like knee osteoarthritis but it affects the net outcome in almost every type of arthritis. Reduction of weight is the obvious first advice by a treating physician in such cases. In the absence of a clear roadmap however to reach the goal, It remains an unmet advise for most arthritis patients. Obesity combined with arthritis, becomes a morbid combination where addition of weight adds to intensity of arthritis and arthritis induced limitation of movements adds to the weight. Weight reduction is much tougher in arthritis due to the physical limitations. Noticing this gap of knowledge between desired and achieved, Ayurveda -arthritis treatment and advanced research center at Lucknow has designed a strategic plan as a real help to such people and executed it through the activities focusing upon educating the obese arthritis patients for causes and concerns of obesity in general and individualized management plan through an interactive workshop. A workshop of its own kind was conducted on 24 April 2022. 28 obese arthritics as participants had offered to understand the real need and feasibility of doing these strategically focused activities aiming at weight reduction. This has come up as a new opportunity of help to the obese arthritis patients by empowering them with practical knowledge and tools to reduce weight suiting to their individual capacities and needs. The feedback of the participants provided at the end of the workshop was highly encouraging and has shown that strategically focused activities to bridge the gaps in clinical practice are highly desired and useful.

On the linkage of thermodynamics and pathogenicity.

This review outlines the effect of disease-causing mutations on proteins' thermodynamics. Two major thermodynamics quantities, which are essential for structural integrity, the folding and binding free energy changes caused by missense mutations, are considered. It is emphasized that disease effects in case of complex diseases may originate from several mutations over several genes, while monogenic diseases are caused by mutation is a single gene. Nevertheless, in both cases it is shown that pathogenic mutations cause larger perturbations of the above-mentioned thermodynamics quantities as compared with the benign mutations. Recent works demonstrating the effect of pathogenic mutations on the above-mentioned thermodynamics quantities, as well as on structural dynamics and allosteric pathways, are reviewed.

Development and validation of an ama instrument for assessing the disease activity on the basis of constitutional features in Amavata (Rheumatoid Arthritis).

BACKGROUND: Rheumatoid Arthritis (RA), having a striking clinical resemblance to amavata in traditional Indian medicine (Ayurveda) presents an opportunity to look at disease from two different healthcare perspectives. This differential information may potentially supplement one system with the knowledge of the other for optimal application. This study is the first of its kind, where Ayurvedic concepts of amavata have been adopted to enhance the knowledge about RA where optimal care is still beyond the common reach. OBJECTIVE: The study was conducted to develop and validate a novel ama score based upon constitutional features of ama as depicted in ayurvedic literature as a disease activity indicator in RA. MATERIAL AND METHODS: The study was conducted in two parts comprising development and textual validation of the ama assessment instrument (AAI) followed by its clinical testing. AAI comprising ten items, was developed where each item was provided with a range of scores to offer the assessment close to the patient's observations. The score obtained through AAI was clinically and statistically tested on 79 RA/amavata patients randomly selected for validity and reliability. The score obtained through AAI was tested for its correlation with the DAS-28 score and ESR. RESULTS: Ama Assessment Instrument could find a slight correlation with acute phase reactant ESR (r-value between ESR and AMA at baseline is 0.287, and at 1st, 2nd, and 3rd follow-up is 0.276, 0.276 and 0.160 respectively) and DAS-28 (The r value between DAS and AMA at baseline is 0.231, and at 1st, 2nd and 3rd follow up is 0.218, 0.201 and 0.247 respectively). It however emerged as an independent disease status marker since it could mark the changes in the study population on a time scale more precisely as compared to DAS -28 or ESR. When the ama values at different follow-ups were compared, a significant difference was observed consistent with disease activity marker catching constitutional and GI related domain of the patients. When reducing values of ama score were compared to overall improvements as reported by the patients, a similar trend was observed showing that a change in ama score is reflective of a change in disease status and the impact of the disease on the patient. CONCLUSION: This study provided a quantitative measure for the abstract concept of ama which could be used to mark the disease activity in amavata or RA. The change in ama based scores can be used to assess disease status and the intervention related benefits. The observations prompt for the possible inclusion of AAI in RA composite score to make it more dynamic in terms of disease activity identification in RA.

