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Background: Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection., Methods: This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness., Results: At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2., Conclusions: While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.

Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8 + cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam , was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c–EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3 + CD8 + T cell population. Patients with melanoma with a LAG + immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG - immunotype ( P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG + immunotype was significantly associated with response ( P = 0.007), survival ( P < 0.001), and progression-free survival ( P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG + immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG + immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Compared to general anesthesia, regional anesthesia confers several benefits including improved pain control and decreased postoperative opioid consumption. While the benefits of peripheral nerve blocks (PNB) have been well studied, there are little epidemiological data on PNB usage in mastectomy and lumpectomy procedures. The primary objective of our study was to assess national trends of the annual proportion of PNB use in breast surgery from 2010 to 2018. We also identified factors associated with PNB use for breast surgery., Methods: We identified lumpectomy and mastectomy surgical cases with and without PNB between 2010 and 2018 using the Anesthesia Quality Institute National Anesthesia Clinical Outcomes Registry (AQI NACOR). We modeled the nonlinear association between year of procedure and PNB use with segmented mixed-effects logistic regression clustered on facility identifier. The association between PNB use and year of procedure, age, sex, American Society of Anesthesiologists physical status (ASA PS), facility type, facility region, weekday, and tissue expander use was also modeled using mixed-effects logistic regression., Results: Of the 189,854 surgical cases from 2010 to 2018 that met criteria, 86.2% were lumpectomy cases and 13.8% were mastectomy cases. The proportion of lumpectomy cases with PNB was <0.1% in 2010 and increased each subsequent year to 1.9% in 2018 (trend P < .0001). The proportion of mastectomy cases with PNB was 0.5% in 2010 and 13% in 2018 (trend P < .0001). The year 2014 was the breakpoint selected for segmented regression. Before 2014, the odds of PNB among the mastectomy cases was not significantly different from year to year. After 2014, the odds of PNB increased by 2.24-fold each year (95% confidence interval [CI], 2.00-2.49; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. Similar trends were seen in the lumpectomy cases, where after 2014, the odds of PNB increased by 2.03-fold (95% CI, 1.81-2.27; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. In the mastectomy cohort, year of procedure ≥2014, female sex, facility region, and tissue expander use were associated with higher odds of PNB. For lumpectomy cases, year of procedure ≥2014 and facility region were associated with higher odds of PNB use., Conclusions: We found increased annual utilization of PNB for mastectomy and lumpectomy since 2010, although absolute prevalence is low. PNB use was associated with year of procedure for both lumpectomy and mastectomy, particularly post-2014., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Multi-modal molecular profiling data in bulk tumors or single cells are accumulating at a fast pace. There is a great need for developing statistical and computational methods to reveal molecular structures in complex data types toward biological discoveries. Here, we introduce Nebula, a novel Bayesian integrative clustering analysis for high dimensional multi-modal molecular data to identify directly interpretable clusters and associated biomarkers in a unified and biologically plausible framework. To facilitate computational efficiency, a variational Bayes approach is developed to approximate the joint posterior distribution to achieve model inference in high-dimensional settings. We describe a pan-cancer data analysis of genomic, epigenomic, and transcriptomic alterations in close to 9000 tumor samples across canonical oncogenic signaling pathways, immune and stemness phenotype, with comparisons to state-of-the-art clustering methods. We demonstrate that Nebula has the unique advantage of revealing patterns on the basis of shared pathway alterations, offering biological and clinical insights beyond tumor type and histology in the pan-cancer analysis setting. We also illustrate the utility of Nebula in single cell data for immune cell decomposition in peripheral blood samples.

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure., Methods: We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided., Results: Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors., Conclusions: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC., Methods: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data., Results: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells., Conclusions: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

While quality programs have been shown to improve provider compliance, few have demonstrated conclusive improvements in patient outcomes. We hypothesized that there would be increased metric compliance and decreased postoperative complications after initiation of an anesthesiology quality improvement program at our institution. We performed a retrospective study of all adult inpatients having anesthesia for a twelve-month period that spanned six months before and after program implementation. The primary outcome was the rate of complications in the post-implementation period. Secondary outcomes included the change in proportion of complications and compliance with quality metrics. We studied a total of 9620 adult inpatient cases, subdivided into pre- and post-implementation groups (4832 vs 4788.) After multivariate model adjustment, the rate of any complication (our primary outcome) was not significantly changed (32% to 31%; adjusted P = 0.410.) Of the individual complications, only wound infection (2.0% to 1.5%; adjusted P = 0.020) showed a statistically significant decrease. Statistically and clinically significant increases in compliance were seen for the BP-02 Avoiding Monitoring Gaps metric (81% to 93%, P < 0.001), both neuromuscular blockade metrics (NMB-01 76% to 91%, P < 0.001; NMB-02 95% to 97%, P = 0.006), both tidal volume metrics (PUL-01 84% to 93%, P < 0.001; PUL-02 30% to 45%, P < 0.001), and the TEMP-02 Core Temperature Measurement metric (88% to 94%, P < 0.001). Implementation of a comprehensive quality feedback program improved metric compliance but was not associated with a change in postoperative complications.

