International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

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

Projected Employment and Population Impacts of Oil Shale Development in Uintah County, Utah

This study provides a critique of regional base method for population and employment impacts. It uses a new approach to calculate the regional employment multiplier. The new approach tries to preserve the advantages of the regional base method and at the same time avoid some of the problems associated with it. This study estimates the changes in local service employment by industry and population in Uintah County, Utah, resulting from an oil shale development project with a 100,000 barrel-per-day capacity and an operating labor force of 2500. It also estimates the changes in total local service employment and population on a yearly basis for a period of 20 years

Drugs That Bind to α‑Synuclein: Neuroprotective or Neurotoxic?

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson’s disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry. The antinausea drugs, cinnarizine and metoclopramide, do not bind to α-synuclein, whereas amphetamine and the herbicides, paraquat and rotenone, bind tightly and cause α-synuclein to adopt a more compact conformation. The recreational drug, cocaine, binds to α-synuclein, whereas heroin and methadone do not. Metformin, which is prescribed for diabetes and is neuroprotective, binds well without causing α-synuclein to adopt a more compact conformation. Methylphenidate (ritalin) binds to sites in both the N- and C-terminus and causes α-synuclein to adopt a loop conformation. In contrast, amphetamine only binds to the N-terminus. Except for cinnarizine and metoclopramide, there is a good correlation between the mode of binding to α-synuclein and whether a drug is neuroprotective or neurotoxic

Novel Dimer Compounds That Bind α‑Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α‑Synuclein. A Possible Prevention Strategy for Parkinson’s Disease

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson’s disease. Previously, it was suggested that drugs, which bind to α-synuclein and form a loop structure between the N- and C-termini, tend to be neuroprotective, whereas others, which cause a more compact structure, tend to be neurotoxic. To improve the binding to α-synuclein, eight novel compounds were synthesized from a caffeine scaffold attached to (<i>R</i>,<i>S</i>)-1-aminoindan, (<i>R</i>,<i>S</i>)-nicotine, and metformin, and their binding to α-synuclein determined through nanopore analysis and isothermal titration calorimetry. The ability of the dimers to interact with α-synuclein in a cell system was assayed in a yeast model of PD which expresses an AS-GFP (α-synuclein-Green Fluorescent Protein) construct under the control of a galactose promoter. In 5 mM galactose this yeast strain will not grow and large cytoplasmic foci are observed by fluorescent microscopy. Two of the dimers, C₈-6-I and C₈-6-N, at a concentration of 0.1 μM allowed the yeast to grow normally in 5 mM galactose and the AS-GFP became localized to the periphery of the cell. Both dimers were superior when compared to the monomeric compounds. The presence of the dimers also caused the disappearance of preformed cytoplasmic foci. Nanopore analysis of C₈-6-I and C₈-6-N were consistent with simultaneous binding to both the N- and C-terminus of α-synuclein but the binding constants were only 10⁵ M^–1

Impact of easing COVID-19 safety measures on trauma computed tomography imaging volumes.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has led to substantial disruptions in healthcare staffing and operations. Stay-at-home (SAH) orders and limitations in social gathering implemented in spring 2020 were followed by initial decreases in healthcare and imaging utilization. This study aims to evaluate the impact of subsequent easing of SAH on trauma volumes, demand for, and turnaround times for trauma computed tomography (CT) exams, hypothesizing that after initial decreases, trauma volumes have increased as COVID safety measures have been reduced.MethodsPatient characteristics, CT imaging volumes, and turnaround time were analyzed for all adult activated emergency department trauma patients requiring CT imaging at a single Level-I trauma center (1/2018-2/2022) located in the sixth most populous county in the USA. Based on COVID safety measures in place in the state of California, three time periods were compared: baseline (PRE, 1/1/2018-3/19/2020), COVID safety measures (COVID, 3/20/2020-1/25/2021), and POST (1/26/2021-2/28/2022).ResultsThere were 16,984 trauma patients across the study (PRE = 8289, COVID = 3139, POST = 5556). The average daily trauma patient volumes increased significantly in the POST period compared to the PRE and COVID periods (13.9 vs. 10.3 vs. 10.1, p &lt; 0.001), with increases in both blunt (p &lt; 0.001) and penetrating (p = 0.002) trauma. The average daily number of trauma CT examinations performed increased significantly in the POST period compared to the PRE and COVID periods (56.7 vs. 48.3 vs. 47.6, p &lt; 0.001), with significant increases in average turnaround time (47&nbsp;min vs. 31 and 37, p &lt; 0.001).ConclusionAfter initial decreases in trauma radiology volumes following stay-at-home orders, subsequent easing of safety measures has coincided with increases in trauma imaging volumes above pre-pandemic levels and longer exam turnaround times

Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?

Background: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. Methods: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. Results: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. Conclusions: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time