A survey of patients visiting an Ayurvedic teaching hospital for factors influencing the decision to choose ayurveda as a health care provider.

STUDY BACKGROUND: In a pluralistic health care delivery model, it is important to assess whether the individual's health care choices are based upon evidences of efficacy and safety. Since the essence of medical pluralism lies in the fact that all such systems are equally accessible to a seeker, in such situation, it is highly relevant to check what defines such choices in real life. OBJECTIVE: To identify the factors influencing the health care choices in a subpopulation seeking Ayurveda health care in an Ayurvedic teaching hospital. MATERIALS AND METHOD: The study was an all-inclusive cross sectional survey, done on randomly selected out patients visiting an Ayurveda teaching hospital. The data was collected using a 21 items questionnaire refined through pilot testing from 7.9.2017 to 30.9.2017. RESULTS: The data of 289 respondents who have given their consent were included in statistical analysis. Out of 21 variables studied for their agreement or disagreement in the study population 8 were found to have a significant proportion in favour of agreement. Among these relative safety (Item 9); disease eradicating potential (Item 14); belief (Item 3) and indirect evidences of efficacy (Item 4) were found to have high significance (p < 0.001). CONCLUSION: Participants chose Ayurveda treatment due to its perceived safety and probability of helping in a particular clinical condition. Contrary to the common perception, enabling factors like availability, accessibility and affordability were given less importance by the participants in making health care choices related to Ayurveda.

Idiosyncratic adversity reported after oral consumption of an ayurvedic formulation containing bhallataka (Semecarpus anacardium): A case report.

Drugs associated adversities are common in health care practice. These adversities are often associated with the dose-related, time-related and methods of drug intake and their rationality in a given condition but can also be unrelated to either of these causes. Such unpredictable drug reactions are highly important from the perspective of safe use of a drug and to prevent complications from any such adversity which is relatively uncommon. The case reported here is a likely case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) like idiosyncratic adversity after oral consumption of an ayurvedic formulation containing Bhallataka (Semecarpus anacardium). DRESS is found associated with many other classes of drugs but its association with ayurvedic drug has not yet been reported. Upon Naranjo probability scale the event scored 6, putting it into the category of probable drug related adversity. This report widens our understanding towards the possibility of delayed and idiosyncratic drug adversities upon the consumption of certain ayurvedic drugs.

Fabrication and Characterization of Clozapine Nanoemulsion Sol-Gel for Intranasal Administration.

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, it causes many adverse drug reactions (ADRs), which lead to poor treatment outcomes. Nose-to-brain (N2B) drug delivery offers a promising approach to reduce peripheral ADRs by minimizing systemic drug exposure. The aim of the present study was to develop and characterize clozapine-loaded nanoemulsion sol-gel (CLZ-NESG) for intranasal administration using high energy sonication method. A range of oils, surfactants, and cosurfactants were screened with the highest clozapine solubility selected for the development of nanoemulsion. Pseudoternary phase diagrams were constructed using a low-energy (spontaneous) method to identify the microemulsion regions (i.e., where mixtures were transparent). The final formulation, CLZ-NESG (pH 5.5 ± 0.2), comprising 1% w/w clozapine, 1% w/w oleic acid, 10% w/w polysorbate 80/propylene glycol (3:1), and 20% w/w poloxamer 407 (P407) solution, had an average globule size of ≤30 nm with PDI 0.2 and zeta potential of -39.7 ± 1.5 mV. The in vitro cumulative drug release of clozapine from the nanoemulsion gel at 34 °C (temperature of nasal cavity) after 72 h was 38.9 ± 4.6% compared to 84.2 ± 3.9% with the control solution. The permeation study using sheep nasal mucosa as diffusion barriers confirmed a sustained release of clozapine with 56.2 ± 2.3% cumulative drug permeated after 8 h. Additionally, the histopathological examination found no severe nasal ciliotoxicity on the mucosal tissues. The thermodynamic stability studies showed that the gel strength and viscosity of CLZ-NESG decreased after temperature cycling but was still seen to be in "gel" form at nasal temperature. However, the accelerated storage stability study showed a decrease in drug concentration after 3 months, which can be expected at elevated stress conditions. The formulation developed in this study showed desirable physicochemical properties for intranasal administration, highlighting the potential value of a nanoemulsion gel for improving drug bioavailability of clozapine for N2B delivery.

