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Abstract In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success. Currently, cancer screening in the general population is recommended for a limited set of cancers; as a result, most cancer types are not regularly screened. Thus, in recent years, we have seen a wave of novel, non‐invasive, single‐ and multi‐cancer detection tests (SCD and MCD), promising detection of cancer signals prior to the onset of symptoms and/or clinical diagnosis. To accelerate the development, access, and adoption of these tests, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices, established the Early Detection & Screening (ED&S) Working Group. The early detection space is in need of consensus around definitions for SCD and MCD tests that harmonize terminology across diverse stakeholders, thereby reducing communication barriers and ultimately advancing the discipline. To this end, the ED&S Working Group compiled a lexicon of terms, chosen based on perceived importance, frequency of use, lack of clarity, and unique challenges in the context of SCD and MCD tests. This lexicon was submitted to the FDA for their feedback, which was incorporated. In this work, we present the first installment of the lexicon, consisting of 14 primary terms, that will be part of an online dictionary and provide a foundation for future projects of BLOODPAC's ED&S Working Group.

Abstract Introduction: Researchers and policymakers recognize that leveraging data routinely collected in clinical practice can support improved research and patient care. Embedding elements of clinical trials, such as patient identification and trial data acquisition, into clinical practice can enable research access and increase efficiencies by reducing duplication of trial and care activities. Yet, cultural, administrative, and data barriers exist. The Clinical Trials Transformation Initiative (CTTI) developed evidenced-based, multi-partner recommendations to facilitate embedding interventional, randomized trials into clinical practice. Methods: We conducted in-depth interviews (IDIs) with trial designers and implementers to describe their motivations for embedding interventional, randomized trials into clinical practice. Additionally, we aimed to identify barriers and potential solutions to implementing such trials. Interviews were audio-recorded and analyzed using applied thematic analysis. Results: We conducted 16 IDIs with 18 trial designers and implementers. Motivations for embedding trials into clinical practice included the desire to implement a learning health system and evaluate trials in real-world settings. Barriers to trial implementation focused on limited staff time and availability, the lack of buy-in, and difficulties using electronic health record data. Solutions included minimizing healthcare settings and patient burden, having a sufficient data and research infrastructure in place, and creating a culture change. Conclusion: The results informed CTTI recommendations to facilitate the design and operation of embedded trials. These recommendations emphasize areas where sponsors and investigators can rethink the design and conduct of clinical trials to ultimately realize an aligned system of research and care.

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.

To ensure uncertainty in match outcomes, professional sporting leagues have used various competitive balance policies, including player salary caps, revenue sharing among teams and player drafts. The Australian Football League (AFL) introduced a player draft in 1986, and to refine its operation, a draft value index (DVI) was introduced in 2015. The DVI allocates a numeric value to each individual player draft pick, with these values determined by the AFL using historic player compensation or wage and salary data. The AFL DVI plays an essential role in the operation of its player draft; however, other research has questioned the validity of such indexes. This paper aims to produce an alternative to the AFL DVI. The former index uses career compensation as the determinant of value, whereas we use other measures of player performance. First, various models were developed to predict on-field performance, such as games played (both in a recruit's career and season) after a draftee was selected for the first time by a team. This was then retrofitted to the pick used to select these draftees to create the new DVIs. Even though the predicted DVI followed an inverse monotonic function like the existing index, the decline in value for the DVI produced here was less steep, unlike the AFL's. This allowed us to conclude that players' salaries did not always strongly correlate to performance. The change in performance between players selected at different points in the draft did not vary as much as their wages. Though this scheme is applied to the AFL, the underlying concept could be directly exported to other player drafts.

During physiological stress responses such as vigorous exercise, emotional states of fear and rage, and asphyxia, the nervous system induces a massive release of systemic catecholamines that prepares the body for survival by increasing cardiac output and redirecting blood flow from non-essential organs into the cardiopulmonary circulation. A curious byproduct of this vital response is a sudden, transient, and redistributive leukocytosis provoked mostly by the resultant shear forces exerted by rapid blood flow on marginated leukocytes. Generalized convulsive seizures, too, result in catecholamine surges accompanied by similar leukocytoses, the magnitude of which appears to be rooted in semiological factors such as convulsive duration and intensity. This manuscript reviews the history, kinetics, physiology, and clinical significance of post-convulsive leukocyte elevations and discusses their clinical utility, including a proposed role in the scientific investigation of sudden unexpected death in epilepsy (SUDEP).

Review of Mel Stanfill, Exploiting fandom: How the media industry seeks to manipulate fans. Iowa City: University of Iowa Press, 2019, paperback, $75 (262p), ISBN 978-1609386238.

