A Randomized Controlled Trial of Intrathecal versus Caudal Morphine-Bupivacaine on Postoperative Analgesia and Cortisol Levels in Pediatric Patients.

BACKGROUND: Morphine is commonly used in pediatric caudal blocks. We compared the analgesic efficacy and effect on cortisol levels of intrathecal morphine and bupivacaine with caudal morphine and bupivacaine in children undergoing lower abdominal surgeries. METHODS: Forty children undergoing lower abdominal surgeries were randomized to receive 4 µg/kg of intrathecal morphine and 0.5% hyperbaric bupivacaine (n = 20), or caudal morphine 40 µg/kg and 0.25% bupivacaine (n = 20). Postoperative analgesia was provided with intravenous (IV) paracetamol (PCM). The primary outcome was time to reach Face, Legs, Activity, Cry, and Consolability (FLACC) score ≥4 postoperatively. Secondary outcomes were perioperative serum cortisol levels, analgesic requirement, and parent satisfaction. RESULTS: Since seventy 5% of patients receiving intrathecal morphine and bupivacaine did not reach a FLACC score ≥4 within 24 hours, the primary outcome was presented as the Kaplan-Meier curve. The probability of FLACC score <4 was significantly higher with intrathecal morphine and bupivacaine than with caudal morphine and bupivacaine (P < .001). The unadjusted and adjusted (for gender) hazard ratio (95% confidence interval [CI]) of occurrence of pain (FLACC score ≥4) was 0.07 (0.03-0.15, P < .001) and 0.06 (0.03-0.14, P < .001), respectively. The difference in means (95% CI) of cortisol levels between caudal morphine (with bupivacaine) and intrathecal morphine (with bupivacaine) groups were after intubation -0.667 (-4.99 to 3.65, P = .76), at 2 hours intraoperatively 7.88 (3.55-12.2, P < .001), 6 hours postoperatively 16.8 (12.5-21.1, P < .001), and 24 hours postoperatively 15.4 (11.1-19.7, P < .001) µg/dL. Intraoperatively, rescue fentanyl was required by 60% of patients on caudal morphine and bupivacaine against 20% of patients receiving intrathecal morphine and bupivacaine (absolute risk-reduction [95% CI] of 40% [12%-68%]; P = .010). Postoperative rescue fentanyl was required in 45% of patients on caudal morphine and bupivacaine and 5% of patients on intrathecal morphine and bupivacaine. All (100%) patients on caudal morphine and bupivacaine required postoperative PCM against 6 (30%) patients on intrathecal morphine and bupivacaine (absolute risk-reduction [95% CI] of 70% [50%-90%]; P < .001).The median (interquartile range [IQR]) parent satisfaction score for patients on caudal morphine (with bupivacaine) and intrathecal morphine (with bupivacaine) was 0(0-0) and 2(2-2) at 12 hours postoperatively (P < .001) and 0(0-1) and 2(1.5-2) at 24 hours postoperatively (P < .001). One patient in each group developed nausea and vomiting, and 1 patient in the intrathecal group developed pruritus. There was no incidence of respiratory depression. CONCLUSIONS: Intrathecal morphine and bupivacaine results in longer duration of analgesia, lower analgesic consumption, prevents surgical-stress-related elevation of serum cortisol, and improves parent satisfaction compared to caudal morphine with bupivacaine in children undergoing lower abdominal surgeries.

Guggulsterone protects against cigarette smoke-induced COPD linked lung inflammation.

