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BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

AIMS: The purpose of this study is to evaluate the accuracy and validity of the determination of cause of death (COD) and manner of death (MOD) at the completion of the forensic autopsy prosection. METHODS: We analysed 952 autopsy cases conducted from 2019 to 2020 and compared every patients COD, other significant contributing factors to death (OSC), and MOD after prosection to their COD, OSC and MOD after completion of the final autopsy report. RESULTS: We found that 83% of cases (790 patients) did not have an unexpected change and 17% of cases (162 patients) exhibited a true change in their final diagnosis; the relationship between age and changes in COD and MOD was significant. CONCLUSIONS: Our findings indicate that in the majority of forensic autopsy cases, medical professionals can reasonably complete death certification after the autopsy prosection. In addition to improving the accuracy of COD and MOD, advances in this field will enhance timely decedent affairs management, timely investigations of crimes and timely closure to families who have lost loved ones. We recommend implementing combined interventional education and consultation with expert pathologists, and a well-followed structured method of death classification as the best course of practice.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery β = 0.0561, Q = 4.05 × 10-10; β  = 0.0421, Q = 1.12 × 10-3; and β = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q

Plastic pollution is distributed patchily around the worlds oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

Physics-based circuit parameters like series and shunt resistance are essential to provide insights into the degradation status of photovoltaic (PV) arrays. However, calculating these parameters typically requires a full current–voltage characteristic (I-V curve), the acquisition of which involves specific measurement devices and costly methods. Thus, I-V curves of the PV system level are often not available. This paper proposes a methodology (PVPRO) to estimate these I-V curve parameters using only operation (string-level DC voltage and current) and weather data (irradiance and temperature). PVPRO first performs multi-stage data pre-processing to remove noisy data. Next, the time-series DC data are used to fit an equivalent circuit single-diode model (SDM) to estimate the circuit parameters by minimizing the differences between the measured and estimated values. In this way, the time evolutions of the SDM parameters are obtained. We evaluate PVPRO on synthetic datasets and find an excellent estimation of both SDM and the key I-V parameters (e.g., open-circuit voltage, short-circuit current, maximum power, etc.) with an average relative error of 0.55%. The performance, especially the extracted degradation rate of parameters, is robust to various measurement noises and the presence of faults. In addition, PVPRO is applied to a 271 kW PV field system. The relative error between the real and estimated operation voltage and current is less than 1%, suggesting that degradation trends are well captured. PVPRO represents a promising open-source tool to extract the time-series degradation trends of key PV parameters from routine operation data.

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or "known" and 2,342 nontargeted or "unknown" compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)-a community cohort of self-identified African Americans-who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of

The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.

PurposeDiphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).MethodsMolecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.ResultsDPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.ConclusionWe provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

BackgroundQuantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases.ObjectiveTo determine if quantitative measurements of eye movements may reveal subtle progression of fragile X-associated tremor and ataxia (FXTAS).MethodsProsaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non-FXTAS carriers, and 46 carriers with FXTAS.ResultsSymptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non-FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages.ConclusionAS deficits differentiated FXTAS from non-FXTAS premutation carriers implicating top-down control and frontostriatal deterioration. However, the absence of group differences between non-FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression.

The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empowerment as follows: perceived ability to understand and seek new information related to the genomic sequencing, manage emotions related to the diagnostic process and outcomes, and utilize genomic sequencing information to the betterment of the individual/child and family. The GEmS consists of four scales, two are primarily emotion-focused (Meaning of a Diagnosis, and Emotional Management of the Process) and two are action-oriented (Seeking Information and Support, and Implications and Planning). The purpose of this research was to provide a strategy for interpreting results from the GEmS and present illustrative cases. These illustrations should serve to facilitate use of the GEmS in the clinical and research arena, particularly with respect to guiding genetic counseling processes for parents of children with undiagnosed conditions.

