Advancements in increasing efficiency of hydrogen sulfide in therapeutics: Strategies for targeted delivery as prodrugs.

Hydrogen sulfide (H2S) has emerged as a potent therapeutic agent with diverse physiological functions, including vasodilation, anti-inflammation, and cytoprotection. However, its clinical application is limited due to its volatility and potential toxicity at high concentrations. To address these challenges, researchers have developed various H2S prodrugs that release H2S in a controlled and targeted manner. The review underscores the importance of targeting and delivery strategies in maximizing the therapeutic potential of H2S, a gasotransmitter with diverse physiological functions and therapeutic effects. By summarizing recent advancements, the review provides valuable insights for researchers and clinicians interested in harnessing the therapeutic benefits of H2S while minimizing off-target effects and toxicity. The integration of novel targeting and delivery approaches not only enhances the efficacy of H2S-based therapeutics but also expands the scope of potential applications, offering promising avenues for the development of new treatments for a variety of diseases and disorders.

Biophysical characterization of hydrogen sulfide: A fundamental exploration in understanding significance in cell signaling.

Hydrogen sulfide (H2S) has emerged as a significant signaling molecule involved in various physiological processes, including vasodilation, neurotransmission, and cytoprotection. Its interactions with biomolecules are critical to understand its roles in health and disease. Recent advances in biophysical characterization techniques have shed light on the complex interactions of H2S with proteins, nucleic acids, and lipids. Proteins are primary targets for H2S, which can modify cysteine residues through S-sulfhydration, impacting protein function and signaling pathways. Advanced spectroscopic techniques, such as mass spectrometry and NMR, have enabled the identification of specific sulfhydrated sites and provided insights into the structural and functional consequences of these modifications. Nucleic acids also interact with H2S, although this area is less explored compared to proteins. Recent studies have demonstrated that H2S can induce modifications in nucleic acids, affecting gene expression and stability. Techniques like gel electrophoresis and fluorescence spectroscopy have been utilized to investigate these interactions, revealing that H2S can protect DNA from oxidative damage and modulate RNA stability and function. Lipids, being integral components of cell membranes, interact with H2S, influencing membrane fluidity and signaling. Biophysical techniques such as electron paramagnetic resonance (EPR) and fluorescence microscopy have elucidated the effects of H2S on lipid membranes. These studies have shown that H2S can alter lipid packing and dynamics, which may impact membrane-associated signaling pathways and cellular responses to stress. In the current work we have integrated this with key scientific explainations to provide a comprehensive review.

Quality-by-design-based microemulsion of disulfiram for repurposing in melanoma and breast cancer therapy.

Aim: The current study aims to develop and optimize microemulsions (ME) through Quality-by-Design (QbD) approach to improve the aqueous solubility and dissolution of poorly water-soluble drug disulfiram (DSF) for repurposing in melanoma and breast cancer therapy.Materials & methods: The ME was formulated using Cinnamon oil & Tween® 80, statistically optimized using a D-optimal mixture design-based QbD approach to develop the best ME with low vesicular size (Zavg) and polydispersity index (PDI).Results: The DSF-loaded optimized stable ME showed enhanced dissolution, in-vitro cytotoxicity and improved cellular uptake in B16F10 and MCF-7 cell lines compared with their unformulated free DSF.Conclusion: Our investigations suggested the potential of the statistically designed DSF-loaded optimized ME for repurposing melanoma and breast cancer therapy.

Identifying new medicinal uses of an existing marketed drug can save both money and time in the process of drug development. From many of the recently reported literature, disulfiram (a drug used for alcoholism) has shown its activity against various cancers, including breast and skin cancer. However, it possesses poor water solubility and absorption, leading to low medicinal activity. The current study aims to develop a novel microemulsion dosage form through a statistical design approach to enhance the solubility, dissolution and anticancer activity for repurposing in melanoma and breast cancer treatment. The novel microemulsion was prepared, statistically analyzed and optimized. The optimized microemulsion was found to be stable and showed improved medicinal activity against breast and skin cancer compared with the pure drug. Our research showed the potential of the developed microemulsion of the disulfiram for its new therapeutic use in skin cancer and breast cancer.