Recently, we have shown that guggulsterone is the principal constituent responsible for protective effects of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease (COPD)-linked inflammation/emphysema. Given that cigarette smoke (CS) exposure is a primary risk factor for COPD and beneficial effects of guggulsterone have not been investigated in CS-induced COPD-linked lung inflammation. The present work was designed to validate the potential of guggulsterone in amelioration of COPD-linked lung inflammation by using a CS-based mouse model of the condition. Male BALB/c mice were exposed to 9 cigarettes/day with 1 h interval for 4 days daily. Guggulsterone was administered daily at a dose of 10 mg/kg orally for 4 consecutive days, 1 h before initiation of CS exposure. Mice were subjected to measurement of lung function followed by procurement of bronchoalveolar lavage fluid (BALF)/lung tissue. BALF was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung tissue was subjected to RT-PCR for gene expression analysis. Data showed that CS exposure resulted in a significant increase in total BALF cells, predominantly neutrophils, and macrophages. Interestingly, guggulsterone administration significantly blunted CS-induced inflammation as reflected by reduced neutrophil and macrophage count. Further, the compound inhibited CS-induced gene expression of pro-inflammatory mediators TNF-α/ IL-1ß/ G-CSF/and KC in lungs along with the production of pro-inflammatory mediators TNF-α/ IL-1ß/ IL-6/ G-CSF/ KC/and MCP-1 in BALF. Further, guggulsterone improved the lung function parameters upon CS exposure. Analysis of mRNA expression of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 suggests that guggulsterone may restore the fine balance between matrix-degrading proteases and its inhibitor in lung tissue upon CS exposure, which may contribute in the development of emphysema at later stages. Overall, our data show that guggulsterone protects against CS-induced COPD-linked lung inflammation by modulating relevant molecular players. Based on the potential effects of guggulsterone in the amelioration of CS-induced lung inflammation, we speculate that guggulsterone might alter chronic CS-induced emphysema.

Assessment of Efficacy of Various Bracket Base Retention Qualities on Shear Bond Strength.

Introduction: Numerous manufacturers have improved bracket retention systems as a result of the frequent bond failure that occurs during orthodontic treatment. One of the elements affecting the adhesive's bond strength is the bracket retention mechanism. Objectives: This study's objective was to assess how various bracket base retention characters affected shear bond strength. Materials and Methods: Four distinct base features for brackets were evaluated. The basic design was examined using a scanning electron microscope. On the Universal testing equipment, brackets were glued to human teeth and then released. Results: The findings indicate that the polymer-coated base's overall mean SBS, which had a mean value of 21.64 ± 4.14 MPa, was considerably greater than that of the other brackets (P 0.05). The foil meshpad, photochemically etched base, and laser-structured base had mean SBS values of 15.12 ± 5.75 MPa, 16.86 ± 3.76 MPa, and 19.32 ± 4.23MPa, respectively. Conclusions: Following laser-structured base and photochemically etched base brackets in terms of shear bond strength were polymer-coated base brackets. The shear bond strength was the lowest in the plain foil mesh pads.

Evaluation of Antimicrobial Effectiveness of Root Canal Sealers Modified with Various Herbal Extracts against Candida Albicans and E Faecalis.

Objectives: The aim of the study was to assess the effectiveness of ZOE-based, calcium hydroxide, and epoxy resin-based sealers on modification with three herbal extracts. Materials and Methods: Methanolic extracts of selected herbs were combined with ZOE-based, calcium hydroxide, and epoxy resin-based sealers. Cultures were prepared from E. faecalis and C. albicans and agar plates prepared. Prepared mixtures were inoculated in punched holes, and inhibitory zones were measured. Results: No statistical significance was obtained on comparing mean scores of test groups. Conclusion: None of the combinations used was found to be significantly better than others.

Efficacy of Aloe Vera, Amlexanox (5%), and Triamcinolone Acetonide (0.1%) in the Management of Oral Lichen Planus.

Objective: This research assessed the efficiencies of aloe vera, 0.1% triamcinolone acetonide, and 5% amlexanox in the management of OLP. Materials and Methods: A total of 120 participants diagnosed with oral lichen planus (OLP) were equally divided into three groups and treated with: aloe vera, (Group A), 0.1% triamcinolone acetonide (Group B), and 5% amlexanox (Group C) topical medicaments. The patients were evaluated for pain, using the visual analogue scale (VAS). They were also evaluated for ulcerative lesion type and erosive area on days 1, 7, and 15 of the study. Results: There was a statistically considerable decrease in the VAS pain scale score, reduction in the erosive area on buccal mucosa, and healing of ulcer from day 1st to 15th day with all three tested drugs. Conclusion: All drugs used in this study; aloe vera, triamcinolone acetonide, and amlexanox were effective in treating OLP patients.

Evaluation of the Circulatory Levels of Heat Shock Protein 60 Levels in Periodontitis and Cardiovascular Disease Patients.

