Kinetics of the viral cycle influence pharmacodynamics of antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>More and more antiretroviral therapies are being developed for treatment of HIV infection. The <it>in-vivo </it>efficacy of these drugs is commonly predicted based on <it>in-vitro </it>measures of antiviral effect. One primary <it>in-vitro </it>measure is the IC50, the amount of drug required for 50% inhibition of viral replication. We have previously shown that HIV life-cycle kinetics impact clinically observed HIV viral dynamics. Here we present a mathematical model of how they affect the pharmacodynamics of antiretroviral drugs.</p> <p>Results</p> <p>We find that experimentally measured antiretroviral IC50s are determined by three factors: (i) intrinsic drug properties (e.g. drug-target binding), (ii) kinetics of the HIV life cycle, and (iii) kinetics of drug-inhibited infected cells. Our model predicts that the IC50 is a declining function of the duration of the drug-susceptible stage in the host cell. We combine our model with known viral life-cycle kinetics to derive a measure of intrinsic properties, reflecting drug action, for known antiretroviral drugs from previously measured IC50s. We show that this measure of intrinsic drug property correlates very well with <it>in vitro</it>-measured antiviral activity, whereas experimentally measured IC50 does not.</p> <p>Conclusions</p> <p>Our results have implications for understanding pharmacodynamics of and improving activity of antiretroviral drugs. Our findings predict that drug activity can be improved through co-administration of synergistic drugs that delay the viral life cycle but are not inhibitory by themselves. Moreover, our results may easily extend to treatment of other pathogens.</p> <p>This article was reviewed by Dr. Ruy Ribeiro, Dr. Ha Youn Lee, Dr. Alan Perelson and Dr. Christoph Adami.</p

Characterization of aeroallergen sensitivities in children with allergic rhinitis and chronic rhinosinusitis

Allergic rhinitis is a common comorbid condition in pediatric chronic rhinosinusitis (CRS). Testing for aeroallergen sensitization should therefore be considered in the evaluation of children with CRS. At present the aeroallergen sensitivity profile of children with CRS remains uncharacterized. In this study, we retrospectively identify a consecutive series of children with CRS and allergic rhinitis who have undergone joint otolaryngology and allergy evaluation at a single tertiary care center. We describe the aeroallergen sensitivity profiles (based upon formal skin testing) of these children, stratifying them according to co-morbidity status: 1) CRS with cystic fibrosis (CF), 2) CRS with immune deficiency and 3) uncomplicated CRS (without co-morbid CF, immune deficiency or primary ciliary dyskinesia). We identify 208 children (average age 9.3 years, standard deviation 4.8 years) with CRS and allergic rhinitis meeting inclusion criteria, 140 with uncomplicated CRS, 64 with co-morbid immune deficiency and 4 with co-morbid CF. The prevalence of indoor aeroallergen sensitivities (62.9–100.0%) was more common than that of outdoor aeroallergen sensitivities (43.8–50.0%) in all three cohorts of children. In all three cohorts, the most common indoor aeroallergen sensitivity was to dust mites (50.0–75.0%) and the most common outdoor aeroallergen sensitivity was to tree pollens (43.8–50.0%). The aeroallergen sensitivity profile of children with CRS and allergic rhinitis appears to be similar to that of the general pediatric population with allergic rhinitis, and parallels the aeroallergen sensitivities previously described for adults with CRS and allergic rhinitis. Knowledge of the aeroallergen sensitivities in children with CRS and allergic rhinitis will enhance both diagnostic and treatment strategies

Disparities in health in the United States: An overview of the social determinants of health for otolaryngologists

Objectives: Social determinants of health include social and demographic factors such as poverty, education status, race and ethnicity, gender, insurance status, and other factors that influence (1) development of illness, (2) ability to obtain and utilize healthcare, and (3) health and healthcare outcomes. In otolaryngology, as in other subspecialty surgical fields, we are constantly confronted by patients’ social and demographic circumstances including poverty, language barriers, and lack of health insurance and yet there is limited research on how these factors impact health equity in our field, or how attention to these patient characteristics may improve health equity. This review provides the reader with a framework to understand the social determinants of health including how socioeconomic status, insurance status, race, gender, and other factors impact health. Data Sources and Review Methods Foundational papers on the social determinants of health are reviewed, as well as otolaryngology publications focused on health and healthcare disparities. Results: The social determinants of health have a major impact on patient health as well as healthcare utilization, but there is a relative lack of data on these factors and how they can be addressed within otolaryngology. Incorporating tools to measure social and demographic characteristics and actually report on these measures is a first simple step to increase the data on the social determinants of health as they pertain to otolaryngology. Conclusion: More research is needed on the social determinants of health, and how they impact otolaryngic disease. Medicare's Accountable Care Organization models will increasingly change the way in which physicians are reimbursed, making the social determinants of health central not only to our moral conscience but also the bottom line. Level of Evidence

