Epidemiology of maxillofacial injuries during monsoon and non-monsoon season in India: a data-based retrospective study from a tertiary care dental teaching hospital.

Background: Maxillofacial Injury (MFI) is a major public health concern that is multifactorial in etiology-road traffic accidents (RTAs), falls and violence. RTAs are the major cause of maxillofacial injuries (MFIs) in countries like India. Recent studies have shown that maxillofacial fractures (MFF) constitute a significant proportion of facial injuries seen in hospitals (56.5%). The incidence of maxillofacial fractures can vary depending on several factors, including age, gender, and environmental factors. Of particular concern is the impact of seasonal variations, such as the monsoon season, which lead to high incidence of maxillofacial fractures due to hazardous conditions. Methods: A retrospective review of medical records was done in a tertiary-care dental teaching hospital was done. Results: Data of 200 subjects including 154 males (77%) and 46 females (23%) with a mean age of 35.38 ± 16.541 years; age range: 1 - 80 years was analyzed. A total of 200 MFI's were recorded between 2021 and 2022. Soft tissue injuries were reported in 37.5% of the cases in non-monsoon season and 42.3% of the cases during the monsoon season. Dentoalveolar fractures were reported in 6.2% of the cases during the non-monsoon seasons and 7.7% during the monsoon season. In this study, mandible was the most fractured bone (n=104,52%) followed by zygomatic complex (n=50, 25%). The frequently observed pattern among mandibular fracture was condyle 8.3% during the non-monsoon season and 2.9% during the monsoon season). Conclusions: The results of the study indicate that mandibular fractures are most commonly seen in maxillofacial fractures, followed by fractures of the zygomatic complex. The study also reveals a higher incidence of soft tissue injuries and dentoalveolar fractures during the monsoon season. Further research is warranted to explore the factors that contribute to the seasonal variation in maxillofacial fractures for effective interventions to reduce their occurrence.

STimulator of INterferon Genes Agonism Accelerates Antitumor Activity in Poorly Immunogenic Tumors.

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective antitumor activity. Mechanistic studies in immune-deficient mice suggested that antitumor activity of intratumorally dosed STING agonists is in part due to necrosis and/or innate immune responses such as TNF-α activity, but development of a robust adaptive antitumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models showed that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action.

Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size. Here we report the cryo-electron microscopy structures of potent and inhibitory anti-hArg antibodies bound to hArg1 which form distinct macromolecular complexes that are greater than 650 kDa. With local resolutions of 3.5 Å or better we unambiguously mapped epitopes and paratopes for all five antibodies and determined that the antibodies act through orthosteric and allosteric mechanisms. These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

Evaluation of JAK3 Biology in Autoimmune Disease Using a Highly Selective, Irreversible JAK3 Inhibitor.

Reversible janus associated kinase (JAK) inhibitors such as tofacitinib and decernotinib block cytokine signaling and are efficacious in treating autoimmune diseases. However, therapeutic doses are limited due to inhibition of other JAK/signal transducer and activator of transcription pathways associated with hematopoiesis, lipid biogenesis, infection, and immune responses. A selective JAK3 inhibitor may have a better therapeutic index; however, until recently, no compounds have been described that maintain JAK3 selectivity in cells, as well as against the kinome, with good physicochemical properties to test the JAK3 hypothesis in vivo. To quantify the biochemical basis for JAK isozyme selectivity, we determined that the apparent Km value for each JAK isozyme ranged from 31.8 to 2.9 µM for JAK1 and JAK3, respectively. To confirm compound activity in cells, we developed a novel enzyme complementation assay that read activity of single JAK isozymes in a cellular context. Reversible JAK3 inhibitors cannot achieve sufficient selectivity against other isozymes in the cellular context due to inherent differences in enzyme ATP Km values. Therefore, we developed irreversible JAK3 compounds that are potent and highly selective in vitro in cells and against the kinome. Compound 2, a potent inhibitor of JAK3 (0.15 nM) was 4300-fold selective for JAK3 over JAK1 in enzyme assays, 67-fold [interleukin (IL)-2 versus IL-6] or 140-fold [IL-2 versus erythropoietin or granulocyte-macrophage colony-stimulating factor (GMCSF)] selective in cellular reporter assays and >35-fold selective in human peripheral blood mononuclear cell assays (IL-7 versus IL-6 or GMCSF). In vivo, selective JAK3 inhibition was sufficient to block the development of inflammation in a rat model of rheumatoid arthritis, while sparing hematopoiesis.

