Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome.

Complement-mediated hemolytic uremic syndrome (CM-HUS) is a thrombotic microangiopathy characterized by germline variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors'' by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-HUS and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies IgM-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ~50% of CM-HUS patients who lack an alternative pathway "driving" variant and suggests at least a subset of CM-HUS is characterized by a breakdown of IgM immunologic tolerance. Key Points: CM-HUS has a CP stimulus driven by polyreactive IgM, addressing the mystery of why 40% of CM-HUS lack complement specific variantsComplement biosensors and the bioluminescent mHam can be used to aid in diagnosis of CM-HUS and monitor complement inhibitor therapy.

Complement biomarkers in the antiphospholipid syndrome - Approaches to quantification and implications for clinical management.

Complement is a major driver of antiphospholipid syndrome (APS) and a promising therapeutic target in refractory and catastrophic APS. Complement testing in APS is largely limited to research settings, and reliable, rapid-turnaround biomarkers are needed to predict those at risk for adverse clinical outcomes and most likely to benefit from complement inhibition. We review complement biomarkers and their association with thrombosis and obstetric outcomes, including: (i) complement proteins and activation fragments in the fluid phase; (ii) assays that evaluate complement on cell membranes (e.g. in vivo cell-bound complement fragments, hemolytic assays, and ex vivo 'functional' cell-based assays, and (iii) sequencing of complement genes. Current studies highlight the inconsistencies in testing both between studies and various aPL/APS subgroups, suggesting that either cell-based testing or multiplex panels employing a combination of biomarkers simultaneously may be most clinically relevant. Standardization of complement assays is needed to ensure reproducibility and establish clinically relevant applications.

On the horizon-the value and promise of the global pipeline of Alzheimer's disease therapeutics.

INTRODUCTION: The recent failure of several late-stage Alzheimer's disease (AD) clinical trials focused on amyloid beta (Aß) highlights the challenges of finding effective disease-modifying therapeutics. Despite major advances in our understanding of the genetic risk factors of disease and the development of clinical biomarkers, and that not all Aß-based approaches are equivalent, these failures may engender skepticism regarding the value of the AD pipeline. METHODS: To investigate these concerns, we compiled a database of current Phase 2 and 3 trials based on disease-modifying targets through a query of the National Institutes of Health's ClinicalTrials.gov. We then assessed the financial value of the pipeline. Financial modeling utilized risk-adjusted net present value (rNPV) measurements and included sensitivity analyses to help inform the drug development process. RESULTS: Results indicate that the preponderance of current Phase 3 trials were indeed targeting Aß, with only 15% addressing other targets. In contrast, the pipeline of Phase 2 trials was more diverse. The estimated rNPV of Phase 2 and 3 therapeutics was estimated to be $338 billion over 10 years. This figure increased to a theoretical cumulative value of $788 billion when incorporating the assumption that diagnostics will be developed to identify individuals at high risk for developing AD. Results from model sensitivity analyses showed that speed of market penetration and patient access contributed the most weight to financial value. In contrast, decreasing drug development costs had minimal impact on rNPV. DISCUSSION: These findings argue in favor of conducting thorough biomarker-driven Phase 2 proof of concept studies to avoid prematurely advancing assets into Phase 3. Insights from these analyses are also discussed in the context of the financial ecosystem needed to maintain a healthy AD pipeline.

A Theory-based Didactic Offering Physicians a Method for Learning and Teaching Others About Human Trafficking.