Assessment of phytodiversity and phytoremediation potential of plants in the vicinity of a thermal power plant.

A study was carried out to evaluate phytodiversity along with the metal accumulation potential of native plants growing in the vicinity of a thermal power plant (TPP). We documented 26 tree species, six shrubs, and 35 herbs. Importance value index (IVI), which measures the extent to which a species dominates in an area, was found highest for Senna siamea (95.7) followed by Tectona grandis (56.5), and Pithecellobium dulce (19.6). Soil was acidic (pH 5.4) in nature with higher concentrations of Al and Fe. The pH of ground water was found acidic while pH of nearby river was found slightly alkaline. Values of PM2.5 and PM10 were slightly higher than NAAQS standards for industrial areas. The concentration of metals was found higher in aquatic plants than in terrestrial plants. In general, herbs and shrubs showed more metal accumulation potential than trees. Our results suggest that Senna siamea could be used for revegetation purposes in FA landfills. Further, terrestrial and aquatic plants such as Ageratina adenophora and Stuckenia pectinata could be used for reclamation of Mn, Zn, Al, and Fe from contaminated soils. Hydrilla verticillata (Ni and Mn), Nelumbo nucifera, and Ipomoea aquatica (Cr) can be used for metal removal from contaminated water.

The study focuses on the assessment of phytodiversity, soil and water analysis, ambient air quality, and bioaccumulation of heavy metals in plants growing in and around a thermal power plant. The study assumes significance as more than 65% of India's electricity generation is still by coal-fired power plants, having major implications for air, soil, and water pollution. By selecting native plant species adapted to the region, we can enhance biodiversity, restore habitats, and contribute to the overall ecological health of the area surrounding the power plant.

Tunable optical bistability of two-dimensional tilted Dirac system.

We study the phenomenon of controlling the light by light known as the optical bistability for the two-dimensional tilted Dirac system. Using the Boltzmann approach under relaxation time approximation, we find that the optical bistability can be controlled by the nonlinear response of the system. For the prototype, we consider an inversion symmetry broken system. We find that the optical bistability associated with the nonlinear response is tunable with the strength of the tilt, gap and chemical potential. The resulting features suggest the inputs for the development of future-generation optical devices.

Understanding the bio-crystallization: An insight to therapeutic relevance.

In the realm of biomedical engineering and materials science, the synthesis of biomaterials plays a pivotal role in advancing therapeutic strategies for regeneration of tissues. The deliberate control of crystallization processes in biomaterial synthesis has emerged as a key avenue for tailoring the properties of these materials, enabling the design of innovative solutions for a wide array of medical applications. This review delves into the interplay between controlled crystallization and biomaterial synthesis, exploring its multifaceted applications in the therapeutic domains. The investigation encompasses a wide spectrum of matrices, ranging from small molecules to large biomolecules, highlighting their unique contributions in modulating crystallization processes. Furthermore, the review critically assesses the analytical techniques and methodologies employed to probe and characterize the depths of crystallization dynamics. Advanced imaging, spectroscopic, and computational tools are discussed in the context of unraveling the intricate mechanisms governing nucleation and crystallization processes within the organic matrix. Finally we delve in the applications of such advance material in therapeutics of hard and soft tissues.

Ozone-induced oxidative stress alleviation by biogenic silver nanoparticles and ethylenediurea in mung bean (Vigna radiata L.) under high ambient ozone.

