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The rise in markups and market power documented by De Loecker, Eeckhout, and Unger (2020) has recently generated much discussion in economics. We measure the correlation between the change in firm level markups and the change in industry level prices as measured by the Producer Price Index and find little to no relationship both for 1980-2018 and 2018-present. While a “false negative” result due to mismeasurement is possible, it also raises the possibility that firms have not passed along declines in marginal costs to consumers or that there have been significant changes in scale elasticities.

In an April 1962 article previewing the First International Webern Festival, Hans Moldenhauer promised that Anton Webern's music would one day be known as ‘the music of the space age’. Moldenhauer chose his words carefully. The Webern Festival was set to take place in Seattle at the same time as the World's Fair (an event also known as the ‘Century 21 Exposition’ and ‘America's Space Age World's Fair’) and its opening night concert would be held on the grounds of the World's Fair. Yet the two ‘W.F.s’ made for an awkward pairing. Far from space-age music, the lush textures and sweeping gestures of the Webern's Festival's posthumous premieres revealed a young Webern rooted in nineteenth-century Romanticism. Critics and scholars’ responses to these premieres reveal much about the contested place of Webern's music – and modernist music more generally – within mid-century mainstream culture.

Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification.Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts.Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P.05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015).We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

We evaluate the association of familial factors and suicidality among transgender adults in the U.S. by estimating the odds of lifetime suicide ideation and attempt using the 2015 U.S. Transgender Survey. Predictors include family support, family rejection, and specific experiences related to both. About 79% of sample respondents have experienced suicidal ideation and nearly 43% have made a suicide attempt. The predicted probability of suicide attempt is 0.35 for those with no family rejection experiences, 0.75 for those who have had all five experiences in our models. Rejection predicts both outcomes and experiences of rejection have a cumulative impact.

Eosinophilic gastrointestinal (GI) disorders are a group of conditions marked by pathologic eosinophilic infiltration of one or multiple locations in the GI tract. Conditions include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis. The site and depth of eosinophilic infiltration of the GI tract usually determines clinical presentation. These conditions should be considered in the differential diagnosis for several GI symptoms, such as food impaction or dysphagia. Histopathology is the gold standard for diagnosis of eosinophilic disorders. Nevertheless, findings from endoscopy, barium studies, computed tomography or magnetic resonance imaging, can aid in the diagnosis, by allowing for earlier diagnosis as well as proper management. Eosinophilic gastrointestinal disorders are typically managed with corticosteroids or dietary elimination. A high index of suspicion is required for diagnosis as it can often be challenging.

_ The increasing availability of affordable finite element modeling software and computational fluid dynamics codes have given today’s sailing yacht designers tools that, in the past, were only available to designers of yachts competing in the most high-profile events. This paper provides a case study on the structural design of the International America’s Cup Class Yacht Stars & Stripes USA-34, which won the U.S. defender series, the Citizen Cup, leading up to the 29th America’s Cup competition in 1995. The authors have recently been able to publicly share this information, and feel that the problem-solving approach is of direct use to many of today’s designers. The design approach is twofold, the first being the use of Finite Element Analysis to minimize drag-inducing local deformations. Over 80 finite element models were analyzed with varying configurations, starting with an initial baseline structure based on the previous boat, USA-11. These structural improvements reduced local hull deflection from5 to 6 mm per meter on the previous design to less than 1 mm per meter on the USA-34 design. The second part of the design approach isolates the hydrodynamic effects of global bending under rig tension. Illustrative tank tests are provided to demonstrate how the global sagging of the hull, caused by rig tension, can often increase the resistance of a yacht (especially one built for racing). As part of a series of steps taken to mitigate the effect of rig tension, a novel design was developed, with soft patches and flexible structure to permit low-cost modification of the hull in the boatyard, giving approximately a 225mm increase in waterline length and 75 mm reduction in beam if needed—a modification that was made to USA-34 prior to winning the finals of the Citizen Cup, and at a cost of under $500. The reduction of drag-inducing local hull form deformations, and the development of the cost-saving hull modification concept, demonstrate how a creative designer can take advantage of the finite element modeling tools that are now widely available.

Background & aimsTumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration.MethodsClinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a-/- and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. Invivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine exvivo regenerative potential.ResultsDr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC enteroids.ConclusionsOur findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.