Emergency clinicians are on the frontlines of identifying and caring for trafficked persons. However, most emergency providers have never received training on trafficking, and studies report a significant knowledge gap involving this important topic. Workshops often employ a "train-the-trainer" model to address clinicians' knowledge gaps involving various topics (including trafficking). By offering participants knowledge and skills needed to both understand relevant content and teach this content to future learners, this model aims at promoting widespread dissemination of essential information. However, current train-the-trainer workshops typically involve full or multiday sessions and employ multimodal instructional techniques, making them time and resource intensive for both participants and facilitators. To address these challenges, we created a 50-minute train-the-trainer workshop to teach emergency clinicians the knowledge and skills needed to recognize and care for trafficked patients while providing instructional techniques to teach learners this content in the clinical environment. Learning theory and principles informed the choice of instructional methods and were employed when designing the paper-based learning guides that functioned as this intervention's primary instructional resource. Guides contained detailed scripts used to perform role-playing exercises. These "scripted guides" were designed for participants to learn important content while simultaneously practicing techniques to teach this content to one another. They provided the scaffolding necessary to independently direct learning during the workshop (with minimal facilitator intervention), while also being carefully formatted and organized to create an accessible tool for future use during clinical teaching. The session was implemented at the 2018 Society for Academic Emergency Medicine Annual Meeting in Indianapolis, Indiana. Based on participants' self-assessment using a retrospective pre-post test, the workshop was successful in creating a train-the-trainer model that is brief, requiring minimal facilitator resources and offers instruction on both content knowledge and instructional methods to disseminate this knowledge to future learners.

A Conceptual Model for Navigating a Career Path in Medical School Leadership.

There is a paucity of literature providing guidance to physicians hoping to attain a position as a medical school dean. Realizing this gap, the Society for Academic Emergency Medicine (SAEM) Faculty Development Committee organized an educational session focused on offering faculty guidance for obtaining a position in medical school leadership. The session involved panelists who are nationally known leaders in medical school administration and was successfully presented at the SAEM 2018 annual meeting in Indianapolis, Indiana. Knowledge and perspective gained both during this session and through literature review was analyzed using a conceptual thinking skills framework. This process offered insights that promoted the development of a conceptual model informed by current evidence and expert insight and rooted in educational, economic, and cognitive theory. This model provides a step-by-step guide detailing a process that physicians can use to create a plan for professional development that is informed, thoughtful, and individualized to their own needs to optimize their future chances of advancing to a career in medical school leadership.

Strong terahertz absorption in all-dielectric Huygens' metasurfaces.

We propose an all dielectric metamaterial that acts as a perfect terahertz absorber without a ground plane. The unit cell consists of a dielectric cylinder embedded in a low index material. In order to achieve near-perfect terahertz absorption (99.5%) we employ impedance matching of the electric and magnetic resonances within the cylinders of the Huygens' metasurface. The impedance matching is controlled by changing the aspect ratio between the height and diameter of the cylinder. We show that the absorption resonance can be tuned to particular frequencies from 0.3 to 1.9 THz via changing the geometry of the structure while keeping a nearly constant aspect ratio of the cylinders.

Simultaneous Treatment of Neurocognitive and Psychiatric Symptoms in Veterans with Post-Traumatic Stress Disorder and History of Mild Traumatic Brain Injury: A Pilot Study of Mindfulness-Based Stress Reduction.

Treating patient populations with significant psychiatric and neurocognitive symptomatology can present a unique clinical dilemma: progress in psychotherapy can be significantly fettered by cognitive deficits, whereas neurocognitive rehabilitation efforts can be ineffective because of psychiatric overlay. Application of mindfulness-based interventions to address either cognitive or psychiatric symptoms in isolation appears efficacious in many contexts; however, it remains unclear whether this type of intervention might help address simultaneous neurocognitive and psychiatric symptomatology. In a pre-post mixed methods design pilot study, nine Veterans with post-traumatic stress disorder (PTSD) and a history of mild traumatic brain injury with chronic cognitive complaints participated in Mindfulness-Based Stress Reduction (MBSR). Clinical interview, questionnaires, and attention and PTSD measures were administered immediately before, immediately after, and 3 months after MBSR completion. Qualitative and quantitative findings suggest high levels of safety, feasibility, and acceptability. Measurement of attention revealed significant improvement immediately following MBSR (p < 0.05, d = 0.57) and largely sustained improvement 3 months after completion of MBSR (p < 0.10, d = 0.48). Significant reduction in PTSD symptoms was found immediately after MBSR (p < 0.05, d = -1.56), and was sustained 3 months following MBSR completion (p < 0.05, d = -0.93). These results warrant a randomized controlled trial follow-up. Potential mechanisms for the broad effects observed will be explored.

