Evaluation of effects of different sizes and shapes of attachments during rotation, tipping, and torquing in clear aligner therapy - A finite element study.

OBJECTIVE: To evaluate the effect of different shapes and sizes of attachments used for rotation, tipping, and torquing tooth movement in clear aligner therapy. MATERIAL AND METHODS: Using computer-aided design/computer-aided manufacturing technology, 15 replicas of the upper right human canines were produced. Finite element analysis (FEA) was utilized to mimic tooth movement by applying a constant force of 2.942 N to these models, which contained various forms and sizes of composite attachments. Analysis was done on the stress on different dental structures and the displacement of the attachments. RESULTS: The outcomes demonstrated that tooth movement during clear aligner treatment was considerably impacted by attachment size and shape. Rectangular beveled attachments with dimensions of 3.5 mm × 1.2 mm × 3.5 mm showed the greatest rotating mobility. Triangular beveled attachments with dimensions of 5 mm by 0.8 mm by 2 mm produced the most displacement during tipping motion. For torquing motions, rectangular power ridge attachments with dimensions of 0.5 mm × 0.5 mm × 5 mm worked well. CONCLUSION: The size and geometry of composite attachments were shown to be extremely important in regulating tooth movement during clear aligner treatment, according to this FEA research. Greater displacement is produced when smaller attachments with less surface area dissipate more force. When using clear aligner therapy, orthodontists may optimize treatment plans, shorten treatment times, and provide more predictable results by having a better understanding of the biomechanics of various attachment designs.

Greater sphenoid wing reconstruction with 3D printed anatomical intracranial implant for a child with spheno-orbital encephalocele.

Sphenoid wing dysplasia is a characteristic finding in children with neurofibromatosis type 1 (NF1). Some of these children develop proptosis and vision loss secondary to the spheno-orbital encephalocele. A 6-year-old boy presented to us with complaints of painless progressive uni-ocular vision loss and progressive pulsatile proptosis. Imaging revealed spheno-orbital encephalocele into the orbit through the dysplastic posterior orbital wall. 3D printed customized implant was designed and placed to fit the defect. This prevented further herniation of the temporal lobe into the orbit, leading to reduction of proptosis and improvement in vision of the child.

Kerala's progress towards universal health coverage: the road travelled and beyond.

BACKGROUND: Kerala has initiated many Universal Health Coverage (UHC) reforms in the last decade. The Aardram Mission launched in 2017 stands out owing to its scope, objectives, and commitments for strengthening Primary Health Care (PHC) in the State. The current study proposes to explore access and financial protection through the lens of equity in Kerala especially in the context of major UHC reforms carried out during the last decade. This paper will also highlight the key lessons from Kerala's approach towards UHC and health systems strengthening through a political economy approach. METHODS: Data from the Kerala state sample of 75th Round (2017-18) National Sample Survey is used for this study. Comparison is also drawn from the 71st Round Sample Survey, 2014, to measure the state's progress in terms of access and financial protection. Logistic regression was used for the calculation. The findings were further explored through a political economy approach. RESULTS: The share of public facilities for outpatient care is 47.5%, which is a significant increase from 34.0% (in 2014) in the state. The share of public sector for out-patient care has increased for the lower socio-economic population in the state. The share of public sector for in-patient care has also increased to 37.3% in 2017-18 from 33.9% in 2014, but not to the extent as the increase shown in outpatient care. The average out-of-pocket-expenditure during hospitalization has increased more in private facilities as compared to public for both outpatient care and hospitalization. CONCLUSIONS: Overall increase in the share of public facilities for both outpatient care and hospitalization is indicative of the enhanced trust among the people at large of the public healthcare delivery system in Kerala, post the launch of UHC reforms in the State. The insurance linked UHC reforms would be insufficient for the State to progress further towards UHC. Kerala with a long and successful history in 'public provisioning' should focus more on strengthening PHC through Aardram Mission in its journey towards pursuit of UHC.

A Comparative Evaluation of Frictional Resistance of Various Lingual Brackets With Nitinol (NiTi) Archwires of Different Dimensions: An In Vitro Study.