BackgroundIndividuals with Tourette Syndrome and Persistent Tic Disorders (collectively TS) often experience premonitory urges-aversive physical sensations that precede tics and are temporarily relieved by tic expression. The relationship between tics and premonitory urges plays a key role in the neurobehavioral treatment model of TS, which underlies first-line treatments such as the Comprehensive Behavioral Intervention for Tics (CBIT). Despite the efficacy of CBIT and related behavioral therapies, less than 40% of adults with TS respond to these treatments. Further examination of the relationship between premonitory urges, tic severity, and tic impairment can provide new insights into therapeutic targets to optimize behavioral treatment outcomes. This study examined whether urge intolerance-difficulty tolerating premonitory urges-predicted tic severity and tic-related impairment among adults with TS.MethodsParticipants were 80 adults with TS. Assessments characterized premonitory urge, distress tolerance, tic severity, and tic impairment. We used structural equation modeling (SEM) to examine the construct of urge intolerance-comprised of premonitory urge ratings and distress tolerance ratings. We first evaluated a measurement model of urge intolerance through bifactor modeling, including tests of the incremental value of subfactors that reflect premonitory urge severity and distress tolerance within the model. We then evaluated a structural model where we predicted clinician-rated tic severity and tic impairment by the latent variable of urge intolerance established in our measurement model.ResultsAnalyses supported a bifactor measurement model of urge intolerance among adults with TS. Consistent with theoretical models, higher levels of urge intolerance predicted greater levels of clinician-rated tic severity and tic impairment.ConclusionThis investigation supports the construct of urge intolerance among adults with TS and distinguishes it from subcomponents of urge severity and distress tolerance. Given its predictive relationship with tic severity and tic impairment, urge intolerance represents a promising treatment target to improve therapeutic outcomes in adults with TS.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

In 1993 Stanley showed that if a simplicial complex is acyclic over some field, then its face poset can be decomposed into disjoint rank $1$ boolean intervals whose minimal faces together form a subcomplex. Stanley further conjectured that complexes with a higher notion of acyclicity could be decomposed in a similar way using boolean intervals of higher rank. We provide an explicit counterexample to this conjecture. We also prove a version of the conjecture for boolean trees and show that the original conjecture holds when this notion of acyclicity is as high as possible.Mathematics Subject Classifications: 05E45, 55U10

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.

The Karlsruhe Tritium Neutrino (KATRIN) experiment aims at measuring the effective electron neutrino mass with a sensitivity of 0.2 eV/c2, i.e., improving on previous measurements by an order of magnitude. Neutrino mass data taking with KATRIN commenced in early 2019, and after only a few weeks of data recording, analysis of these data showed the success of KATRIN, improving on the known neutrino mass limit by a factor of about two. This success very much could be ascribed to the fact that most of the system components met, or even surpassed, the required specifications during long-term operation. Here, we report on the performance of the laser Raman (LARA) monitoring system which provides continuous high-precision information on the gas composition injected into the experiment's windowless gaseous tritium source (WGTS), specifically on its isotopic purity of tritium-one of the key parameters required in the derivation of the electron neutrino mass. The concentrations cx for all six hydrogen isotopologues were monitored simultaneously, with a measurement precision for individual components of the order 10-3 or better throughout the complete KATRIN data taking campaigns to date. From these, the tritium purity, εT, is derived with precision of

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290.

The determination of the neutrino mass is one of the major challenges in astroparticle physics today. Direct neutrino mass experiments, based solely on the kinematics of β -decay, provide a largely model-independent probe to the neutrino mass scale. The Karlsruhe Tritium Neutrino (KATRIN) experiment is designed to directly measure the effective electron antineutrino mass with a sensitivity of 0.2eV (90 % CL). In this work we report on the first operation of KATRIN with tritium which took place in 2018. During this commissioning phase of the tritium circulation system, excellent agreement of the theoretical prediction with the recorded spectra was found and stable conditions over a time period of 13 days could be established. These results are an essential prerequisite for the subsequent neutrino mass measurements with KATRIN in 2019.