Fibrotic lung diseases represent a large subset of diseases with an unmet clinical need. Oligonucleotide therapies (ONT) are a promising therapeutic approach for the treatment of pulmonary disease as they can inhibit pathways that are otherwise difficult to target. Additionally, targeting the lung specifically with ONT is advantageous because it reduces the possibilities of systemic side effects and tolerability concerns.This review presents the chemical basis of designing various ONTs currently known to treat fibrotic lung diseases. Further, the authors have also discussed the delivery vehicle, routes of administration, physiological barriers of the lung, and toxicity concerns with ONTs.ONTs provide a promising therapeutic approach for the treatment of fibrotic diseases of the lung, particularly because ONTs directly delivered to the lung show little systemic side effects compared to current therapeutic strategies. Dry powder aerosolized inhalers may be a good strategy for getting ONTs into the lung in humans. However, as of now, no dry powder ONTs have been approved for use in the clinical setting, and this challenge must be overcome for future therapies. Various delivery methods that can aid in direct targeting may also improve the use of ONTs for lung fibrotic diseases.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

Despite advances in neuroscience, limited progress has been made in developing new and better medications for psychiatric disorders. Available treatments in psychiatry rely on a few classes of drugs that have a broad spectrum of activity across disorders with limited understanding of mechanism of action. While the added value of more targeted therapies is apparent, a dearth of pathophysiologic mechanisms exists to support targeted treatments, and where mechanisms have been identified and drugs developed, results have been disappointing. Based on serendipity and early successes that led to the current drug armamentarium, a haunting legacy endures that new drugs should align with outdated and overinclusive diagnostic categories, consistent with the idea that "one size fits all". This legacy has fostered clinical trial designs focused on heterogenous populations of patients with a single diagnosis and non-specific outcome variables. Disturbingly, this approach likely contributed to missed opportunities for drugs targeting the hypothalamic-pituitary-adrenal axis and now inflammation. Indeed, cause-and-effect data support the role of inflammatory processes in neurotransmitter alterations that disrupt specific neurocircuits and related behaviors. This pathway to pathology occurs across disorders and warrants clinical trial designs that enrich for patients with increased inflammation and use primary outcome variables associated with specific effects of inflammation on brain and behavior. Nevertheless, such trial designs have not been routinely employed, and results of anti-inflammatory treatments have been underwhelming. Thus, to accelerate development of targeted therapeutics including in the area of inflammation, regulatory agencies and the pharmaceutical industry must embrace treatments and trials focused on pathophysiologic pathways that impact specific symptom domains in subsets of patients, agnostic to diagnosis. Moreover, closer collaboration among basic and clinical investigators is needed to apply neuroscience knowledge to reveal disease mechanisms that drive psychiatric symptoms. Together, these efforts will support targeted treatments, ultimately leading to new and better therapeutics in psychiatry.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver worldwide. Noninvasive diagnosis of HCC is possible based on imaging features, without the need for tissue diagnosis. Liver Imaging Reporting and Data System (LI-RADS) CT/MRI diagnostic algorithm allows for standardized radiological interpretation and reporting of imaging studies for patients at high risk for HCC. Diagnostic categories of LR-1 to LR-5 designate each liver observation to reflect the probability of overall malignancy, HCC, or benignity based on imaging features, where LR-5 category has 95% probability of HCC. Optimal imaging protocol and scanning technique as described by the technical recommendations for LI-RADS are essential for the depiction of features to accurately characterize liver observations. The LI-RADS MRI technical guidelines recommend the minimum required sequences of T1-weighted out-of-phase and in-phase Imaging, T2-weighted Imaging, and multiphase T1-weighted Imaging. Additional sequences, including diffusion-weighted imaging, subtraction imaging, and the hepatobiliary phase when using gadobenate dimeglumine as contrast, improve diagnostic confidence, but are not required by the guidelines. These optional sequences can help differentiate true lesions from pseudolesions, detect additional observations, identify parenchymal observations when other sequences are suboptimal, and improve observations conspicuity. This manuscript reviews the optional sequences, the advantages they offer, and discusses technical optimization of these sequences to obtain the highest image quality and to avoid common artifacts.

Acute promyelocytic leukemia (APL) is associated with severe coagulopathy leading to rapid morbidity and mortality if left untreated. The definitive diagnosis of APL is made by identifying a balanced reciprocal translocation between chromosomes 15 and 17. This t(15;17) results in a fusion transcript of promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes and the expression of a functional PML/RARA protein. Detection of a fused PML/RARA genomic DNA sequence using fluorescence in situ hybridization (FISH) or by detection of the PML/RARA fusion transcript via reverse transcriptase polymerase chain reaction (RT-PCR) has revolutionized the diagnosis and monitoring of APL. Once confirmed, APL is cured in over 90% of cases, making it the most curable subtype of acute leukemia today. Patients with low-risk APL are successfully treated using a chemotherapy-free combination of all-trans retinoic acid and arsenic trioxide (ATO). In this review, we explore the work that has gone into the modern-day diagnosis and highly successful treatment of this once devastating leukemia.