Introduction Orthodontic mechanics involves transferring some of the applied force to the tooth's supporting components via friction, which in turn allows the tooth to move more easily. Aim The purpose of this in vitro experiment was to examine the frictional resistance (FR) of different lingual brackets utilizing Instron universal testing machines and nitinol (NiTi) archwires of varying sizes. Materials and methods Twenty-four sectional anterior die stones were replicated from a study model. They were categorized into eight categories, with the Libral lingual bracket and the JJ lingual bracket having 0.012" and 0.014" inch NiTi archwire, which were further subdivided into six subgroups. Three brackets were bonded to the anterior teeth of the upper and lower segments and replicated on other models with the help of silicon putty. Elastomeric modules were ligated to two diameters of NiTi wire (0.012" and 0.014") in each model. An Instron universal testing machine was used to measure the frictional force. Numerical data and descriptive statistics such as mean and standard deviation have been shown. Results In the overall analysis, it was observed that among JJ Orthodontics samples using 0.012" NiTi archwires, the maxilla exhibited a higher FR (4.205N) compared to the mandible (4.092N). Similarly, in the case of Libral Orthodontics samples with 0.012" NiTi archwires, the maxilla also demonstrated a higher FR (5.10N) than the mandible (4.97N). However, this trend did not hold for samples using 0.014" NiTi archwires. There was a statistically nonsignificant difference (p > 0.05) in the values between all the pairs of groups. Conclusion The present study concludes that Libral lingual brackets produced overall more FR than JJ lingual brackets.

Antinuclear antibody (ANA) positivity pattern by line immunoassay in a hospital from eastern India: Update from a laboratory perspective.

Context: The existence of more than one antibody in systemic autoimmune rheumatic diseases (SARDs) or connective tissue disease (CTD) along with features of more than one autoimmune disease (AD) in an individual is suggestive of overlap syndrome (OS). Line immunoassay (LIA) can target many autoantibodies in a single approach, thus making the identification of OS feasible. Aims and Objectives: This study aimed to identify the pattern of distribution of antinuclear antibodies by LIA prevalent in a hospital population in eastern India and identify common forms of SARD in this belt based on laboratory findings. Material and Methods: A total of 1660 samples received for ANA profile testing by LIA were analysed. Statistical Analysis: Factor analysis was performed with factor loading scores used in the k-means algorithm to identify clustering of various autoantibodies. Results: U1-snRNP positivity was the highest at 16.69%, and the least frequent autoantibody noted was anti-Jo-1 at 0.71% positivity. Based on the outcome of factor analysis, three clusters were determined. Cluster 1 showed a predominance of anti-PM/Scl antibodies, cluster 2 showed a predominance of anti-dsDNA, anti-histone, anti-SmD1, anti-nucleosomes, anti-PCNA, anti-Po, anti-SSA/Ro52, anti-SSA-Ro60, anti-SSB/La, anti-Scl-70, anti-Mi-2, anti-Ku and anti-AMA-M2, and cluster 3 showed a predominance of anti-U1-snRNP. Conclusions: Mixed connective tissue disease (MCTD) and overlap syndrome (OS) are prevalent more than pure form of an AD in our study population. OS may be missed out by monospecific immunoassays and hence adds to diagnostic challenges. LIA may be more useful in identifying specific autoantibodies by a single approach rather than monospecific immunoassays in populations after a positive screen by indirect immunofluorescence (IIF).

Association of Diabetic Peripheral Neuropathy with Micronutrients.

INTRODUCTION: Diabetes mellitus (DM) is a common metabolic disorder that has been defined by hyperglycemia. Diabetic patients usually have high levels of oxidative stress. Mitochondrial dysfunction and inflammation of blood vessels are associated with a greater need for micronutrients in diabetic patients. These micronutrients may have an association with the complications in diabetics. The purpose of this study was to show the association of diabetic peripheral neuropathy (DPN) with levels of micronutrients such as copper (Cu), zinc (Zn), magnesium (Mg), and vitamin B12 (Vit B12). MATERIALS AND METHODS: This cross-sectional study was conducted in the Department of Medicine, Lala Lajpat Rai Memorial Medical College, Meerut. A total of 130 randomly selected cases of confirmed type-2 diabetic patients were included in this study. DPN cases were identified using the Michigan neuropathy screening instrument. Out of 130 diabetic patients, 28 patients were found to have diabetic neuropathy. The level of various micronutrients was assessed and correlated with the development of DPN. RESULTS: The association of DPN with Zn (p-value of 0.02) and Vit B12 (p-value of 0.008) was found to be significant, whereas Cu (p-value of 0.57) and Mg (p-value of 0.24) were found to be insignificant.