Introduction: Clinical alert systems (CAS) have been used to analyze deviations from hospital standards in the electronic medical record to identify missing documentations and send alerts to the appropriate providers to increase adherence to required elements. To improve compliance, an alert system for documentation of the Immediate Preoperative Assessment (IPOA) was implemented at our institution in August 2018 with the goal of improving documentation compliance rates. We hypothesized that implementation of this alert system would increase the compliance of on-time documentation of the IPOA., Methods: An initial data query in our institutional data warehouse was made for all patients who had a completed anesthetic during our study period. This date range corresponded to 6 months before and after August 2nd, 2018, the date when the IPOA alert was implemented and the anesthesiology department. The following analyses were performed: testing the proportion of cases compliant with on-time documentation of the IPOA pre- versus post-implementation for the full cohort and among subsets of interest, testing the time when the IPOA was completed relative to anesthesia end, and testing whether time of day of when surgery occurred had an impact on the time when the IPOA was completed relative to the drapes off/IPOA alert sent time. The proportion of compliance for pre- versus post-implementation was tested by Chi-square test., Results: Through retrospective chart review of electronic patient records, 47,417 cases matched our inclusion criteria of patients that had a completed anesthetic between February 2nd, 2018 to February 2nd, 2019. In total, we excluded 5132 cases. The compliance rate of IPOA completion increased from 76% to 88% (P < 0.001) before and after the alert implementation date. In the initial month following alert implementation, the compliance rate immediately increased to 83% and stayed in the high 80's for the balance of the study period., Conclusion: In summary, we demonstrate that automated Clinical Alert Systems operating via a single page notification can improve the compliance rate for documentation of key anesthesia events and that this observation is sustained six months after the implementation date. Furthermore, improvement in compliance is highest shorter cases and cases that occur early in the day. This study shows promising results in the use of automatic CAS system alerts to help hospitals meet the Center for Medicare and Medicaid Services (CMS) and The Joint Commission (TJC) standards., Competing Interests: Declaration of Competing Interests LET is a grant recipient through Merck Investigator Studies Program (MISP) to fund clinical trial at MSKCC (NCT03808077). LET serves a consultancy and advisory role for Merck & Co. Pharmaceutical Company., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients with unresectable locally advanced NSCLC who refuse or are not candidates for chemotherapy often receive radiation therapy (RT) alone. Hypofractionated RT (HFRT) regimens are becoming increasingly common. An analysis of the National Cancer Database (NCDB) was performed to evaluate the practice patterns and outcomes of HFRT vs. conventionally fractionated RT (CFRT) in patients with stage III NSCLC undergoing definitive RT alone. Material and methods: The NCDB was queried for all patients with stage III NSCLC diagnosed between 2004 and 2014 who received RT alone. CFRT was defined as patients treated to a total dose of 60-80 Gy in 1.8-2 Gy daily fractions. HFRT was defined as patients treated to a total dose of 50-80 Gy in 2.25-4 Gy fractions. Logistic regression, univariable and multivariable analyses (MVAs) for overall survival (OS) and propensity score matched analyses (PSMAs) were performed. Results: A total of 6490 patients were evaluated: 5378 received CFRT and 1112 received HFRT. Median CFRT dose was 66 Gy in 2 Gy fractions vs. 58.5 Gy in 2.5 Gy fractions for HFRT. HFRT was associated with older age, lower biological effective dose (BED 10 ), academic facility type, higher T-stage and lower N-stage. On initial analysis, HFRT was associated with inferior OS (median 9.9 vs. 11.1 months, p <.001), but after adjusting for the imbalance in covariates such as age, BED 10 , T-stage and N-stage using PSMA, the difference in survival was no longer significant ( p =.1). Conclusions: In the appropriate clinical context, HFRT can be an option for patients with locally advanced NSCLC who are not candidates for chemotherapy or surgical resection. HFRT needs to be further studied in prospective trials to evaluate toxicity and tumor control.

