To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic ...traumatic encephalopathy (CTE).
A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES
April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298).
Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features.
New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.
Introduction
The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of ...WMH, and their association with years of play, age of first exposure, and clinical function in former American football players.
Methods
A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45–74 years) completed fluid‐attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self‐report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60.
Results
In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log‐WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log‐WMH was associated with younger age of first exposure to football and worse executive function.
Discussion
In older former football players, WMH may have unique presentations, risk factors, and etiologies.
Highlights
Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same‐age asymptomatic unexposed men.
Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players.
In former football players, greater WMH was associated with worse executive function and verbal memory.
NendoU from SARS-CoV-2 is responsible for the virus’s ability to evade the innate immune system by cleaving the polyuridine leader sequence of antisense viral RNA. Here we report the room-temperature ...structure of NendoU, solved by serial femtosecond crystallography at an X-ray free-electron laser to 2.6 Å resolution. The room-temperature structure provides insight into the flexibility, dynamics, and other intrinsic properties of NendoU, with indications that the enzyme functions as an allosteric switch. Functional studies examining cleavage specificity in solution and in crystals support the uridine-purine cleavage preference, and we demonstrate that enzyme activity is fully maintained in crystal form. Optimizing the purification of NendoU and identifying suitable crystallization conditions set the benchmark for future time-resolved serial femtosecond crystallography studies. This could advance the design of antivirals with higher efficacy in treating coronaviral infections, since drugs that block allosteric conformational changes are less prone to drug resistance.
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•The first room-temperature structure of NendoU from SARS-CoV-2 is solved at an XFEL•Designed RNA substrates are cleaved within microcrystals of NendoU•High B factors indicate varying flexibility between trimers of the NendoU hexamer•Alternating trimer flexibility suggests a binding-change mechanism
NendoU from SARS-CoV-2 is a protein responsible for the virus’s ability to evade the immune system. Jernigan et al. report the room-temperature structure of NendoU, finding indications that it functions by an alternate-switch mechanism. This sets a benchmark for studies targeting this enzyme in treating coronavirus infections.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American ...football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome TES); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project.
The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined.
Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021.
Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE.
NCT02798185.
Serial femtosecond crystallography (SFX) is a powerful technique that exploits X‐ray free‐electron lasers to determine the structure of macromolecules at room temperature. Despite the impressive ...exposition of structural details with this novel crystallographic approach, the methods currently available to introduce crystals into the path of the X‐ray beam sometimes exhibit serious drawbacks. Samples requiring liquid injection of crystal slurries consume large quantities of crystals (at times up to a gram of protein per data set), may not be compatible with vacuum configurations on beamlines or provide a high background due to additional sheathing liquids present during the injection. Proposed and characterized here is the use of an immiscible inert oil phase to supplement the flow of sample in a hybrid microfluidic 3D‐printed co‐flow device. Co‐flow generation is reported with sample and oil phases flowing in parallel, resulting in stable injection conditions for two different resin materials experimentally. A numerical model is presented that adequately predicts these flow‐rate conditions. The co‐flow generating devices reduce crystal clogging effects, have the potential to conserve protein crystal samples up to 95% and will allow degradation‐free light‐induced time‐resolved SFX.
The development and characterization are described of a co‐flow injector for liquid‐jet crystal delivery applied for serial crystallography with X‐ray free‐electron lasers.
Effects of Bardoxolone Methyl in Alport Syndrome Warady, Bradley A; Pergola, Pablo E; Agarwal, Rajiv ...
Clinical journal of the American Society of Nephrology,
12/2022, Volume:
17, Issue:
12
Journal Article
Peer reviewed
Open access
Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.
We ...randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m
, to bardoxolone methyl (
=77) or placebo (
=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight.
Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 97.5% confidence interval, 5.1 to 13.4;
<0.001 and 7.4 95% confidence interval, 3.1 to 11.7;
=0.0008 ml/min per 1.73 m
, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1;
<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1;
=0.02) ml/min per 1.73 m
at 52 and 104 weeks, respectively. In a
analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 95% confidence interval, -1.9 to 4.9 ml/min per 1.73 m
). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure.
In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.
A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.
Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union 1, 2. It is the second ...most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m 2 , and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m 2 , and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m 2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/Conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
Introduction Patients with primary glomerular disease (GN) have unique management needs. We describe the design of a user-centered, patient-facing electronic health (eHealth) tool to support GN ...management. Methods We surveyed patients and GN expert nephrologists on disease management tasks, educational needs, and barriers and facilitators of eHealth tool use. Results were summarized and presented to patients, nephrologists, engineers, and a behavioral and implementation science expert in stakeholder meetings to jointly design an eHealth tool. Key themes from the meetings are described using rapid qualitative analysis. Results Sixty-six patients with minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, and membranous nephropathy responded to the survey, as well as 25 nephrologists from the NIH-funded Cure Glomerulonephropathy study network. Overall, patients performed fewer management tasks and acknowledged fewer informational needs than recommended by nephrologists. Patients were more knowledgeable about eHealth tools than nephrologists. Nine patient stakeholders reflected on the survey findings and noted a lack of awareness of key recommended management tasks and receiving little guidance from nephrologists on using eHealth. Key themes and concepts from the stakeholder meetings about eHealth tool development included the need for customizable design, trustworthy sources, seamless integration with other apps and clinical workflow, and reliable data tracking. The final design of our eHealth tool, the UrApp System, has 5 core features: “Profile” generates personalized data tracking, educational information, facilitation with provider discussions and inputting other preferences; “Data Tracking” displays patient health data with the ability to communicate important trends to patients and nephrologists; “Resources” provides trusted education information in a personalized manner; “Calendar” displays key events and generate reminders; and “Journal” facilitates information documentation using written or audio notes. Conclusion Our theory- and evidenced-based, stakeholder-engaged design process created designs for an eHealth tool to support the unique needs of patients with GN, optimized for effectiveness and implementation.
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