Ground-level ozone (O3) is the most phytotoxic secondary air pollutant in the atmosphere, severely affecting crop yields worldwide. The role of nanoparticles (NP) in the alleviation of ozone-induced yield losses in crops is not known. Therefore, in the present study, we investigated the effects of biogenicB-AgNPs on the mitigation of ozone-induced phytotoxicity in mung bean and compared its results with ethylenediurea (EDU) for the first time. Two mung bean cultivars (Vigna radiata L., Cv. SML-668 and PDM-139) were foliar sprayed with weekly applications of B-AgNPs (0 = control, 10 and 25 ppm) and EDU (0 = control, 200 and 300 ppm) until maturation phase. Morphological, physiological, enzymatic, and non-enzymatic antioxidant data were collected 30 and 60 days after germination (DAG). The mean O3 and AOT40 values (8 h day-1) during the cultivation period were approximately 52 ppb and 4.4 ppm.h, respectively. More biomass was accumulated at the vegetative phase due to the impact of B-AgNPs and EDU, and more photosynthates were transported to the reproductive phase, increasing yield. We observed that the 10 ppm B-AgNPs treatment had a more noticeable impact on yield parameters and lower Ag accumulation in seeds for both cultivars. Specifically, SML-668 cultivar treated with 10 ppm B-AgNPs (SN1) showed greater increases in seed weight plant-1 (124.97%), hundred seed weight (33.45%), and harvest index (37.53%) in comparison to control. Our findings suggest that B-AgNPs can enhance growth, biomass, yield, and seed quality, and can improve mung bean ozone tolerance. Therefore, B-AgNPs may be a promising protectant for mung bean.

Reconstruction Considerations Following Complete Excision of Mucoid-Degenerated Anterior Cruciate Ligament: A Retrospective Study.

INTRODUCTION: Mucoid degeneration (MD) of the anterior cruciate ligament (ACL) is an unusual cause of knee pain and restricted movement, predominantly affecting the middle-aged population. Arthroscopic partial or total debridement of the mucoid ACL is the surgical treatment of choice. However, little is discussed in the literature regarding subsequent knee instability and functional outcomes following complete ACL excision. METHODS: A retrospective study was conducted on patients who underwent arthroscopic total ACL excision for mucoid ACL. Pre- and post-operatively, the Tegner-Lysholm score, the International Knee Documentation Committee (IKDC) Subjective Knee Form, and subjective functional instability were used to grade the clinical outcomes. RESULTS: Ten out of the 13 patients who underwent complete ACL excision were available for evaluation. All patients presented with knee pain on deep flexion or extension with a painfully limited range of motion. Post-operatively, all patients were relieved of their original pain and dysfunction. The mean post-operative IKDC and Tegner-Lysholm scores were 74.96 and 83.6, respectively. All patients had a Lachman test positive, while only two had a grade 1 pivot shift test positive. Two patients had occasional functional instability only after strenuous exercises. None of the patients underwent subsequent ACL reconstruction. CONCLUSION: All patients reported improved functional outcomes. Only two out of 10 reported occasional instability during strenuous activity. Therefore, complete debridement of mucoid ACL in sedentary patients is safe and efficacious. However, active young patients may experience instability and require ACL reconstruction if it hinders their daily activities.

Prevalence of prediabetes in patients with idiopathic frozen shoulder: a prospective study.

Background: The association between diabetes and frozen shoulder is well established. However, the data regarding prediabetes and primary frozen shoulder (PFS) are still lacking. Methods: In a prospective study, 158 patients with PFS were included. The prediabetes status was ascertained by estimating serum hemoglobin A1c (HbA1c) levels in patients with PFS. According to the level of HbA1c, patients were classified into normoglycemic, prediabetic, and diabetic. In addition, random blood sugar (RBS) was also performed. Results: Out of 158 participants, 84 (53.2%) were male and 74 (46.8%) were female. Nine patients had bilateral shoulder involvement, and all were diabetics; 47.5% (n = 75) of the patients were in the age group of 51-60 years, 16.5% (n = 26) of the participants were normoglycemic, 37.3% (n = 59) were prediabetics, and 46.2% (n = 73) were diabetics. The difference in mean HbA1c values between the 3 groups was statistically significant (P < .001). However, there was no statistical difference in various age groups (P = .86) or gender (P = .68) between normoglycemics, prediabetics, and diabetics. The difference in mean RBS values between diabetic-nondiabetic and diabetic-prediabetic groups were statistically significant (P < .001), whereas no significant difference was detected between nondiabetic and prediabetic (P = .355). Conclusion: The prevalence of prediabetes is 37.5% in patients with PFS. Single-point HbA1c estimation is an acceptable tool to detect prediabetes, whereas RBS estimation should not be used to detect prediabetes.

