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Introduction There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK) -positive NSCLC and thromboembolic events. Methods A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK -positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. Results The study included 4762 patients, of which 155 (3.2%) were ALK -positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK -positive patients had a higher VTE risk compared to ALK -negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK -negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). Conclusions In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK- rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK -positive NSCLC. [ABSTRACT FROM AUTHOR]

S190426c/GW190426_152155 was the first probable neutron star–black hole merger candidate detected by the LIGO-Virgo Collaboration. We undertook a tiled search for optical counterparts of this event using the 0.7-m GROWTH-India Telescope. Over a period of two weeks, we obtained multiple observations over a 22.1 deg2 area, with a 17.5 per cent probability of containing the source location. Initial efforts included obtaining photometry of sources reported by various groups, and a visual search for sources in all galaxies contained in the region. Subsequently, we have developed an image subtraction and candidate vetting pipeline with |$\sim 94{{\ \rm per\ cent}}$| efficiency for transient detection. Processing the data with this pipeline, we find several transients, but none that are compatible with kilonova models. We present the details of our observations, the working of our pipeline, results from the search, and our interpretations of the non-detections that will work as a pathfinder during the O4 run of LVK. [ABSTRACT FROM AUTHOR]

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices. (J Thorac Cardiovasc Surg 2022;-:1–8) [ABSTRACT FROM AUTHOR]

We determine the viability of exploiting lensing time delays to observe strongly gravitationally lensed supernovae (gLSNe) from first light. Assuming a plausible discovery strategy, the Legacy Survey of Space and Time (LSST) and the Zwicky Transient Facility (ZTF) will discover ∼110 and ∼1 systems per year before the supernova (SN) explosion in the final image, respectively. Systems will be identified |$11.7^{+29.8}_{-9.3}$|  d before the final explosion. We then explore the possibility of performing early-time observations for Type IIP and Type Ia SNe in LSST-discovered systems. Using a simulated Type IIP explosion, we predict that the shock breakout in one trailing image per year will peak at ≲24.1 mag (≲23.3) in the B -band (F 218 W), however evolving over a time-scale of ∼30 min. Using an analytic model of Type Ia companion interaction, we find that in the B -band we should observe at least one shock cooling emission event per year that peaks at ≲26.3 mag (≲29.6) assuming all Type Ia gLSNe have a 1 M⊙ red giant (main sequence) companion. We perform Bayesian analysis to investigate how well deep observations with 1 h exposures on the European Extremely Large Telescope would discriminate between Type Ia progenitor populations. We find that if all Type Ia SNe evolved from the double-degenerate channel, then observations of the lack of early blue flux in 10 (50) trailing images would rule out more than 27 per cent (19 per cent) of the population having 1 M⊙ main sequence companions at 95 per cent confidence. [ABSTRACT FROM AUTHOR]

Summary: Judges, doctors and managers are among those decision makers who must often choose a course of action under limited time, with limited knowledge and without the aid of a computer. Because data‐driven methods typically outperform unaided judgements, resource‐constrained practitioners can benefit from simple, statistically derived rules that can be applied mentally. In this work, we formalize long‐standing observations about the efficacy of improper linear models to construct accurate yet easily applied rules. To test the performance of this approach, we conduct a large‐scale evaluation in 22 domains and focus in detail on one: judicial decisions to release or detain defendants while they await trial. In these domains, we find that simple rules rival the accuracy of complex prediction models that base decisions on considerably more information. Further, comparing with unaided judicial decisions, we find that simple rules substantially outperform the human experts. To conclude, we present an analytical framework that sheds light on why simple rules perform as well as they do. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the efficacy of treatments is crucial for patients, physicians, and policymakers. Median survival, the most common measure used in the outcome reporting of oncology clinical trials, is easy to understand; however, it describes only a single time point. The interpretation of the hazard ratio is difficult, and its underlying statistical assumptions are not always met. The objective of this study was to evaluate alternative measures based on the mean benefit of novel oncology treatments. Materials and Methods: We reviewed all U.S. Food and Drug Administration (FDA) approvals for oncology agents between 2013 and 2017. We digitized survival curves as reported in the clinical trials used for the FDA approvals and implemented statistical transformations to calculate for each trial the restricted mean survival time (RMST), as well as the mean survival using Weibull distribution. We compared the mean survival with the median survival benefit in each clinical trial. Results: The FDA approved 83 solid tumor indications for oncology agents between 2013 and 2017, of which 27 approvals based on response rates, whereas 49 approvals were based on survival endpoints (progression‐free survival and overall survival). The average improvement in median overall survival or progression‐free survival was 4.6 months versus 3.6 months improvement in the average RMST and 6.1 months improvement in mean survival using Weibull distribution. Conclusion: Mean survival may supply valuable information for different stakeholders. Its inclusion should be considered in the reporting of prospective clinical trials. Implications for Practice: Mean survival may supply valuable information for different stakeholders. Its inclusion should be considered in the reporting of clinical trials. Understanding the efficacy of cancer treatments is essential for patients, physicians, and policymakers. This article explores the value of using mean survival as an endpoint for outcome reporting of oncology clinical trials. [ABSTRACT FROM AUTHOR]