Introduction: HSP is arguably the most thoroughly studied self-antigens connected to Cardio Vascular Diseases (CVD) and periodontal disease. Hence, the major goal of this analysis was to determine the amount of HSP60 in patients' Chronic Periodontitis (CP) patients' serum. Materials and Methods: The current investigation involved 100 patients in all. Based on the patients' periodontal and cardiovascular health, the patients were divided. The patients were made aware that this research had no direct bearing on disease treatment or cure. Results: In contrast to periodontal disease, which had a mean serum HSP60 of 59.94 ng/dl, CVD had a mean serum HSP60 of 85.98 ng/dl. When compared to periodontal disease, the CVD increased significantly (P < 0.05, 0.03). Discussion and Conclusion: We emphasize the function of HSP60 in the pathophysiology of individuals with chronic periodontitis based on the findings of the current investigation. Serum HSP60 concentrations can serve as a biomarker for periodontal inflammation. More longitudinal and interventional research with a larger sample size is required to validate the present findings. In periodontal therapies, targeting HSP60 may enhance results.

Evaluation of Extraction of Teeth without Alteration in Aspirin Therapy: A Cross Sectional Study.

Aim: The study was done to evaluate extraction of teeth without altering the aspirin therapy. Materials and Method: Hundred patients taking aspirin therapy requiring extraction of teeth were separated into two groups with 50 samples in each. Group I continued the aspirin therapy during extraction of teeth on one occasion, and the same patients who discontinued the aspirin therapy 72 hours before extraction of teeth on another occasion become Group II. Result: The mean blood loss showed slightly increased bleeding in Group I in comparison to Group II. The average bleeding time and mean INR was statistically significant among both groups. The mean clotting time and mean platelet count were not statistically significant among groups. Conclusion: There was no alteration in bleeding after extraction in patients with low doses of aspirin therapy.

Comparative Assessment of Herbal Mouthwash with Chlorhexidine on Plaque Accumulation, Gingivitis, and Salivary Streptococcus mutans Growth.

Objectives: The goal of the current study was to assess the effectiveness of a commercially available herbal mouthwash with chlorhexidine on the number of Streptococcus mutans in the saliva, the condition of the gingival tissue, and plaque development. Materials and Methods: Twenty-two adults in all, ranging in age from 20 to 30, were divided into two groups at random. Throughout the 14-day clinical trial, Group A (11) and Group B (11) received 10 mL of test herbal mouthwash and chlorhexidine, respectively. Result: Herbal mouthwash was discovered to be equally as effective as chlorhexidine in lowering the salivary mutans streptococci count and in affecting plaque and gingival scores. Conclusion: Alternatives from the herbal world may show to be a reliable and secure therapy option.

Effect of video distraction on preoperative anxiety scores in pediatric patients undergoing general anesthesia in ophthalmic daycare procedures: A randomized controlled trial.

Background and Aims: Parental separation, fear, and exposure to the operating room environment lead to stress and anxiety in pediatric patients. This study aims to identify the research gaps in the effect of video distraction on pediatric patients of Indian origin. We hypothesized that video distraction along with parental presence would reduce preoperative anxiety in pediatric patients undergoing ophthalmic procedures under general anesthesia compared with parental presence alone. Material and Methods: In this prospective randomized trial, 145 patients aged 2-8 years, ASA I-II, with at least one functional eye undergoing elective ophthalmic daycare procedures were enrolled. They were randomly allocated to two Groups: Group V had distraction by watching a video/playing a video game together with parental presence, whereas control Group C had parental presence alone without any video distraction. The primary objective of the study was to compare preoperative anxiety using the Modified Yale Preoperative Anxiety score (mYPAS) and heart rate (HR), whereas the secondary objective was to compare child fear, emergence delirium, and parental satisfaction between the two groups. The three time points for intergroup comparisons were the preoperative holding area 10 min before induction (T0), transport of the child to the operating room (T1), and face mask introduction (T2). Results: There was a statistically significant difference between mYPAS score in groups V and C at all time points (P = 0.036, P = 0.0001, P = 0.0000), parental satisfaction score at all three time points (P = 0.0049, P = 0.0000, P = 0.0000), and Child Fear Score at T1 and T2 (P = 0.0001, P = 0.0001, respectively). However, there was no statistically significant difference in the emergence of delirium between the two groups. Conclusions: Video distraction together with parental presence has a promising role for implementation in hospitals with heavy workload settings where pharmacological intervention would not be feasible, to alleviate preoperative anxiety in children. However, preoperative anxiety may not translate into increased postoperative emergence delirium as was earlier believed.