Although histopathological differences have been reported between acute graft-versus-host disease (aGVHD) rash and non-aGVHD rash in CD34 + -selected peripheral blood stem cell transplantation (PBSCT) recipients, skin biopsy alone is usually insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes, such as drug eruptions, from cutaneous aGVHD after CD34 + -selected PBSCT remains challenging and relies on clinical presentation. This study aimed to identify etiologies of skin rash in the first year after CD34 + -selected PBSCT and to assess whether laboratory serologic markers, transplant characteristics, and rash morphology and symptomatology aid in differentiation of cutaneous aGVHD rash versus non-aGVHD rash. We conducted a retrospective study of 243 adult patients who underwent CD34 + -selected PBSCT at Memorial Sloan Kettering Cancer Center between 2008 and 2011. Among this cohort of transplant recipients, only 43 patients (17.7%) developed cutaneous aGVHD. A total of 152 patients (63%) were identified with rash within 1 year after PBSCT. The proportion of patients who experienced peripheral eosinophilia was not different between those with an aGVHD versus non-aGVHD rash (P ≥ .90), nor when stratified by CD34 + selection method (Isolex, P = .70; CliniMACS, P≥ .90). The proportion of patients with pruritus was also not different between those with an aGVHD rash versus non-aGVHD rash (P= .20), or when stratified by CD34 + selection modality (Isolex, P = .20; CliniMACS, P = .50). The most common cause of non-aGVHD rash among those with a clear etiology was drug (39% of Isolex; 26% of CliniMACS). Single drug culprits were identified in 51% of drug rashes. The most commonly reported offending agents included antibiotics, keratinocyte growth factor, chemotherapy, and recombinant glycosylated human IL-7., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

To explore how contextual information streams are processed and prioritized during consumer studies, we manipulated the congruency of visual, auditory and olfactory cues using immersive technologies and assessed the impact on context recall, evaluation time, and preference and liking for cold brewed coffee. Each consumer (n = 50) was exposed to two identical control conditions, a visually incongruent condition, an auditory incongruent condition, an olfactory incongruent condition, and an all-incongruent condition. The control condition simulated a coffeehouse environment complete with the sights, sounds and smells commonly experienced in that venue. A laboratory setting, construction noise, and laundry detergent represented the individual incongruent visual, auditory, and aroma streams, respectively. Results revealed that olfactory information had a lesser priority than visual or auditory information in the simulated environments when assessed by subject's ability to recall encountered information streams. Panelists also spent more time evaluating coffees in the first presented control condition compared to the incongruent conditions or the repeated control condition. Finally, although the averaged combined liking score for subjects' least to most preferred coffees was significantly lowered in the all-incongruent condition compared to the control condition, this decrease was not substantial. Understanding how the saliency of contextual information influences consumer behavior and attention can inform immersive testing methodologies., (Published by Elsevier Ltd.)

The Duality of Smell hypothesis suggests odorants delivered orthonasally elicit different sensations compared with those delivered retronasally despite activating the same receptors in the olfactory epithelium. Presently, we investigated this further using a matching paradigm free from odorant or semantic memory bias. Subjects were asked to evaluate an aroma delivered in one condition (orthonasal or retronasal delivery) and match the same aroma from 4 unknowns evaluated in the same or different delivery conditions. Panelists matched flavors in 4 delivery conditions: orthonasal-orthonasal, retronasal-retronasal, retronasal-orthonasal, and orthonasal-retronasal. For orthonasal presentation, panelists smelled samples using their nostrils, and for retronasal presentation, panelists swallowed aqueous flavors. In Experiment 1, panelists were instructed to match familiar flavors (banana, grape, orange, raspberry). In Experiments 2 and 3, panelists used the same experimental design with either 4 unfamiliar flavors (kinnow, longan, pawpaw, prunus) or 4 distinct subtypes of a strawberry flavor (woody, green, ripe, candy). In Experiment 1, the number of correct matches in each condition did not significantly differ suggesting stability in the perceptual construct across delivery routes. However, in Experiments 2 and 3, significantly more samples were correctly matched in the orthonasal-orthonasal and retronasal-retronasal conditions compared with the retronasal-orthonasal or orthonasal-retronasal conditions suggesting aroma perception is dependent on delivery route. Additionally, across the 4 delivery methods, the ability to correctly match flavors decreased as flavor familiarity decreased or similarity increased and may reflect the different cognitive strategies employed by subjects when matching these stimuli. Our results suggest odorant percepts are route-dependent and consistent with the Duality of Smell phenomenon.