Viral PIC-pocketing: RSV sequestration of translational preinitiation complexes into bi-phasic biomolecular condensates.

Orthopneumoviruses characteristically form membrane-less cytoplasmic inclusion bodies (IBs) wherein RNA replication and transcription occur. Here, we report a strategy whereby the orthopneumoviruses sequester various components of the translational preinitiation complex machinery into viral inclusion bodies to facilitate translation of their own mRNAs-PIC-pocketing. Electron microscopy of respiratory syncytial virus (RSV)-infected cells revealed bi-phasic organization of IBs, specifically, spherical "droplets" nested within the larger inclusion. Using correlative light and electron microscopy, combined with fluorescence in situ hybridization, we showed that the observed bi-phasic morphology represents functional compartmentalization of the inclusion body and that these domains are synonymous with the previously reported inclusion body-associated granules (IBAGs). Detailed analysis demonstrated that IBAGs concentrate nascent viral mRNA, the viral M2-1 protein as well as components of eukaryotic translation initiation factors (eIF), eIF4F and eIF3, and 40S complexes involved in translation initiation. Interestingly, although ribopuromycylation-based imaging indicates that the majority of viral mRNA translation occurs in the cytoplasm, there was some evidence for intra-IBAG translation, consistent with the likely presence of ribosomes in a subset of IBAGs imaged by electron microscopy. Mass spectrometry analysis of sub-cellular fractions from RSV-infected cells identified significant modification of the cellular translation machinery; however, interestingly, ribopuromycylation assays showed no changes to global levels of translation. The mechanistic basis for this pathway was subsequently determined to involve the viral M2-1 protein interacting with eIF4G, likely to facilitate its transport between the cytoplasm and the separate phases of the viral inclusion body. In summary, our data show that these viral organelles function to spatially regulate early steps in viral translation within a highly selective bi-phasic biomolecular condensate. IMPORTANCE: Respiratory syncytial viruses (RSVs) of cows and humans are a significant cause of morbidity and mortality in their respective populations. These RNA viruses replicate in the infected cells by compartmentalizing the cell's cytoplasm into distinct viral microdomains called inclusion bodies (IBs). In this paper, we show that these IBs are further compartmentalized into smaller structures that have significantly different density, as observed by electron microscopy. Within smaller intra-IB structures, we observed ribosomal components and evidence for active translation. These findings highlight that RSV may additionally compartmentalize translation to favor its own replication in the cell. These data contribute to our understanding of how RNA viruses hijack the cell to favor replication of their own genomes and may provide new targets for antiviral therapeutics in vivo.

Sports Concussion and Chronic Traumatic Encephalopathy: Finding a Path Forward.

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225.

Expanding the Health Narrative Frame.

How might we expand the frame of health narratives so as to avoid genre calcification and more effectively harness these stories' transformative potential? This essay builds on the continued success of the "Defining Moments" forum while responding to Harter et al.'s 2020 call for "new stories shaped and shared in novel ways." Drawing on interdisciplinary research and theorizing, I suggest three narrative strategies for storytelling based on, respectively, the extended duration of a health context, the agentic power of nonhuman kinds, and the implicit collectivity of polyphonic narratives. Brief examples precede my discussion of each strategy. I invite others to join me in shaping innovative narratives that further challenge tacit assumptions of embodied health.

Reliability assessment of new radiographic scales to evaluate radiolucency and bony in-between fin growth of partially cemented all-polyethylene glenoid components.