Estimating the minimal clinically important difference of shoulder functional scores after arthroscopic rotator cuff repair: a prospective study.

INTRODUCTION: The minimal clinically important difference (MCID) is a valuable tool for patient-based outcome analysis, for which limited data is available in the literature, especially after arthroscopic rotator cuff repair (ARCR). Although several studies have reported MCID after ARCR, few have studied the impact of various clinical factors such as Diabetes, pseudoparalysis, type of cuff repair, and retear over MCID. This study attempts to determine the MCID in shoulder functional scores after ARCR and the impact of various factors on MCID. METHODS: 144 patients undergoing ARCR were prospectively evaluated at six and 12 months by ASES and UCLA scores. MCID for American Shoulder and Elbow Surgeons (ASES) and the University of California and Los Angeles (UCLA) scores were calculated using an anchor-based and distribution-based approach. MCID was also calculated for diabetic and non-diabetic patients, smokers vs. non-smokers, presence or absence of pseudoparalysis, type of cuff repair (single row vs. suture bridge), and presence of retears. Uni- and multivariate analysis was performed to identify factors affecting the MCID of both scores. RESULTS: Mean MCID for ASES score was 13.3 and 16.6 using an anchor-based and distribution-based approach, respectively. For the UCLA score, the mean MCID was 10.0 and 12.6 by anchor-based and 12.6 by distribution-based approach, respectively. Patients with higher pre-operative ASES scores demonstrated lower MCID values. No significant difference was observed in MCID scores of diabetic vs. non-diabetic patients, smoker vs. non-smoker, patients with or without pseudoparalysis, and type of cuff repair. The age, gender, and presence of retear did not affect MCID values. CONCLUSION: This study establishes the MCID values of ASES and UCLA scores for rotator cuff repair by anchor and distribution methods. No patient or surgical factors appear to affect the MCID except pre-operative ASES scores. STUDY DESIGN: Prospective cohort, Level II.

Hydrogen sulfide (H2S) metabolism: Unraveling cellular regulation, disease implications, and therapeutic prospects for precision medicine.

Hydrogen sulfide (H2S), traditionally recognized as a noxious gas with a pungent odor, has emerged as a fascinating metabolite originating from proteinaceous foods. This review provides a comprehensive examination of H2S regulatory metabolism in cell. Dysregulation of cellular processes plays a pivotal role in the pathogenesis of numerous diseases. Recent development explores the chemistry of biosynthesis and degradation of H2S in cells. The consequences of dysregulation causing diseases and the emerging role of hydrogen sulfide (H2S) modulation as a promising therapeutic platform has not been explored much. These disturbances can manifest as oxidative stress, inflammation, and aberrant cellular signaling pathways, contributing to the development and progression of diseases such as cancer, cardiovascular disorders, neurodegenerative diseases, and diabetes. Hydrogen sulfide has gained recognition as a key player in cellular regulation. H2S is involved in numerous physiological processes, including vasodilation, inflammation control, and cytoprotection. Recent advances in research have focused on modulating H2S levels to restore cellular balance and mitigate disease progression. This approach involves both exogenous H2S donors and inhibitors of H2S -producing enzymes. By harnessing the versatile properties of H2S, researchers and clinicians may develop innovative therapies that address the root causes of dysregulation-induced diseases. As our understanding of H2S biology deepens, the potential for precision medicine approaches tailored to specific diseases becomes increasingly exciting, holding the promise of improved patient outcomes and a new era in therapeutics.