Limits on Replenishment of the Resting CD4+ T Cell Reservoir for HIV in Patients on HAART

Whereas cells productively infected with human immunodeficiency virus type 1 (HIV-1) decay rapidly in the setting of highly active antiretroviral therapy (HAART), latently infected resting CD4+ T cells decay very slowly, persisting for the lifetime of the patient and thus forming a stable reservoir for HIV-1. It has been suggested that the stability of the latent reservoir is due to low-level viral replication that continuously replenishes the reservoir despite HAART. Here, we offer the first quantitative study to our knowledge of inflow of newly infected cells into the latent reservoir due to viral replication in the setting of HAART. We make use of a previous observation that in some patients on HAART, the residual viremia is dominated by a predominant plasma clone (PPC) of HIV-1 not found in the latent reservoir. The unique sequence of the PPC serves as a functional label for new entries into the reservoir. We employ a simple mathematical model for the dynamics of the latent reservoir to constrain the inflow rate to between 0 and as few as 70 cells per day. The magnitude of the maximum daily inflow rate is small compared to the size of the latent reservoir, and therefore any inflow that occurs in patients on HAART is unlikely to significantly influence the decay rate of the reservoir. These results suggest that the stability of the latent reservoir is unlikely to arise from ongoing replication during HAART. Thus, intensification of standard HAART regimens should have minimal effects on the decay of the latent reservoir

Removal of a Wire Brush Bristle from the Hypopharynx Using Suspension, Microscope, and Fluoroscopy

Wire brush bristles are an increasingly recognized hazard that can present as a foreign body in the aerodigestive tract. Due to their small size and tendency to become embedded in surrounding tissue, these small metallic bristles present a unique operative challenge to otolaryngologists. Here we present a case of a 40-year-old woman who underwent endoscopic extraction of a wire bristle from the posterior pharyngeal wall using suspension, microscopy, and C-arm fluoroscopy. We believe this is the first published case of an endoscopic removal of a buried foreign body in the hypopharynx using these methods of localization concurrently. By leveraging multiple techniques for visualization, surgeons can avoid open exploration while ensuring complete removal of the object. Additionally, this case highlights the importance of regulatory oversight and consumer awareness of the hazards of grill brushes

A Rare Finding of Schwannoma of the Vidian Canal: A Case Report

Background: Schwannomas of the vidian canal are an extremely rare type of intracranial tumor that can have variable clinical presentations including headache, facial pain, facial muscle paralysis, decreased lacrimation, or nasal dryness. We present an atypical case of an incidentally identified asymptomatic vidian canal schwannoma. Case Description A 49-year-old woman with a history of multiple sclerosis presented for routine surveillance magnetic resonance imaging that detected an ovoid mass originating in the vidian canal. Given the unusual location of the lesion, an endoscopic endonasal biopsy was performed and confirmed the diagnosis of a vidian canal schwannoma, for which the patient chose to receive fractionated radiation therapy. Conclusion: When a vidian canal tumor is identified, endoscopic endonasal biopsy can be used to confirm the diagnosis before pursuing either surgical or radiotherapy treatment. In particular, fractionated radiation therapy offers a radiobiologically safe means of delivering radiation when there is concern for late radiation-related side effects following treatment completion

Development of a Deep Learning Algorithm for Periapical Disease Detection in Dental Radiographs

Periapical radiolucencies, which can be detected on panoramic radiographs, are one of the most common radiographic findings in dentistry and have a differential diagnosis including infections, granuloma, cysts and tumors. In this study, we seek to investigate the ability with which 24 oral and maxillofacial (OMF) surgeons assess the presence of periapical lucencies on panoramic radiographs, and we compare these findings to the performance of a predictive deep learning algorithm that we have developed using a curated data set of 2902 de-identified panoramic radiographs. The mean diagnostic positive predictive value (PPV) of OMF surgeons based on their assessment of panoramic radiographic images was 0.69(± 0.13), indicating that dentists on average falsely diagnose 31% of cases as radiolucencies. However, the mean diagnostic true positive rate (TPR) was 0.51(± 0.14), indicating that on average 49% of all radiolucencies were missed. We demonstrate that the deep learning algorithm achieves a better performance than 14 of 24 OMF surgeons within the cohort, exhibiting an average precision of 0.60(± 0.04), and an F1 score of 0.58(± 0.04) corresponding to a PPV of 0.67(± 0.05) and TPR of 0.51(± 0.05). The algorithm, trained on limited data and evaluated on clinically validated ground truth, has potential to assist OMF surgeons in detecting periapical lucencies on panoramic radiographs

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023

Background: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document. Methods: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- A nd middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs