Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma.

Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.

Adding oscillometry to spirometry in guidelines better identifies uncontrolled asthma, future exacerbations, and potential targeted therapy.

The objective of this review is to provide new advances in our understanding of the clinical importance of establishing peripheral airway impairment (PAI) by impulse oscillometry (IOS) and targeted therapy, which could result in better asthma outcomes. Data sources include PubMed and Google search, limited to English language and human disease, with key words IOS and asthma. Key findings include PAI being consistently associated with uncontrolled asthma across ethnicities, using IOS reference equations factoring Hispanic and White reference algorithms. It is noted that PAI is common even in patients considered well-controlled by asthma guidelines. In a large longitudinal analysis (Assessment of Small Airways Involved in Asthma or ATLANTIS study), a composite of R5-R20, AX, and X5 ordinal scores were independently predictive of asthma control and exacerbation in a multivariate analysis, but forced expiratory volume in 1 second was not significantly predictive of morbidities. However, combining forced expiratory volume in 1 second less than 80% with PAI resulted in greater odds of identifying uncontrolled asthma and exacerbations, than either alone. Applying an external validation method in children with asthma offers the clinician the IOS reference equations best fit for their own specific population. Several clinical phenotypes can also identify PAI with high probability, useful when IOS is not available. Poor asthma outcomes for obese patients with asthma are associated with dysanapsis and PAI, not obesity alone. Extrafine inhaled corticosteroids achieve better asthma control and improve peripheral airway function with fewer exacerbations at lower dosages than nonextrafine inhaled corticosteroid aerosols. In conclusion, these data support the benefit of adding IOS to spirometry in future asthma guidelines and suggest the potential benefit from targeted therapy.

Physical activity and arterial stiffness: is body fat a mediator?

PURPOSE: Physical activity (PA) and body fat percentage (%BF) are independently associated with arterial stiffness, but it has not been explored if there is an associative pathway among these variables. This study examined whether %BF mediates the relationship between PA or sedentary behavior levels with arterial stiffness. METHODS: Fifty adults (1:1 men:women; age 28 ± 11 year) had carotid-femoral pulse wave velocity (CF-PWV) measured by applanation tonometry, %BF by bioelectrical impedance, and PA levels by accelerometry. Accelerometer data determined minutes per day spent in sedentary, light, moderate-to-vigorous physical activity (MVPA), and Total PA. RESULTS: Pearson correlation indicated statistically significant associations among age, %BF, CF-PWV, MVPA, and Total PA (r = 0.34-0.65, p < 0.05). Sedentary and light PA were not associated with CF-PWV. Mediation analysis indicated significant total effects of MVPA (ß = - 0.34, p = 0.044) and age (ß = 0.65, p < 0.001) on CF-PWV. %BF mediated the relationship between Total PA and CF-PWV due to indirect effect of Total PA on %BF (ß = - 0.34, p = 0.02) and %BF on CF-PWV (ß = 0.44, p = 0.002), and partially mediated the relationship between age and CF-PWV (ß = 0.54, p < 0.001). Total PA retained its significant effect on %BF (ß = - 0.28, p = 0.04) and the effect of %BF on CF-PWV remained significant (ß = 0.26, p = 0.03), despite age having a significant effect on both %BF (ß = 0.31, p = 0.023) and CF-PWV (ß = 0.54, p < 0.001). CONCLUSIONS: %BF mediated the relationship between Total PA and arterial stiffness, even after accounting for age. Engagement in more Total PA may help to reduce %BF, resulting in decreased arterial stiffness.

From COVID-19 to future electrification: Assessing traffic impacts on air quality by a machine-learning model.

