Stress Distribution on Short Implants with Varying Crown Heights - An In vitro Study.

The aim of this study is to determine the stress in short implants loaded with varying crown heights using a 3D finite element analysis. A total of three mandibular sectional bone blocks depicting the mandibular left first molar region were modeled. Each block carried Bicon implants of the same size and was designated B1, B2, and B3. The implant- crown ratio is 1:1.5, 1:2.5, and 1:3 respectively. The loading protocol included axial and oblique loads. The von Misses' equivalent stresses at the implant-bone interface were evaluated. Intergroup comparison was determined using one-way ANOVA analysis, and P values were calculated. Under an axial load of 600N, the models B1, B2, and B3 do not show any statistically significant P-values at the crestal module of the implant, abutment, and bone, whereas in crowns, the P-values were highly significant. Under an oblique load of 225 N at 0°, 45°, and 90°, model B3 showed the highest values in the crestal module, abutment, and crown. Based on the intergroup comparison and P value the study concluded that the variance in the crown height does not affect the bone and therefore microfracture of the bone and failure of osseointergration is not likely.

Sapindus Mukurossi - An Effective Biocleanser for Removable Dental Prostheses? An In vitro Study.

This study aims to determine the efficient concentration of Sapindus mukorossi that can be used as a denture cleanser. 60 heat cure denture base resin specimens of dimensions 10*10*2 mm were fabricated. Among these, 30 were fabricated by compression moulding technique and the remaining 30 by an injection moulding technique. The samples inoculated with Candida albicans and Streptococcus mutans were subjected to denture cleansing protocols using a medicinal herbal extract from the Sapindus mukorossi, at various concentrations [15%, 20%, and 25%]. The colony-forming unit [CFU] values were evaluated using a microprocessor colony counter. The statistical analysis was performed. The intragroup comparison showed a statistically significant difference between all groups except the compression moulded samples inoculated with Streptococcus mutans. The intergroup comparison revealed no statistically significant differences between the compared groups. The reduction in CFU values is evident in the effective anti-microbial activity of Sapindus mukorossi. A concentration of 25% Sapindus mukorossi solution showed the greatest efficiency. The maximum anti-microbial activity was observed against Candida albicans in a 25% concentration of Sapindus mukorossi. Among all, injection moulded samples showed better results.

Comparison of Surface Topography Changes from Conventional Metal Brackets and Self-Ligating Metal Brackets after Immersion in Three Different Mouthwashes using Atomic Force Microscopy: An in vitro Study.

In orthodontics, the surface roughness and corrosion behavior due to metal ion releases in orthodontic brackets and archwires affect the effectiveness of tooth movement. Atomic force microscopy (AFM) can provide three-dimensional information measurements which are used to evaluate the quantitative analysis of the surface changes of orthodontic brackets. Stainless steel orthodontic brackets and wires can release metal ions which lead to corrosion when exposed to various types of mouthwash. Aim: The main aim of this study is to compare and evaluate the surface changes from conventional metal brackets and self-ligating metal brackets after immersion in three different mouthwashes. Materials and Methods: Sixteen conventional metal brackets and sixteen metal self-ligating brackets were evenly grouped and immersed in deionized water, chlorhexidine mouthwash, herbal mouthwash, and betadine mouthwash for seven days and the surface changes were evaluated using nondestructive AFM. Results: The surface roughness was evaluated at 30 µm and the results showed that more surface roughness was observed P < 0.05 in betadine mouthwash groups and followed by herbal mouthwash and least in chlorhexidine mouthwash. Conclusion: Based on the AFM results, the surface changes were more pronounced in both groups which were immersed in betadine and herbal mouthwash than others and the choice of mouthwash should be considered before prescribing to the patients.

Visual respiratory biofeedback to improve visuospatial cognition and cardiac interoception in migraineurs: a study protocol for a randomized controlled trial.

Objectives: Migraine is a complex neurological disorder that typically presents with unilateral cephalgia associated with cognitive impairment and reduced interoception. These symptoms result in socio-economic repercussions due to reduced productivity, efficiency, and work performance. Therefore, along with headache management, improving cognition and interoception should also be significant therapeutic targets to effectively manage migraine. To achieve this, we propose to explore the role of a yoga-based visual respiratory biofeedback (VRB) as a possible therapeutic strategy. Methods and analysis: At least 64 participants will be recruited for the trial after screening for eligibility criteria, using the migraine screening questionnaire and Montreal cognitive assessment test. They will be randomly allocated (1:1) to either the experimental group receiving a 20-min session of yoga-based VRB or the control group who will be asked to watch a documentary film for the same duration. Visuospatial cognition will be assessed by the Corsi block-tapping task, and cardiac interoceptive accuracy will be assessed by the heartbeat counting task at baseline and immediately after the intervention. Based on the distribution and variance of the data obtained, analysis will be conducted based on linear mixed models using SPSS version 28.0.1.0, with a two-sided p-value of < 0.05 considered to be statistically significant. Discussion: To the best of our knowledge, this is the first study to design and assess the effects of yoga-based biofeedback therapy on cognition and cardiac interoception in migraineurs. Furthermore, we postulated that pranayama's therapeutic effects might be enhanced by using visual yogic respiratory biofeedback. Considering the socio-economic burden of migraine, if found effective, VRB investigated in the trial could be considered as a therapeutic strategy. Clinical trial registration: ClinicalTrials.gov CTRI, CTRI/2023/03/050430.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Mixed azo dyes degradation by an intracellular azoreductase enzyme from alkaliphilic Bacillus subtilis: a molecular docking study.