PURPOSE: Artificial intelligence (AI) has high diagnostic accuracy for coronary artery disease (CAD) from myocardial perfusion imaging (MPI). However, when trained using high-risk populations (such as patients with correlating invasive testing), the disease probability can be overestimated due to selection bias. We evaluated different strategies for training AI models to improve the calibration (accurate estimate of disease probability), using external testing. METHODS: Deep learning was trained using 828 patients from 3 sites, with MPI and invasive angiography within 6-months. Perfusion was assessed using upright (U-TPD) and supine total perfusion deficit (S-TPD). AI training without data augmentation (Model 1) was compared to training with augmentation (increased sampling) of patients without obstructive CAD (Model 2), and patients without CAD and TPD

Individuals with lower limb amputation exhibit lower residual limb strength compared to their sound limb. Deficits in residual limb knee flexion and extension strength may impact functional performance during tasks relevant to daily living.Does knee flexor and extensor strength in the residual limb impact functional outcome measures, such as walking energetics and performance metrics, in individuals with unilateral transtibial amputation?Fourteen individuals with traumatic unilateral transtibial amputation were recruited for this observational study. Participants completed metabolic testing at three standardized speeds based on leg length, as well maximum isokinetic knee flexion and extension strength for both residual and sound limbs. Participants also completed a series of functional outcome tests, including a two-minute walk test, timed stair ascent test, and four-square step test. Walking energetics (metabolic cost, heart rate, and rating of perceived exertion) and performance metrics were compared to percent deficit of residual limb to sound limb knee flexion and extension muscle strength. A linear regression assessed significant relationships (p 0.05).A significant relationship was observed between percent deficit of knee extension strength and heart rate (p = 0.024) at a fast walking speed. Additionally, percent deficit knee flexion strength related to rating of perceived exertion at slow and moderate walking speeds (p = 0.038, p = 0.024). Percent deficit knee extension strength related to two-minute walk time performance (p = 0.035) and percent deficit knee flexion strength related to timed stair ascent time (p = 0.025).These findings suggest the importance of strength retention of the residual limb knee flexion and extension musculature to improve certain functional outcomes in individuals with unilateral transtibial amputation.

To evaluate if preoperative MRI can predict the most frequent HCC subtypes in North American and European patients treated with surgical resection.A total of 119 HCCs in 97 patients were included in the North American group and 191 HCCs in 176 patients were included in the European group. Lesion subtyping was based on morphologic features and immuno-histopathological analysis. Two radiologists reviewed preoperative MRI and evaluated the presence of imaging features including LI-RADS major and ancillary features to identify clinical, biologic, and imaging features associated with the main HCC subtypes.Sixty-four percent of HCCs were conventional. The most frequent subtypes were macrotrabecular-massive (MTM-15%) and steatohepatitic (13%). Necrosis (OR = 3.32; 95% CI: 1.39, 7.89; p = .0064) and observation size (OR = 1.011; 95% CI: 1.0022, 1.019; p = .014) were independent predictors of MTM-HCC. Fat in mass (OR = 15.07; 95% CI: 6.57, 34.57; p.0001), tumor size (OR = 0.97; 95% CI: 0.96, 0.99; p = .0037), and absence of chronic HCV infection (OR = 0.24; 95% CI: 0.084, 0.67; p = .0068) were independent predictors of steatohepatitic HCC. Independent predictors of conventional HCCs were viral C hepatitis (OR = 3.20; 95% CI: 1.62, 6.34; p = .0008), absence of fat (OR = 0.25; 95% CI: 0.12, 0.52; p = .0002), absence of tumor in vein (OR = 0.34; 95% CI: 0.13, 0.84; p = .020), and higher tumor-to-liver ADC ratio (OR = 1.96; 95% CI: 1.14, 3.35; p = .014) CONCLUSION: MRI is useful in predicting the most frequent HCC subtypes even in cohorts with different distributions of liver disease etiologies and tumor subtypes which might have future treatment and management implications.• Representation of both liver disease etiologies and HCC subtypes differed between the North American and European cohorts of patients. • Retrospective two-center study showed that liver MRI is useful in predicting the most frequent HCC subtypes.

