Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.

Sunlight can convert atmospheric aerosols into a glassy solid state and modify their environmental impacts.

Secondary organic aerosol (SOA) plays a critical, yet uncertain, role in air quality and climate. Once formed, SOA is transported throughout the atmosphere and is exposed to solar UV light. Information on the viscosity of SOA, and how it may change with solar UV exposure, is needed to accurately predict air quality and climate. However, the effect of solar UV radiation on the viscosity of SOA and the associated implications for air quality and climate predictions is largely unknown. Here, we report the viscosity of SOA after exposure to UV radiation, equivalent to a UV exposure of 6 to 14 d at midlatitudes in summer. Surprisingly, UV-aging led to as much as five orders of magnitude increase in viscosity compared to unirradiated SOA. This increase in viscosity can be rationalized in part by an increase in molecular mass and oxidation of organic molecules constituting the SOA material, as determined by high-resolution mass spectrometry. We demonstrate that UV-aging can lead to an increased abundance of aerosols in the atmosphere in a glassy solid state. Therefore, UV-aging could represent an unrecognized source of nuclei for ice clouds in the atmosphere, with important implications for Earth's energy budget. We also show that UV-aging increases the mixing times within SOA particles by up to five orders of magnitude throughout the troposphere with important implications for predicting the growth, evaporation, and size distribution of SOA, and hence, air pollution and climate.

Rate of atmospheric brown carbon whitening governed by environmental conditions.

Biomass burning organic aerosol (BBOA) in the atmosphere contains many compounds that absorb solar radiation, called brown carbon (BrC). While BBOA is in the atmosphere, BrC can undergo reactions with oxidants such as ozone which decrease absorbance, or whiten. The effect of temperature and relative humidity (RH) on whitening has not been well constrained, leading to uncertainties when predicting the direct radiative effect of BrC on climate. Using an aerosol flow-tube reactor, we show that the whitening of BBOA by oxidation with ozone is strongly dependent on RH and temperature. Using a poke-flow technique, we show that the viscosity of BBOA also depends strongly on these conditions. The measured whitening rate of BrC is described well with the viscosity data, assuming that the whitening is due to oxidation occurring in the bulk of the BBOA, within a thin shell beneath the surface. Using our combined datasets, we developed a kinetic model of this whitening process, and we show that the lifetime of BrC is 1 d or less below ∼1 km in altitude in the atmosphere but is often much longer than 1 d above this altitude. Including this altitude dependence of the whitening rate in a chemical transport model causes a large change in the predicted warming effect of BBOA on climate. Overall, the results illustrate that RH and temperature need to be considered to understand the role of BBOA in the atmosphere.

Metabolic Theory of Preeclampsia: Implications for Maternal Cardiovascular Health.

Preeclampsia (PE) is a multisystemic disorder of pregnancy that not only causes perinatal mortality and morbidity but also has a long-term toll on the maternal and fetal cardiovascular system. Women diagnosed with PE are at greater risk for the subsequent development of hypertension, ischemic heart disease, cardiomyopathy, cerebral edema, seizures, and end-stage renal disease. Although PE is considered heterogeneous, inefficient extravillous trophoblast migration leading to deficient spiral artery remodeling and increased uteroplacental vascular resistance is the likely initiation of the disease. The principal pathophysiology is placental hypoxia, causing subsequent oxidative stress, leading to mitochondrial dysfunction, mitophagy, and immunological imbalance. The damage imposed on the placenta in turn results in the 'stress response' categorized by the dysfunctional release of vasoactive components including oxidative stressors, pro-inflammatory factors, and cytokines into the maternal circulation. These bioactive factors have deleterious effects on systemic endothelial cells and coagulation leading to generalized vascular dysfunction and hypercoagulability. A better understanding of these metabolic factors may lead to novel therapeutic approaches to prevent and treat this multisystemic disorder. In this review, we connect the hypoxic-oxidative stress and inflammation involved in the pathophysiology of PE to the resulting persistent cardiovascular complications in preeclamptic patients.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies.

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns.

Characterization of Quantitative Trait Loci for Leaf Rust Resistance from CI 13227 in Three Winter Wheat Populations.