The large fluctuations in traffic during the COVID-19 pandemic provide an unparalleled opportunity to assess vehicle emission control efficacy. Here we develop a random-forest regression model, based on the large volume of real-time observational data during COVID-19, to predict surface-level NO2, O3, and fine particle concentration in the Los Angeles megacity. Our model exhibits high fidelity in reproducing pollutant concentrations in the Los Angeles Basin and identifies major factors controlling each species. During the strictest lockdown period, traffic reduction led to decreases in NO2 and particulate matter with aerodynamic diameters <2.5 µm by -30.1% and -17.5%, respectively, but a 5.7% increase in O3 Heavy-duty truck emissions contribute primarily to these variations. Future traffic-emission controls are estimated to impose similar effects as observed during the COVID-19 lockdown, but with smaller magnitude. Vehicular electrification will achieve further alleviation of NO2 levels.

Societal shifts due to COVID-19 reveal large-scale complexities and feedbacks between atmospheric chemistry and climate change.

The COVID-19 global pandemic and associated government lockdowns dramatically altered human activity, providing a window into how changes in individual behavior, enacted en masse, impact atmospheric composition. The resulting reductions in anthropogenic activity represent an unprecedented event that yields a glimpse into a future where emissions to the atmosphere are reduced. Furthermore, the abrupt reduction in emissions during the lockdown periods led to clearly observable changes in atmospheric composition, which provide direct insight into feedbacks between the Earth system and human activity. While air pollutants and greenhouse gases share many common anthropogenic sources, there is a sharp difference in the response of their atmospheric concentrations to COVID-19 emissions changes, due in large part to their different lifetimes. Here, we discuss several key takeaways from modeling and observational studies. First, despite dramatic declines in mobility and associated vehicular emissions, the atmospheric growth rates of greenhouse gases were not slowed, in part due to decreased ocean uptake of CO2 and a likely increase in CH4 lifetime from reduced NO x emissions. Second, the response of O3 to decreased NO x emissions showed significant spatial and temporal variability, due to differing chemical regimes around the world. Finally, the overall response of atmospheric composition to emissions changes is heavily modulated by factors including carbon-cycle feedbacks to CH4 and CO2, background pollutant levels, the timing and location of emissions changes, and climate feedbacks on air quality, such as wildfires and the ozone climate penalty.

Analysis of sedentary behaviour levels and patterns in adults with Down syndrome.

BACKGROUND: Sedentary behaviour (SB) among adults with Down syndrome (DS) may differ based on personal or environmental factors. OBJECTIVE: Investigate differences in SB levels and patterns of adults with DS based on sex, age, and residence-type across weekdays and weekends. METHODS: Thirty-four adults with DS (15 men; 37 ± 12 years) underwent accelerometry-based measurements of sedentary time, bouts, and breaks for 7 days. We evaluated differences with 2 × 2 mixed-model (group-by-day) ANOVA. RESULTS: Younger (19-36 years) individuals had less sedentary time (p = .042), and shorter (p = .048) and fewer (p = .012) bouts than older (37-60 years) individuals. Group home residents had more bouts on weekends than adults living with parent/guardians (p = .015). CONCLUSIONS: Adults with DS spent half their waking hours in SB of short bouts. Age and residence may influence SB.

Lymphoscintigraphy Using Tilmanocept Detects Multiple Sentinel Lymph Nodes in Melanoma Patients.

BACKGROUND: Technetium-99m-labeled Tilmanocept, a multivalent mannose, is readily internalized by the CD206 surface receptor on macrophages and dendritic cells which are abundantly present in lymph nodes. We want to examine the drainage patterns of Technetium-99m-labeled Tilmanocept to sentinel lymph nodes (SLNs) in melanoma patients following the 10% rule. METHODS: Multi-center retrospective review of patients with cutaneous melanoma undergoing SLN biopsy using Technetium-99m-labeled Tilmanocept between 2008 and 2014 was conducted. Statistical methods were used for data analyses. RESULTS: Of the 564 patients (mean age of 60.3 and 62% male) with preoperative lymphoscintigraphy showing at least one SLN, several primary tumor sites were included: 27% head/neck, 33% trunk, 21% upper extremity and 19% lower extremity. For the head/neck primary site, 36.5% of patients had multiple draining basins; for the trunk site, 36.4% of patients; for the upper extremity site, 13% of patients; and for the lower extremity, 27.4% of patients. A median of 3 (range 1-18) SLNs were identified and resected. Overall, 78% of patients had >1 SLN identified by Technetium-99m-labeled Tilmanocept. In a multivariate model, patients with >1 SLN were significantly associated with age, Breslow depth, tumor location and higher AJCC tumor stage. A total of 17.7% of patients (100/564) had a positive SLN identified. A total of 145 positive SLNs were identified out of 1,812 SLNs with a positive SLN rate of 8%. Positive SLN status was significantly associated with younger age, greater Breslow depth, mitosis rate, higher AJCC tumor stage, presence of ulceration and angiolymphatic invasion. CONCLUSIONS: Using the 10% rule, Technetium-99m-labeled Tilmanocept detects multiple SLNs in most melanoma patients.