Differential learning and memory performance in OEF/OIF veterans for verbal and visual material.

OBJECTIVE: Memory complaints are particularly salient among veterans who experience combat-related mild traumatic brain injuries and/or trauma exposure, and represent a primary barrier to successful societal reintegration and everyday functioning. Anecdotally within clinical practice, verbal learning and memory performance frequently appears differentially reduced versus visual learning and memory scores. We sought to empirically investigate the robustness of a verbal versus visual learning and memory discrepancy and to explore potential mechanisms for a verbal/visual performance split. METHOD: Participants consisted of 103 veterans with reported history of mild traumatic brain injuries returning home from U.S. military Operations Enduring Freedom and Iraqi Freedom referred for outpatient neuropsychological evaluation. RESULTS: Findings indicate that visual learning and memory abilities were largely intact while verbal learning and memory performance was significantly reduced in comparison, residing at approximately 1.1 SD below the mean for verbal learning and approximately 1.4 SD below the mean for verbal memory. This difference was not observed in verbal versus visual fluency performance, nor was it associated with estimated premorbid verbal abilities or traumatic brain injury history. In our sample, symptoms of depression, but not posttraumatic stress disorder, were significantly associated with reduced composite verbal learning and memory performance. CONCLUSIONS: Verbal learning and memory performance may benefit from targeted treatment of depressive symptomatology. Also, because visual learning and memory functions may remain intact, these might be emphasized when applying neurocognitive rehabilitation interventions to compensate for observed verbal learning and memory difficulties.

Brain and cognitive reserve: mediator(s) and construct validity, a critique.

The concept of "reserve" has traditionally been defined on the basis of a single indicator (e.g., education or intracranial volume) that purports to moderate or buffer the effects of brain damage on different clinical outcomes. While studies have shown modest effects for some indicators, it has left the concept of "reserve" wanting as an explanatory construct. More recently efforts have been made to identify groups of indicators hypothesized to represent a construct for brain or cognitive reserve. These efforts have also proved wanting because of the lack of evidence to justify such a priori groupings of variables into a brain or cognitive reserve construct. This theoretical paper addresses the issue of construct validity (convergent and discriminant) for both brain and cognitive reserve as single or multiple reserve factors. Conceptual models are proposed that are (a) derived from the current extant reserve literature and (b) empirically testable in order to facilitate establishment of construct validity for the commonly used, and perhaps misused, brain and cognitive reserve concepts.

A chemical approach to immunoprotein engineering: chemoselective functionalization of thioester proteins in their native state.

Less than 6 feet under: Serum proteins C3, C4, and alpha(2)M each contain a thioester domain buried within a hydrophobic pocket, which is thought to shield the labile thioester from hydrolysis. Herein, we make use of the inherent reactivity of the hydrazide for thioester moieties to chemoselectively label these crucial serum regulators in their native conformation; this demonstrates that access to the thioester site is much greater than previously supposed.

Relationship between psychiatric status and frontal-subcortical systems in HIV-infected individuals.

Human immunodeficiency virus (HIV)-infected adults frequently evidence both neurocognitive and psychiatric dysfunction. It was hypothesized that apathy and irritability, but not anxiety and depression, are related to HIV effects on frontal-subcortical systems. This hypothesis was evaluated by determining the degree to which these psychiatric features are associated with neurocognitive functioning that is dependent upon frontal-subcortical circuitry and, therefore, thought to be sensitive to the central nervous system effects of HIV. Rating scales assessing irritability, apathy, depression, and anxiety and a dual-task paradigm were administered to 189 HIV-seropositive (HIV+) and 53 HIV-seronegative participants. Deficits in dual-task performance and greater anxiety, depression, apathy, and irritability were observed in HIV+ participants. Simultaneous multivariate regression and communality analyses revealed that only apathy and irritability were associated with dual-task performance in HIV+ participants. Thus, these findings suggest that apathy and irritability, but not depression and anxiety, are likely associated with the effects of HIV on frontal-subcortical circuitry.