Leaf rust is a widespread foliar wheat disease causing substantial yield losses worldwide. Slow-rusting is "adult plant" resistance that significantly slows epidemic development and thereby reduces yield loss. Wheat accession CI 13227 was previously characterized as having slow-rusting resistance. To validate the quantitative trait loci (QTL) and develop diagnostic markers for slow rusting resistance in CI 13227, a new population of recombinant inbred lines (RILs) of CI 13227 × Everest was evaluated for latent period (LP), final severity (FS), area under disease progress curve (AUDPC), and infection type (IT) in greenhouses and genotyped using genotyping-by-sequencing (GBS). Four QTL were identified on chromosome arms 2BL, 2DS, 3BS, and 7BL, explaining 6.82 to 28.45% of the phenotypic variance for these traits. Seven kompetitive allele specific polymorphism (KASP) markers previously reported to be linked to the QTL in two other CI 13227 populations were validated. In addition, the previously reported QLr.hwwg-7AL was remapped to 2BL (renamed QLr.hwwg-2BL) after adding new markers in this study. Phenotypic data showed that the RILs harboring two or three of the QTL had a significantly longer LP. QLr.hwwg-2DS on 2DS showed a major effect on all rust resistance traits and was finely mapped to a 2.7 Mb interval by two newly developed flanking markers from exome capture. Three disease-resistance genes and two transporter genes were identified as the putative candidates for QLr.hwwg-2DS. The validated QTL can be used as slow rusting resistance resources and the markers developed in this study will be useful for marker-assisted selection.

Coexistence of three liquid phases in individual atmospheric aerosol particles.

Individual atmospheric particles can contain mixtures of primary organic aerosol (POA), secondary organic aerosol (SOA), and secondary inorganic aerosol (SIA). To predict the role of such complex multicomponent particles in air quality and climate, information on the number and types of phases present in the particles is needed. However, the phase behavior of such particles has not been studied in the laboratory, and as a result, remains poorly constrained. Here, we show that POA+SOA+SIA particles can contain three distinct liquid phases: a low-polarity organic-rich phase, a higher-polarity organic-rich phase, and an aqueous inorganic-rich phase. Based on our results, when the elemental oxygen-to-carbon (O:C) ratio of the SOA is less than 0.8, three liquid phases can coexist within the same particle over a wide relative humidity range. In contrast, when the O:C ratio of the SOA is greater than 0.8, three phases will not form. We also demonstrate, using thermodynamic and kinetic modeling, that the presence of three liquid phases in such particles impacts their equilibration timescale with the surrounding gas phase. Three phases will likely also impact their ability to act as nuclei for liquid cloud droplets, the reactivity of these particles, and the mechanism of SOA formation and growth in the atmosphere. These observations provide fundamental information necessary for improved predictions of air quality and aerosol indirect effects on climate.

Dysplastic Hips Have Decreased Iliofemoral Ligament Thickness on Coronal Sequences in Magnetic Resonance Imaging: A Matched Cohort Analysis.

PURPOSE: To characterize hip capsule thickness on advanced imaging in patients with and without hip dysplasia and to also evaluate differences in capsular thickness between borderline and true dysplastic patients. METHODS: Patients evaluated by the senior author for concerns of hip pathology from June 2020 to June 2021 were queried and images reviewed to determine dysplasia status by lateral center edge angle (LCEA) ≤ 25 degrees. A group of non-dysplastic patients was identified and matched for age, sex, and body mass index (BMI). Hip capsular thickness was quantified using MRI. A sub-analysis was conducted to compare true dysplastic patients (LCEA < 20°) to borderline dysplastic patients (LCEAs between 20 - 25°). Analysis included independent samples t-tests, Chi-square tests, and multivariable regression. RESULTS: Eighty total patients were included, with a mean age of 31.8 ± 11.7 years, a mean BMI of 26.6 ± 6.5 points, and 70% (56) female patients. Dysplastic patients had a mean LCEA of 19.8 ± 4.3 degrees. Dysplastic individuals had decreased capsular thickness compared to their non-dysplastic controls (2.75 ± 0.96 vs 3.52 ± 1.22 mm, p = 0.003). Multivariable regression showed decreased capsular thickness associated with decreased LCEAs (ß = 2.804, R = 0.432, p<0.001) and dysplasia (ß = -0.709, R2 = 0.056, p = 0.004). Results of a sub-analysis of the dysplastic group examining differences between accepted definitions of borderline dysplasia and true dysplasia showed no significant differences in capsular thickness between the two groups (p = 0.379). CONCLUSIONS: Patients with hip dysplasia were found to have thinner iliofemoral ligaments in the coronal plane on magnetic resonance imaging on magnetic resonance imaging. Further investigation is needed to evaluate any potential implications with hip instability given the thinner hip capsule demonstrated in this study.

Common radiographic indices used to measure patellar height do not consistently identify patella alta and lack interchangeability between measurements.