Analysis of Molecular Genetic Variants of Lgals4 in Esophageal Cancer: A Preliminary Report.

Esophageal cancer is the eighth most common cancer worldwide and fourth most common in developing countries. Altered glycosylation pattern of cell membrane molecules along with inflammation is a characteristic attribute of oncogenesis. Galectin-4, a tandem repeat galectin, has shown effect on cancer progression/metastasis in digestive system cancers. This role of galectin-4 can be attributed to variations in LGALS4, gene encoding galectin-4. The present case-control study was designed to analyze four intronic SNPs in LGALS4 with susceptibility toward esophageal cancer.Esophageal cancer cases and age- and gender-matched apparently healthy individuals were recruited for the present study. Genotyping of rs8113319, rs4802886, rs4802887, and rs12610990 was carried out using Sanger sequencing and PCR-RFLP. MedCalc software, SNPStats and SHEsis online platform were used for statistical analysis.Genotypic analyses revealed an overall increased heterozygosity of rs12610990, rs4802886, and rs4802887, and AA genotype of rs8113319 in the study participants. Haplotypic analyses also revealed a predominance of AAAT haplotype in the cases. Moreover, combined presence of wild alleles of rs4802886 and rs4802887 could influence protection toward disease, and combined presence of wild alleles of rs12610990 and rs8113319 could influence disease susceptibility. Furthermore, a strong linkage disequilibrium was also observed between the SNPs. Further studies are underway to validate galectin-4 and its genetic variants as blood-based biomarkers in early disease diagnosis, improving treatment outcome.

Porphyrin Metal-organic Framework Sensors for Chemical and Biological Sensing.

Porphyrins and porphyrin derivatives have been intensively explored for a number of applications such as sensing, catalysis, adsorption, and photocatalysis due to their outstanding photophysical properties. Their usage in sensing applications, however, is limited by intrinsic defects such as physiological instability and self-quenching. To reduce self-quenching susceptibility, researchers have developed porphyrin metal-organic frameworks (MOFs). Metal-organic frameworks (MOFs), a unique type of hybrid porous coordination polymers comprised of metal ions linked by organic linkers, are gaining popularity. Porphyrin molecules can be integrated into MOFs or employed as organic linkers in the production of MOFs. Porphyrin-based MOFs are a separate branch of the huge MOF family that combines the distinguishing qualities of porphyrins (e.g., fluorescent nature) and MOFs (e.g., high surface area, high porosity) to enable sensing applications with higher sensitivity, specificity, and extended target range. The key synthesis techniques for porphyrin-based MOFs, such as porphyrin@MOFs, porphyrinic MOFs, and composite porphyrinic MOFs, are outlined in this review article. This review article focuses on current advances and breakthroughs in the field of porphyrin-based MOFs for detecting a variety of targets (for example, metal ions, anions, explosives, biomolecules, pH, and toxins). Finally, the issues and potential future uses of this class of emerging materials for sensing applications are reviewed.

Underutilized fruit lasoda (Cordia myxa L.): Review on bioactive compounds, antioxidant potentiality and applications in health bioactivities and food.

Underutilized fruits are thought to be nutrient and antioxidant gold mines. Despite their high nutritive value, therapeutic properties, and ability to grow in adverse soil and climatic conditions, they have received little attention. However, these underutilized fruits are an important component of traditional foods, particularly in arid and semiarid regions of Rajasthan. Lasoda (Cordia myxa) contains numerous phytochemicals that contribute to its antioxidant potential, including tannins, flavonoids, phenolic acids, xanthones, terpenes, and saponins. The primary goal of this review is to emphasize the importance of extracting bioactive compounds from lasoda and evaluating their antioxidant potential. Furthermore, this review emphasizes the major areas for the application of lasoda and its extract as prospective positive health agents that can be used in the preparation of functional foods. The use of lasoda may also improve the value of bakery products and meat quality and prevent postharvest losses. This review is a pilot article that can aid in the nutritional profiling of Cordia fruits and seeds, and it provides information on the effective and efficient use of this underutilized fruit in the food and nutraceutical industries.