Does glenoid version affect the post-operative clinical outcome after repair of posterior labral tear: A retrospective study.

Introduction: Posterior shoulder instability and consequent labral tear have been predominantly associated with retroversion of the bony glenoid and chondrolabral version. However, literature concerning the degree of glenoid and chondrolabral version and clinical outcomes following labral repair is scarce. Methods: A retrospective cohort study was undertaken among patients with posterior shoulder instability who had undergone arthroscopic isolated posterior labral repair. The MRI was used to assess the bony and labral variations of the glenoid using the Friedman method and further categorized as either anteverted or retroverted glenoid. American Shoulder and Elbow Surgeons (ASES), Oxford Shoulder Score (OSS), and Single Assessment Numeric Evaluation (SANE) scores were used to evaluate pre- and postoperative clinical outcomes at a minimum follow-up of one year. Results: 33 shoulder MRIs performed at our institution were available for radiographic analysis. Among the 33 shoulders that underwent posterior shoulder capsulolabral repair, 23 were available for clinical follow-up for at least one year (range, 12-108 months). The mean (±SD) labral version and bony version were -3.98 (±5.68) and -2.83 (±5.20), respectively. The mean (±SD) postoperative ASES, Oxford score, and SANE scores for all participants were 84.04 (±14.14), 43.38 (±3.81), and 78.57 (±17.40), respectively. However, the difference in clinical outcomes in patients with anteverted or retroverted glenoid versions was not statistically significant. Conclusion: Our study concludes a strong correlation between posterior glenohumeral instability and higher degree of glenoid retroversion. Nevertheless, variations in the glenoid version appear to have no significant impact on clinical outcomes. Level of study: Level IV, retrospective cohort.

Variants in exon 2 of MED12 gene causes uterine leiomyoma's through over-expression of MMP-9 of ECM pathway.

AIMS: To study the impact of Mediator complex subunit 12 (MED12) gene variants on the encoded protein's function and pathogenic relevance for genesis of uterine leiomyoma's (ULs). METHODS: Mutational analysis in exon-2 of MED12 gene was performed by PCR amplification and DNA sequencing in 89 clinically diagnosed ULs tissues. Pathogenicity prediction of variation was performed by computational analysis. The functional effects of missense variation were done by quantity RT-PCR and western blot analysis. RESULT(S): Out of 89 samples, 40 (44.94%) had missense variation in 14 different CDS position of exon-2 of MED12 gene. Out of 40 missense variation, codon 44 had 25 (62.5%) looking as a hotspot region for mutation for ULs, because CDS position c130 and c131present at codon 44 that have necleotide change G>A, T, C at c130 and c131 have necleotide change G>A and C. We also find somenovel somatic mutations oncodon 36 (T > C), 38 (G>T) of exon-2 and 88 (G>C) of intron-2. No mutations were detected in uterine myometrium samples. Our computational analysis suggests that change in Med12c .131 G>A leads to single substitution of amino acid [Glycine (G) to Aspartate (D)] which has a pathogenic and lethal impact and may cause instability of MED12 protein. Further, analysis of extracellular matrix (ECM) component (MMP-2 & 9, COL4A2 and α-SMA) mRNA and protein expression levels in the set of ULs having MED12 mutation showed significantly higher expression of MMP-9 and α-SMA. CONCLUSION(S): The findings of present study suggest that missense variation in codon 44 of MED12 gene lead to the genesis of leiomyoma's through over-expression of MMP-9 of ECM pathway which could be therapeutically targeted for non-surgical management of ULs.

