Sport-related concussion (SRC) has become a major health problem, affecting millions of athletes each year. Despite the increasing occurrence and prevalence of SRC, its underlying mechanism and ...recovery course have yet to be fully elucidated. The National Collegiate Athletic Association–Department of Defense Grand Alliance: Concussion Assessment, Research and Education (CARE) Consortium is a large-scale, multisite study of the natural history of concussion across multiple sports. The Advanced Research Core (ARC) of CARE is focused on the advanced biomarker assessment of a reduced subject cohort. This paper reports findings from two ARC sites to evaluate cerebral blood flow (CBF) changes in acute SRC, as measured using advanced arterial spin labeling (ASL) magnetic resonance imaging (MRI). We compared relative CBF maps assessed in 24 concussed contact sport athletes obtained at 24–48 h after injury to those of a control group of 24 matched contact sport players. Significantly less CBF was detected in several brain regions in concussed athletes, while clinical assessments also indicated clinical symptom and performance impairments in SRC patients. Correlations were found between decreased CBF in acute SRC and clinical assessments, including Balance Error Scoring System total score and Immediate Post-Concussion Assessment and Cognitive Test memory composite and impulse control composite scores, as well as days from injury to asymptomatic. Although using different ASL MRI sequences, our preliminary results from two sites are consistent with previous reports and suggest that advanced ASL MRI methods might be useful for detecting acute neurobiological changes in acute SRC.
Abstract Background Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease. Objective To evaluate the utility of a four kallikrein (4K) panel ...in predicting the presence of high-grade cancer in men on active surveillance. Design, setting, and participants Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA). Outcome measurements and statistical analysis The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit. Results and limitations Significant predictors for reclassification were 4Kpanel (odds ratio OR 1.54, 95% confidence interval CI 1.31–1.81) or PSA (OR 2.11, 95% CI 1.53–2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33–3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04–0.85), prostate volume (OR 0.47, 95% CI 0.31–0.70), and body mass index (OR 1.09, 95% CI 1.04–1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use. Conclusions The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies. Patient summary Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.
Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a ...policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages.
Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023.
Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% 1·9–3·3 per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million 903·5–1040·3) residing in south Asia.
The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC.
Bill & Melinda Gates Foundation.
•Loss of perirhinal cortex spares mirror-imaged landmark discriminations.•Perirhinal cortex lesions do not disrupt latent spatial learning.•Further underlines dissociation between perirhinal and ...hippocampal function.
Rats with lesions in the perirhinal cortex and their control group learnt to discriminate between mirror-imaged visual landmarks to find a submerged platform in a watermaze. Rats initially learnt this discrimination passively, in that they were repeatedly placed on the platform in one corner of a square watermaze with walls of different appearance, prior to swimming to that same location for the first time in a subsequent probe trial. Perirhinal cortex lesions spared this passively learnt ability, despite the common visual elements shared by the guiding landmarks. These results challenge models of perirhinal function that emphasise its role in solving discriminations between stimuli with ambiguous or overlapping features, while underlining how this cortical region is often not required for spatial processes that involve the hippocampus.
To determine the variance in virtual monochromatic computed tomography (CT) numbers from the same lesion, comparing the two clinically available dual-energy multidetector CT hardware implementations ...(single-source projection-based and dual-source image-based), in a phantom-based simulated abdominal environment.
This phantom-based study was exempt from institutional review board oversight. Polyethylene terephthalate spheres (15 and 18 mm) with two iodine-to-saline dilutions (0.8 and 1.2 mg of iodine per millilliter) were serially suspended in a cylindrical polypropylene bottle filled with diluted iodinated contrast material. The bottle was placed into a 36-cm-wide torso-shaped water phantom simulating the abdomen of a medium-sized patient. Dual-energy (80/140 kVp) and single-energy (100 and 120 kVp) scans were obtained with single-source and dual-source multidetector CT implementations. Virtual monochromatic images were reconstructed at energy levels of 40-140 keV (in 10-keV increments) in either the projection-space or image-space domain. A multivariate regression analysis approach was used to investigate the effect of energy level, lesion size, lesion iodine content, and implementation type on measured CT numbers.