BACKGROUND: Current methods available for assessment of radiolucency and in-between fin (IBF) growth of a glenoid component have not undergone interobserver reliability testing for an all-polyethylene fluted central peg (FCP) glenoid. The purpose of this study was to evaluate anteroposterior radiographs of an FCP glenoid component at ≥48 months comparing commonly used scales to a new method adapted to the FCP. Our hypothesis was that the new method would result in acceptable intra- and interobserver agreement and a more accurate description of radiographic findings. METHODS: We reviewed ≥48-month follow-up radiographs of patients treated with a primary aTSA using an FCP glenoid. Eighty-three patients were included in the review. Radiographs were evaluated by 5 reviewers using novel IBF radiodensity and radiolucency assessments and the Wirth and Lazarus methods. To assess intraobserver reliability, a subset of 40 images was reviewed. Kappa statistics were calculated to determine intra- and interobserver reliability; correlations were assessed using Pearson correlation. RESULTS: Interobserver agreement (κ score) was as follows: IBF 0.71, radiolucency 0.68, Wirth 0.48, and Lazarus 0.22. Intraobserver agreement ranges were as follows: IBF radiodensity 0.36-0.67, radiolucency 0.55-0.62, Wirth 0.11-0.73, and Lazarus 0.04-0.46. Correlation analysis revealed the following: IBF to Wirth r = 0.93, radiolucency to Lazarus r = 0.92 (P value <.001 for all). CONCLUSION: This study introduces a radiographic assessment method developed specifically for an FCP glenoid component. Results show high interobserver and acceptable intraobserver reliability for the method presented in this study. The new scales provide a more accurate description of radiographic findings, helping to identify glenoid components that may be at risk for loosening.

Membrane Interactions and Uncoating of Aichi Virus, a Picornavirus That Lacks a VP4.

Kobuviruses are an unusual and poorly characterized genus within the picornavirus family and can cause gastrointestinal enteric disease in humans, livestock, and pets. The human kobuvirus Aichi virus (AiV) can cause severe gastroenteritis and deaths in children below the age of 5 years; however, this is a very rare occurrence. During the assembly of most picornaviruses (e.g., poliovirus, rhinovirus, and foot-and-mouth disease virus), the capsid precursor protein VP0 is cleaved into VP4 and VP2. However, kobuviruses retain an uncleaved VP0. From studies with other picornaviruses, it is known that VP4 performs the essential function of pore formation in membranes, which facilitates transfer of the viral genome across the endosomal membrane and into the cytoplasm for replication. Here, we employ genome exposure and membrane interaction assays to demonstrate that pH plays a critical role in AiV uncoating and membrane interactions. We demonstrate that incubation at low pH alters the exposure of hydrophobic residues within the capsid, enhances genome exposure, and enhances permeabilization of model membranes. Furthermore, using peptides we demonstrate that the N terminus of VP0 mediates membrane pore formation in model membranes, indicating that this plays an analogous function to VP4. IMPORTANCE To initiate infection, viruses must enter a host cell and deliver their genome into the appropriate location. The picornavirus family of small nonenveloped RNA viruses includes significant human and animal pathogens and is also a model to understand the process of cell entry. Most picornavirus capsids contain the internal protein VP4, generated from cleavage of a VP0 precursor. During entry, VP4 is released from the capsid. In enteroviruses this forms a membrane pore, which facilitates genome release into the cytoplasm. Due to high levels of sequence similarity, it is expected to play the same role for other picornaviruses. Some picornaviruses, such as Aichi virus, retain an intact VP0, and it is unknown how these viruses rearrange their capsids and induce membrane permeability in the absence of VP4. Here, we have used Aichi virus as a model VP0 virus to test for conservation of function between VP0 and VP4. This could enhance understanding of pore function and lead to development of novel therapeutic agents that block entry.

The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins.