PURPOSE: Abnormal patellar height has been identified as a source of aberrant mechanical functioning within the patellofemoral joint. The purpose of this study is to examine the statistical agreement among three commonly used classification methods: Blackburne-Peel (BPI), Caton-Deschamps (CDI) and Insall-Salvati (ISR), by evaluating (1) the rates of patella alta identification and (2) the ability for one index to predict another. METHODS: One hundred lateral knee radiographs were evaluated using BPI, CDI and ISR to classify each knee as patella normal, patella alta or patella baja. Linear regression analysis was performed to evaluate the relationship between each index. Conversion equations were then derived using the reported linear regression best-fit line, comparing each pair of indices. RESULTS: Patella alta was identified in 15 knees using BPI, 15 using CDI and 25 using ISR. A total of seven knees were classified as patella alta by all BPI, CDI and ISR. Statistical analysis revealed significant correlation (p ≤ 0.001) among BPI and CDI (R2 = 0.706), BPI and ISR (R2 = 0.328) and CDI and ISR (R2 = 0.288). Wilcoxon Signed-Rank test between the three indices revealed no significant difference between the means of converted and original indices. CONCLUSION: Despite their significant correlations and adequate reproducibility, variability between common patellar height indices render predictions and conversions between BPI, CDI and ISR inequivalent. Users of these indices must be aware of their incongruent properties when considering application to patients in the clinical setting. Furthermore, it remains unclear which patellar height measurement technique is the correct index to use in a given knee. This study highlights the need for further investigation to create a reliable and standardised method for identifying patella height. LEVEL OF EVIDENCE: Level IV.

Distribution of cholinergic nerve terminals in the aged human brain measured with [18F]FEOBV PET and its correlation with histological data.

INTRODUCTION: [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain. MATERIALS AND METHODS: [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data. RESULTS: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene. DISCUSSION: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo.

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study.

BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level. RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comprehensive History and Physicals are Common Before Low-Risk Surgery and Associated With Preoperative Test Overuse.

INTRODUCTION: The Centers for Medicare and Medicaid Services (CMS) recently eliminated the requirement for preoperative history and physicals (H&Ps) prior to ambulatory surgery. We sought to assess variations in separately billed preoperative H&P utilization prior to low-risk ambulatory surgery, describe any relationship with preoperative testing, and identify independent predictors of these consultations prior to this policy change to help characterize the potential unnecessary utilization of these consultations and potential unnecessary preoperative testing prior to low-risk surgery. MATERIALS AND METHODS: A retrospective cohort study was performed using claims data from a hospital value collaborative in Michigan from January 2015 to June 2019 and included patients undergoing one of three ambulatory procedures: breast lumpectomy, laparoscopic cholecystectomy, and laparoscopic inguinal hernia repair. Rates of preoperative H&P visits within 30 d of surgical procedure were determined. H&P and preoperative testing associations were explored, and patient-level, practice-level, and hospital-level determinants of utilization were assessed with regression models. Risk and reliability-adjusted caterpillar plots were generated to demonstrate hospital-level variations in utilization. RESULTS: 50,775 patients were included with 50.5% having a preoperative H&P visit, with these visits being more common for patients with increased comorbidities (1.9 ± 2.2 vs 1.4 ± 1.9; P < 0.0001). Preoperative testing was associated with H&P visits (57.2% vs 41.4%; P < 0.0001). After adjusting for patient case-mix and interhospital and intrahospital variations in H&P visits, utilization remained with significant associations in patients with increased comorbidities. CONCLUSIONS: Preoperative H&P visits were common before three low-risk ambulatory surgical procedures across Michigan and were associated with higher rates of low-value preoperative testing, suggesting that preoperative H&P visits may create clinical momentum leading to unnecessary testing. These findings will inform strategies to tailor preoperative care before low-risk surgical procedures and may lead to reduced utilization of low-value preoperative testing.

Phase Behavior and Viscosity in Biomass Burning Organic Aerosol and Climatic Impacts.

