Cost-Effectiveness Analysis of Atezolizumab Versus Durvalumab as First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer in the USA.

BACKGROUND AND OBJECTIVES: Durvalumab and atezolizumab are approved as first-line therapy in extensive-stage small-cell lung cancer. Although cost-effectiveness analyses compared these immunotherapy drugs with standard chemotherapy-alone regimens, no head-to-head cost-effectiveness comparisons for these treatments exist. The aim of the present analysis is to determine the cost-effectiveness of durvalumab and atezolizumab as first-line therapy for extensive-stage small-cell lung cancer from the US payers' perspective. METHODS: This study is based on two placebo-controlled, phase 3 clinical trials: CASPIAN and IMpower133. A Markov model was developed to simulate the three health states: progression-free survival, progressed disease, and death in patients with extensive-stage small-cell lung cancer. Transition probabilities were estimated from the clinical trial survival curves and extended with life-time modelling. Health utilities and direct costs of adverse event treatment were included. Main outcome was the incremental cost-effectiveness ratio (ICER) using quality-adjusted life-years saved (QALYS). Sensitivity analysis was performed to assess the impact of variables on the ICER. RESULTS: Durvalumab group has a cost of $187,503 with an effectiveness of 1.08 while atezolizumab has a cost of $160,219 and an effectiveness of 0.932. Durvalumab is not cost-effective compared to atezolizumab with an ICER of $165,182 QALYS, which is over the willingness-to-pay threshold of $150,000. The model was most sensitive to durvalumab cost and the cost of treating durvalumab adverse effects. CONCLUSIONS: With the ICER of durvalumab treatment group being very close to $150,000, setting a higher willingness-to-pay threshold or decreasing the drug cost through contract pricing can increase the cost-effectiveness of durvalumab compared to atezolizumab.

Crash and disengagement data of autonomous vehicles on public roads in California.

Autonomous Vehicles (AVs) are being widely tested on public roads in several countries such as the USA, Canada, France, Germany, and Australia. For the transparent deployment of AVs in California, the California Department of Motor Vehicles (CA DMV) commissioned AV manufacturers to draft and publish reports on disengagements and crashes. These reports must be processed before any statistical analysis, which is cumbersome and time-consuming. Our dataset presents the processed disengagement data from 2014 to 2019, crash data till the 10th of March 2020 and supplementary road network and land-use data extracted from OpenStreetMap. Primary data are manually assessed and converted into an easily processed format. Our processed data will be advantageous to the research community and enable accelerated research in this domain. For example, the data can be utilised to discern trends in disengagement, observe the distribution of disengagement causes, and investigate the contributory factors of the crashes. Such investigations can subsequently improve the reporting protocols and make policies and laws for the smooth deployment of this disruptive technology.

Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy.

BACKGROUND: Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection. METHODS: We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S. RESULTS: Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4. CONCLUSIONS: We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.

Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS).

BACKGROUND: Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. METHODS: Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. RESULTS: At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96. CONCLUSIONS: HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. CLINICAL TRIALS REGISTRATION: NCT00537394.

Bilateral abducens nerve palsy due to septic thrombophlebitis.

PURPOSE: To report a case of septic thrombophlebitis producing bilateral abducens nerve palsy. OBSERVATION: A 65 year-old woman with recent sinus surgery experienced the onset of horizontal diplopia during treatment for bacteremia. Computer tomography of head and a neck ultrasonography showed right internal jugular vein occlusion. Ophthalmology examination was consistent with bilateral abducens nerve palsy. She was treated with systemic antibiotics and antiplatelet therapy with resolution of the internal jugular vein occlusion. The diplopia improved over a six-months. CONCLUSION AND IMPORTANCE: Our patient had Lemierre syndrome with an unusual presentation. The patient was treated for septic thrombophlebitis with a resolution of her ocular symptoms.

Ledipasvir/Sofosbuvir for 8 Weeks to Treat Acute Hepatitis C Virus Infections in Men With Human Immunodeficiency Virus Infections: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals.

