Mutational pathway maps and founder effects define the within-host spectrum of hepatitis C virus mutants resistant to drugs.

Knowledge of the within-host frequencies of resistance-associated amino acid variants (RAVs) is important to the identification of optimal drug combinations for the treatment of hepatitis C virus (HCV) infection. Multiple RAVs may exist in infected individuals, often below detection limits, at any resistance locus, defining the diversity of accessible resistance pathways. We developed a multiscale mathematical model to estimate the pre-treatment frequencies of the entire spectrum of mutants at chosen loci. Using a codon-level description of amino acids, we performed stochastic simulations of intracellular dynamics with every possible nucleotide variant as the infecting strain and estimated the relative infectivity of each variant and the resulting distribution of variants produced. We employed these quantities in a deterministic multi-strain model of extracellular dynamics and estimated mutant frequencies. Our predictions captured database frequencies of the RAV R155K, resistant to NS3/4A protease inhibitors, presenting a successful test of our formalism. We found that mutational pathway maps, interconnecting all viable mutants, and strong founder effects determined the mutant spectrum. The spectra were vastly different for HCV genotypes 1a and 1b, underlying their differential responses to drugs. Using a fitness landscape determined recently, we estimated that 13 amino acid variants, encoded by 44 codons, exist at the residue 93 of the NS5A protein, illustrating the massive diversity of accessible resistance pathways at specific loci. Accounting for this diversity, which our model enables, would help optimize drug combinations. Our model may be applied to describe the within-host evolution of other flaviviruses and inform vaccine design strategies.

From an Open Bite to a Harmonious Smile: Orthodontic Intervention With Bluegrass Appliance and Tongue Thrust Resolution.

The tongue-thrusting habit significantly contributes to the development of the anterior open bite (AOB), particularly when an infantile swallowing pattern persists into the later stages of childhood and adolescence. This habit results in the protrusion of the anterior teeth. Treatment typically involves addressing the underlying causes, incorporating retraining exercises, and utilizing mechanical appliances to control tongue positioning. However, commonly used devices such as palatal cribs or spurs may present challenges, including speech impediments, chewing difficulties, and the potential for unintended injuries. This paper presents a case report detailing the treatment of a patient with an AOB, dental protrusion, and spacing. The treatment approach included the application of a fixed tongue trainer, in the form of a modified bluegrass appliance. Subsequent fixed orthodontic therapy was employed to rectify proclined teeth within the dental arch.

Addressing Missing Permanent Premolars With Retained Deciduous Teeth: Orthodontic Solutions and Outcomes.

This case report presents an orthodontic treatment approach involving retained deciduous teeth. The patient presented with a Class I malocclusion and buccal crossbite. Despite the presence of retained deciduous teeth, a non-extraction treatment plan was devised to address the malocclusion and achieve optimal dental alignment. The treatment protocol included the use of fixed appliances and quad helix to facilitate the alignment of permanent dentition. The progress of treatment was closely monitored through regular follow-up appointments and adjustments to the treatment plan as necessary. Upon completion of treatment, the patient achieved a harmonious occlusion, improved dental alignment, and a pleasing aesthetic outcome. This case report highlights the successful management of a challenging orthodontic case through a non-extraction approach with retained deciduous teeth, emphasizing the importance of individualized treatment planning and careful consideration of each patient's unique dental anatomy.

Comparative Evaluation and Correlation of Hyoid Bone Position, Airway Dimension, and Psychological Status in Class II Vertical and Horizontal Malocclusion Cases With Temporomandibular Disorder Compared to Class I Non-Temporomandibular Disorder Cases.