A Retrospective Study on the Efficacy, Safety, and Clinical and Radiological Outcomes of PEEK Anchors (CEPTRE® Knotted Suture Anchor and VIPLOK® Knotless Anchor) in the Treatment of Rotator Cuff Repairs.

BACKGROUND: Rotator cuff tears are a common cause of disability in the shoulder of the aging population. Rotator cuff repair is performed to address disability arising from rotator cuff tears, which fails to improve by conservative treatment. The present retrospective study was undertaken to explore the efficacy, safety, clinical, and radiological outcomes of PEEK suture anchors (Ceptre® suture anchor and Viplok® knotless anchor; Sironix, Healthium MedTech, India) in the treatment of arthroscopic rotator cuff repairs. METHOD: This is a retrospective cohort study of arthroscopic rotator cuff repair of posterosuperior tears, which was performed between January 2019 and December 2020 with a minimum follow-up of one year. The demographic data, history, preoperative clinical, magnetic resonance imaging report, and intraoperative details of each patient operated on were obtained from medical records. Post-operative clinical assessments of patients were done based on American Shoulder and Elbow Score (ASES) and Single Sssessment Numeric Evaluation (SANE) scores. Ultrasonography (USG) was done to assess any anchor pull-out and structural healing of the cuff. X-rays were performed to look for the anchor's metallic tip migration. RESULTS: A total of 65 patients were included in the study. There were 43 males (66.2%) and 22 females (33.8%). The mean age was 55.98 (±7.9) years (range: 40-69 years). The mean follow-up was 21.9 months (range: 12-46). Mean (±SD) postoperative ASES and SANE scores at the end of one year were 81.5 (±14.27) and 83.55 (±13.83), respectively. There was significant improvement with respect to the preoperative scores (p<0.0001). USG revealed complete healing in 80% of cases, partial tears in 10.8 %, and full-thickness tears in 9.2% of cases. No anchor pull-outs were noted on USG. X-rays did not reveal unusually large cystic areas in the humeral head or metallic tip migration from the humeral head at their last follow-up. CONCLUSIONS: The results of this study suggest that PEEK suture anchors (Ceptre® knotted suture anchor and Viplok® knotless anchor; Sironix, Healthium MedTech, India) are a viable option for successful surgery in the treatment of arthroscopic rotator cuff repairs without any major anchor related complications.

Unilateral Syndactyly, Hemihypertrophy, and Hyperpigmentation with Mosaic 2q35 Deletion.

Pigmentary mosaicism (PM) is a clinical condition of dyspigmentation with chromosomal abnormality. PM presents with both cutaneous and extracutaneous manifestation. Hypomelanosis of Ito and linear and whorled nevoid hypermelanosis are syndromic disorders in which PM is one of the manifestations. We present a case of a 1-year-old child with a unique constellation of symptoms of unilateral syndactyly, hemihypertrophy, and skin hyperpigmentation. Karyotype from peripheral blood was normal. We found genetic aberration (mosaic 2q35 deletion) in the present case from fibroblast cultured from the affected area. This unique constellation of symptoms was previously reported once but genetic study was not done from the affected tissue. This case highlights the need of considering fibroblast culture-based genetic study rather than doing simple karyotype from peripheral blood. Genetic study also established the molecular basis of symptoms in the above case.

Emerging Roles of SPT5 in Transcription.

Suppressor of Ty homolog-5 (SPT5) discovered in the yeast mutant screens as a suppressor of mutation caused by the insertion of the Transposons of yeast (Ty) element along with SPT4, with which it forms a holoenzyme complex known as DRB sensitivity-inducing factor (DSIF) and plays an essential role in the regulation of transcription. SPT5 is a highly conserved protein across all three domains of life and performs critical functions in transcription, starting from promoter-proximal pausing to termination. We also highlight the emerging role of SPT5 in other non-canonical functions, such as the regulation of post-translational modifications (PTM) and the transcriptional regulation of non-coding genes. Also, in brief, we highlight the clinical implications of SPT5 dysregulation.