Scalable Transdiagnostic Early Assessment of Mental Health (STREAM): a study protocol.

INTRODUCTION: Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant 'detection gap' where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions. METHODS AND ANALYSIS: The STREAM project will enrol and assess 4000 children aged 0-6 years from Malawi (n=2000) and India (n=2000). It integrates three established developmental assessment tools measuring motor, social and cognitive functioning using gamified tasks, observation checklists, parent-report and audio-video recordings. Domain scores for motor, social and cognitive functioning will be developed and assessed for their validity and reliability. These domain scores will then be used to construct age-adjusted developmental reference curves. ETHICS AND DISSEMINATION: Ethical approval has been obtained from local review boards at each site (India: Sangath Institutional Review Board; All India Institute of Medical Science (AIIMS) Ethics Committee; Indian Council of Medical Research-Health Ministry Screening Committee; Malawi: College of Medicine Research and Ethics Committee; Malawi Ministry of Health-Blantyre District Health Office). The study adheres to Good Clinical Practice standards and the ethical guidelines of the 6th (2008) Declaration of Helsinki. Findings from STREAM will be disseminated to participating families, healthcare professionals, policymakers, educators and researchers, at local, national and international levels through meetings, academic journals and conferences.

Comparative Evaluation of Shear Bond Strength, Enamel Microfracture, and Adhesive Remnant Index of APC Flash-Free System Versus Traditional Bonding: An In-Vitro Study.

INTRODUCTION: In orthodontics, shear bond strength plays an important role because it provides a good bond between the brackets and tooth surface; it avoids fracture of the tooth surface and prevents debonding of brackets from the tooth surface. All of these allow sufficient treatment time. Many factors, including the adhesive, its thickness, its strength, the bonding procedure, the clinician's ability, the base design, the geometry of the bracket, the material, and the kind of bracket all contribute to the shear bond strength. Brackets joined using conventional adhesive and adhesive pre-coated (APC) flash-free glue were the subjects of this comparison and evaluation research, which aimed to measure shear bond strength, enamel microfracture, and adhesive residual index. METHOD: 60 recently removed premolars from humans were used in this investigation. Before mounting on the acrylic block, the teeth were meticulously cleaned and preserved in artificial saliva. Two groups were formed from the collected premolars the control group and the experimental group. For the control group, we used American Orthodontics (AO) Master/Mini Master series brackets glued with resin composite kits. To make sure the adhesive was uniformly thick, we flashed extra adhesive around the brackets. In the meantime, samples were bonded using 3M Unitek APC flash-free technology in the experimental group. RESULTS: The research indicated that there was a statistically significant difference between the two groups to the adhesive remnant index (ARI) and mean shear bond strength. The shear bond strength of the experimental group averaged 10.96 megapascals (MPa), whereas the control group's was 5.70 MPa. The control group's ARI score was 2.97, whereas the experimental group's score was 2.4. There was no statistically significant change seen in enamel microfracture. CONCLUSION: A more robust shear bond may be possible using APC flash-free brackets. Compared to conventional bonding techniques and brackets, APC flash-free brackets have a lower adhesive residual index. The APC flash-free bracket technology also causes more enamel microfracture than conventional bonding and bracketing methods.

Organ- and Cell-Selective Delivery of mRNA In Vivo Using Guanidinylated Serinol Charge-Altering Releasable Transporters.

Selective RNA delivery is required for the broad implementation of RNA clinical applications, including prophylactic and therapeutic vaccinations, immunotherapies for cancer, and genome editing. Current polyanion delivery relies heavily on cationic amines, while cationic guanidinium systems have received limited attention due in part to their strong polyanion association, which impedes intracellular polyanion release. Here, we disclose a general solution to this problem in which cationic guanidinium groups are used to form stable RNA complexes upon formulation but at physiological pH undergo a novel charge-neutralization process, resulting in RNA release. This new delivery system consists of guanidinylated serinol moieties incorporated into a charge-altering releasable transporter (GSer-CARTs). Significantly, systematic variations in structure and formulation resulted in GSer-CARTs that exhibit highly selective mRNA delivery to the lung (∼97%) and spleen (∼98%) without targeting ligands. Illustrative of their breadth and translational potential, GSer-CARTs deliver circRNA, providing the basis for a cancer vaccination strategy, which in a murine model resulted in antigen-specific immune responses and effective suppression of established tumors.

Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells.

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.

Development of Predictive Models Based on Biochemical Parameters to Triage COVID-19 Patients: A Study Conducted in a Tertiary Care Hospital.

Background The COVID-19 disease continues to cause severe mortality and morbidity. Biochemical parameters are being used to predict the severity of the infection. This study aims to predict disease severity and mortality to help reduce mortality through timely intervention in a cost-effective way. Methods A total of 324 COVID-19 cases admitted at our hospital (All India Institute of Medical Sciences, Patna, BR, India) between June 2020 to December 2020 (phase 1: 190 patients) and April 2021 to May 2021 (phase 2: 134 patients) were recruited for this study. Statistical analysis was done using SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA) and model prediction using Python (The Python Software Foundation, Wilmington, DE, USA). Results There were significant differences in biochemical parameters at the time of admission among COVID-19 patients between phases 1 and 2, ICU and non-ICU admissions, and expired and discharged patients. The receiver operating characteristic (ROC) curves predicted mortality solely based on biochemical parameters. Using multiple logistic regression in Python, a total of four models (two each) were developed to predict ICU admission and mortality. A total of 92 out of 96 patients were placed into the correct management category by our model. This model would have allowed us to preserve 17 of the 21 patients we lost. Conclusions We developed predictive models for admission (ICU or non-ICU) and mortality based on biochemical parameters at the time of admission. A predictive model with a significant predictive capability for IL-6 and procalcitonin values using normal biochemical parameters was proposed. Both can be used as machine learning tools to prognosticate the severity of COVID-19 infections. This study is probably the first of its kind to propose triage for admission in the ICU or non-ICU at the medical emergency department during the first presentation for the necessary optimal treatment of COVID-19 based on a predictive model.

Congenital cardiac anomalies in non-syndromic cleft lip and cleft palate patients: A systematic review and meta-analysis.

The aim was to establish a specific and definite connection between non-syndromic orofacial cleft patients and associated congenital heart disease (CHD). Following PRISMA guidelines, selective databases were searched for data collection. Studies showing a definite association of CHD with orofacial cleft were included, and studies non-specific of the association of orofacial cleft with CHD were excluded. Data extraction criteria were study design, frequency of CHD in overall non-syndromic orofacial cleft and in specific cleft type, and most prevalent congenital cardiac anomaly. DerSimonian Laird random effects model was used to estimate the pooled proportion of CHD, along with corresponding 95% confidence intervals (CIs) for each measure. Publication bias was assessed using Fail-Safe N analysis and the Rosenthel approach. Of a total of 182 articles searched, only 30 studies were assessed. The overall pooled estimate of the proportion of CHD in total cleft lips/palates was 16% (95% CI: 13-19). The odds of developing CHD in cleft palates was 4.08 times more as compared to cleft lips with 95% CIs of 3.86-4.33, and 1.65 more as compared to cleft lips and palates both with 95% CI of 1.52-1.68. We affirm the upsurging prevalence of CHD in non-syndromic cleft children and vehemently propose that it is of utmost importance to inculcate it in practice and policy-making to screen all non-syndromic orofacial cleft children for congenital cardiac anomaly. This study was registered on PROSPERO (ID no. CRD42023391597) on February 24, 2023.

Cadmium toxicity: its' uptake and retaliation by plant defence system and ja signaling.