Introduction Temporomandibular disorder (TMD) involves discomfort and impaired function in the masticatory muscles and temporomandibular joint (TMJ), with a multifaceted etiology that includes biomechanical, neuromuscular, psychological, and biological factors. This research aims to assess and correlate the hyoid bone position, airway dimensions, and psychological status in class II Hz (horizontal) and Vt (vertical) malocclusion cases with TMD in contrast to non-TMD class I cases. Methodology This research was carried out at the Orthodontics Department, Sharad Pawar Dental College and Hospital, Sawangi, with consent obtained from the ethical committee. A total of 63 adult patients with class I, class II horizontal, and class II vertical malocclusions were selected. TMD was diagnosed using the Helkimo index, and patients were categorized accordingly. Psychological status was evaluated using the Warwick-Edinburgh scale, while the placement of hyoid bone and airway dimensions were assessed using lateral cephalograms. Statistical analysis involved descriptive and inferential statistics using SPSS version 27.0, with a significance level of p < 0.05. Results The research showed a noteworthy difference in the hyoid bone's location, airway dimensions, and psychological status among the three groups. Class II TMD patients (both vertical and horizontal) exhibited higher hyoid bone positions and larger Go-Hy-Me angles (angle formed by the gonion-hyoid line and the hyoid-menton line) compared to class I patients. In addition, class II vertical TMD patients showed the most reduced airway dimensions. Psychological assessments indicated higher stress, anxiety, and depression levels in class II TMD patients, particularly in the vertical group, compared to class I non-TMD patients. Conclusion This study highlights the intricate relationships between hyoid bone position, airway dimensions, and psychological status in TMD patients. TMD patients present with hyoid bones positioned closer to the cranium and mandible, larger Go-Hy-Me angles, and reduced airway dimensions. Psychological distress exacerbates TMD symptoms, negatively impacting overall well-being and quality of life. Orthodontists should consider these interrelated factors when devising treatment plans to improve patient outcomes. Future longitudinal studies with larger samples and advanced imaging techniques are recommended to further elucidate these interactions.

Comparison of multi-column chromatography configurations through model-based optimization.

Integrated continuous bioprocessing has been identified as the next important phase of evolution in biopharmaceutical manufacturing. Multiple platform technologies to enable continuous processing are being developed. Multi-column counter-current chromatography is a step in this direction to provide increased productivity and capacity utilization to capture biomolecules like monoclonal antibodies (mAbs) present in the reactor harvest and remove impurities. Model-based optimization of two prevalent multi-column designs, 3-column and 4-column periodic counter-current chromatography (PCC) was carried out for different concentrations of mAbs in the feed, durations of cleaning-in-place and equilibration protocols. The multi-objective optimization problem comprising three performance measures, namely, product yield, productivity, and capacity utilization was solved using the Radial basis function optimization technique. The superficial velocities during load, wash, and elute operations, along with durations of distinct stages present in the multi-column operations were considered as decision variables. Optimization results without the constraint on number of wash volumes showed that 3-Column PCC performs better than 4-Column PCC. For example, at a feed concentration of 1.2 mg/mL, productivity, yield and capacity utilization, respectively, were 0.024 mg/mL.s, 0.94, and 0.94 for 3-Column PCC and 0.017 mg/mL.s, 0.87, and 0.83 for 4-column PCC. Similar trends were observed at higher feed concentrations also. However, when the constraint on number of wash volumes is included, 4-Column PCC was found to result in consistent productivity and product yield under different operating conditions but at the expense of reduced capacity utilization.

Modeling drug release through stimuli responsive polymer hydrogels.

There is a rising interest in stimuli-responsive hydrogels to achieve controlled and self-regulated drug delivery. Stimuli responsive polymer hydrogels with their ability to swell/de-swell under varying pH conditions present themselves as a potential candidate for controlled drug delivery. It is important to develop a mechanistic understanding of the underlying phenomena that will help suggest ways to control the drug release from a polymer hydrogel. We present a mathematical model that couples Nernst-Planck, Poisson and force balance equations to incorporate diffusion of ionic species and drug along with deformation of hydrogel under osmotic pressure. The model can be used to simulate swelling behaviour of the hydrogel along with the kinetics of drug release. It has been validated with published experimental data for swelling of polyhydroxyl methacrylate-co-methacrylic acid (pHEMA-co-MA) gels and release kinetics of Phenylpropanolamine from these gels. Effect of formulation parameters such as polymer concentration and cross-linker concentration has also been evaluated. The model can be used to reduce the number of exploratory experiments required during design of a drug delivery system.