Does Taste Perception Effect Body Mass Index in Preschool Children?

INTRODUCTION: Eating trends established early in life leads to chronic life style disorders such as obesity, which is hard to overcome as child comes of age. Energy expenditure is less but caloric intake is high leading to disparity of energy balance in turn leading to obesity. Obesity is the outcome of a disparity between energy expenditure and caloric intake. Genes play a role in establishing eating habits, which is termed as genetic sensitivity to taste. AIM: To determine taste perception effect on body mass index (BMI) in preschool central Indian urban children. MATERIALS AND METHODS: A total of 500 children of 3-6 years were selected and genetic taste perception was assessed using PROP sensitivity test. Anthropometric measurements were recorded to obtain BMI value. Categorical variables were analysed using Pearson's Chi square test. RESULTS: Non tasters were mostly in overweight category i.e. 73.30% where as more number of tasters i.e. 59.70% were in underweight category. A significant correlation is seen between BMI and taste perception. No statistically significant correlation was seen between oral hygiene and taste perception. Females were predominant in both the tasters and non tasters categories. CONCLUSION: Taste perception showed significant relationship with BMI of children between 3-6-year-old children.

Development and optimization of a high-throughput micro-computed tomography imaging method incorporating a novel analysis technique to evaluate bone mineral density of arthritic joints in a rodent model of collagen induced arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease resulting in joint inflammation, pain, and eventual bone loss. Bone loss and remodeling caused by symmetric polyarthritis, the hallmark of RA, is readily detectable by bone mineral density (BMD) measurement using micro-CT. Abnormalities in these measurements over time reflect the underlying pathophysiology of the bone. To evaluate the efficacy of anti-rheumatic agents in animal models of arthritis, we developed a high throughput knee and ankle joint imaging assay to measure BMD as a translational biomarker. A bone sample holder was custom designed for micro-CT scanning, which significantly increased assay throughput. Batch processing 3-dimensional image reconstruction, followed by automated image cropping, significantly reduced image processing time. In addition, we developed a novel, automated image analysis method to measure BMD and bone volume of knee and ankle joints. These improvements significantly increased the throughput of ex vivo bone sample analysis, reducing data turnaround from 5 days to 24 hours for a study with 200 rat hind limbs. Taken together, our data demonstrate that BMD, as quantified by micro-CT, is a robust efficacy biomarker with a high degree of sensitivity. Our innovative approach toward evaluation of BMD using optimized image acquisition and novel image processing techniques in preclinical models of RA enables high throughput assessment of anti-rheumatic agents offering a powerful tool for drug discovery.

Stability and survival of bone-anchored hearing aid implant systems in post-irradiated patients.

Bone-anchored hearing aids (BAHAs) are based on the principle of osseointegration, which is fundamental to implant stability and survival. Previous exposure to ionising radiation may compromise this, as evidenced in relation to dental and craniofacial implants. There is a dearth of data, however, regarding BAHA implant systems in patients with previously irradiated implant sites. We sought, therefore, to investigate implant stability and survival in such patients. Patients were identified retrospectively from our electronic BAHA database. Hospital records were reviewed for demographics; operative technique; complications; and details regarding previous irradiation. Implant stability was assessed by resonance frequency analysis (RFA), generating a numerical value-implant stability quotient (ISQ). Extrapolating from dental studies, successfully loaded implants typically have ISQs of ≥60. Readings were, therefore, interpreted with respect to this. Seven patients were identified for inclusion. Mean time between irradiation and implant insertion was 33 months (range 16-72 months), and mean time from implant insertion to RFA measurement was 41 months (range 3-96 months). Operatively, all patients underwent single-stage procedures under local anaesthesia. One patient suffered a Holger's grade 2 skin reaction, while two suffered significant skin flap failure, requiring revision procedures. The implant survival rate was 100 %. All ISQ values were >60, with a mean of 66.9 (95 % confidence interval 63.1-70.6). Our data support sufficient osseointegration of BAHA implant systems in post-irradiated patients, but highlight issues with wound healing. Contemporary soft tissue preservation operative techniques will likely overcome this, facilitating safe and efficacious BAHA insertion in this ever-increasing group of patients.

Etanercept ameliorates inflammation and pain in a novel mono-arthritic multi-flare model of streptococcal cell wall induced arthritis.

