I. Executive Summary Background The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS.

Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4؉ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4 ؉ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4 ؉ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4 ؉ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4 ؉ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4 ؉ T cells.Treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART) reduces viremia to below the detection limit of ultrasensitive clinical assays (15,16,37). However, HIV-1 persists in resting CD4 ϩ T cells (6,8,9,12,51) and possibly other reservoirs (4, 58). The latent reservoir in resting CD4ϩ T cells has a long half-life (11,41,44,47,56) that will likely preclude virus eradication unless novel approaches (5, 24-28, 42) can purge latently infected cells.In patients on HAART, HIV-1 persistence is evidenced not only by the latent reservoir in resting CD4 ϩ T cells but also by free virus in the plasma (10,17,19,36,41,48,52). Free virions can be found with special methods, even in patients who do not have clinically detectable viremia (10,18,19,36,52). Given the short half-life of free virus (20,49), this residual viremia indicates active virus production. This virus production may reflect low-level ongoing replication that continues despite HAART (7,10,13,14,18,21,33,48,56) and/or release of virus from latently infected cells that become activated (19,22,34,48,55) or from other stable cellular reservoirs (4, 58). The characterization of residual viremia may provide a means for determining the importance of different mechanisms of viral persistence.Although the presence of free virus can be detected ...

Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

Resting CD4؉ T-cell populations from human immunodeficiency virus type 1 (HIV- 1

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.

Objective Olfactory dysfunction (OD)—hyposmia or anosmia—is a symptom of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to better determine prevalence, severity, and timing of OD in COVID-19 relative to other sinonasal and pulmonary symptoms. Study Design Prospective, cross-sectional. Setting Regional/cantonal hospital. Subjects In total, 103 patients diagnosed with COVID-19 with reverse transcription polymerase chain reaction (RT-PCR)–based testing. Methods All patients testing positive for COVID-19 at Kantonsspital Aarau over a 6-week period were approached. Timing and severity (at its worst, on scale of 0 [none], 1 [mild], 2 [moderate], and 3 [severe]) of OD, loss of taste, nasal obstruction, rhinorrhea/mucus production, fever, cough and shortness of breath (SOB) were assessed for each patient. Results Prevalence of OD was 61.2%, and severity of OD was strongly correlated with severity of loss of taste experienced (ρ = 0.87, P < .001). OD was experienced on the first day of COVID-19 by 8.7% and overall occurred at median infection day 3 (mean, 3.4; range, 0-12). Most experiencing OD reported anosmia, and mean severity of all with OD was moderate to severe (mean [SD], 2.7 [0.6]). Nasal obstruction (49.5%) and rhinorrhea (35.0%) were frequently reported but not correlated with OD. SOB was more severe in patients with OD. OD was associated negatively with older age (OR, 0.96; 95% CI, 0.93-0.99; P = .007) and positively with female sex (OR, 2.46; 95% CI, 0.98-6.19; P = .056). Conclusions OD is highly prevalent during COVID-19, occurring early and severely, often in conjunction with loss of taste. OD is associated negatively with older age and positively with female sex. Patients with OD may also experience more severe SOB.

Objective The minimal clinically important difference (MCID) of a patient-reported outcome measure (PROM) represents a threshold value of change in PROM score deemed to have an implication in clinical management. The MCID is frequently used to interpret the significance of results from clinical studies that use PROMs. However, an understanding of the many caveats of the MCID, as well as its strengths and limitations, is necessary. The objective of this article is to provide a review of the calculation, interpretation, and caveats of MCID. Data Sources MEDLINE and PubMed Central. Review Methods Literature search—including primary studies, review articles, and consensus statements—pertinent to the objectives of this review using PubMed. Conclusions The MCID of a PROM may vary depending on the patients and clinical context in which the PROM is given. The primary approaches for calculating MCID are distribution-based and anchor-based methods. Each methodology has strengths and limitations, and the ideal determination of a PROM MCID includes synthesis of results from both approaches. The MCID of a PROM is also not perfect in detecting patients experiencing a clinically important improvement, and this is reflected in its accuracy (eg, sensitivity and specificity). Implications for Practice Interpretation or application of MCID requires consideration of all caveats underlying the MCID, including the patients in whom it was derived, the limitations of the methodologies used to calculate it, and its accuracy for identifying patients who have experienced clinically significant improvement.

The use of the 4-subdomain structure for SNOT-22 (reflecting sleep, nasal, otologic/facial pain, and emotional symptoms of CRS) was validated as the most appropriate to calculate SNOT-22 subdomain scores for patients from different geographic regions using CFA.