SARS Coronavirus 2 (SARS-CoV-2) emerged in late 2019, leading to the Coronavirus Disease 2019 (COVID-19) pandemic that continues to cause significant global mortality in human populations. Given its sequence similarity to SARS-CoV, as well as related coronaviruses circulating in bats, SARS-CoV-2 is thought to have originated in Chiroptera species in China. However, whether the virus spread directly to humans or through an intermediate host is currently unclear, as is the potential for this virus to infect companion animals, livestock, and wildlife that could act as viral reservoirs. Using a combination of surrogate entry assays and live virus, we demonstrate that, in addition to human angiotensin-converting enzyme 2 (ACE2), the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in the amino acids at the Spike receptor binding site on these proteins. Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors. The absence of a significant tropism for any of the 3 genetically distinct bat ACE2 proteins we examined indicates that SARS-CoV-2 receptor usage likely shifted during zoonotic transmission from bats into people, possibly in an intermediate reservoir. Comparison of SARS-CoV-2 receptor usage to the related coronaviruses SARS-CoV and RaTG13 identified distinct tropisms, with the 2 human viruses being more closely aligned. Finally, using bioinformatics, structural data, and targeted mutagenesis, we identified amino acid residues within the Spike-ACE2 interface, which may have played a pivotal role in the emergence of SARS-CoV-2 in humans. The apparently broad tropism of SARS-CoV-2 at the point of viral entry confirms the potential risk of infection to a wide range of companion animals, livestock, and wildlife.

Implementation of virtual OSCE in health professions education: A systematic review.

INTRODUCTION: The Objective Structured Clinical Examination (OSCE) has been widely used in health professions education since the 1970s. The global disruption caused by the COVID-19 pandemic restricted in-person assessments and medical educators globally sought alternative means to assess and certify students and trainees to meet the acute demand for health-care workers. One such solution was through virtual OSCE (vOSCE), which modified traditional in-person OSCE using videoconference platforms. This meta-ethnography sought to synthesise qualitative literature on candidates' and assessors' experiences of vOSCE to evaluate whether it may have a role in future assessment practices. METHODS: In June 2022, we systematically searched PsycINFO, Medline and ERIC for peer-reviewed qualitative and mixed-methods articles that described candidates' and assessors' experiences of virtual OSCE in health professions education. Of 1069 articles identified, 17 were synthesised using meta-ethnography. RESULTS: The final synthesis represented 1190 candidates and assessors from faculties of medicine, dentistry, nursing, pharmacy and osteopathy. We developed our findings into four key concepts. 'Strengthening confidence in a virtual environment' highlighted attempts to overcome and mitigate concerns associated with transitioning from in-person to virtual assessment. 'Understanding the scope of use as an assessment' reflected on the suitability of vOSCE in assessing various skills. 'Refining operational processes' emphasised the technical challenges of implementing vOSCE and impacts on accessibility and resources. 'Envisioning its future role' considered the applicability of vOSCE in the climate of rapid development in telehealth. CONCLUSION: This meta-ethnography highlighted that although vOSCE was primarily considered a temporary and crisis response, candidates and assessors recognised positive, as well as negative, consequences of the transition towards them. Moving forward, medical education policymakers should carefully consider the extent to which elements of vOSCE could be incorporated into assessment systems, particularly in light of the rise of telehealth in clinical practice.

PM2.5-Attributable Mortality Burden Variability in the Continental U.S.

Epidemiologic studies have consistently observed associations between fine particulate matter (PM2.5) exposure and premature mortality. These studies use air quality concentration information from a combination of sources to estimate pollutant exposures and then assess how mortality varies as a result of differing exposures. Health impact assessments then typically use a single log-linear hazard ratio (HR) per health outcome to estimate counts of avoided human health effects resulting from air quality improvements. This paper estimates the total PM2.5-attributable premature mortality burden using a variety of methods for estimating exposures and quantifying PM2.5-attributable deaths in 2011 and 2028. We use: 1) several exposure models that apply a wide range of methods, and 2) a variety of HRs from the epidemiologic literature that relate long-term PM2.5 exposures to mortality among the U.S. population. We then further evaluate the variability of aggregated national premature mortality estimates to stratification by race and/or ethnicity or exposure level (e.g., below the current annual PM2.5 National Ambient Air Quality Standards). We find that unstratified annual adult mortality burden incidence estimates vary more (e.g., ~3-fold) by HR than by exposure model (e.g., <10%). In addition, future mortality burden estimates stratified by race/ethnicity are larger than the unstratified estimates of the entire population, and studies that stratify PM2.5-attributable mortality HRs by an exposure concentration threshold led to substantially higher estimates. These results are intended to provide transparency regarding the sensitivity of mortality estimates to upstream input choices.