The Karlsruhe Tritium Neutrino (KATRIN) experiment aims at measuring the effective electron neutrino mass with a sensitivity of 0.2 eV/c2, i.e., improving on previous measurements by an order of magnitude. Neutrino mass data taking with KATRIN commenced in early 2019, and after only a few weeks of data recording, analysis of these data showed the success of KATRIN, improving on the known neutrino mass limit by a factor of about two. This success very much could be ascribed to the fact that most of the system components met, or even surpassed, the required specifications during long-term operation. Here, we report on the performance of the laser Raman (LARA) monitoring system which provides continuous high-precision information on the gas composition injected into the experiment's windowless gaseous tritium source (WGTS), specifically on its isotopic purity of tritium-one of the key parameters required in the derivation of the electron neutrino mass. The concentrations cx for all six hydrogen isotopologues were monitored simultaneously, with a measurement precision for individual components of the order 10-3 or better throughout the complete KATRIN data taking campaigns to date. From these, the tritium purity, εT, is derived with precision of

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

The purpose of this article is to review conventional and advanced neuroimaging techniques performed in the setting of traumatic brain injury (TBI). The primary goal for the treatment of patients with suspected TBI is to prevent secondary injury. In the setting of a moderate to severe TBI, the most appropriate initial neuroimaging examination is a noncontrast head computed tomography (CT), which can reveal life-threatening injuries and direct emergent neurosurgical intervention. We will focus much of the article on advanced neuroimaging techniques including perfusion imaging and diffusion tensor imaging and discuss their potentials and challenges. We believe that advanced neuroimaging techniques may improve the accuracy of diagnosis of TBI and improve management of TBI.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

BackgroundOur group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.ObjectiveTo compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).MethodsFDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.ResultsFDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).ConclusionThis first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

BackgroundOur group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.ObjectiveTo compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).MethodsFDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.ResultsFDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).ConclusionThis first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Fluorescent GTP analogues are utilized for an assortment of nucleic acid and protein characterization studies. Non-hydrolysable analogues such as GTPγS offer the advantage of keeping proteins in a GTP-bound conformation due to their resistance to hydrolysis into GDP. Two novel fluorescent GTPγS molecules were developed by linking fluorescein and tetramethylrhodamine to the γ-thiophosphate of GTPγS. Chemical and biological analysis of these two compounds revealed their successful synthesis and ability to bind to the nucleotide-binding site of tubulin. These two new fluorescent non-hydrolysable nucleotides offer new possibilities for biophysical and biochemical characterization of GTP-binding proteins.

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

BackgroundAn international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.MethodsFourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.ResultsThe agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).ConclusionsThe HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

Abstract Background The purpose of the present study was to investigate activation of inflammatory markers in human macrophages derived from the U937 cell line after exposure to particulate matter (PM) collected on dairy farms in California and to identify the most potent components of the PM. Methods PM from different dairies were collected and tested to induce an inflammatory response determined by the expression of various pro-inflammatory genes, such as Interleukin (IL)-8, in U937 derived macrophages. Gel shift and luciferase reporter assays were performed to examine the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like-receptor 4 (TLR4). Results Macrophage exposure to PM derived from dairy farms significantly activated expression of pro-inflammatory genes, including IL-8, cyclooxygenase 2 and Tumor necrosis factor-alpha, which are hallmarks of inflammation. Acute phase proteins, such as serum amyloid A and IL-6, were also significantly upregulated in macrophages treated with PM from dairies. Coarse PM fractions demonstrated more pro-inflammatory activity on an equal-dose basis than fine PM. Urban PM collected from the same region as the dairy farms was associated with a lower concentration of endotoxin and produced significantly less IL-8 expression compared to PM collected on the dairy farms. Conclusion The present study provides evidence that the endotoxin components of the particles collected on dairies play a major role in mediating an inflammatory response through activation of TLR4 and NF-κB signaling.

