Generative AI Platform for Automating Social Media Posts From Urology Journal Articles: A Cross-Sectional Study and Randomized Assessment.

PURPOSE: This cross-sectional study assessed a generative-AI platform to automate the creation of accurate, appropriate, and compelling social-media (SoMe) posts from urological journal articles. MATERIALS AND METHODS: One hundred SoMe-posts from the top 3 journals in urology X (Twitter) profiles were collected from Aug-2022 to Oct-2023 A freeware GPT-tool was developed to auto-generate SoMe posts, which included title-summarization, key findings, pertinent emojis, hashtags, and DOI links to the article. Three physicians independently evaluated GPT-generated posts for achieving tetrafecta of accuracy and appropriateness criteria. Fifteen scenarios were created from 5 randomly selected posts from each journal. Each scenario contained both the original and the GPT-generated post for the same article. Five questions were formulated to investigate the posts' likability, shareability, engagement, understandability, and comprehensiveness. The paired posts were then randomized and presented to blinded academic authors and general public through Amazon Mechanical Turk (AMT) responders for preference evaluation. RESULTS: Median (IQR) time for post auto-generation was 10.2 seconds (8.5-12.5). Of the 150 rated GPT-generated posts, 115 (76.6%) met the correctness tetrafecta: 144 (96%) accurately summarized the title, 147 (98%) accurately presented the articles' main findings, 131 (87.3%) appropriately used emojis and hashtags 138 (92%). A total of 258 academic urologists and 493 AMT responders answered the surveys, wherein the GPT-generated posts consistently outperformed the original journals' posts for both academicians and AMT responders (P < .05). CONCLUSIONS: Generative-AI can automate the creation of SoMe posts from urology journal abstracts that are both accurate and preferable by the academic community and general public.

Real-time estimation of nephron activity with a linear measurement system (RENAL-MS) predicts postoperative estimated glomerular filtration rate.

OBJECTIVE: To determine whether a simple point-of-care measurement system estimating renal parenchymal volume using tools ubiquitously available could be used to replace nuclear medicine renal scintigraphy (NMRS) in current clinical practice to predict estimated glomerular filtration rate (eGFR) after nephrectomy by estimating preoperative split renal function. PATIENTS AND METHODS: We performed a retrospective review of patients who underwent abdominal cross-sectional imaging (computed tomography/magnetic resonance imaging) and mercaptoacetyltriglycine (MAG3) NMRS prior to total nephrectomy at a single institution. We developed the real-time estimation of nephron activity with a linear measurement system (RENAL-MS) method of estimating postoperative renal function via the following technique: renal parenchymal volume of the removed kidney relative to the remaining kidney was estimated as the product of renal length and the average of six renal parenchymal thickness measurements. The utility of this value was compared to the utility of the split renal function measured by MAG3 for prediction of eGFR and new onset Stage 3 chronic kidney disease (CKD) at ≥90 days after nephrectomy using uni- and multivariate linear and logistic regression. RESULTS: A total of 57 patients met the study criteria. The median (interquartile range [IQR]) age was 69 (61-80) years. The median (IQR) pre- and postoperative eGFR was 74 (IQR 58-90) and 46 (35-62) mL/min/1.73 m2 , respectively. [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] Correlations between actual and predicted postoperative eGFR were similar whether the RENAL-MS or NMRS methods were used, with correlation using RENAL-MS being slightly numerically but not statistically superior (R = 0.82 and 0.76; P = 0.138). Receiver operating characteristic curve analysis using logistic regression estimates incorporating age, sex, and preoperative creatinine to predict postoperative Stage 3 CKD were similar between RENAL-MS and NMRS (area under the curve 0.93 vs. 0.97). [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] CONCLUSION: A point-of-care tool to estimate renal parenchymal volume (RENAL-MS) performed equally as well as NMRS to predict postoperative eGFR and de novo Stage 3 CKD after nephrectomy in our population, suggesting NMRS may not be necessary in this setting.

Transperineal versus Transrectal MRI/TRUS fusion-guided prostate biopsy in a large, ethnically diverse, and multiracial cohort.