Application of Sol-Gels for Treatment of Gynaecological Conditions-Physiological Perspectives and Emerging Concepts in Intravaginal Drug Delivery.

Approaches for effective and sustained drug delivery to the female reproductive tract (FRT) for treating a range of gynaecological conditions remain limited. The development of versatile delivery platforms, such as soluble gels (sol-gels) coupled with applicators/devices, holds considerable therapeutic potential for gynaecological conditions. Sol-gel systems, which undergo solution-to-gel transition, triggered by physiological conditions such as changes in temperature, pH, or ion composition, offer advantages of both solution- and gel-based drug formulations. Furthermore, they have potential to be used as a suitable drug delivery vehicle for other novel drug formulations, including micro- and nano-particulate systems, enabling the delivery of drug molecules of diverse physicochemical character. We provide an anatomical and physiological perspective of the significant challenges and opportunities in attaining optimal drug delivery to the upper and lower FRT. Discussion then focuses on attributes of sol-gels that can vastly improve the treatment of gynaecological conditions. The review concludes by showcasing recent advances in vaginal formulation design, and proposes novel formulation strategies enabling the infusion of a wide range of therapeutics into sol-gels, paving the way for patient-friendly treatment regimens for acute and chronic FRT-related conditions such as bacterial/viral infection control (e.g., STDs), contraception, hormone replacement therapy (HRT), infertility, and cancer.

A polymeric Brønsted acid ionic liquid mediated liquefaction of municipal solid waste.

The rapid industrialization and population explosion continuously generate massive amounts of municipal waste. Several conventional processes are in practice for the treatment of municipal waste, but the requirement of stringent operating conditions, incomplete conversion, longer processing time and emission of toxic gases, etc., are the major associated barriers. Thus, there is an urgent requirement for a sustainable, environmentally feasible process that can process waste into energy and fuel products. In the present manuscript, polyethylenimine functionalized polymeric Bronsted acid ionic liquid (PolyE-IL) catalysts have been explored for the Catalytic Thermo Liquefaction (CTL) of organic biodegradable municipal solid waste (MSW). A series of PolyE-IL catalysts with variable counter ions were examined for CTL of MSW. Of all the tested PolyE-IL catalysts, the integration of [PEI]+[HSO4]- gave excellent MSW conversion (>85%) and yield (>80%) of liquefied products (CTL-Oil) under non-stringent reaction conditions and without any formation char and gases. The influence of reaction conditions such as catalyst concentration, reaction temperature, time, slurry concentration, and type of feedstock of conversion and yield are studied. The column adsorption and membrane separation process was integrated to facilitate the catalyst and CTL-Oil separation. A series of commercially available hydrophobic resins were tested to separate catalyst and CTL-Oil. ICT005 showed the highest adsorption efficiency of all tested resins with 35.46 mg/mL of binding capacity and Kd of 0.02159. The physicochemical properties of CTL-Oil were studied in detail by using various analytical tools, which exhibited that CTL-Oil comprises a mixture of small and large molecular weight organic compounds and has a calorific value of 4000 kcal/kg; hence it could be used for further energy and fuel applications. Thus, the reported CTL process can be beneficial to resolve both environmental and fossil fuel dependency issues simultaneously by converting MSW into CTL-Oil.

Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol-Gels for Intranasal Administration.

(1) Background: Clozapine is the most effective antipsychotic. It is, however, associated with many adverse drug reactions. Nose-to-brain (N2B) delivery offers a promising approach. This study aims to develop clozapine-encapsulated thermosensitive sol-gels for N2B delivery. (2) Methods: Poloxamer 407 and hydroxypropyl methylcellulose were mixed and hydrated with water. Glycerin and carbopol solutions were added to the mixture and stirred overnight at 2-8 °C. Clozapine 0.1% w/w was stirred with polysorbate 20 (PS20) or polysorbate 80 (PS80) at RT (25 °C) before being added to the polymer solution. The final formulation was made to 10 g with water, stirred overnight at 2-8 °C and then adjusted to pH 5.5. (3) Results: Formulations F3 (3% PS20) and F4 (3% PS80) were selected for further evaluation, as their gelation temperatures were near 28 °C. The hydrodynamic particle diameter of clozapine was 18.7 ± 0.2 nm in F3 and 20.0 ± 0.4 nm in F4. The results show a crystallinity change in clozapine to amorphous. Drug release studies showed a 59.1 ± 3.0% (F3) and 53.1 ± 2.7% (F4) clozapine release after 72 h. Clozapine permeated after 8 h was 20.8 ± 3.0% (F3) and 17.8 ± 3.1% (F4). The drug deposition was higher with F4 (144.8 ± 1.4 µg/g) than F3 (110.7 ± 2.7 µg/g). Both sol-gels showed no phase separation after 3 months. (4) Conclusions: Binary PS80-P407 mixed micelles were more thermodynamically stable and rigid due to the higher synergism of both surfactants. However, binary mixed PS20-P407 micelles showed better drug permeation across the nasal mucosa tissue and may be a preferable carrier system for the intranasal administration of clozapine.

Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines.

Telemedicine for Ayurveda consultation: Devising collateral methods during the COVID-19 lockdown impasse.

COVID-19 pandemic and subsequent measures to mitigate it have presented the world with certain unprecedented situations. Lockdown with effective closure of all services including routine health care services has tested the nerves of health care providers for finding novel ways of providing services without getting into the risk of exposure. Telemedicine had been an ideal option for such situations allowing all channels of communication that leverage Information Technology platforms, including voice, audio, text and digital data exchange as a help to diagnosis, prescription and follow up evaluation. Unfortunately this versatility of Telemedicine as a patient -physician interface could not be harnessed well for its technical complexities and unpreparedness of institutions and individuals. Smartphone based video calling using whatsapp messenger has been proposed as a feasible Telemedicine application to provide outpatient services in this scenario. A pilot run of outpatient services during lockdown period through whatsapp facilitated video calling at Ayurveda Gathiya Clinic, State Ayurvedic College and Hospital, Lucknow has shown a way forward of running such services with a mass appeal, ease of operation and high interface gratification among users and service providers. Within its limitations related to the quality and quantity of information sought, this comes as a viable method of patient -physician interfacing during the phase of lockdown.

Critical current fluctuations in graphene Josephson junctions.

We have studied 1/f noise in critical current [Formula: see text] in h-BN encapsulated monolayer graphene contacted by NbTiN electrodes. The sample is close to diffusive limit and the switching supercurrent with hysteresis at Dirac point amounts to [Formula: see text] nA. The low frequency noise in the superconducting state is measured by tracking the variation in magnitude and phase of a reflection carrier signal [Formula: see text] at 600-650 MHz. We find 1/f critical current fluctuations on the order of [Formula: see text] per unit band at 1 Hz. The noise power spectrum of critical current fluctuations [Formula: see text] measured near the Dirac point at large, sub-critical rf-carrier amplitudes obeys the law [Formula: see text] where [Formula: see text] and [Formula: see text] at [Formula: see text] Hz. Our results point towards significant fluctuations in [Formula: see text] originating from variation of the proximity induced gap in the graphene junction.