The prevalence of vertebral fractures on routine chest radiographs of elderly Caucasian women was only 1.3 times higher than in African American (AA) women, a difference considerably smaller than reported in population studies. AAs with medical problems may have higher risk of vertebral fractures than previously suspected.IntroductionEarlier studies noted a 1.9- to 3.7-fold higher prevalence of vertebral fractures in Caucasian (CA) compared to African American (AA) women. These studies, however, may have suffered from selection bias. We reported that among women referred for bone density testing, the prevalence of vertebral fractures in AA was the same as in CA women. Suspecting that the latter might have been due to a referral bias, we examined the racial difference in the prevalence of vertebra fractures on chest radiographs of patients seeking general medical care, not selected for osteoporosis.MethodsConsecutive chest radiographs (N = 1,200) of women over age 60 were evaluated using Genant's semi-quantitative method. Patients' race and the presence of diseases or medications associated with increased fracture risk were ascertained from the electronic medical records.ResultsAmong 1,011 women (76% AA) with usable radiographs, 11% had moderate or severe vertebral fractures. The prevalence of vertebral fractures was 10.3% in 773 AA and 13% in 238 CA women (p = 0.248 for difference between races). The lack of difference persisted after controlling for age, smoking, use of glucocorticoids, or presence of cancer, rheumatoid arthritis, organ transplantation, and end-stage renal disease. Among all subjects, CA women were more likely to be diagnosed and treated for osteoporosis (p

The prevalence of vertebral fractures on routine chest radiographs of elderly Caucasian women was only 1.3 times higher than in African American (AA) women, a difference considerably smaller than reported in population studies. AAs with medical problems may have higher risk of vertebral fractures than previously suspected.IntroductionEarlier studies noted a 1.9- to 3.7-fold higher prevalence of vertebral fractures in Caucasian (CA) compared to African American (AA) women. These studies, however, may have suffered from selection bias. We reported that among women referred for bone density testing, the prevalence of vertebral fractures in AA was the same as in CA women. Suspecting that the latter might have been due to a referral bias, we examined the racial difference in the prevalence of vertebra fractures on chest radiographs of patients seeking general medical care, not selected for osteoporosis.MethodsConsecutive chest radiographs (N = 1,200) of women over age 60 were evaluated using Genant's semi-quantitative method. Patients' race and the presence of diseases or medications associated with increased fracture risk were ascertained from the electronic medical records.ResultsAmong 1,011 women (76% AA) with usable radiographs, 11% had moderate or severe vertebral fractures. The prevalence of vertebral fractures was 10.3% in 773 AA and 13% in 238 CA women (p = 0.248 for difference between races). The lack of difference persisted after controlling for age, smoking, use of glucocorticoids, or presence of cancer, rheumatoid arthritis, organ transplantation, and end-stage renal disease. Among all subjects, CA women were more likely to be diagnosed and treated for osteoporosis (p

The Sanctuary mobile code system includes security mechanisms forprotecting mobile agents from malicious servers as well as mechanisms forprotecting mobile agent servers from malicious mobile code. To protect remotelyexecuted mobile code, we integrate several key approaches: (1) securityattributes certification to enable mobile code to avoid nodes in theagent-server network that are untrustworthy, as determined by user-centricsecurity policies; (2) forward secure cryptography to improve detection ofmalicious tampering by servers; and (3) defining separate roles for agentauthor and agent owner, which justifies restricted delegation and externalreference monitors with owner-provided agents to limit potential damage causedby buggy or compromised agent code. Simply put, we enable mobile code to avoidtrouble when possible, and to detect trouble when it is unavoidable. Weexamine security-aware itinerary planning as a means to supplement theseapproaches, and describe our analysis of this problem. Our server uses wellknown approaches to defend itself from malicious code, and custom extensionsthat address the security needs of the mobile code itself. This paperdescribes our mechanisms and how they are integrated into the Sanctuary mobilecode system.Pre-2018 CSE ID: CS2002-0731