The rise of pollution due to the dye industries and textile wastes are evolving rapidly every day. The dyes are used in different trade names by the textile industries. The actual chemistry of dye is vague and difficult to understand even today though we are equipped technically. The toxic effects of the dyes and the reasons behind the acute toxicity are also an undiscovered mystery; therefore, no effective measures can be employed to degrade dyes. Deploying physical or chemical methods to pre-treat the azo dyes are expensive, extremely energy-consuming, and are not environment friendly. Hence, the use of microbes for textile dye degradation will be eco-friendly and is probably a cost-effective alternative to physicochemical methods. The present study was conducted to investigate the degradation of azo dyes isolated from textile effluent contaminated soil by employing the bacterial strains for degradation. The bacterial strains could degrade the optimum concentration of mixed azo dyes (200 mg/L) with an incubation up to 5 days. The decolourization of the dyes was expressed in terms of percentage of decolourization, and was found that about 87.35% of degradation by Bacillus subtilis strain. The enzyme responsible was analyzed as intracellular azoreductase involved in the degradation of mixed azo dyes. The enzymatic pathway and 1-phenyl-2-4(4-methyl phenyl)-diazene 1-oxide was observed as the major metabolite by GC-MS analysis. The in silico study determined the binding of mixed azo dye with azoreductase and hypothesized that their linking could be the main reason for the degradation of mixed azo dye.

Factor VIII associated with lipidic nanoparticles retains efficacy in the presence of anti-factor VIII antibodies in hemophilia A mice.

The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B-domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI-BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors. The efficacy of free and PI-BDD FVIII was studied in inhibitor-positive HA mice using a tail clip assay. Mathematical modeling of these data was conducted to evaluate the hypothesis that lipid association sterically shields the protein from inhibitor binding. The immunization protocol resulted in a mean inhibitory titer level of 198 ± 52 BU/ml. Free BDD FVIII was ineffective at controlling blood loss in inhibitor-positive HA mice as early as 2 h post dose. In contrast, PI-BDD FVIII treated animals retained partial hemostatic efficacy as long as 18 h post dose. Mathematical modeling supports the hypotheses that a greater fraction of lipid-associated FVIII remains unbound to inhibitors and that PI-BDD FVIII has lower binding affinity to inhibitors than does the free protein. In addition, the modeling approaches extend current efforts to model the impact of immunogenicity on PK and the therapeutically meaningful endpoint of efficacy, thereby addressing an important knowledge gap, particularly in the FVIII scientific literature. Clinical translation of these findings could result in a significant improvement in the quality of care of inhibitor-positive HA patients. Copyright © 2016 John Wiley & Sons, Ltd.

Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs.

Soy phosphatidylinositol (PI)-containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain-deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII-treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII-treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients.

Soy phosphatidylinositol containing nanoparticle prolongs hemostatic activity of B-domain deleted factor VIII in hemophilia A mice.

Factor VIII (FVIII) replacement therapy in hemophilia A (HA) is complicated by a short half-life and high incidence of inhibitory antibody response against the protein. Phosphatidylinositol (PI) containing lipidic nanoparticles have previously been shown to reduce the immunogenicity and prolong the half-life of full length FVIII. It has not been established whether this prolongation in half-life improves hemostatic efficacy and whether this approach could be extended to the B-domain deleted form of FVIII (BDD FVIII). In the current study, we evaluated the pharmacokinetics (PK), hemostatic efficacy, and immunogenicity of BDD FVIII associated with PI nanoparticles (PI-BDD FVIII) in HA mice. Comparative human PK was predicted using an "informed scaling" approach. PI-BDD FVIII showed an approximate 1.5-fold increase in terminal half-life compared with free BDD FVIII following i.v. bolus doses of 40 IU/kg. PI-BDD FVIII-treated animals retained hemostatic efficacy longer than the free FVIII-treated group in a tail vein transection model of hemostasis. PI association reduced the development of inhibitory and binding antibodies against BDD FVIII after a series of i.v. injections. The combined improvements in circulating half-life and hemostatic efficacy could significantly prolong the time above clinically established therapeutic thresholds of prophylactic FVIII replacement therapy in humans.

Effects of replacement of factor VIII amino acids Asp519 and Glu665 with Val on plasma survival and efficacy in vivo.

Proteolytic cleavage of factor VIII (FVIII) to activated FVIIIa is required for participation in the coagulation cascade. The A2 domain is no longer covalently bound in the resulting activated heterotrimer and is highly unstable. Aspartic acid (D) 519 and glutamic acid (E) 665 at the A1-A2 and A2-A3 domain interfaces were identified as acidic residues in local hydrophobic pockets. Replacement with hydrophobic valine (V; D519V/E665V) improved the stability and activity of the mutant FVIII over the wild-type (WT) protein in several in vitro assays. In the current study, we examined the impact of mutations on secondary and tertiary structure as well as in vivo stability, pharmacokinetics (PK), efficacy, and immunogenicity in a murine model of Hemophilia A (HA). Biophysical characterization was performed with far-UV circular dichroism (CD) and fluorescence emission studies. PK and efficacy of FVIII was studied following i.v. bolus doses of 4, 10 and 40 IU/kg with chromogenic and tail clip assays. Immunogenicity was measured with the Bethesda assay and ELISA after a series of i.v. injections. Native secondary and tertiary structure was unaltered between variants. PK profiles were similar at higher doses, but at 4 IU/kg plasma survival of D519V/E665V was improved. Hemostasis at low concentrations was improved for the mutant. Immune response was similar between variants. Overall, these results demonstrate that stabilizing mutations in the A2 domain of FVIII can improve HA therapy in vivo.