In young children with asthma, obesity and uncontrolled disease are highly associated with peripheral airway impairment.

BACKGROUND: Despite the fact that impulse oscillometry (IOS)-determined peripheral airway impairment (PAI) phenotype is a major risk factor for uncontrolled asthma, IOS is seldom used clinically. OBJECTIVE: To identify clinical characteristics that can best identify the PAI phenotype. METHODS: Clinical characteristics and spirometry results were compared in 227 patients with asthma with the PAI phenotype determined by resistance and reactance values that exceeded IOS­predictive normal values using Gochicoa-Rangel equations. Logistic regression analyses determined factors associated with PAI phenotype, with risk classification based on predicted probability from the final adjusted model. RESULTS: Analysis for identifying PAI, present in 37% of our population, revealed statistically significant odds ratio (OR) for age (4-7 years), of 3.75 (1.47-9.55) (P = .006), obesity OR of 2.59 (1.36-4.96) (P = .004), uncontrolled asthma OR of 2.77 (1.34-5.74) (P = .006), and abnormal forced expiratory flow between 25% and 75% (FEF25%-75%) (<65%) OR of 4.22 (1.59-11.20) (P = .004). For identifying PAI in those considered well controlled, key characteristics were age (4-7 years), OR of 2.81 (1.10-7.18) (P = .03), and obesity, OR of 2.18 (1.09-4.39) (P = .03). For those 4 to 7 years old, who were obese and had uncontrolled disease, probability of PAI was greater than or equal to 80%, regardless of FEF 25%-75%. Probabilities from logistic regression analyses to identify PAI were associated with an area under the curve of 0.750, and applying standard threshold of greater than or equal to 0.50 probability for identification produced sensitivity at 49.4%, specificity at 85.3%, positive predictive value at 66.1%, negative predictive value at 74.4%, and accuracy at 72.1%. CONCLUSION: Clinical characteristics of age at 4 to 7 years, obesity, uncontrolled asthma, and FEF 25%-75% (<65%) identify PAI with high specificity and accuracy. This approach offers the clinician a practical method for strongly considering the presence of PAI when IOS is not available.

Acetonyl Peroxy and Hydroperoxy Self- and Cross-Reactions: Temperature-Dependent Kinetic Parameters, Branching Fractions, and Chaperone Effects.