Smoke particles generated by burning biomass consist mainly of organic aerosol termed biomass burning organic aerosol (BBOA). BBOA influences the climate by scattering and absorbing solar radiation or acting as nuclei for cloud formation. The viscosity and the phase behavior (i.e., the number and type of phases present in a particle) are properties of BBOA that are expected to impact several climate-relevant processes but remain highly uncertain. We studied the phase behavior of BBOA using fluorescence microscopy and showed that BBOA particles comprise two organic phases (a hydrophobic and a hydrophilic phase) across a wide range of atmospheric relative humidity (RH). We determined the viscosity of the two phases at room temperature using a photobleaching method and showed that the two phases possess different RH-dependent viscosities. The viscosity of the hydrophobic phase is largely independent of the RH from 0 to 95%. We use the Vogel-Fulcher-Tamman equation to extrapolate our results to colder and warmer temperatures, and based on the extrapolation, the hydrophobic phase is predicted to be glassy (viscosity >1012 Pa s) for temperatures less than 230 K and RHs below 95%, with possible implications for heterogeneous reaction kinetics and cloud formation in the atmosphere. Using a kinetic multilayer model (KM-GAP), we investigated the effect of two phases on the atmospheric lifetime of brown carbon within BBOA, which is a climate-warming agent. We showed that the presence of two phases can increase the lifetime of brown carbon in the planetary boundary layer and polar regions compared to previous modeling studies. Hence, the presence of two phases can lead to an increase in the predicted warming effect of BBOA on the climate.

QTL Pyramiding Provides Marginal Improvement in 2NvS-Based Wheat Blast Resistance.

Wheat blast, caused by the fungus Magnaporthe oryzae Triticum pathotype (MoT), is a devastating disease affecting South America, Bangladesh, and Zambia. Resistance to wheat blast has strongly relied on the 2NvS translocation; however, newer MoT isolates have increased aggressiveness, threatening the 2NvS translocation's effectiveness and durability. To identify genomic regions associated with wheat blast resistance, we performed a quantitative trait loci (QTL) mapping study using 187 double-haploid (DH) lines from a cross between the Brazilian wheat cultivars 'TBIO Alvorada' and 'TBIO Sossego', which are moderately resistant and susceptible to blast, respectively. The DH population was evaluated in a greenhouse in Brazil and Bolivia, and field conditions in Bolivia. Contrasting models best explained the relationship between traits evaluated according to differences in disease levels and the presence of the 2NvS. A large effect-locus, derived from 'TBIO Sossego', was identified on chromosome 2AS, which was confirmed to be 2NvS translocation and explained 33.5 to 82.4% of the phenotypic variance. Additional significant loci were identified on 5AL, 1DS, 4DS, 5DL, and 6DL chromosome arms with phenotypic variance <6%, but they were not consistent across trait-environment combinations. QTL pyramiding analyses showed that some specific loci had an additive effect when combined with the 2NvS, suggesting that stacking multiple loci may be an effective strategy to help manage wheat blast. The markers associated with the 2NvS can be used as dominant diagnostic markers for this alien translocation. Additional characterization of these loci using a broader set of MoT isolates is critical to validate their effectiveness against current MoT populations.

Review of Cancer-Specific Quality Measures Promoting the Avoidance of Low-Value Care.

BACKGROUND: With rising healthcare costs and campaigns aimed at avoiding low-value care, reducing cancer overtreatment has emerged as an important measure of cancer care quality. The extent to which avoidance of low-value care has been incorporated in cancer-specific quality measures is unknown. We aimed to identify and characterize cancer quality measures that promote the avoidance of low-value care, and identify gaps that may guide future measure development. METHODS: We systematically identified cancer-specific quality measures from leading quality measure organizations [e.g., National Quality Forum (NQF), National Quality Measures Clearinghouse (NQMC)]. We reviewed measures promoting the avoidance of low-value cancer care and subclassified them into disease site- or non-disease site-specific categories and the phase of care they targeted. RESULTS: We reviewed 313 quality measures from six organizations. Of these, 18% (n = 55) focused on avoidance of low-value care. Quality measures focused on end-of-life care were most likely to focus on low-value care [n = 13 (50%)], followed by breast [n = 12 (18%)], lung [n = 9 (31%)], colon [n = 8 (20%)], prostate [n = 5 (38%)], general cancer care [n = 4 (3%)], symptoms and toxicities [n = 2 (40%)], and palliative cancer care [n = 2 (11%)] measures. The phases of care quality measures targeted included low-value screening [n = 5 (9%)], diagnostic testing and staging [n = 7 (13%)], treatment [n = 19 (34%)], surveillance [n = 6 (11%)], and clinical outcomes [n = 18 (33%)]. All categories had a treatment-specific quality measure, but no category had a representative measure for every phase of care. DISCUSSION: A minority of cancer quality measures are aimed at avoiding low-value care, and multiple evidence-based recommendations targeting low-value care have not been incorporated.

Vectorial capacities for malaria in eastern Amazonian Brazil depend on village, vector species, season, and parasite species.