PURPOSE: To compare transperineal (TP) vs transrectal (TR) magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) fusion-guided prostate biopsy (PBx) in a large, ethnically diverse and multiracial cohort. MATERIALS AND METHODS: Consecutive patients who underwent multiparametric (mp) MRI followed by TP or TR TRUS-fusion guided PBx, were identified from a prospective database (IRB #HS-13-00663). All patients underwent mpMRI followed by 12-14 core systematic PBx. A minimum of two additional target-biopsy cores were taken per PIRADS≥3 lesion. The endpoint was the detection of clinically significant prostate cancer (CSPCa; Grade Group, GG≥2). Statistical significance was defined as p<0.05. RESULTS: A total of 1491 patients met inclusion criteria, with 480 undergoing TP and 1011 TR PBx. Overall, 11% of patients were Asians, 5% African Americans, 14% Hispanic, 14% Others, and 56% White, similar between TP and TR (p=0.4). For PIRADS 3-5, the TP PBx CSPCa detection was significantly higher (61% vs 54%, p=0.03) than TR PBx, but not for PIRADS 1-2 (13% vs 13%, p=1.0). After adjusting for confounders on multivariable analysis, Black race, but not the PBx approach (TP vs TR), was an independent predictor of CSPCa detection. The median maximum cancer core length (11 vs 8mm; p<0.001) and percent (80% vs 60%; p<0.001) were greater for TP PBx even after adjusting for confounders. CONCLUSIONS: In a large and diverse cohort, Black race, but not the biopsy approach, was an independent predictor for CSPCa detection. TP and TR PBx yielded similar CSPCa detection rates; however the TP PBx was histologically more informative.

Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest.

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, the authors examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest.

IRBs and the Protection-Inclusion Dilemma: Finding a Balance.

Institutional review boards, tasked with facilitating ethical research, are often pulled in competing directions. In what we call the protection-inclusion dilemma, we acknowledge the tensions IRBs face in aiming to both protect potential research participants from harm and include under-represented populations in research. In this manuscript, we examine the history of protectionism that has dominated research ethics oversight in the United States, as well as two responses to such protectionism: inclusion initiatives and critiques of the term vulnerability. We look at what we know about IRB decision-making in relation to protecting and including "vulnerable" groups in research and examine the lack of regulatory guidance related to this dilemma, which encourages protection over inclusion within IRB practice. Finally, we offer recommendations related to how IRBs might strike a better balance between inclusion and protection in research ethics oversight.

Antibody-Mediated Immunogenicity Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Following Priming, Boosting, and Hybrid Immunity: Insights From 11 Months of Follow-up of a Healthcare Worker Cohort in Israel, December 2020-October 2021.

BACKGROUND: We determined circulating anti-S severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody titers in a vaccinated healthcare workers (HCWs) cohort from Northern Israel in the 11 months following primary vaccination according to age, ethnicity, and previous infection status. METHODS: All consenting HCWs were invited to have their IgG levels measured before vaccination and at 6 subsequent timepoints using a quantitative S1/S2 IgG assay. All HCWs with suspected coronavirus disease 2019 (COVID-19) were polymerase chain reaction (PCR) tested. We described trends in circulating IgG geometric mean concentration (GMC) by age, ethnicity, timing of boosting, and previous infection status and compared strata using Kruskall-Wallis tests. RESULTS: Among 985 vaccinated HCWs, IgG titers between 1 month post 2nd dose to pre-boosting gradually decreased in all age groups. Younger or previously infected individuals had higher initial post-vaccination IgG levels (P < .001 in both cases); differences substantially decreased or disappeared at 7-9 months, before boosting. The proportion of individuals infected prior to initiating vaccination and re-infected after dose 1 was comparable to the proportion of breakthrough infection post-dose 2 in those not previously infected (4.2 vs 4.7%). Pre-infection IgG levels in the 40 participants with breakthrough infection after dose 2 were similar to levels measured at the same timepoint in vaccinated HCWs who remained uninfected (P > .3). Post-dose3 IgG levels were more than 10-fold those 1 month post-dose 2. CONCLUSIONS: Immunity waned in all age groups and previously infected individuals, reversed by boosting. IgG titers decrease and reinfections in individuals with hybrid immunity (infection + vaccination) suggests they may also require further doses. Our study also highlights the difficulty in determining protective IgG levels.