The temperature-dependent kinetic parameters, branching fractions, and chaperone effects of the self- and cross-reactions between acetonyl peroxy (CH3C(O)CH2O2) and hydro peroxy (HO2) have been studied using pulsed laser photolysis coupled with infrared (IR) wavelength-modulation spectroscopy and ultraviolet absorption (UVA) spectroscopy. Two IR lasers simultaneously monitored HO2 and hydroxyl (OH), while UVA measurements monitored CH3C(O)CH2O2. For the CH3C(O)CH2O2 self-reaction (T = 270-330 K), the rate parameters were determined to be A = (1.5-0.3+0.4) × 10-13 and Ea/R = -996 ± 334 K and the branching fraction to the alkoxy channel, k2b/k2, showed an inverse temperature dependence following the expression, k2b/k2 = (2.27 ± 0.62) - [(6.35 ± 2.06) × 10-3] T(K). For the reaction between CH3C(O)CH2O2 and HO2 (T = 270-330 K), the rate parameters were determined to be A = (3.4-1.5+2.5) × 10-13 and Ea/R = -547 ± 415 K for the hydroperoxide product channel and A = (6.23-4.4+15.3) × 10-17 and Ea/R = -3100 ± 870 K for the OH product channel. The branching fraction for the OH channel, k1b /k1, follows the temperature-dependent expression, k1b/k1 = (3.27 ± 0.51) - [(9.6 ± 1.7) × 10-3] T(K). Determination of these parameters required an extensive reaction kinetics model which included a re-evaluation of the temperature dependence of the HO2 self-reaction chaperone enhancement parameters due to the methanol-hydroperoxy complex. The second-law thermodynamic parameters for KP,M for the formation of the complex were found to be ΔrH250K° = -38.6 ± 3.3 kJ mol-1 and ΔrS250K° = -110.5 ± 13.2 J mol-1 K-1, with the third-law analysis yielding ΔrH250K° = -37.5 ± 0.25 kJ mol-1. The HO2 self-reaction rate coefficient was determined to be k4 = (3.34-0.80+1.04) × 10-13 exp [(507 ± 76)/T]cm3 molecule-1 s-1 with the enhancement term k4,M″ = (2.7-1.7+4.7) × 10-36 exp [(4700 ± 255)/T]cm6 molecule-2 s-1, proportional to [CH3OH], over T = 220-280 K. The equivalent chaperone enhancement parameter for the acetone-hydroperoxy complex was also required and determined to be k4,A″ = (5.0 × 10-38 - 1.4 × 10-41) exp[(7396 ± 1172)/T] cm6 molecule-2 s-1, proportional to [CH3C(O)CH3], over T = 270-296 K. From these parameters, the rate coefficients for the reactions between HO2 and the respective complexes over the given temperature ranges can be estimated: for HO2·CH3OH, k12 = [(1.72 ± 0.050) × 10-11] exp [(314 ± 7.2)/T] cm3 molecule-1 s-1 and for HO2·CH3C(O)CH3, k15 = [(7.9 ± 0.72) × 10-17] exp [(3881 ± 25)/T] cm3 molecule-1 s-1. Lastly, an estimate of the rate coefficient for the HO2·CH3OH self-reaction was also determined to be k13 = (1.3 ± 0.45) × 10-10 cm3 molecule-1 s-1.

Conformer-Dependent Chemistry: Experimental Product Branching of the Vinyl Alcohol + OH + O2 Reaction.

The concentration of formic acid in Earth's troposphere is underestimated by detailed chemical models compared to field observations. Phototautomerization of acetaldehyde to its less stable tautomer vinyl alcohol, followed by the OH-initiated oxidation of vinyl alcohol, has been proposed as a missing source of formic acid that improves the agreement between models and field measurements. Theoretical investigations of the OH + vinyl alcohol reaction in excess O2 conclude that OH addition to the α carbon of vinyl alcohol produces formaldehyde + formic acid + OH, whereas OH addition to the ß site leads to glycoaldehyde + HO2. Furthermore, these studies predict that the conformeric structure of vinyl alcohol controls the reaction pathway, with the anti-conformer of vinyl alcohol promoting α OH addition, whereas the syn-conformer promotes ß addition. However, the two theoretical studies reach different conclusions regarding which set of products dominate. We studied this reaction using time-resolved multiplexed photoionization mass spectrometry to quantify the product branching fractions. Our results, supported by a detailed kinetic model, conclude that the glycoaldehyde product channel (arising mostly from syn-vinyl alcohol) dominates over formic acid production with a 3.6:1.0 branching ratio. This result supports the conclusion of Lei et al. that conformer-dependent hydrogen bonding at the transition state for OH-addition controls the reaction outcome. As a result, tropospheric oxidation of vinyl alcohol creates less formic acid than recently thought, increasing again the discrepancy between models and field observations of Earth's formic acid budget.

Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes. CASE-DIAGNOSIS: We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia. CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.

Graft dislocation following Descemet stripping automated endothelial keratoplasty: a comparative cohort analysis of Optisol GS and organ culture preserved corneas.

Previous studies have suggested risk factors for graft dislocation after Descemet stripping automated endothelial keratoplasty (DSAEK). We aimed to investigate the influence of eye bank storage solution as a risk factor for graft dislocation, as this could have significant implications for eye banking practices. This retrospective analysis compared cohorts from the QEII Health Sciences Center, Halifax, Canada (donor corneas preserved in Optisol GS) and the Royal Victorian Eye and Ear Hospital, Melbourne, Australia (donor corneas preserved in organ culture). Patient, surgical, and post-operative data were collected for consecutive DSAEK surgeries performed between 2012 and 2020. Risk factors were analyzed using univariate and multivariate logistic regression modeling. 654 DSAEK surgeries were performed during the study period: 271 in the Optisol GS storage cohort and 383 in the organ culture cohort. The most common indications were pseudophakic bullous keratopathy, Fuchs endothelial dystrophy, and failed previous DSAEK. The incidence of graft dislocation requiring surgical repositioning was 9.6% (n = 26) in the Optisol GS cohort and 12.0% (n = 46) in the organ culture cohort (OR, 0.50, 95% CI, 0.20-1.13). Development of graft dislocation was associated with intraoperative venting incisions (OR, 2.50, 95% CI, 1.12-5.51) and a post-operative wound leak (OR, 55.24, 95% CI, 10.20-514.85). The incidence of DSAEK dislocation was similar between study sites using Optisol GS and organ culture, suggesting changes in eye bank storage solution would not mitigate this post-operative complication. Intraoperative creation of venting incisions and post-operative wound leaks and were factors associated with graft dislocation.

Is the presence of tumor-infiltrating lymphocytes predictive of outcomes in patients with melanoma?

BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.

Is There a Relationship Between TILs and Regression in Melanoma?

BACKGROUND: The relationship between tumor-infiltrating lymphocytes (TILs) and regression in melanoma is unknown. This report describes a large multicenter study assessing the association between TILs and regression. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with TILs and regression data. Clinicopathologic factors were correlated with regression and TIL status, sentinel lymph node (SLN) status, and overall survival (OS). RESULTS: The study enrolled 2450 patients. In 1811 cases, TILs (73.9%) were present, with regression present in 328 of these 1811 (18.1%) cases and in 49 (7.7%) of 639 cases without TILs. The presence of TILs was significantly associated with regression (p < 0.0001) as well as a negative SLN (p < 0.05). However, when TILs were stratified by regression status, only absence or presence of both TILs and regression were significantly associated with SLN metastases (p = 0.038). Although the presence of TILs was associated with OS (p < 0.05), regression status by itself was not (p = 0.2058 and 0.252, respectively). Furthermore, when TILs were stratified by regression status, only the presence of TILs with or without regression was significantly associated with improved OS (p = 0.0081 and 0.0137, respectively) versus the absence of both TILs and regression, with regression status not significantly affecting OS for patients with or without TILs (p = 0.2314 and 0.65, respectively). CONCLUSIONS: Regression is highly correlated with TILs, but only TILs are significantly associated with SLN metastasis and OS in melanoma patients, whereas regression is not. The impact of regression on outcomes ultimately appears dependent upon the absence or presence of TILs.

Regression in melanoma is significantly associated with a lower regional recurrence rate and better recurrence-free survival.

