<div> <div> <p>The emergence of the 2019 novel coronavirus (COVID-19), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important COVID-19 protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar, which is far from ideal. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of COVID-19 and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked-based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches were published at <a href="http://www.insilico.com/ncov-sprint/">www.insilico.com/ncov-sprint/</a>. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. <br></p> </div> </div>

IMPORTANCE Smoking is a highly prevalent risk factor among patients with head and neck cancer. However, few studies have examined the association of this modifiable risk factor on postoperative outcomes following microvascular reconstruction of the head and neck.OBJECTIVE To analyze the risk associated with smoking in patients undergoing free flap surgery of the head and neck.DESIGN, SETTING, AND PARTICIPANTS In this retrospective, population, database study, the National Quality Improvement Program data sets from 2005 to 2014 were queried for all cases of head and neck surgery involving free flap reconstruction in the United States. The 2193 cases identified were stratified into smoking and nonsmoking cohorts and compared using χ 2 and binary logistic regression analyses. Pack-years of smoking data were used to assess the degree of risk associated with a prolonged history of smoking. All analyses were conducted between January 2018 and June 2018.MAIN OUTCOMES AND MEASURES Smoking and nonsmoking cohorts were compared for rates of demographic characteristics, comorbidities, and complications. Following correction for differences in patient demographics and comorbidities, smoking and nonsmoking cohorts were compared for rates of postoperative complications. Complication rates were further assessed within the smoking cohort by number of pack years smoked. RESULTSOf the 2193 patients identified as having undergone free flap reconstruction of the head and neck, 624 (28.5%) had a history of recent smoking. After accounting for differences in demographic variables and patient comorbidities using regression analyses, smoking status was found to be independently associated with wound disruption (odds ratio, 1.74; 95% CI, 1.17-2.59; P = .006) and unplanned reoperation (odds ratio, 1.50; 95% CI, 1.15-1.95; P = .003). An analysis by pack-years of smoking showed that a longer smoking history was significantly associated with higher rates of numerous comorbidities but not with a corresponding increase in rates of complications.CONCLUSIONS AND RELEVANCE Smokers undergoing free flap reconstruction of the head and neck may be at significantly higher risk of postoperative wound disruption and subsequent reoperation. These risks were independent of pack-years of smoking history, suggesting that both risks were associated with perioperative smoke exposure, and preoperative smoking cessation may be of benefit.LEVEL OF EVIDENCE NA.

Objective To characterize the clinical features, risk factors, symptom time‐course, and quality of life implications for parosmia among coronavirus disease (COVID)‐related olfactory dysfunction patients. Methods Individuals with olfactory dysfunction associated with laboratory‐confirmed or clinically suspected COVID‐19 infection were recruited from otolaryngology and primary care practices over a period from August 2020 to March 2021. Participants completed olfactory dysfunction and quality of life surveys. Results A total of 148 (64.1%) of 231 respondents reported parosmia at some point. Parosmia developed within 1 week of any COVID‐19 symptom onset in 25.4% of respondents, but more than 1 month after symptom onset in 43.4% of respondents. Parosmia was associated with significantly better quantitative olfactory scores on Brief Smell Identification Test (8.7 vs. 7.5, P = .006), but demonstrated worse quality of life scores, including modified brief Questionnaire of Olfactory Dysfunction—Negative Statements and Sino‐Nasal Outcome Test‐22 scores (12.1 vs. 8.5, P < .001; 26.2 vs. 23.2, P = .113). Participants who developed parosmia at any point were significantly younger and less likely to have history of chronic sinusitis than those who did not develop parosmia (40.2 vs. 44.9 years, P = .007; 7.2% vs. 0.7%, P = .006). Conclusion COVID‐19‐associated olfactory dysfunction is frequently linked with development of parosmia, which often presents either at onset of smell loss or in a delayed fashion. Despite better quantitative olfactory scores, respondents with parosmia report decreased quality of life. A majority of respondents with persistent parosmia have sought treatment. Level of Evidence 3 Laryngoscope, 132:633–639, 2022

<div> <div> <p>The emergence of the 2019 novel coronavirus (COVID-19), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important COVID-19 protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar, which is far from ideal. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of COVID-19 and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked-based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches were published at <a href="http://www.insilico.com/ncov-sprint/">www.insilico.com/ncov-sprint/</a>. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. <br></p> </div> </div>

<div> <div> <div> <p>The emergence of the 2019 novel coronavirus (2019-nCoV), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important 2019-nCoV protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of 2019-nCoV and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked- based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches are being published at www.insilico.com/ncov-sprint/ and will be continuously updated. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. </p> </div> </div> </div>