BACKGROUND: The vector species in the Amazon River Basin are regionally and locally diverse, which makes it imperative to understand and compare their roles in malaria transmission to help select appropriate methods of intervention and evaluation. The major aim of this study was to measure the vectorial capacity of five Anopheles species in three neighbouring villages, for two Plasmodium parasite species affecting humans. METHODS: From 32 consecutive months of sampling in three villages, 1.5-7.0 km apart, on the Matapi River, Amapá State, Brazil, vectorial capacities (C) were estimated as time series for An. darlingi, An. marajoara, An. nuneztovari, An. triannulatus, and An. intermedius. Monthly parity measurements for each vector species were used to estimate daily survivorship and compared to estimates of survivorship from mark-release-recapture experiments. Gonotrophic cycle lengths were estimated through a time-series analysis of parity data, and durations of sporogony at study site temperatures for the two malaria parasite species were estimated from previous literature. RESULTS: The absolute abundances of five vector species were strongly tracked by the spatial variation in C among villages. Temporally, C varied between wet and dry seasons, with An. darlingi, An. marajoara and An. triannulatus exhibiting higher C in the dry season from August to December, and An. nuneztovari its highest C early in the rainy season in January and February. Anopheles intermedius exhibited higher C in the rainy season from April to June than in the dry season. Significant differences in overall survival for each independent variable, and a significant difference in C between wet and dry seasons, among villages, and among vector species for both Plasmodium falciparum and Plasmodium vivax. A generalized linear mixed model (GLMM) analysis by village showed significant effects of vector species on C in only one village, but significant effects of parasite species in all three. Although the GLMM analysis detected no significant parasite x vector species interaction effects on C, effects on C of spline regressions of C dynamics x vector species interactions were significant in all villages. CONCLUSIONS: These detailed analyses of entomological and parasitological variables revealed hidden complexities of malaria epidemiology at local scales in neighbouring riverine villages of the Amazon Region.

Can Epigenetics Help Solve the Puzzle Between Concomitant Cardiovascular Injury and Severity of Coronavirus Disease 2019?

ABSTRACT: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has significant implications in patients with concomitant cardiovascular disease (CVD) because they are the population at the greatest risk of death. The treatment of such patients and complications may represent a new challenge for the fields of cardiology and pharmacology. Thus, understanding the involvement of this viral infection in CVD might help to reduce the aggressiveness of SARS-CoV-2 in causing multiorgan infection and damage. SARS-CoV-2 disturbs the host epigenome and several epigenetic processes involved in the pathophysiology of COVID-19 that can directly affect the function and structure of the cardiovascular system (CVS). Hence, it would be relevant to identify epigenetic alterations that directly impact CVS physiology after SARS-CoV-2 infection. This could contribute to the view of this virus-induced CVS injury and direct forthcoming tackles for COVID-19 treatment to reduce mortality in patients with CVD. Targeting epigenetic marks could offer strong evidence for the development of novel antiviral therapies, especially in the context of COVID-19-related CVS damage. In this review, we address some of the main signaling pathways that are currently known as being involved in COVID-19 pathophysiology and the importance of this glint on epigenetics and some of its modifiers (epidrugs) to control the unregulated epitope activity in the context of SARS-CoV-2 infection, COVID-19, and underlying CVD.

Phase Behavior of Internal Mixtures of Hydrocarbon-like Primary Organic Aerosol and Secondary Aerosol Based on Their Differences in Oxygen-to-Carbon Ratios.

The phase behavior, the number and type of phases, in atmospheric particles containing mixtures of hydrocarbon-like organic aerosol (HOA) and secondary organic aerosol (SOA) is important for predicting their impacts on air pollution, human health, and climate. Using a solvatochromic dye and fluorescence microscopy, we determined the phase behavior of 11 HOA proxies (O/C = 0-0.29) each mixed with 7 different SOA materials generated in environmental chambers (O/C 0.4-1.08), where O/C represents the average oxygen-to-carbon atomic ratio. Out of the 77 different HOA + SOA mixtures studied, we observed two phases in 88% of the cases. The phase behavior was independent of relative humidity over the range between 90% and <5%. A clear trend was observed between the number of phases and the difference between the average O/C ratios of the HOA and SOA components (ΔO/C). Using a threshold ΔO/C of 0.265, we were able to predict the phase behavior of 92% of the HOA + SOA mixtures studied here, with one-phase particles predicted for ΔO/C < 0.265 and two-phase particles predicted for ΔO/C ≥ 0.265. The threshold ΔO/C value provides a relatively simple and computationally inexpensive framework for predicting the number of phases in internal SOA and HOA mixtures in atmospheric models.

Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson's disease.

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson's disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson's disease. We examined 93 subjects (40 healthy controls and 53 Parkinson's disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson's disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson's disease, which may eventually direct research towards potential novel treatment approaches.