L-Ascorbic Acid Restricts Vibrio cholerae Survival in Various Growth Conditions.

Cholera, a deadly diarrheal disease, continues to ravage various parts of the world. It is caused by Vibrio cholerae, an important member of the gamma-proteobacteria. Based on certain genetic and phenotypic tests, the organism is classified into two major biotypes, namely classical and El Tor. The El Tor and its variants are majorly responsible for the ongoing seventh pandemic across the globe. Previously, we have shown that cross-feeding of glucose metabolic acidic by-products of gut commensals can severely affect the viability of the biotypes. In this work, we examined the effect of L-ascorbic acid on the survival of Vibrio cholerae strains belonging to both biotypes and different serotypes. We observed that L-ascorbic acid effectively restricts the growth of all strains under various conditions including strains adapted to acid stress. In addition, L-ascorbic acid is also effective in decreasing bile-induced biofilms of Vibrio cholerae.

Essential oils and their blends: mechanism of antibacterial activity and antibiofilm potential on food-grade maize starch packaging films.

Essential oils are highly complex volatile chemical compounds utilized for food preservation. The present study compares the antibacterial, and antibiofilm activities of essential oils (EOs) and their blends. Three EOs-basil, clove, and lemongrass-and their blends were evaluated against five food-borne bacterial pathogens. A concentration-dependent effect with maximum inhibition at minimum inhibitory concentration values was recorded while no synergistic activity was observed on blending of EOs. The mechanism of antibacterial action was identified as ROS burst, leakage of cytoplasmic content, and DNA degradation through fluorescence microscopy, electrical conductivity, and DNA cleavage studies. The role of EOs on biofilm growth was deciphered with lemongrass EO being most effective as it curbed biofilm formation on the surface of corn-starch packaging films. This work highlights the antibacterial action mechanism of EOs and their potential role in curtailing biofilm growth on food-grade packaging material.

Hybrid de novo and haplotype-resolved genome assembly of Vechur cattle - elucidating genetic variation.

Cattle contribute to the nutritional needs and economy of a place. The performance and fitness of cattle depend on the response and adaptation to local climatic conditions. Genomic and genetic studies are important for advancing cattle breeding, and availability of relevant reference genomes is essential. In the present study, the genome of a Vechur calf was sequenced on both short-read Illumina and long-read Nanopore sequencing platforms. The hybrid de novo assembly approach was deployed to obtain an average contig length of 1.97 Mbp and an N50 of 4.94 Mbp. By using a short-read genome sequence of the corresponding sire and dam, a haplotype-resolved genome was also assembled. In comparison to the taurine reference genome, we found 28,982 autosomal structural variants and 16,926,990 SNVs, with 883,544 SNVs homozygous in the trio samples. Many of these SNPs have been reported to be associated with various QTLs including growth, milk yield, and milk fat content, which are crucial determinants of cattle production. Furthermore, population genotype data analysis indicated that the present sample belongs to an Indian cattle breed forming a unique cluster of Bos indicus. Subsequent FST analysis revealed differentiation of the Vechur cattle genome at multiple loci, especially those regions related to whole body growth and cell division, especially IGF1, HMGA2, RRM2, and CD68 loci, suggesting a possible role of these genes in its small stature and better disease resistance capabilities in comparison with the local crossbreeds. This provides an opportunity to select and engineer cattle breeds optimized for local conditions.

A large open access dataset of brain metastasis 3D segmentations on MRI with clinical and imaging information.

Resection and whole brain radiotherapy (WBRT) are standard treatments for brain metastases (BM) but are associated with cognitive side effects. Stereotactic radiosurgery (SRS) uses a targeted approach with less side effects than WBRT. SRS requires precise identification and delineation of BM. While artificial intelligence (AI) algorithms have been developed for this, their clinical adoption is limited due to poor model performance in the clinical setting. The limitations of algorithms are often due to the quality of datasets used for training the AI network. The purpose of this study was to create a large, heterogenous, annotated BM dataset for training and validation of AI models. We present a BM dataset of 200 patients with pretreatment T1, T1 post-contrast, T2, and FLAIR MR images. The dataset includes contrast-enhancing and necrotic 3D segmentations on T1 post-contrast and peritumoral edema 3D segmentations on FLAIR. Our dataset contains 975 contrast-enhancing lesions, many of which are sub centimeter, along with clinical and imaging information. We used a streamlined approach to database-building through a PACS-integrated segmentation workflow.