Investing for retirement is one of the most consequential yet daunting decisions consumers face. We present a way to both aid and understand consumers as they construct preferences for retirement income. The method enables consumers to build desired probability distributions of wealth constrained by market forces and the amount invested. We collect desired wealth distributions from a sample of working adults, provide evidence of the technique's reliability and predictive validity, characterize individual- and cluster-level differences, and estimate parameters of risk aversion and loss aversion. We discuss how such an interactive method might help people construct more informed preferences. [ABSTRACT FROM AUTHOR]

Background: The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first‐line treatment of intermediate‐ to poor‐risk patients, the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib. The high cost of combined immune‐modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost‐effectiveness of nivolumab and ipilimumab compared with sunitinib for first‐line treatment of intermediate‐ to poor‐risk advanced RCC from the U.S. payer perspective. Materials and Methods: A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first‐line treatment of intermediate‐ to poor‐risk advanced RCC. Health outcomes were measured in life‐years and quality‐adjusted life‐years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. Results: The total mean cost per‐patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. Nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost‐effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. Conclusion: Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness‐to‐pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost‐effective. Implications for Practice: This article assessed the cost‐effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate‐ to poor‐risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality‐adjusted life‐year with nivolumab and ipilimumab versus sunitinib in these patients. The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. This article reports on the cost‐effectiveness of nivolumab and ipilimumab compared with sunitinib for first‐line treatment of poor‐ to intermediate‐risk advanced RCC from the U.S. payer perspective. [ABSTRACT FROM AUTHOR]

Background. In the U.S., the addition of bevacizumab to first- line chemotherapy in metastatic colorectal cancer (mCRC) has been demonstrated to provide 0.10 quality-adjusted life years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $571,000/QALY. Due to variability in pricing, value for money may be different in other countries. Our objective was to establish the cost-effectiveness of bevacizumab in mCRC in the U.S., U.K., Canada, Australia, and Israel. Methods. We performed the analysis using a previously established Markov model for mCRC. Input data for efficacy, adverse events, and quality of life were considered to be generalizable and therefore identical for all countries. We used country-specific prices for medications, administration, and other health service costs. All costs were converted from local currency to U.S. dollars at the exchange rates in March 2016. We conducted one-way and probabilistic sensitivity analyses (PSA) to assess the model robustness across parameter uncertainties. Results. Base case results demonstrated that the highest ICER was in the U.S. ($571,000/QALY) and the lowest was in Australia ($277,000/QALY). In Canada, the U.K., and Israel, ICERs ranged between $351,000 and $358,000 per QALY. PSA demonstrated 0% likelihood of bevacizumab being cost-effective in any country at a willingness to pay threshold of $150,000 per QALY. Conclusion. The addition of bevacizumab to first-line chemotherapy for mCRC consistently fails to be cost-effective in all five countries. There are large differences in cost-effectiveness between countries. This study provides a framework for analyzing the value of a cancer drug from the perspectives of multiple international payers. [ABSTRACT FROM AUTHOR]

Although the principles of both patient‐centered health care goals and population‐centered health care goals are thoughtful and well‐meaning, they are frequently in conflict. This commentary discusses these conflicts with examples specific to the oncology clinic, with a focus on the question of how society wants medicine to be practiced and the resulting trade‐offs that answer will require. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a newly-described condition affecting individuals who are HIV-positive and are infected with human herpesvirus 8 (HHV-8). This is a syndrome that in some ways mimics severe sepsis with associated acute respiratory distress syndrome, possibly requiring a ventilator and vasopressor support. However, unlike severe sepsis, antibiotics provide no benefit.Management of KICS has not been fully elucidated because of its high mortality rate. However, the syndrome has been successfully treated in some cases with immunomodulatory therapy. It is crucial for oncologists to be able to recognize this syndrome and to institute the appropriate therapy. [ABSTRACT FROM AUTHOR]

Steinhaus asked in the 1950s whether there exists a set in ℝ2 meeting every isometric copy of ℤ2 in precisely one point. Such a ‘Steinhaus set’ was constructed by Jackson and Mauldin. What about ℝ3? Is there a subset S of ℝ3 meeting every isometric copy of ℤ3 in exactly one point? We offer heuristic evidence that the answer is ‘no’. [ABSTRACT FROM AUTHOR]

Older people exhibit increased morbidity and mortality after viral infections than younger people. Additionally, vaccines are less protective in older people than in younger people. As the immune system is critical for host defense to viral infections and for vaccine efficacy, the implications are that aging negatively affects immunity. The immune system is broadly categorized into adaptive and innate systems. The innate immune system acts as a first line of defense to pathogen invasion. In this review, I focus on how aging affects the innate immune response to viral infection. [ABSTRACT FROM PUBLISHER]