Abstract Glaucoma is one of the leading causes of blindness, and there is an ongoing need for new therapies. Recent studies indicate that cell transplantation using Müller glia may be beneficial, but there is a need for novel sources of cells to provide therapeutic benefit. In this study, we have isolated Müller glia from retinal organoids formed by human induced pluripotent stem cells (hiPSCs) in vitro and have shown their ability to partially restore visual function in rats depleted of retinal ganglion cells by NMDA. Based on the present results, we suggest that Müller glia derived from retinal organoids formed by hiPSC may provide an attractive source of cells for human retinal therapies, to prevent and treat vision loss caused by retinal degenerative conditions. Stem Cells Translational Medicine 2019;8:775&784

Abstract Breath holding divers display extraordinary voluntary control over involuntary reactions during apneic episodes. After an initial easy phase to the breath hold, this voluntary control is applied against the increasing involuntary effort to inspire. We quantified an electromyographic (EMG) signal associated with respiratory movements derived from broad bandpass ECG recordings taken from experienced breath holding divers during prolonged dry breath holds. We sought to define their relationship to involuntary respiratory movements and compare these signals with what is known to occur in obstructive sleep apnea (OSA) and epileptic seizures. ECG and inductance plethysmography records from 14 competitive apneists (1 female) were analyzed. ECG records were analyzed for intervals and the EMG signal was extracted from a re‐filtered version of the original broad bandpass signal and ultimately enveloped with a Hilbert transform. EMG burst magnitude, quantified as an area measure, increased over the course of the struggle phase, correlated with inductance plethysmography measures, and corresponded to significant variance in heart rate variability. We conclude that an EMG signal extracted from the ECG can complement plethysmography during breath holds and may help quantify involuntary effort, as reported previously for obstructive sleep apnea. Further, given the resemblance between cardiac and respiratory features of the breath hold struggle phase to obstructive apnea that can occur during sleep or in association with epileptic seizure activity, the struggle phase may be a useful simulation of obstructive apnea for controlled experimentation that can help clarify aspects of acute and chronic apnea‐associated physiology.

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of death in young adults with uncontrolled seizures. First aid guidance to prevent SUDEP, though, has not been previously published because the rarity of monitored cases has made the underlying mechanism difficult to define. This starkly contrasts with the first aid guidelines for sudden cardiac arrest that have been developed based on retrospective studies and expert consensus and the discussion of resuscitation challenges in various American Heart Association certificate courses. However, an increasing amount of evidence from documented SUDEP cases and near misses and from animal models points to a consistent sequence of events that starts with sudden airway occlusion and suggests a mechanistic basis for enhancing seizure first aid. In monitored cases, this sudden airway occlusion associated with seizure activity can be accurately inferred from inductance plethysmography or (depending on recording bandwidth) from electromyographic (EMG) bursts that are associated with inspiratory attempts appearing on the electroencephalogram (EEG) or the electrocardiogram (ECG). In an emergency setting or outside a hospital, seizure first aid can be improved by (1) keeping a lookout for sudden changes in airway status during a seizure, (2) distinguishing thoracic and abdominal movements during attempts to inspire from effective breathing, (3) applying a simple maneuver, the laryngospasm notch maneuver, that may help with airway management when aggressive airway management is unavailable, (4) providing oxygen early as a preventative step to reduce the risk of death, and (5) performing cardiopulmonary resuscitation before the limited post-ictal window of opportunity closes. We propose that these additions to first aid protocols can limit progression of any potential SUDEP case and prevent death. Risk stratification can be improved by recognition of airway occlusion, attendant hypoxia, and need for resuscitation.

BackgroundThe COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments.MethodsElectronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined.ResultsNeither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events.ConclusionAdministration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

Sudden unexpected death in epilepsy (SUDEP) claims the lives of one in every thousand epileptic patients each year. Autonomic, cardiac, and respiratory pieces to a mechanistic puzzle have not yet been completely assembled. We propose a single sequence of causes and effects that unifies disparate and competitive concepts into a single algorithm centered on ictal obstructive apnea. Based on detailed animal studies that are sometimes impossible in humans, and striking parallels with a growing body of clinical examples, this framework (1) accounts for the autonomic, cardiac, and respiratory data to date by showing the causal relationships between specific elements, and (2) highlights specific kinds of data that can be used to precisely classify various patient outcomes. The framework also justifies a “near miss” designation to be applied to any cases with evidence of obstructive apnea even, and perhaps especially, in individuals that do not require resuscitation. Lastly, the rationale for preventative oxygen therapy is demonstrated. With better mechanistic understanding of SUDEP, we suggest changes for detection and classification to increase survival rates and improve risk stratification.

Background Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.Methods Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.Results Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.Conclusions Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

Field potential oscillations reflect repetitive firing and synaptic activity by ensembles of neurons in certain areas of the brain. They can be distinguished as slow (e.g., alpha, delta, and theta), fast (e.g., beta and gamma), and high frequency oscillations (HFOs). Neuronal oscillations are involved in a variety of physiological and pathophysiological states such as cognition, consciousness, and seizures. The laminar structure of rat hippocampus affords a way to study these oscillations in hippocampal slices. Rat ventral hippocampal brain slices were cut and maintained in a recording chamber that permitted 64 simultaneous extracellular recordings in the presence of artificial CSF. Brief single stimulus pulses were applied with bipolar electrodes to the CA3 or CA1 regions of hippocampus. Single pulses triggered epileptiform population events that included HFOs in the 150–250 Hz range in the presence of GABAA receptor blockade or kainic acid. HFOs also occurred spontaneously in the presence of kainic acid. The oscillations had the largest amplitude in the CA3c cell layer, regardless of the drug, and were synchronized throughout the cell layer. AMPA receptor blockade stopped these HFOs, whereas NMDA receptor blockade did not. Gap junction activation did not restore HFOs in the presence of AMPA receptor blockade. Our findings suggest that a population of excitatory neurons in CA3c may be a primary focus of seizure-like activity in Ammon's Horn. We suggest that the interconnection of CA3c is different from the rest of CA3.