Stabilization of guinea pig transglutaminase 2 solutions.

Mammalian transglutaminase 2 exhibits poor long-term stability in solution. Reconstituting lyophilized transglutaminase 2 in solutions containing dithiothreitol and EDTA alone and together with glycerol stabilizes the activity of this enzyme for several weeks.

Tackling the Lead Gremlins: A Response to Take-Home Lead Exposure in a Minnesota Industrial Facility, 2019.

Lead exposure that occurs from contamination inadvertently brought home from a workplace is known as take-home exposure. Take-home exposures are a public health hazard that adversely affects health equity for families and communities. This article describes coordinated action by agencies in Minnesota to curb lead exposure among children of workers at a facility that produces fishing sinkers and battery terminals. (Am J Public Health. 2022;112(S7):S655-S657. https://doi.org/10.2105/AJPH.2022.306982).

A Double-Blind Placebo-Controlled, Randomized Trial of Divalproex Sodium for Posttraumatic Irritability Greater Than 1 Year After Mild to Moderate Traumatic Brain Injury.

OBJECTIVE: Posttraumatic irritability after traumatic brain injury (TBI) may become a chronic problem and contribute to impaired everyday function, either alone or in combination with alcohol use disorder. The authors hypothesized that divalproex sodium (VPA) would improve posttraumatic irritability and result in lessened alcohol use. METHODS: This randomized, placebo-controlled double-blind clinical trial recruited participants with an index TBI occurring 1 or more years prior to enrollment, a history of alcohol use disorder, and posttraumatic irritability corroborated by a knowledgeable informant. An 8-item subset of the Agitated Behavior Scale served as the primary outcome measure of VPA efficacy. Doses of VPA were titrated to standard serum concentrations of 50 µg/ml to 100 µg/ml. RESULTS: Forty-eight persons completed this clinical trial (VPA, N=22; placebo, N=26). At baseline, participants rated their posttraumatic irritability as less severe than did their informants (p<0.05). During the trial, informants reported significant and sustained reduction of posttraumatic irritability (p=0.03) in the study participants. Biweekly averages during drug exposure confirmed this (p<0.03, Cohen's d=0.44). Treatment efficacy was not related to measures of anxiety, posttraumatic stress disorder, sedation, or veteran versus nonveteran status. Alcohol use did not change as a result of treatment. There were no serious adverse events. CONCLUSIONS: This study demonstrated an effect of VPA on posttraumatic irritability, and VPA was well tolerated. Further definition of treatment efficacy and safety requires a large-scale multisite trial, using a randomized, double-blind placebo-controlled design.

PET Tracers for Imaging Cardiac Function in Cardio-oncology.

PURPOSE OF REVIEW: Successful treatment of cancer can be hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the injury to the heart is detected before the onset to irreversible cardiac impairment. The gold standard for cardiac imaging in cardio-oncology is echocardiography. Despite improvements in the application of this modality, it is not typically sensitive to sub-clinical or early-stage dysfunction. We identify in this review some emerging tracers for detecting incipient cardiotoxicity by positron emission tomography (PET). RECENT FINDINGS: Vectors labeled with positron-emitting radionuclides (e.g., carbon-11, fluorine-18, gallium-68) are now available to study cardiac function, metabolism, and tissue repair in preclinical models. Many of these probes are highly sensitive to early damage, thereby potentially addressing the limitations of current imaging approaches, and show promise in preliminary clinical evaluations. The overlapping pathophysiology between cardiotoxicity and heart failure significantly expands the number of imaging tools available to cardio-oncology. This is highlighted by the emergence of radiolabeled probes targeting fibroblast activation protein (FAP) for sensitive detection of dysregulated healing process that underpins adverse cardiac remodeling. The growth of PET scanner technology also creates an opportunity for a renaissance in metabolic imaging in cardio-oncology research.