Vernal pool fairy shrimp, Branchinecta lynchi, is a freshwater crustacean endemic to California and Oregon, including California’s Central Valley. B. lynchi is listed as a Federally Threatened species under the US Endangered Species Act, and as a vulnerable species on the IUCN Red List. Threats that may negatively impact vernal pool fairy shrimp populations include pesticide applications to agricultural land use (e.g., agrochemicals such as organophosphate pesticides) and climate changes that impact vernal pool hydrology. Pop-GUIDE (Population model Guidance, Use, Interpretation, and Development for Ecological risk assessment) is a comprehensive tool that facilitates development and implementation of population models for ecological risk assessment and can be used to document the model derivation process. We employed Pop-GUIDE to document and facilitate the development of a population model for investigating impacts of organophosphate pesticides on vernal pool fairy shrimp populations in California’s Central Valley. The resulting model could be applied in combination with field assessment and laboratory-based chemical analysis to link effects from pesticide exposure to adverse outcomes in populations across their range. B. lynchi has a unique intra-annual life cycle that is largely dependent upon environmental conditions. Future deployment of this population model should include complex scenarios consisting of multiple stressors, whereby the model is used to examine scenarios that combine chemical stress resulting from exposure to pesticides and climate changes.

This article proposes a transdimensional (trans-D) geoacoustic inversion method adapted to range-dependent (RD) propagation tracks based on prior information from a high-resolution seismic survey. Most trans-D inversions to date model the seabed as a stack of range-independent homogeneous layers, with unknown geoacoustic parameters and an unknown number of layers. The proposed method models the seabed as an unknown number of homogeneous sediment layers with an RD thickness structure and applies an adiabatic normal-mode model to predict acoustic propagation. To do so, the method extrapolates trans-D seabed models proposed at the receiver position over the range of the propagation track using reflector-interface information from a seismic survey. The method is applied successfully to modal time–frequency dispersion data collected over an RD track during the 2017 Seabed Characterization Experiment (SBCEX).

In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K).Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score.At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]).Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

We analyzed calls of three related sandpipers to document species’ similarities and differences. We hypothesized that functionally different calls would differ in degree of divergence. We studied two nuptial calls (complex “Song” and rhythmically repeated aerial call, RRC) of males, and a general-purpose call (“alarm” trill, AT) given by parents of both sexes in the presence of humans and other potential predators, in a small clade: great knot, Calidris tenuirostris (Horsfeld, 1821); surfbird, C. virgata (Gmelin, 1789); and red knot, C. canutus (Linnaeus 1758). Calls diverged unevenly across species, but RRCs and Song diverged most and ATs least. Vocalizations of great knot and surfbird were most similar to one another, in agreement with a recently proposed phylogeny. Despite species differences in single acoustic traits, calls were evolutionarily conservative at higher structural levels, such as rhythmic temporal delivery of RRCs and harmonic structure (e.g., the fundamental frequency was commonly suppressed). Some acoustic qualities that differed across species were similar across call types within species (e.g., tonality in red knot calls). Trait similarity across different calls suggests that a species’ calls cannot evolve independently of one another: common mechanisms of vocal production across different calls may impede differentiation within a species’ repertoire.

Allometric analyses of sexually selected structures have revealed many patterns of evolutionary and behavioural significance (e.g. in weapons, ornaments, genitalia). We investigated allometry of the baculum (penis bone) relative to body size in adults of three large mustelids: wolverine (Gulo gulo (Linnaeus, 1758)), northern river otter (Lontra canadensis (Schreber, 1776)), and sea otter (Enhydra lutris (Linnaeus, 1758)). Bacular growth took place over a longer period than body growth. Correlations among bacular variables were positive. No regression slopes expressed positive allometry (i.e. slope > 1 for linear variables). These trends point to the possibility that bacular size is adapted to average size of the reproductive tract of sexually mature female northern river otters and possibly sea otters, and that pre-ejaculatory (“pre-copulatory”) selection is highest in those species. Bacular size varied more than skull or limb-bone size; bacular shape also varied greatly. Species differed in size and complexity of the urethral groove and bacular apex, suggesting functional differences in intromission. Substantial variation in bacular shape resulted from healed fractures, especially in sea otter. Knowledge of copulatory behaviour, age of breeding, female reproductive anatomy, and genitalic interactions during intromission is needed for fuller understanding of bacular anatomy, allometry, and variation for these species.