BACKGROUND: The impact of anti-TNF, corticosteroid and analgesic therapy on inflammation and pain was evaluated in a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model using Etanercept, Dexamethasone and Buprenorphine. METHODS: Multiple flares of arthritis were induced with an intra-articular injection of SCW in the hind ankle on day 1, followed by intravenous challenges on days 21 and 42. Inflammation and pain were monitored in the hind paws. Cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed. RESULTS: Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle which resolved within 4 days (Flare 1). Intravenous injection 20 days after sensitization resulted in an increase in ankle diameter and pain, which partially resolved in 8 days (Flare 2). The subsequent intra-venous injection in the same animals 14 days after resulted in a more chronic disease with inflammation and pain persisting over a period of 10 days (Flare 3). In Flare 2, therapeutic administration of Dexamethasone inhibited paw swelling (95%; P<0.001) and pain (55%; P<0.05). Therapeutic administration of Buprenorphine inhibited pain (80%; P<0.001) without affecting paw swelling (0%). Prophylactic administration of Etanercept in Flare 2 inhibited paw swelling (≥60%; P<0.001) and pain by ≥30%. Expression of IL-1ß, IL-6, MCP-1 and CINC was reduced by >50% (P<0.001). Treatment with Etanercept in Flare 3 inhibited paw swelling by 60% (P<0.001) and pain by 25%. Prior treatment with Etanercept in Flare 2 followed by re-administration in Flare 3 led to a complete loss in the efficacy of Etanercept. Systemic exposure of Etanercept corroborated with lack of efficacy. Dexamethasone inhibited inflammation and pain in both Flares 2 and 3 (P<0.001). CONCLUSIONS: We established a novel multi-flare SCW arthritis model enabling drug intervention in different stages of disease. We show for the first time the evaluation of inflammation and pain simultaneously in this model. Etanercept and Dexamethasone inhibited inflammation, pain and proinflammatory cytokines in this model. Taken together, this model facilitates the assessment of anti-rheumatic agents targeting inflammation and pain in the multiple flare paradigm and offers a powerful tool for drug discovery.

Osseointegrated hearing implant surgery using a novel hydroxyapatite-coated concave abutment design.

OBJECTIVE: Recently, a novel hydroxyapatite-coated concave bone-anchored hearing device abutment was introduced, the first designed specifically to improve outcomes in soft-tissue preservation osseointegrated hearing implant surgery. We sought to evaluate our early experience with this abutment. STUDY DESIGN: A single-center case series with planned data collection including patient-reported outcomes. SETTING: Tertiary referral center. SUBJECTS AND METHODS: The first 30 consecutive patients undergoing osseointegrated hearing implant surgery using the Cochlear DermaLock (BA400) abutment at our institution (February-September 2013) were studied. Follow-up was for a minimum of 6 months. The following data were collected: operative duration; wound healing; postoperative complications, chiefly soft-tissue reactions graded by Holger's classification; and postintervention patient-perceived health-related quality of life, as assessed by the Glasgow Benefit Inventory (GBI). RESULTS: The mean operating time was 16 minutes (range, 9-22 minutes). Favorable and rapid wound healing was observed in all cases. Three patients (10%) reported transient periabutment paraesthesia. Four patients (13.3%) suffered adverse soft-tissue reactions, all of which were successfully managed conservatively and graded as follows: Holger's grade 1 (n = 2), 2 (n = 1), and 3 (n = 1). Respective overall general health, social support, and physical health GBI mean scores were +38 (95% confidence interval [CI], 31 to 45), +51 (95% CI, 42 to 60), +19 (95% CI, 8 to 30), and +8 (95% CI, -1 to 17). CONCLUSION: Our preliminary clinical and patient-reported outcomes support soft-tissue preservation surgery and indicate that the technology on which the Cochlear DermaLock (BA400) abutment is based may enhance soft-tissue outcomes in this context. We recommend further appraisal of this approach on a larger scale with more extensive follow-up.

Recurrent cutaneous metaplastic synovial cyst.

Reported here is the first case of a recurrent cutaneous metaplastic synovial cyst (CMSC). The CMSC is a recently described lesion that is histologically characterized by a cystic cavity lined by cells resembling metaplastic synovium overlying villous connective tissue cores. The lesion clinically appears as a tender subcutaneous nodule and may often be misdiagnosed as a suture granuloma. Although the actual cause is unclear, a history of trauma usually precedes its onset. Here we present a case of CMSC in a 34-year-old white male, which recurred at the same site following excision of an epidermoid cyst. CMSCs are unique lesions that should be included in the differential diagnosis of tender subcutaneous swellings following surgical trauma.