Early clinical and radiographic outcomes of anatomic total shoulder arthroplasty with a biconvex posterior augmented glenoid for patients with posterior glenoid erosion: minimum 2-year follow-up.

BACKGROUND: Glenoid bone loss in anatomic total shoulder arthroplasty (aTSA) remains a controversial and challenging clinical problem. Previous studies have shown high rates of glenoid loosening for aTSA in shoulders with retroversion, posterior bone loss, and posterior humeral head subluxation. This study is the first to present minimum 2-year follow-up data of an all-polyethylene, biconvex augmented anatomic glenoid component for correction of glenoid retroversion and posterior humeral head subluxation. METHODS: This study is a multicenter, retrospective review of prospectively collected data on consecutive patients from 7 global clinical sites. All patients underwent aTSA using the biconvex posterior augmented glenoid (PAG). Inclusion criteria were preoperative computed tomographic (CT) scan, minimum 2 years since surgery, preoperative and minimum 2-year postoperative range of motion examination, and patient-reported outcome measures (PROMs). Glenoid classification, glenoid retroversion, and posterior humeral head subluxation were measured from preoperative CT and radiography and postoperative radiography. Statistical comparisons between pre- and postoperative values were performed with a paired t test. RESULTS: Eighty-six of 110 consecutive patients during the study period (78% follow-up) met the inclusion criteria and were included in our analysis. Mean follow-up was 35 ± 10 months, with a mean age of 68 ± 8 years (range 48-85). Range of motion statistically improved in all planes from pre- to postoperation. Mean visual analog scale score improved from 5.2 preoperation to 0.7 postoperation, Single Assessment Numeric Evaluation score from 43.2 to 89.5, Constant score from 41.8 to 76.9, and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score from 49.8 to 86.7 (all P < .0001). Mean glenoid retroversion improved from 19.3° to 7.4° (P < .0001). Posterior subluxation improved from 69.1% to 53.5% and posterior decentering improved from 5.8% to -3.0% (P < .0001). There was 1 patient with both a prosthetic joint infection and radiographic glenoid loosening that required revision. Seventy-nine of 86 patients had a Lazarus score of 0 (no radiolucency seen about peg or keel) at final follow-up. CONCLUSIONS: This study shows that at minimum 2-year follow-up, a posterior-augmented all-polyethylene glenoid can correct glenoid retroversion and posterior humeral head subluxation. Clinically, there was significant improvement in both range of motion and PROMs.

Mimicking atmospheric photochemical modelling with a deep neural network.

Fast and accurate prediction of ambient ozone (O3) formed from atmospheric photochemical processes is crucial for designing effective O3 pollution control strategies in the context of climate change. The chemical transport model (CTM) is the fundamental tool for O3 prediction and policy design, however, existing CTM-based approaches are computationally expensive, and resource burdens limit their usage and effectiveness in air quality management. Here we proposed a novel method (noted as DeepCTM) that using deep learning to mimic CTM simulations to improve the computational efficiency of photochemical modeling. The well-trained DeepCTM successfully reproduces CTM-simulated O3 concentration using input features of precursor emissions, meteorological factors, and initial conditions. The advantage of the DeepCTM is its high efficiency in identifying the dominant contributors to O3 formation and quantifying the O3 response to variations in emissions and meteorology. The emission-meteorology-concentration linkages implied by the DeepCTM are consistent with known mechanisms of atmospheric chemistry, indicating that the DeepCTM is also scientifically reasonable. The DeepCTM application in China suggests that O3 concentrations are strongly influenced by the initialized O3 concentration, as well as emission and meteorological factors during daytime when O3 is formed photochemically. The variation of meteorological factors such as short-wave radiation can also significantly modulate the O3 chemistry. The DeepCTM developed in this study exhibits great potential for efficiently representing the complex atmospheric system and can provide policymakers with urgently needed information for designing effective control strategies to mitigate O3 pollution.

Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography.

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones.