A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https : //neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

We present the first continuous Holocene fire record of Iceland from a lacustrine archive in the northeast region. We use pyrogenic PAHs (polycyclic aromatic hydrocarbons) to trace shifts in fire regimes, paired to a continuous record of n-alkanes, faecal sterols, perylene, biogenic silica, and 13C, as proxies for soil erosion, lake productivity, and human presence.Paleoclimate research across Iceland provides a template for changes in climate across the northern North Atlantic. The role of orbitally driven cooling, volcanism, and human impact as triggers of local environmental changes, such as fire and soil erosion, is debated. While there are indications that human impact could have reduced environmental resilience in a context of deteriorating climatic conditions, it is still difficult to resolve to what extent human and natural factors affected Iceland landscape instability, due also to a lack of data on natural fire regime prior and during human colonisation.Pyrogenic PAHs can be formed during the incomplete combustion of biomass initiated by humans or natural wildfires. Factors such as fire temperature, biomass typology, and source distance can strongly affect pyrogenic PAH molecular weight and spatial distribution. Faecal sterols/stanols and their ratios have been used in archaeological and paleoclimate studies to detect human and/or livestock/herbivore waste. The absence of large herbivorous mammals and humans in Iceland prior to settlement means that increases in the occurrence of faecal sterols and bile acids over natural background values should mark the arrival of humans and associated livestock in the catchment, which could be traced regionally.Our results indicate that the Icelandic fire regime during the Holocene followed four main phases. Among these, a very long period centred around the Holocene climatic optimum (ca 9.5 – 4.5 ka BP) was characterised by a generally low frequency fire regime, both in the lake catchment as in the whole north-eastern Iceland. This same period was also marked by relatively low background levels of faecal sterols/stanols. At 4.5 ka BP a new phase started, with a general increase of all PAHs values. According to both our PAH and sterol data, there is no apparent human signal around the 9th century C.E., where an increase in man-made fires would likely be expected in connection to the historical data of Viking colonisation of Iceland (870s C.E.), suggesting that fire regimes have primarily been controlled by natural factors. In addition, the pyrogenic PAHs record also differs from the trend of a general stepwise climatic “deterioration” previously highlighted by other lake proxies throughout Iceland, linked to decreasing summer insolation and related cooling, as highlighted also by our other proxies.A comparison to recent palynological data from a nearby site and to δD data from the NW region suggest shifts in NAO regimes as the main forcing behind shifting fire regimes in Iceland. Changes in precipitation regimes would have determined shifts in the composition of the regional vegetational community, increasing fuel availability and flammability with decreasing precipitation, leading to widespread low temperature fires, easily trigged by frequent volcanic episodes.

Most extant small ice caps mantling low-relief Arctic Canada landscapes remained cold-based throughout the late Holocene, preserving in situ bryophytes killed as ice expanded across vegetated landscapes. As Arctic summers warmed after 1900 CE, ice caps receded, exposing entombed vegetation. The calibrated radiocarbon ages of dead moss collected near ice-cap margins (kill-dates) define when ice advanced across the site, killing the moss, and remained over the site until the year of their collection. In an earlier study we reported 94 Last Millennium radiocarbon dates on in situ dead moss collected at the margins of two upland ice complexes on northern Baffin Island, Arctic Canada. Tight clustering of those ages indicated an abrupt onset of the Little Ice Age ~1240 CE, and further expansion ~1480 CE, coincident with episodes of major explosive volcanism. Here we test the confidence in kill dates as reliable predictors of expanding ice caps by re-sampling those previously sampled ice complexes 14 years later, after ~250 m of ice recession. The probability density functions (PDF) of the more recent series of ages matches PDFs of the earlier series, but with a larger fraction of early CE ages; post 2005 CE ice recession has exposed relict ice caps that grew during earlier Common Era advances, and were preserved beneath later ice-cap growth. We compare 107 kill dates from the two ice complexes with 79 kill dates from 62 other ice caps within 250 km of the two densely sampled ice complexes. The PDF of kill dates from the 62 other ice caps cluster in the same time windows as those from the two ice complexes alone, with the PDF of all 186 kill dates documenting episodes of widespread ice expansion restricted almost exclusively to 250–450 CE, 850–1000 CE and a dense early Little Ice Age cluster with peaks at ~1240 and ~1480 CE. Ice continued to expand after 1480 CE, reaching maximum dimensions ~1880 CE, still visible as zones of limited vegetation cover in remotely sensed imagery. Intervals of widespread ice-cap expansion coincide with persistent decreases in mean summer surface air temperature for the region in a Community Earth System Modeling (CESM) fully coupled Common Era simulation, suggesting primary forcing of the observed snowline lowerings were both modest declines in summer insolation, and cooling resulting from explosive volcanism, most likely intensified by positive feedbacks from sea-ice expansion and reduced northward heat transport by the oceans. The clusters of ice cap expansion defined by moss kill-dates are mirrored in an annually resolved Common Era record of ice-cap dimensions in Iceland, suggesting this is a circum-North-Atlantic-Arctic climate signal for the Common Era. During the coldest century of the Common Era, 1780–1880 CE, ice caps mantled > 11,000 km2 of north-central Baffin Island, whereas < 100 km2 is glaciated at present. That state approached conditions expected during the inception phase of an ice age, and was only reversed after 1880 CE by anthropogenic alterations of the planetary energy balance.