There were significant differences in the attenuation values measured in the simulated lesions with the single-source projection-based platform and the dual-source image-based implementation (P < .001 for all comparisons). The magnitude of these differences was greatest at lower monochromatic energy levels and at lower iodine concentrations (average difference at 40 keV: 25.7 HU; average difference at 140 keV: 7 HU). The monochromatic energy level and the lesion iodine concentration had a significant effect on the difference in the measured attenuation values between the two implementations, which indicates that the two imaging platforms respond differently to changes in investigated variables (P < .001 for all comparisons).
There is a statistically significant variance in virtual monochromatic CT numbers from the same lesion examined with single-source projection-based and dual-source image-based implementations. The magnitude of the variance is a function of the selected energy level and the lesion iodine content.
Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types ...forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.
The 17-gene Onco
DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a ...predictor of outcomes in a multicenter active surveillance cohort.
Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group GG ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models.
GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio HR/5 GPS units, 1.18; 95% CI, 1.04 to 1.44;
= .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19;
= .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade (
= .48).
In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.
The ocean provides food, economic activity, and cultural value for a large proportion of humanity. Our knowledge of marine ecosystems lags behind that of terrestrial ecosystems, limiting effective ...protection of marine resources. We describe the outcome of 2 workshops in 2011 and 2012 to establish a list of important questions, which, if answered, would substantially improve our ability to conserve and manage the world's marine resources. Participants included individuals from academia, government, and nongovernment organizations with broad experience across disciplines, marine ecosystems, and countries that vary in levels of development. Contributors from the fields of science, conservation, industry, and government submitted questions to our workshops, which we distilled into a list of priority research questions. Through this process, we identified 71 key questions. We grouped these into 8 subject categories, each pertaining to a broad component of marine conservation: fisheries, climate change, other anthropogenic threats, ecosystems, marine citizenship, policy, societal and cultural considerations, and scientific enterprise. Our questions address many issues that are specific to marine conservation, and will serve as a road map to funders and researchers to develop programs that can greatly benefit marine conservation. Setenta y Un Preguntas Importantes para la Conservación de la Biodiversidad Marina
Metal–organic frameworks (MOFs) capable of mobility and manipulation are attractive materials for potential applications in targeted drug delivery, catalysis, and small‐scale machines. One way of ...rendering MOFs navigable is incorporating magnetically responsive nanostructures, which usually involve at least two preparation steps: the growth of the magnetic nanomaterial and its incorporation during the synthesis of the MOF crystals. Now, by using optimal combinations of salts and ligands, zeolitic imidazolate framework composite structures with ferrimagnetic behavior can be readily obtained via a one‐step synthetic procedure, that is, without the incorporation of extrinsic magnetic components. The ferrimagnetism of the composite originates from binary oxides of iron and transition metals such as cobalt. This approach exhibits similarities to the natural mineralization of iron oxide species, as is observed in ores and in biomineralization.
Using optimal combinations of salts and ligands, zeolitic imidazolate framework composite structures with ferrimagnetic behavior can be readily obtained by a one‐step synthesis. The ferrimagnetism of the composite originates from binary oxides of iron and transition metals. This approach shows similarities to the natural mineralization of iron oxide species, as is observed in ores and in biomineralization.
Abstract
Background
Since 2011, influenza A viruses circulating in US swine exhibited at county fairs are associated with >460 zoonotic infections, presenting an ongoing pandemic risk. Swine “jackpot ...shows” that occur before county fairs each summer intermix large numbers of exhibition swine from diverse geographic locations. We investigated the role of jackpot shows in influenza zoonoses.
Methods
We collected snout wipe or nasal swab samples from 17 009 pigs attending 350 national, state, and local swine exhibitions across 8 states during 2016–2018.
Results
Influenza was detected in 13.9% of swine sampled at jackpot shows, and 76.3% of jackpot shows had at least 1 pig test positive. Jackpot shows had 4.3-fold higher odds of detecting at least 1 influenza-positive pig compared to county fairs. When influenza was detected at a county fair, almost half of pigs tested positive, clarifying why zoonotic infections occur primarily at county fairs.
Conclusions
The earlier timing of jackpot shows and long-distance travel for repeated showing of individual pigs provide a pathway for the introduction of influenza into county fairs. Mitigation strategies aimed at curtailing influenza at jackpot shows are likely to have downstream effects on disease transmission at county fairs and zoonoses.
Exhibition swine at county fairs are the primary source of zoonotic influenza in the United States. Complex networks of swine exhibitions surrounding county fairs drive influenza dissemination and offer mitigation points to reduce public health risk.
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