Subtomographic imaging of a polarisation sensitive phase pattern localised in phase space.

A transparent polarisation-sensitive phase pattern changes the phase of transmitted light without absorption, whereas this change of phase depends on the polarisation of incident light. A position-localised polarisation-dependent phase pattern is imprinted onto the phase-space of atoms by using atomic state dependent velocity-selective hole burning. A phase-space localised pattern is a higher dimensional generalisation of patterns localised in the position-space. Such a pattern cannot be imaged with a lens. The imprinted pattern is localised in a unique three-dimensional subspace of the six-dimensional phase-space of atoms. The phase-space localised pattern transforms the polarisation of light transmitting through it. This pattern is tomographically imaged at room temperature by measuring the intensity of the transmitted imaging laser beam of variable frequency with a camera after its polarisation analysis. Two sub-tomographs of the imprinted phase-space localised pattern are constructed. This paper presents a concept and experiment of imprinting and imaging of a polarisation-sensitive phase pattern localised in the phase-space.

Preferential Impairment of Auditory Working Memory in Long COVID: An Observational Study of Undergraduate Medical Students.

Background Long COVID is a multisystem condition with prolonged symptoms that develop after recovery from the COVID-19 infection, often following a mild infection. Few studies have been conducted on cognitive function among medical students after recovery from mild COVID-19. This study aimed to assess the attention span and working memory (WM) capacity of medical students after six months of recovery. Methods A cross-sectional study was performed on 17 young adult medical students who had suffered a mild COVID-19 infection at least six months prior. Eighteen age-matched healthy medical students served as the controls. Audio-visual WM tasks and attention spans were assessed using computerized software for both the cases and controls. Results The mean ages of the case and control were 19.67±1.6 and 20.0±1.2 years, respectively. The most common symptoms among cases were fatigue (33%), weight loss (26%), and nasal stuffiness (13%). The overall proportion of correct responses across all visual and auditory WM tasks (p=0.085) and reaction times (p=0.609) did not differ between the cases and controls. However, the overall target hit rate of the auditory WM task was significantly lower in cases than in controls (p=0.002). This difference was not observed in the visual WM task (p=0.374). Conclusion In the current study, the overall WM functions (visual and auditory combined) and attention span did not differ between cases and controls. However, auditory WM performance was significantly impaired in patients compared with controls, indicating selective impairment of auditory WM in patients with long COVID.

Group tele-rehabilitation improves quality of life among subjects with Parkinson's disease: A two arm non-parallel non-randomized clinical trial.

INTRODUCTION: Tele-rehabilitation has lately emerged as a promising medium for increasing patient adherence with significant positive results. One of the most prevalent neurological diseases affecting movement is Parkinson's disease (PD), which causes a variety of motor and non-motor symptoms among patients. Consequentially, the study was designed to compare the efficacy of group tele-rehabilitation with individual tele-rehabilitation in improving quality of life (QoL) among subjects with PD. METHOD: A two-group pretest-posttest, non-randomized clinical study recruited 68 subjects and classified them into two groups, i.e., Group A (group therapy, n = 36) and Group B (individual therapy, n = 32). Groups A and B received a supervised protocol consisting of a 40-min session on alternate days/week for twelve weeks via the WhatsApp Messenger application through group and individual therapy, respectively. The Parkinson's disease questionnaire (PDQ-39), mental and physical components of the Short Form Survey (SF-12) were used as primary outcome variables, while the Satisfaction questionnaire was used as a secondary outcome variable. RESULT: The p-values related to within-group analyses were <0.05 except SF-12 PCS >0.05 in Group A and <0.05 in Group B. While the p-values related to between-group analyses were <0.05 except for pre-scores of SF-12 (MCS and PCS). The effect sizes for PDQ-39, SF-12 (MCS), and SF-12 (PCS) were -2.37, 3.36, and 0.66 in Group A and 1.95, 2.69, and 2.03 in Group B, respectively. CONCLUSION: The study concluded that group tele-rehabilitation is more effective in improving QoL among subjects with PD as compared to individual tele-rehabilitation. Clinical trial Registration NoCTRI/2022/04/041818.