The impact of non-pharmaceutical interventions on SARS-CoV-2 transmission across 130 countries and territories.

BACKGROUND: Non-pharmaceutical interventions (NPIs) are used to reduce transmission of SARS coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). However, empirical evidence of the effectiveness of specific NPIs has been inconsistent. We assessed the effectiveness of NPIs around internal containment and closure, international travel restrictions, economic measures, and health system actions on SARS-CoV-2 transmission in 130 countries and territories. METHODS: We used panel (longitudinal) regression to estimate the effectiveness of 13 categories of NPIs in reducing SARS-CoV-2 transmission using data from January to June 2020. First, we examined the temporal association between NPIs using hierarchical cluster analyses. We then regressed the time-varying reproduction number (Rt) of COVID-19 against different NPIs. We examined different model specifications to account for the temporal lag between NPIs and changes in Rt, levels of NPI intensity, time-varying changes in NPI effect, and variable selection criteria. Results were interpreted taking into account both the range of model specifications and temporal clustering of NPIs. RESULTS: There was strong evidence for an association between two NPIs (school closure, internal movement restrictions) and reduced Rt. Another three NPIs (workplace closure, income support, and debt/contract relief) had strong evidence of effectiveness when ignoring their level of intensity, while two NPIs (public events cancellation, restriction on gatherings) had strong evidence of their effectiveness only when evaluating their implementation at maximum capacity (e.g. restrictions on 1000+ people gathering were not effective, restrictions on < 10 people gathering were). Evidence about the effectiveness of the remaining NPIs (stay-at-home requirements, public information campaigns, public transport closure, international travel controls, testing, contact tracing) was inconsistent and inconclusive. We found temporal clustering between many of the NPIs. Effect sizes varied depending on whether or not we included data after peak NPI intensity. CONCLUSION: Understanding the impact that specific NPIs have had on SARS-CoV-2 transmission is complicated by temporal clustering, time-dependent variation in effects, and differences in NPI intensity. However, the effectiveness of school closure and internal movement restrictions appears robust across different model specifications, with some evidence that other NPIs may also be effective under particular conditions. This provides empirical evidence for the potential effectiveness of many, although not all, actions policy-makers are taking to respond to the COVID-19 pandemic.

Monthly Patterns of Ammonia Over the Contiguous United States at 2-km Resolution.

Monthly, high-resolution (∼2 km) ammonia (NH3) column maps from the Infrared Atmospheric Sounding Interferometer (IASI) were developed across the contiguous United States and adjacent areas. Ammonia hotspots (95th percentile of the column distribution) were highly localized with a characteristic length scale of 12 km and median area of 152 km2. Five seasonality clusters were identified with k-means++ clustering. The Midwest and eastern United States had a broad, spring maximum of NH3 (67% of hotspots in this cluster). The western United States, in contrast, showed a narrower midsummer peak (32% of hotspots). IASI spatiotemporal clustering was consistent with those from the Ammonia Monitoring Network. CMAQ and GFDL-AM3 modeled NH3 columns have some success replicating the seasonal patterns but did not capture the regional differences. The high spatial-resolution monthly NH3 maps serve as a constraint for model simulations and as a guide for the placement of future, ground-based network sites.

Examining PM2.5 concentrations and exposure using multiple models.