The U.S. must assess its pricing and reimbursement system for prescription drugs. The current system is attracting intense scrutiny for various reasons. Drug pricing and reimbursement mechanisms used in other countries are described to assess what an optimal system should entail. [ABSTRACT FROM AUTHOR]

Infection with Plasmodium berghei ANKA is a well-established model of human cerebral malaria (CM). We show herein that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA-infected mice. Modulation of outcome was dependent on genetic background, such that deletion of myeloid differentiation factor (MyD) 88 on the susceptible C57BL/6 background resulted in resistance to CM, whereas deletion of MyD88 on the resistant BALB/c background led to increased mortality. Our data show that MyD88 influenced the production of T helper-polarizing cytokines, including interferon (IFN)-γ, interleukin (IL)- 4, and IL-17, as well as the total number of Foxp3+ regulatory T (Treg) cells in a manner dependent on host genetic background. In addition, mRNA levels of IFN-γ, CXCL10, and CXCL9 were strongly up-regulated in the brains of susceptible wild-type but not MyD88-/- infected mice. These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and Treg cell numbers. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the safety and efficacy of multivessel beating heart revascularization in a high-risk group of patients with severe left ventricular dysfunction as well as to provide intermediate survival and quality of life data. Methods: Our prospectively updated database was queried to extract all patients with left ventricular ejection fraction ≤30% who underwent beating heart revascularization. Standard demographics, clinical profiles and outcomes were collected. Outcomes were compared with Society of Thoracic Surgeons (STS) benchmarks for all coronary artery bypass grafting (CABG) patients. Telephone interviews were conducted and survival and quality of life data were tabulated. In addition, morbidity and mortality outcomes were compared with a concurrent cohort of patients with similarly impaired left ventricular function who underwent conventional coronary artery bypass. Results: One hundred off-pump coronary artery bypass grafting patients were identified and follow-up was 93% complete in these patients. Mean age was 67±10.5 years and mean ejection fraction was 26±4%. Twenty-one percent were females. Balloon counterpulsation support was used liberally in the perioperative period. Patients received a mean of 3.5 grafts with 83% internal mammary artery use. Observed mortality was 3% with a predicted mortality of 5.3%. Observed to expected ratio was 0.56. Incidence of adverse events compared favorably with both that reported in the STS for all CABG patients regardless of left ventricular function, and also to a concurrent CABG cohort. One-year survival was 85%. Freedom from cardiac readmission was 88% and freedom from angina was 83%. No patient required repeat percutaneous or surgical intervention. Conclusions: We conclude that multivessel off-pump revascularization in patients with severe left ventricular dysfunction is a safe and effective alternative to conventional grafting. Long-term follow-up is mandatory to confirm these encouraging intermediate outcomes. [Copyright &y& Elsevier]

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime's many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented that focuses on issues related to the cost and value of cancer care including the right of public and private payers to refuse coverage for an expensive therapy that offers only minimal clinical benefit, the different pricing and reimbursement mechanisms used around the world, and the significance of communicating with patients about the cost and benefit of cancer care.

Health care institutions, physicians, and patients can—and should—be more involved in evaluating the role of new therapies such as ramucirumab in metastatic colorectal cancer based on their value. This is especially true in the case of a treatment that adds no additional benefit in terms of efficacy or toxicity compared with the current standard of care and has a higher cost. [ABSTRACT FROM AUTHOR]

Background: In October 2016, pembrolizumab became the new standard of care for firstline treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death ligand 1 in at least 50% of cells. The US Food and Drug Administration-recommended dose is 200 mg every three weeks. Multiple studies have demonstrated equivalent efficacy with weight-based doses between 2 mg/kg and 10 mg/kg. The objective of this study was to compare the economic impact of using personalized dosing (2 mg/kg) vs fixed dosing (200 mg) in the firstline setting of mNSCLC.Methods: We performed a budget impact analysis from the US societal perspective to compare fixed dosing with personalized dosing. We calculated the target population and weight of patients who would be treated with pembrolizumab annually in the firstline setting. Using survival curves from the KEYNOTE 024 trial with Weibull extrapolation, we estimated the mean number of cycles that patients would receive. Using the Medicare average sales price, we calculated the difference in cost between personalized and fixed dosing.Results: Our base case model demonstrates that the total annual cost of pembrolizumab with fixed dosing is US $3 440 127 429, and with personalized dosing it is US $2 614 496 846. The use of personalized dosing would lead to a 24.0% annual savings of US $825 630 583 in the United States.Conclusions: Personalized dosing of pembrolizumab may have the potential to save approximately $0.825 billion annually in the United States, likely without impacting outcomes. This option should be considered for the firstline management of PD-L1-positive advanced lung cancer. [ABSTRACT FROM AUTHOR]