Standard clinical interpretation of myocardial perfusion imaging (MPI) has proven prognostic value for predicting major adverse cardiovascular events (MACE). However, personalizing predictions to a specific event type and time interval is more challenging. We demonstrate an explainable deep learning model that predicts the time-specific risk separately for all-cause death, acute coronary syndrome (ACS), and revascularization directly from MPI and 15 clinical features. We train and test the model internally using 10-fold hold-out cross-validation (n = 20,418) and externally validate it in three separate sites (n = 13,988) with MACE follow-ups for a median of 3.1 years (interquartile range [IQR]: 1.6, 3.6). We evaluate the model using the cumulative dynamic area under receiver operating curve (cAUC). The best model performance in the external cohort is observed for short-term prediction – in the first six months after the scan, mean cAUC for ACS and all-cause death reaches 0.76 (95% confidence interval [CI]: 0.75, 0.77) and 0.78 (95% CI: 0.78, 0.79), respectively. The model outperforms conventional perfusion abnormality measures at all time points for the prediction of death in both internal and external validations, with improvement increasing gradually over time. Individualized patient explanations are visualized using waterfall plots, which highlight the contribution degree and direction for each feature. This approach allows the derivation of individual event probability as a function of time as well as patient- and event-specific risk explanations that may help draw attention to modifiable risk factors. Such a method could help present post-scan risk assessments to the patient and foster shared decision-making.

PURPOSE: To demonstrate the feasibility of using chemical shift fat-water MRI methods to visualize and measure intrahepatic delivery of ethiodized oil to liver tumors following conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS: Twenty-eight participants (mean age, 66 years ± 8 [SD]; 22 men) with hepatocellular carcinoma (HCC) treated with cTACE were evaluated with follow-up chemical shift MRI in this Health Insurance Portability and Accountability Act–compliant prospective, institutional review board–approved study. Uptake of ethiodized oil was evaluated at 1-month follow-up chemical shift MRI. Measurements of tumor size (MRI and CT), attenuation and enhancement (CT), fat content percentage, and tumor:normal ratio (MRI) were compared by lesion for responders versus nonresponders, as assessed with modified Response Evaluation Criteria in Solid Tumors and European Association for the Study of the Liver (EASL) criteria. Adverse events and overall survival by the Kaplan-Meier method were secondary end points. RESULTS: Focal tumor ethiodized oil retention was 46% (12 of 26 tumors) at 24 hours and 47% (18 of 38 tumors) at 1 month after cTACE. Tumor volume at CT did not differ between EASL-defined responders and nonresponders (P = .06). Tumor ethiodized oil volume measured with chemical shift MRI was statistically significantly higher for EASL-defined nonresponders (P = .02). Doxorubicin dosing (P = .53), presence of focal fat (P = .83), and a combined end point of focal fat and low doxorubicin dosing (P = .97) did not stratify overall survival after cTACE. CONCLUSION: Chemical shift MRI allowed for assessment of tumor delivery of ethiodized oil out to 1 month after cTACE in participants with HCC and demonstrated tumor ethiodized oil volume as a potential tool for stratification of tumor response by EASL criteria. Keywords: MRI, Chemical Shift Imaging, CT, Hepatic Chemoembolization, Ethiodized Oil Clinicaltrials.gov registration no.: NCT02173119 Supplemental material is available for this article. © RSNA, 2023

Hundreds of thousands of lives are lost each year due to the brain damage caused by malaria disease. The overwhelming majority of these deaths occur in young children living in sub-Saharan Africa.