BACKGROUND AND OBJECTIVES: The prognostic significance of regression in predicting melanoma recurrences is unknown. We present a large multicenter study correlating regression with recurrence. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with regression data. Clinicopathologic factors were correlated with overall and first-site of recurrence and with recurrence-free survival (RFS). RESULTS: There were 4790 patients and the median follow-up was 39.6 months. Regression and recurrences were seen in 1081 (22.6%) and 773 (16.1%) cases, respectively. First-site locoregional and distant recurrences were seen in 412 (8.6%) and 352 (7.3%) patients, respectively. Regression was seen in 15.8% and 24.7% of all cases with and without recurrences (p < 0.0001), respectively, while regression was seen in 14.3% and 17.9% of first-site locoregional and distant recurrent cases, respectively, compared with 23.3% and 22.9% of patients with regression and without first-site locoregional and distant recurrences, respectively (p = 0.29). On multivariable analysis, after controlling for age, gender, thickness, ulceration, lymphovascular invasion, and sentinel lymph node status, regression significantly predicted improved RFS (p = 0.004) and fewer first-site regional recurrences (p = 0.017). CONCLUSION: Our data suggest that regression is a favorable prognostic marker in melanoma and predicts significantly better RFS and decreased first-site regional recurrences.

Yields of HONO2 and HOONO Products from the Reaction of HO2 and NO Using Pulsed Laser Photolysis and Mid-Infrared Cavity-Ringdown Spectroscopy.

The reaction of HO2 with NO is one of the most important steps in radical cycling throughout the stratosphere and troposphere. Previous literature experimental work revealed a small yield of nitric acid (HONO2) directly from HO2 + NO. Atmospheric models previously treated HO2 + NO as radical recycling, but inclusion of this terminating step had large effects on atmospheric oxidative capacity and the concentrations of HONO2 and ozone (O3), among others. Here, the yield of HONO2, φHONO2, from the reaction of HO2 + NO was investigated in a flow tube reactor using mid-IR pulsed-cavity ringdown spectroscopy. HO2, produced by pulsed laser photolysis of Cl2 in the presence of methanol, reacted with NO in a buffer gas mixture of N2 and CO between 300 and 700 Torr at 278 and 300 K. HONO2 and its weakly bound isomer HOONO were directly detected by their v1 absorption bands in the mid-IR region. CO was used to suppress HONO2 produced from OH + NO2 and exploit a chemical amplification scheme, converting OH back to HO2. Under the experimental conditions described here, no evidence for the formation of either HONO2 or HOONO was observed from HO2 + NO. Using a comprehensive chemical model, constrained by observed secondary reaction products, all HONO2 detected in the system could be accounted for by OH + NO2. At 700 ± 14 Torr and 300 ± 3 K, φHONO2 = 0.00 ± 0.11% (2σ) with an upper limit of 0.11%. If all of the observed HONO2 was attributed to the HO2 + NO reaction, φHONO2 = 0.13 ± 0.07% with an upper limit of 0.20%. At 278 ± 2 K and 718 ± 14 Torr, we determine an upper limit, φHONO2 ≤ 0.37%. Our measurements are significantly lower than those previously reported, lying outside of the uncertainty of the current experimental and recommended literature values.

Educating with Captain America: metabolic and nutritional considerations.

Captain America can bring more than entertainment value to the public. The pop icon can also be used effectively in the science classroom, encouraging students to more effectively learn the content. How Captain America uses nutrients and how often he eats are novel ways to communicate real science. The point is to make a connection using science to explain how the superhero can run faster, jump higher, or lift more than is humanly possible. In this way fun, teachable moments are available for the educator.