Atypical mycobacterium infection following anterior cruciate ligament reconstruction.

A man in his 20s presented with instability of the right knee following an incident of fall from a height. He was clinicoradiologically diagnosed to have an anterior cruciate ligament (ACL) tear for which he underwent ACL reconstruction. Postoperatively, he was started on an accelerated ACL rehabilitation protocol. Six weeks postoperatively, he developed features of subclinical septic arthritis for which he underwent arthroscopic debridement. Intraoperative samples cultured Mycobacterium abscessus complex on MGIT 960 system. The patient subsequently had to undergo another debridement after 1 month as there were clinical signs of persisting infection. The graft was intact even on the second debridement and after removing the implants. This case reports a rare complication of ACL reconstruction with infection by atypical mycobacterium and the clinical outcome. It also emphasises that prompt surgical intervention can save the graft.

Preoperative factors affecting the quality of life after arthroscopic rotator cuff repair: a prospective study.

Background: Rotator cuff tears are well known to cause significant pain and disability, having a marked impact on an individual's quality of life. This prospective study aimed to analyze the various patient factors and their impact on health-related quality of life (HrQoL) post arthroscopic rotator cuff repair (RCR). Material and Methods: We prospectively analyzed 95 patients at one year and 81 patients at two years, with complete rotator cuff tear, who underwent arthroscopic repair of the same. The 36-Item Short Form Survey (physical and mental component score), visual analog scale (pain, function), and QuickDASH questionnaires were administered to all the patients preoperatively and at one- and two-year follow-ups. Relationships between various patient factors (age, gender, side, duration of symptoms, pseudoparalysis, diabetes mellitus [DM], type, and size of tear) and outcome measures were analyzed. Results: All outcome parameters showed significant improvement at one- and two-year follow-ups. Patient factors, such as gender, tear type (traumatic vs degenerative), and DM, affected all outcome parameters and were significant even in the regression analysis model at a 2-year follow-up. Factors such as age and symptoms duration were significant only at 1-year follow-up, with older age and patients with symptoms > 6 weeks showing more disability. Side (dominant or nondominant), tear size, and pseudoparalysis do not affect outcomes. Conclusions: This study showed that arthroscopic RCR significantly improved HrQoL post arthroscopic RCRs. Factors independently affecting HrQoL were noted as gender, tear type, and DM. On the other hand, age, side involved, duration of symptoms, pseudoparalysis, and tear size had no independent effect on HrQoL at a two-year follow-up.

Existence of nodal-arc and its evolution into Weyl-nodes in the presence of spin-orbit coupling in TaAs & TaP.

In this work, we report the existence ofnodal-arc, which acts as the building block of all the nodal-rings in TaAs & TaP. Thisnodal-arcis found to be capable of generating all the nodal-rings in these materials upon the application of space-group symmetry operations including time-reversal symmetry. The arcs are obtained to be dispersive with the energy spread of ∼109 (∼204) meV in TaAs (TaP). Also, the orbitals leading to bands-inversion and thus the formation ofnodal-arcsare found to be Ta-5d& As-4p(P-3p) in TaAs (TaP). The area of nodal-rings is found to be highly sensitive to the change in hybridization-strength, where the increase in hybridization-strength leads to the decrease in the area of nodal-rings. In the presence of spin-orbit coupling (SOC), all the points on these arcs get gaped-up and two pairs of Weyl-nodes are found to evolve from them. Out of the two pair, one is found to be situated close to the joining point of the two arcs forming a ring. This causes the evolution of each nodal-ring into three pairs of Weyl-nodes. The coordinates of these Weyl-nodes are found to be robust to the increase in SOC-strength from ∼ 0.7-3.5 eV. All the results are obtained at thefirst-principlelevel. This work provides a clear picture of the existence of nodal-arc due to accidental degeneracy and its evolution into Weyl-nodes under the effect of SOC.

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

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