Background: Despite increased incorporation of patient-reported outcome (PRO) measures into clinical trials, information generated from PROs remains largely absent from drug labeling and electronic health records, giving rise to concerns that such information is not adequately informing clinical practice. Objective: To evaluate oncologists’ perceptions concerning the availability and quality of information generated from PRO measures. Additionally, to identify whether an association exists between perceptions of availability and attitudes concerning quality. Method: An online, 11-item questionnaire was developed to capture clinician perspectives on the availability and use of PRO data to inform practice. The survey also asked respondents to rate information on the basis of 4 quality metrics: “usefulness,” “interpretability,” “accessibility,” and “scientific rigor.” Results: Responses were received from 298 of 1301 invitations sent (22.9% response rate). Perceptions regarding the availability of PRO information differed widely among respondents and did not appear to be linked to practice setting. Ratings of PRO quality were generally consistent, with average ratings for the 4 quality metrics between “satisfactory” and “good.” A relationship was observed between ratings of PRO data quality and perceptions of the availability. Conclusion: Oncologists’ attitudes toward the quality of information generated from PRO measures are favorable but not enthusiastic. These attitudes may improve as the availability of PRO data increases, given the association we observed between oncologists’ ratings of the quality of PRO information and their perceptions of its availability.

As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and experimental studies in animals, such as mice, in which aspects of brain structure and function can be manipulated to target mechanistic steps. An animal model whose brain is structurally closer to the human brain, that lives much longer than rodents, and whose husbandry is practical may be valuable for mechanistic studies that cannot readily be conducted in rodents. To demonstrate that the long-lived Seba’s short-tailed fruit bat, Carollia perspicillata, may fit this role, we used immunohistochemical labeling for NeuN and three calcium-binding proteins, calretinin, parvalbumin, and calbindin, to define hippocampal formation anatomy. Our findings demonstrate patterns of principal neuron organization that resemble primate and human hippocampal formation and patterns of calcium-binding protein distribution that help to define subregional boundaries. Importantly, we present evidence for a clear prosubiculum in the bat brain that resembles primate prosubiculum. Based on the similarities between bat and human hippocampal formation anatomy, we suggest that Carollia has unique advantages for the study of brain aging and neurodegeneration. A captive colony of Carollia allows age tracking, diet and environment control, pharmacological manipulation, and access to behavioral, physiological, anatomical, and molecular evaluation.

A yearlong U.S. Army field study in Afghanistan examined the demographics and threat perceptions of one of the most-at-risk populations, that of Afghan truck drivers working for NATO’s International Security Assistance Force Afghanistan (ISAF). The study collected data from 766 Afghan truck drivers at the U.S.-operated Kandahar Airfield in ISAF’s Regional Command South. The findings show a wide diversity in age of the Afghan drivers as well as in terms of their home province. The findings also show that although all Afghan truck drivers had acute awareness and understanding of the high risks and dangers of the job, they all noted that the attractive salary and scarcity of jobs were dominant reasons for staying on the job. Findings also reveal a strong resentment among the Afghan truck drivers about their treatment by ISAF soldiers, as for the lack of protection for them and their families after the 2014 departure of NATO forces. The findings can provide significant insights and enhance the understanding of scholars, counterinsurgency strategists, policymakers, and military planners about “Host Country Nationals” as an important population of the human terrain.

Dielectric elastomers are widely investigated as soft electromechanically active polymers (EAPs) for actuators, stretch/force sensors, and mechanical energy harvesters to generate electricity. Although the performance of such devices is limited by the dielectric strength of the constitutive material, the electrical breakdown of soft elastomers for electromechanical transduction is still scarcely studied. Here, we describe a custom-made setup to measure electrical breakdown of soft EAPs, and we present data for a widely studied acrylic elastomer (VHB 4905 from 3M). The elastomer was electrically stimulated via a planar and a hemispherical metal electrode. The breakdown was characterized under different conditions to investigate the effects of the radius of curvature and applied force of the hemispherical electrode. With a given radius of curvature, the breakdown field increased by about 50% for a nearly 10-fold increase of the applied mechanical stress, while with a given mechanical stress the breakdown field increased by about 20% for an approximately twofold increase of the radius of curvature. These results indicate that the breakdown field is highly dependent on the boundary conditions, suggesting the need for reporting breakdown data always in close association with the measurement conditions. These findings might help future investigations in elucidating the ultimate breakdown mechanism/s of soft elastomers.