Epidemiologic studies have found associations between fine particulate matter (PM2.5) exposure and adverse health effects using exposure models that incorporate monitoring data and other relevant information. Here, we use nine PM2.5 concentration models (i.e., exposure models) that span a wide range of methods to investigate i) PM2.5 concentrations in 2011, ii) potential changes in PM2.5 concentrations between 2011 and 2028 due to on-the-books regulations, and iii) PM2.5 exposure for the U.S. population and four racial/ethnic groups. The exposure models included two geophysical chemical transport models (CTMs), two interpolation methods, a satellite-derived aerosol optical depth-based method, a Bayesian statistical regression model, and three data-rich machine learning methods. We focused on annual predictions that were regridded to 12-km resolution over the conterminous U.S., but also considered 1-km predictions in sensitivity analyses. The exposure models predicted broadly consistent PM2.5 concentrations, with relatively high concentrations on average over the eastern U.S. and greater variability in the western U.S. However, differences in national concentration distributions (median standard deviation: 1.00 µg m-3) and spatial distributions over urban areas were evident. Further exploration of these differences and their implications for specific applications would be valuable. PM2.5 concentrations were estimated to decrease by about 1 µg m-3 on average due to modeled emission changes between 2011 and 2028, with decreases of more than 3 µg m-3 in areas with relatively high 2011 concentrations that were projected to experience relatively large emission reductions. Agreement among models was closer for population-weighted than uniformly weighted averages across the domain. About 50% of the population was estimated to experience PM2.5 concentrations less than 10 µg m-3 in 2011 and PM2.5 improvements of about 2 µg m-3 due to modeled emission changes between 2011 and 2028. Two inequality metrics were used to characterize differences in exposure among the four racial/ethnic groups. The metrics generally yielded consistent information and suggest that the modeled emission reductions between 2011 and 2028 would reduce absolute exposure inequality on average.

New horizons: managing antithrombotic dilemmas in patients with cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) most commonly presents with lobar intracerebral haemorrhage, though also with transient focal neurological episodes, cognitive impairment, as an incidental finding and rarely acutely or subacutely in patients developing an immune response to amyloid. Convexity subarachnoid haemorrhage, cortical superficial siderosis and lobar cerebral microbleeds are the other signature imaging features. The main implications of a diagnosis are the risk of intracerebral haemorrhage and frequent co-existence of antithrombotic indications. The risk of intracerebral haemorrhage varies by phenotype, being highest in patients with transient focal neurological episodes and lowest in patients with isolated microbleeds. There is only one relevant randomised controlled trial to CAA patients with antithrombotic indications: RESTART showed that in patients presenting with intracerebral haemorrhage while taking antiplatelets, restarting treatment appeared to reduce recurrent intracerebral haemorrhage and improve outcomes. Observational and indirect data are reviewed relevant to other scenarios where there are antithrombotic indications. In patients with a microbleed-only phenotype, the risk of ischaemic stroke exceeds the risk of intracerebral haemorrhage at all cerebral microbleed burdens. In patients with atrial fibrillation (AF), left atrial appendage occlusion, where device closure excludes the left atrial appendage from the circulation, can be considered where the risk of anticoagulation seems prohibitive. Ongoing trials are testing the role of direct oral anticoagulant (DOACs) and left atrial appendage occlusion in patients with intracerebral haemorrhage/AF but in the interim, treatment decisions will need to be individualised and remain difficult.

The Marcus Institute for Brain Health: an integrated practice unit for the care of traumatic brain injury in military veterans.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) is a signature wound of recent Unites States military conflicts. The National Intrepid Center of Excellence (NICoE) has demonstrated that interdisciplinary care is effective for active-duty military personnel with TBI and related psychological health conditions. This paper details how the Marcus Institute for Brain Health (MIBH), established in 2017 as an Integrated Practice Unit (IPU), is founded on the NICoE model and is dedicated to interdisciplinary care for Veterans with persistent symptoms due to TBI and psychological comorbidities. RESEARCH DESIGN: A highly integrated group of clinicians from diverse disciplines combine their expertise to offer comprehensive evaluation, intensive outpatient treatment, and program outcomes evaluation. METHODS AND PROCEDURES: The role of each discipline in the provision of care, and the regular interaction of all clinicians, are delineated. A strong connection to academic medicine is maintained so that clinical research and education complement patient care. MAIN OUTCOMES AND RESULTS: Over three hundred veterans and family members have received treatment at the MIBH. Program evaluation is underway. CONCLUSIONS: As the understanding of TBI and related psychological conditions continues its rapid evolution, the expert interdisciplinary care at the MIBH has great promise as a Veteran counterpart of the NICoE.