Life Expectancy of 1-Year Survivors of Traumatic Brain Injury, 1988-2019: Updated Results From the TBI Model Systems.

OBJECTIVE: To update the life expectancy estimates according to age, sex, mobility, and feeding skills reported in the 2015 study of Brooks et al. To examine trends in survival over the past decade. DESIGN: Observational cohort study. SETTING: Poisson regression and life table analysis applied to long-term follow-up data on United States (US) Traumatic Brain Injury (TBI) Model Systems patients recorded in the national database. Functional mobility and feeding skills were assessed with FIM. PARTICIPANTS: A total of 14,803 persons with TBI during the years 1988-2019 who underwent inpatient rehabilitation and provided at least 1 long-term assessment of functional skills 1 year or more postinjury (N=14,803). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Survival, mortality rates, and life expectancy. RESULTS: Life expectancy was lower than that of the age- and sex-matched general population. Older age and severity of functional impairments were risk factors for mortality (both P<.0001 in regression models). Among ambulatory individuals, mortality was 51% (95% confidence interval, 35%-69%) higher in men than women. Life expectancy of 20-year-old women who walked well (FIM ambulation score 7) was 55 (SE=0.8) additional years to age 75, representing a reduction of 6.9 years from the normal general population figure. For 20-year-old men who walked well, the life expectancy was 49 (SE=0.5) additional years, representing a reduction of 8.1 years from normal. Life expectancies for men and women who did not walk and were fed by others were much lower. There was no significant change in mortality rates during the study period (hazard ratio, 1.008; P=.07). CONCLUSIONS: There has been no significant change in the long-term survival of persons with TBI in the US since the late 1980s. The life expectancies reported here are similar to those reported in the 2015 study of Brooks et al, although they are more precise because of the larger sample size and longer follow-up.

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

In Vitro Testing of Sunscreens for Dermal Absorption: Method Comparison and Rank Order Correlation with In Vivo Absorption.

Evaluating the dermal absorption of sunscreen UV filters requires the development of a bio-predictable in vitro permeation test (IVPT). This work describes the comparison of two IVPT methods and rank order correlations of in vitro absorption (skin permeation and retention) with the in vivo absorption (AUC and skin retention) of sunscreens. The IVPT was compared regarding the following elements: (1) application of a single finite dose vs. an infinite dose and (2) the use of heat-separated human epidermis vs. dermatomed skin models. The IVPT was used to evaluate dermal absorption of six UV filters (avobenzone, homosalate, octinoxate, octisalate, octocrylene, and oxybenzone) in commercial sunscreens. Both the in vivo and in vitro permeation studies demonstrated that all UV filters were absorbed following a single-dose application. Sunscreens were rank ordered by the amount of the UV filters absorbed. Data obtained from the IVPT method using a single finite dose and heat-separated human epidermis was found to correlate with the clinical data. Rank orders of the cumulative in vitro skin permeation and the in vivo AUC were found comparable for oxybenzone, homosalate, octisalate, and octinoxate. Rank orders of the in vitro and in vivo skin retention of oxybenzone and octinoxate were also comparable. Additional IVPT parameters may be optimized to enhance the discriminatory power for UV filters with low skin permeation potential (e.g., avobenzone and octocrylene).

Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial.

Importance: In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. Objective: To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. Interventions: Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. Main Outcome and Measure: Twenty-four-hour urinary excretion of NDMA. Results: Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. Conclusions and Relevance: In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. Trial Registration: ClinicalTrials.gov Identifier: NCT04397445.

Predicting potential adverse events using safety data from marketed drugs.