Cadmium (Cd+2) renders multifarious environmental stresses and highly toxic to nearly all living organisms including plants. Cd causes toxicity by unnecessary augmentation of ROS that targets essential molecules and fundamental processes in plants. In response, plants outfitted a repertory of mechanisms to offset Cd toxicity. The main elements of these are Cd chelation, sequestration into vacuoles, and adjustment of Cd uptake by transporters and escalation of antioxidative mechanism. Signal molecules like phytohormones and reactive oxygen species (ROS) activate the MAPK cascade, the activation of the antioxidant system andsynergistic crosstalk between different signal molecules in order to regulate plant responses to Cd toxicity. Transcription factors like WRKY, MYB, bHLH, bZIP, ERF, NAC etc., located downstream of MAPK, and are key factors in regulating Cd toxicity responses in plants. Apart from this, MAPK and Ca2+signaling also have a salient involvement in rectifying Cd stress in plants. This review highlighted the mechanism of Cd uptake, translocation, detoxification and the key role of defense system, MAPKs, Ca2+ signals and jasmonic acid in retaliating Cd toxicity via synchronous management of various other regulators and signaling components involved under stress condition.

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and is often resistant to traditional therapies. Evidence suggests that glioma stem cells (GSCs) contribute to this resistance. Mithramycin (Mit-A) targets GSCs and exhibits antitumor activity in GBM by affecting transcriptional targets such as SRY-related HMG-box transcription factor 2 (SOX2), oligodendrocyte lineage transcription factor 2 (OLIG2), and zinc finger E-box binding homeobox 1 (ZEB1). However, its clinical use has been limited by toxicity. This study explored the diagnostic potential of serum extracellular vesicles (EVs) to identify Mit-A responders. Serum EVs were isolated from 70 glioma patients, and targeted gene expression was analyzed using qRT-PCR. Using chemosensitivity assay, we identified 8 Mit-A responders and 17 nonresponders among 25 glioma patients. The M-score showed a significant correlation (p = 0.045) with isocitrate dehydrogenase 1 mutation but not other clinical variables. The genes SOX2 (p = 0.005), OLIG2 (p = 0.003), and ZEB1 (p = 0.0281) were found to be upregulated in the responder EVs. SOX2 had the highest diagnostic potential (AUC = 0.875), followed by OLIG2 (AUC = 0.772) and ZEB1 (AUC = 0.632).The combined gene panel showed significant diagnostic efficacy (AUC = 0.956) through logistic regression analysis. The gene panel was further validated in the serum EVs of 45 glioma patients. These findings highlight the potential of Mit-A as a targeted therapy for high-grade glioma based on differential gene expression in serum EVs. The gene panel could serve as a diagnostic tool to predict Mit-A sensitivity, offering a promising approach for personalized treatment strategies and emphasizing the role of GSCs in therapeutic resistance.

Methyl jasmonate reduces cadmium toxicity by enhancing phenol and flavonoid metabolism and activating the antioxidant defense system in pigeon pea (Cajanus cajan).

Cadmium (Cd) is absorbed by plant roots from soil along with essential nutrients and affects plant growth and productivity. Methyl jasmonate (Me-JA) play important roles to mitigate Cd toxicity in plants. We have investigated the role of Me-JA to ameliorate Cd toxicity in Pigeon pea (Cajanus cajan). Plant root growth, biomass, cellular antioxidant defense system and expression of key regulatory genes in molecular and signaling process have been analyzed. Two Cajanus cajan varieties AL-882 and PAU-881 were grown at 25 °C, 16/8h light/dark conditions in three biological replicates at 5 mM Cd concentration, three concentration of Me-JA (0, 10 nM, 100 nM) and two concentrations in combination of Me-JA + Cd (10 nM Me-JA +5 mM Cd, 100 nM Me-JA +5 mM Cd). The seedlings were exposed to Cd stress consequently plants showed decrease in primary root growth (60.71%, in AL-882 and 8.33%, in PAU-881), shoot and root biomass and antioxidant enzymes activities. Me-JA treatment resulted in increased primary root growth (63.64%, in AL-882) and overall plant biomass. Oxidative stress generated due to Cd stress was counter balanced by Me-JA treatment. Me-JA reduced H2O2 free radicals formation and enhanced antioxidant enzyme activities and phenolic content in stressed seedlings. Me-JA treatment increased expression of CALM, IP3, CDPK2, MPKs (involved in calcium and kinase signaling pathways) and reduced expression of metal transporters (IRT1 and HMA3) genes. This reduction in metal transporters gene expression is a probable reason for low toxicity effect of Cd in root after Me-JA treatment which has potential implications in reducing the risk of Cd in the food chain.

Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors.

Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pulldown and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiotherapy. These results warrant further development of KRB-456 for pancreatic cancer. SIGNIFICANCE: There are no clinically approved drugs directly abrogating mutant KRAS G12D. Here, we discovered a small molecule, KRB-456, that binds a dynamic allosteric binding pocket within the switch-I/II region of KRAS G12D. KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer. This discovery warrants further advanced preclinical and clinical studies in pancreatic cancer.

Acceptance of Annual Booster Doses of COVID-19 Vaccines Among Indian Healthcare Professionals: A Pan-India Cross-Sectional Survey.

Introduction The emergence of coronavirus disease 2019 (COVID-19) posed significant challenges to global health, leading to the declaration of a pandemic by the World Health Organization. Vaccination efforts have effectively reduced severe outcomes and mortality, but breakthrough infections and new variants are of concern. In response, annual booster doses of COVID-19 vaccines are being considered to maintain immunity. Healthcare professionals, as frontline workers, play a pivotal role in vaccination campaigns. This study explores their attitudes toward and willingness to accept annual COVID-19 booster doses in India. Methods A pan-India cross-sectional survey was conducted among healthcare professionals, including faculty, resident doctors, interns, and nursing staff, across Indian medical and nursing colleges. Convenience sampling was used to collect responses via an online questionnaire. The questionnaire assessed demographics, vaccine status, attitudes toward COVID-19 vaccination, and willingness to accept annual booster doses. Multivariate analysis was performed to identify predictors of booster dose acceptance. Results A total of 535 participants responded from 28 states and 8 union territories of India. Most were 34.2 years (± 11.1 SD), and 372 (69.5%) had taken Covishield (Serum Institute of India, Pune, India) as their primary vaccine. While 525 (98.1%) had taken the first dose and 518 (96.8%) of them had taken the second dose, only 333 (62.2%) had received a booster. Around 318 (60%) of healthcare professionals were willing to accept an annual booster dose. The mean attitude score toward annual booster doses was 75.4 (range: 28-111). Healthcare professionals' trust in government recommendations and medical experts significantly influenced their willingness to accept annual booster doses. Conclusion This study provides insights into the attitudes of healthcare professionals in India toward annual COVID-19 booster doses. At the same time, a significant proportion showed a willingness to accept boosters.

Household-level food insecurity and its correlates in rural Bihar: A cross-sectional study.

Introduction: Bihar has experienced high nutritional public health problem among children and women over the years. In this background, this study was planned to find the level of food insecurity and identify contributing factors in rural Bihar. Material and Methods: We conducted community-based cross-sectional study among 255 families residing in villages catered by RHTC, Naubatpur. A pretested semi-structured interview schedule and HFIAS were used. Result: A total of 27.8% of the 255 households were food insecure, of which 73.3% were severely food insecure. Kutcha houses, dispossession of agricultural land, and lower SES were found to be predictors. Conclusion: Around one in three families experienced food insecurity, and it was more among families residing in kutcha houses, without possession of agricultural land and belonging to lower socioeconomic status.

Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism.

The introduction of more effective and selective mRNA delivery systems is required for the advancement of many emerging biomedical technologies including the development of prophylactic and therapeutic vaccines, immunotherapies for cancer and strategies for genome editing. While polymers and oligomers have served as promising mRNA delivery systems, their efficacy in hard-to-transfect cells such as primary T lymphocytes is often limited as is their cell and organ tropism. To address these problems, considerable attention has been placed on structural screening of various lipid and cation components of mRNA delivery systems. Here, we disclose a class of charge-altering releasable transporters (CARTs) that differ from previous CARTs based on their beta-amido carbonate backbone (bAC) and side chain spacing. These bAC-CARTs exhibit enhanced mRNA transfection in primary T lymphocytes in vitro and enhanced protein expression in vivo with highly selective spleen tropism, supporting their broader therapeutic use as effective polyanionic delivery systems.