BACKGROUND: Current guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population. METHODS: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin. RESULTS: We enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 - 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90-100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred. CONCLUSIONS: This multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads. CLINICAL TRIALS REGISTRATION: NCT02128217.

A MULTIVARIATE GAUSSIAN PROCESS FACTOR MODEL FOR HAND SHAPE DURING REACH-TO-GRASP MOVEMENTS.

We propose a Multivariate Gaussian Process Factor Model to estimate low dimensional spatio-temporal patterns of finger motion in repeated reach-to-grasp movements. Our model decomposes and reduces the dimensionality of variation of the multivariate functional data. We first account for time variability through multivariate functional registration, then decompose finger motion into a term that is shared among replications and a term that encodes the variation per replication. We discuss variants of our model, estimation algorithms, and we evaluate its performance in simulations and in data collected from a non-human primate executing a reach-to-grasp task. We show that by taking advantage of the repeated trial structure of the experiments, our model yields an intuitive way to interpret the time and replication variation in our kinematic dataset.

Instillation versus inhalation of multiwalled carbon nanotubes: exposure-related health effects, clearance, and the role of particle characteristics.

Inhaled multiwalled carbon nanotubes (MWCNTs) may cause adverse pulmonary responses due to their nanoscale, fibrous morphology and/or biopersistance. This study tested multiple factors (dose, time, physicochemical characteristics, and administration method) shown to affect MWCNT toxicity with the hypothesis that these factors will influence significantly different responses upon MWCNT exposure. The study is unique in that (1) multiple administration methods were tested using particles from the same stock; (2) bulk MWCNT formulations had few differences (metal content, surface area/functionalization); and (3) MWCNT retention was quantified using a specialized approach for measuring unlabeled MWCNTs in rodent lungs. Male Sprague-Dawley rats were exposed to original (O), purified (P), and carboxylic acid functionalized (F) MWCNTs via intratracheal instillation and inhalation. Blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected at postexposure days 1 and 21 for quantifying biological responses and MWCNTs in lung tissues by programmed thermal analysis. At day 1, MWCNT instillation produced significant BALF neutrophilia and MWCNT-positive macrophages. Instilled O- and P-MWCNTs produced significant inflammation in lung tissues, which resolved by day 21 despite MWCNT retention. MWCNT inhalation produced no BALF neutrophilia and no significant histopathology past day 1. However, on days 1 and 21 postinhalation of nebulized MWCNTs, significantly increased numbers of MWCNT-positive macrophages were observed in BALF. Results suggest (1) MWCNTs produce transient inflammation if any despite persistence in the lungs; (2) instilled O-MWCNTs cause more inflammation than P- or F-MWCNTs; and (3) MWCNT suspension media produce strikingly different effects on physicochemical particle characteristics and pulmonary responses.

Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats.

Glycemic regulation improves myocardial function in diabetic patients, but finding optimal therapeutic strategies remains challenging. Recent data have shown that pharmacological inhibition of soluble epoxide hydrolase (sEH), an enzyme that decreases the endogenous levels of protective epoxyeicosatrienoic acids (EETs), improves glucose homeostasis in insulin-resistant mice. Here, we tested whether the administration of sEH inhibitors preserves cardiac myocyte structure and function in hyperglycemic rats. University of California-Davis-type 2 diabetes mellitus (UCD-T2DM) rats with nonfasting blood glucose levels in the range of 150-200 mg/dl were treated with the sEH inhibitor 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU) for 6 wk. Administration of APAU attenuated the progressive increase of blood glucose concentration and preserved mitochondrial structure and myofibril morphology in cardiac myocytes, as revealed by electron microscopy imaging. Fluorescence microscopy with Ca(2+) indicators also showed a 40% improvement of cardiac Ca(2+) transients in treated rats. Sarcoplasmic reticulum Ca(2+) content was decreased in both treated and untreated rats compared with control rats. However, treatment limited this reduction by 30%, suggesting that APAU may protect the intracellular Ca(2+) effector system. Using Western blot analysis on cardiac myocyte lysates, we found less downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the main route of Ca(2+) reuptake in the sarcoplasmic reticulum, and lower expression of hypertrophic markers in treated versus untreated UCD-T2DM rats. In conclusion, APAU enhances the therapeutic effects of EETs, resulting in slower progression of hyperglycemia, efficient protection of myocyte structure, and reduced Ca(2+) dysregulation and SERCA remodeling in hyperglycemic rats. The results suggest that sEH/EETs may be an effective therapeutic target for cardioprotection in insulin resistance and diabetes.