BACKGROUND: While clinical trials are considered the gold standard for detecting adverse events, often these trials are not sufficiently powered to detect difficult to observe adverse events. We developed a preliminary approach to predict 135 adverse events using post-market safety data from marketed drugs. Adverse event information available from FDA product labels and scientific literature for drugs that have the same activity at one or more of the same targets, structural and target similarities, and the duration of post market experience were used as features for a classifier algorithm. The proposed method was studied using 54 drugs and a probabilistic approach of performance evaluation using bootstrapping with 10,000 iterations. RESULTS: Out of 135 adverse events, 53 had high probability of having high positive predictive value. Cross validation showed that 32% of the model-predicted safety label changes occurred within four to nine years of approval (median: six years). CONCLUSIONS: This approach predicts 53 serious adverse events with high positive predictive values where well-characterized target-event relationships exist. Adverse events with well-defined target-event associations were better predicted compared to adverse events that may be idiosyncratic or related to secondary target effects that were poorly captured. Further enhancement of this model with additional features, such as target prediction and drug binding data, may increase accuracy.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

INTRODUCTION: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. METHODS: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. RESULTS: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Low lead one ratio predicts clinical outcomes in left bundle branch block.

INTRODUCTION: We evaluated the association between a novel electrocardiographic (ECG) marker of late, rightward electrocardiographic forces (termed the lead one ratio [LOR]), and left ventricular ejection fraction (LVEF), myocardial scar, and clinical outcomes in patients with left bundle branch block (LBBB). METHODS AND RESULTS: LOR was calculated in patients with LBBB from a derivation cohort (n = 240) and receiver operator characteristic curves identified optimal threshold values for predicting myocardial scar and LVEF less than 35%. An independent validation cohort of patients with LBBB (n = 196) was used to test the association of LOR with the myocardial scar, LVEF, and the likelihood of death, heart transplant or left ventricular assist device (LVAD) implantation. The optimal thresholds in the derivation cohort were LOR less than 13.7 for identification of scar (sensitivity 55%, specificity 80%), and LOR less than 12.1 for LVEF less than 35% (sensitivity 49%, specificity 80%). In the validation cohort, LOR less than 13.7 was not associated with scar size or presence (P > 0.05 for both). LOR less than 12.1 was associated with lower LVEF (30 [20-40] versus 40 [25-55]%; P = 0.002) and predicted LVEF less than 35% in univariable (odds ratio [OR], 2.2 [1.2-4.1]; P = 0.01) and multivariable analysis (OR, 2.2 [1.2-4.3]; P = 0.02). LOR less than 12.1 was associated with scar presence when patients with nonischemic cardiomyopathy were excluded (OR = 7.2 [1.5-33.2]; P = 0.002). LOR less than 12.1 had an adjusted hazard ratio of 1.53 ([1.05-2.21]; P = 0.03) for death, transplant or LVAD implantation. CONCLUSIONS: In conclusion, ECG LOR less than 12.1 predicts reduced-LV systolic function and poorer prognosis in patients with LBBB.

Preoperative CHA2DS2-VASc Score Predicts Postoperative Atrial Fibrillation after Lobectomy.

BACKGROUND: Postoperative atrial fibrillation (POAF) affects 10 to 20% of noncardiac thoracic surgeries and increases patient morbidity and costs. The purpose of this study is to determine if preoperative CHA2DS2-VASc score can predict POAF after pulmonary lobectomy for nonsmall cell lung cancer. METHODS: Patients with complete CHA2DS2-VASc data who underwent lobectomies from January 2007 to January 2016 at a single institution were analyzed in a retrospective case-control study using a prospective database. An independent samples t-test was used to compare the mean CHA2DS2-VASc scores of POAF and non-POAF groups. A multivariable logistic regression analysis (MVA) evaluated the independent contribution of variables of the CHA2DS2-VASc score in predicting POAF. Chi-square test with univariate odds ratios (ORs) was used to determine a statistically significant cutoff score for predicting POAF. RESULTS: Of 525 total patients, 82 (15.6%) developed POAF (mean CHA2DS2-VASc score: 2.7) and 443 (84.4%) did not develop POAF (mean score: 2.3). Mean difference between these groups was significant at 0.43 (p = 0.01; 95% confidence interval [CI]: 0.09-0.76). In the MVA, significant predictors of POAF were age 65 to 74 years (adjusted OR [aOR] = 2.45; 95% CI: 1.31-4.70; p = 0.006) and age ≥75 years (aOR = 3.11; 95% CI: 1.62-5.95; p = 0.0006). Patients with CHA2DS2-VASc scores ≥5 had significantly increased OR for POAF (OR = 2.59; 95% CI: 1.22-5.50). CONCLUSIONS: Preoperatively calculated CHA2DS2-VASc score can predict POAF in patients undergoing pulmonary lobectomy. Age is the most statistically significant independent predictor, and patients with scores ≥5 have significantly increased risk. Trials for POAF prophylaxis should target this population.