Parametric manipulation of working memory load in traumatic brain injury: behavioral and neural correlates.

Traumatic brain injury (TBI) is often associated with enduring impairments in high-level cognitive functioning, including working memory (WM). We examined WM function in predominantly chronic patients with mild, moderate and severe TBI and healthy comparison subjects behaviorally and, in a small subset of moderate-to-severe TBI patients, with event-related functional magnetic resonance imaging (fMRI), using a visual n-back task that parametrically varied WM load. TBI patients showed severity-dependent and load-related WM deficits in performance accuracy, but not reaction time. Performance of mild TBI patients did not differ from controls; patients with moderate and severe TBI were impaired, relative to controls and mild TBI patients, but only at higher WM-load levels. fMRI results show that TBI patients exhibit altered patterns of activation in a number of WM-related brain regions, including the dorsolateral prefrontal cortex and Broca's area. Examination of the pattern of behavioral responding and the temporal course of activations suggests that WM deficits in moderate-to-severe TBI are due to associative or strategic aspects of WM, and not impairments in active maintenance of stimulus representations. Overall, results demonstrate that individuals with moderate-to-severe TBI exhibit WM deficits that are associated with dysfunction within a distributed network of brain regions that support verbally mediated WM.

Steady-state visual evoked potentials reveal frontally-mediated working memory activity in humans.

Steady-state visual evoked potentials (SSVEPs) reflect power changes at the stimulus driving frequency and have been used to assess brain activity reflecting cognitive processing. Only one study has demonstrated SSVEP modulation associated with working memory (WM), and none have compared the spatial localization of SSVEP modulations during WM performance with other brain imaging methods. Here we examined WM-related activity recorded with dense-array SSVEPs, analyzed using low resolution electromagnetic tomography, and compared the results to our previous findings using functional magnetic resonance imaging (fMRI). WM was associated with increased SSVEP activity over the right dorsolateral prefrontal cortex, paralleling our previous fMRI findings. Frontal WM-related SSVEP power correlated selectively with task performance. These results demonstrate the utility of SSVEPs for studying representational aspects of cognition.

Neonatal handling enhances contextual fear conditioning and alters corticosterone stress responses in young rats.

Previous studies have indicated that neonatal handling influences development of hypothalamic-pituitary-adrenal (HPA) control of corticosterone. In addition, corticosterone influences memory consolidation processes in contextual fear conditioning. Therefore, neonatal handling may affect hippocampal-dependent memory processes present in contextual fear conditioning by influencing the development of HPA control of corticosterone. To investigate the effects of neonatal handling on early learning, rat pups were either handled (15-min removal from home cage) on the first 15 days after birth or left undisturbed in their home cage. Handled rats and nonhandled rats were fear conditioned at 18, 21, or 30 days of age and then tested at two time points--24 h following conditioning and at postnatal day 45. Subsequently, at approximately postnatal day 60, rats were exposed to restraint stress and corticosterone levels were assessed during restraint and recovery. Handled and nonhandled rats did not differ significantly in their freezing response immediately following footshock on the conditioning day. However, when tested for contextual fear conditioning at 24 h following conditioning and at postnatal day 45, handled rats showed more freezing behavior than nonhandled rats. When exposed to restraint stress, handled rats had a more rapid return of corticosterone to basal levels than nonhandled rats. These results indicate that neonatal handling enhances developmentally early memory processes involved in contextual fear conditioning and confirms previously reported effects of neonatal handling on HPA control of corticosterone.