ENCODING AND DECODING V1 FMRI RESPONSES TO NATURAL IMAGES WITH SPARSE NONPARAMETRIC MODELS.

Functional MRI (fMRI) has become the most common method for investigating the human brain. However, fMRI data present some complications for statistical analysis and modeling. One recently developed approach to these data focuses on estimation of computational encoding models that describe how stimuli are transformed into brain activity measured in individual voxels. Here we aim at building encoding models for fMRI signals recorded in the primary visual cortex of the human brain. We use residual analyses to reveal systematic nonlinearity across voxels not taken into account by previous models. We then show how a sparse nonparametric method [bJ. Roy. Statist. Soc. Ser. B71 (2009b) 1009-1030] can be used together with correlation screening to estimate nonlinear encoding models effectively. Our approach produces encoding models that predict about 25% more accurately than models estimated using other methods [Nature452 (2008a) 352-355]. The estimated nonlinearity impacts the inferred properties of individual voxels, and it has a plausible biological interpretation. One benefit of quantitative encoding models is that estimated models can be used to decode brain activity, in order to identify which specific image was seen by an observer. Encoding models estimated by our approach also improve such image identification by about 12% when the correct image is one of 11,500 possible images.

Information in the nonstationary case.

Information estimates such as the direct method of Strong, Koberle, de Ruyter van Steveninck, and Bialek (1998) sidestep the difficult problem of estimating the joint distribution of response and stimulus by instead estimating the difference between the marginal and conditional entropies of the response. While this is an effective estimation strategy, it tempts the practitioner to ignore the role of the stimulus and the meaning of mutual information. We show here that as the number of trials increases indefinitely, the direct (or plug-in) estimate of marginal entropy converges (with probability 1) to the entropy of the time-averaged conditional distribution of the response, and the direct estimate of the conditional entropy converges to the time-averaged entropy of the conditional distribution of the response. Under joint stationarity and ergodicity of the response and stimulus, the difference of these quantities converges to the mutual information. When the stimulus is deterministic or nonstationary the direct estimate of information no longer estimates mutual information, which is no longer meaningful, but it remains a measure of variability of the response distribution across time.

Coverage-adjusted entropy estimation.

Data on 'neural coding' have frequently been analyzed using information-theoretic measures. These formulations involve the fundamental and generally difficult statistical problem of estimating entropy. We review briefly several methods that have been advanced to estimate entropy and highlight a method, the coverage-adjusted entropy estimator (CAE), due to Chao and Shen that appeared recently in the environmental statistics literature. This method begins with the elementary Horvitz-Thompson estimator, developed for sampling from a finite population, and adjusts for the potential new species that have not yet been observed in the sample-these become the new patterns or 'words' in a spike train that have not yet been observed. The adjustment is due to I. J. Good, and is called the Good-Turing coverage estimate. We provide a new empirical regularization derivation of the coverage-adjusted probability estimator, which shrinks the maximum likelihood estimate. We prove that the CAE is consistent and first-order optimal, with rate O(P)(1/log n), in the class of distributions with finite entropy variance and that, within the class of distributions with finite qth moment of the log-likelihood, the Good-Turing coverage estimate and the total probability of unobserved words converge at rate O(P)(1/(log n)(q)). We then provide a simulation study of the estimator with standard distributions and examples from neuronal data, where observations are dependent. The results show that, with a minor modification, the CAE performs much better than the MLE and is better than the best upper bound estimator, due to Paninski, when the number of possible words m is unknown or infinite.