Correction of the QRS duration for heart rate.

OBJECTIVE: To determine the clinical value of correcting the QRS duration for heart rate. BACKGROUND: We recently observed [1] that the QRS duration shortens during spontaneous increases in heart rate. In the current study, we analyzed ECG and pharmacokinetic data of 21 subjects who received quinidine in a recent study [2]. They experienced the expected post-quinidine increase in heart rate, allowing us to determine if quinidine's well-known QRS prolongation might be attenuated due to the concomitant rate increase. METHODS: In a crossover-designed study, after baseline ECG recording, the subjects received quinidine 400 mg orally or placebo, and ECGs and quinidine plasma concentrations were then obtained at 15 prespecified timepoints over 24 h. The previously determined QRS-RR regression slope (0.0125) [1] was used to rate-correct QRS. Change in QRS from baseline (dQRS) and rate-corrected change in QRS from baseline (dQRSc) over time were plotted with the mean quinidine concentration and the correlation of plasma concentration with dQRS and dQRSc was assessed by pairwise correlation and linear regression. RESULTS: There was a statistically significantly greater increase in heart rate at all timepoints combined in the quinidine arm compared with the placebo arm (9.9 ±â€¯6.80 vs. 5.2 ±â€¯7.42, respectively, p < 0.0001). dQRSc was significantly greater at all timepoints combined compared with dQRS (1.99 ±â€¯4.824 vs -0.68 ±â€¯4.640 msec, respectively, p < 0.0001). dQRS correlated poorly with quinidine plasma concentration (p = 0.127), with no clear change in QRS observed. On the other hand, dQRSc correlated well with quinidine concentration (p = 0.010), with a clear rise and fall in dQRSc that mirrored the rise and fall of quinidine concentration. CONCLUSION: Rate correction of the QRS duration improves detection of QRS prolongation in the presence of heart rate change. CONDENSED ABSTRACT: Using the mean QRS - RR slope determined previously in normal volunteers [1], we corrected the QRS duration for its known dependency on heart rate in 21 subjects who received quinidine and experienced the expected post-quinidine increase in heart rate in a recent clinical trial [2]. We found that uncorrected QRS did not correlate with quinidine concentration (p = 0.127), while rate-corrected QRS correlated well (p = 0.010) and mirrored the rise and fall of quinidine concentration. Rate correction of the QRS duration improves detection of QRS prolongation in the presence of heart rate change.

A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium.

INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Life Expectancy after Stroke Based On Age, Sex, and Rankin Grade of Disability: A Synthesis.

BACKGROUND: Stroke is a leading cause of death and disability in the developed world. The major factor affecting long term survival (other than age) is known to be the severity of disability. Yet to our knowledge there are no studies reporting life expectancies stratified by both age and severity. Remaining life expectancy is a key measure of health. METHODS: We identified 11 long-term follow-up studies of stroke patients that reported the multivariate effects of age, sex, the modified Rankin Scale (mRS) grade of disability, and other factors. From these we computed the composite effects of these factors on survival, then used these to calculate age-, sex-, and mRS-specific mortality rates. Finally we used the rates to construct life tables, and hence obtain life expectancies. RESULTS: Life expectancy varies by age, sex, and mRS. The life expectancies of males age 70, for example, were 13, 13, 11, 8, 6, and 5 years for Rankin Grades 0-5, respectively, representing reductions of 1, 1, 3, 6, 8, and 9 years from the corresponding general population figure. CONCLUSIONS: These figures demonstrate the importance of rehabilitation following stroke, and can be used in discussion of public policy and benchmarking of future results.