Sentinel Lymph Node Biopsy Is Prognostic in Thickest Melanoma Cases and Should Be Performed for Thick Melanomas.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended for intermediate thickness melanoma, but for thick melanoma, guidelines are less definitive about the use of SLNB in this population. We present a study on thick melanoma evaluating for prognostic factors. PATIENTS AND METHODS: The Sentinel Lymph Node Working Group database was queried for thick (> 4 mm) melanoma cases that had a SLNB from 1993 to 2018. Clinicopathologic characteristics were correlated with SLN status and melanoma-specific survival (MSS). RESULTS: There were 1235 patients. Median follow-up was 28 months. Median thickness was 5.9 mm, with 956, 175, and 104 cases presenting thickness > 4-8, > 8-12, and > 12 mm, respectively. SLN metastases were seen in 439 of 1235 (35.5%) cases and in 33.9%, 40.6%, and 42.3% of melanomas > 4-8, > 8-12, and > 12 mm, respectively. In each thickness group, MSS was significantly worse for SLN-positive compared with SLN-negative cases (all P < 0.005). Multivariable analysis showed that SLN metastasis, male gender, increasing thickness, lymphovascular invasion, and microsatellitosis significantly predicted worse MSS for melanomas > 4-8 mm, with SLN metastasis showing the greatest risk (HR 2.17, 95% CI 1.64-2.87, P < 0.0001). For melanomas > 8 mm, only SLN metastasis significantly predicted MSS (> 8-12 mm: HR 3.93, 95% CI 2.00-7.73, P < 0.0001; > 12 mm: HR 3.58, 95% CI 1.56-8.22, p < 0.0027). CONCLUSIONS: Thick melanoma patients with SLN metastasis have significantly worse MSS compared with SLN-negative patients, even in the thickest cases, and SLN status is the most powerful and/or only predictor of MSS. Given these results, SLNB shows important prognostic value in this population and is indicated for clinically localized thick melanoma.

Micrometastatic cancer cells in lymph nodes, bone marrow, and blood: Clinical significance and biologic implications.

Cancer metastasis may be regarded as a progressive process from its inception in the primary tumor microenvironment to distant sites by way of the lymphovascular system. Although this type of tumor dissemination often occurs in an orderly fashion via the sentinel lymph node (SLN), acting as a possible gateway to the regional lymph nodes, bone marrow, and peripheral blood and ultimately to distant metastatic sites, this is not a general rule as tumor cells may enter the blood and spread to distant sites, bypassing the SLN. Methods of detecting micrometastatic cancer cells in the SLN, bone marrow, and peripheral blood of patients have been established. Patients with cancer cells in their SLN, bone marrow, or peripheral blood have worse clinical outcomes than patients with no evidence of spread to these compartments. The presence of these cells also has important biologic implications for disease progression and the clinician's understanding of the process of cancer metastasis. Further characterization of these micrometastatic cancer cells at each stage and site of metastasis is needed to design novel selective therapies for a more "personalized" treatment.

Evaluating the impact of coronavirus disease 2019 on asthma morbidity: A comprehensive analysis of potential influencing factors.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic period is experiencing better asthma control, fewer exacerbations, and health care utilization, with limited data on factors that could explain this phenomenon. OBJECTIVE: To confirm these improved asthma outcomes during COVID-19 and evaluate potential contributing factors. METHODS: In 18,912 pediatric patients with asthma treated in the Children's Hospital of Orange County network from 2017 to 2020, monthly asthma-related encounters and medication summaries were extracted from electronic health records, particulate matter 2.5 (PM2.5) air pollution from the California Air Resources Board, and influenza-like illness from Illness Surveillance Network for the first 6 months of each year. Changes in outcomes between January to March and April to June (post-COVID-19 shutdown in 2020) were compared with historical data using generalized estimating equations analyses for patient outcomes and generalized linear models for pollution exceedance, influenza-positive, and telehealth visit rates. RESULTS: During COVID-19, we found 78%, 90%, 68% reductions in hospitalization, emergency department visits, and exacerbations, respectively, compared with pre-COVID-19 2020, with significantly greater changes than the same time period of 2017 to 2019 and significant reductions in albuterol and inhaled corticosteroid use (P < .05). Emergency department visit reduction was not seen for African Americans. The PM2.5 and influenza rates were also significantly reduced during COVID-19 (P < .05). Increased rates in telehealth visits were greater in the publicly insured group when compared with commercially insured. CONCLUSION: Our data confirm reduced health care utilization and suggest better asthma control during COVID-19, except for African Americans. This was associated with a significant increase in telehealth visits and reductions in PM2.5 and influenza infections, but not better asthma controller adherence.