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Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear-distinct philosophical traditions suggest different views of wisdoms cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions-Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets-as perceived by participants-score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

Abstract Background Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. Aims We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. Methods In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher’s exact test for categorical data. Results We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). Conclusions These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

Abstract Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear—distinct philosophical traditions suggest different views of wisdom’s cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets’ wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions—Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets—as perceived by participants—score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

Abstract Background Body weight unloaded treadmill training has shown limited efficacy in further improving functional capacity after subacute rehabilitation of ischemic stroke patients. Dynamic robot assisted bodyweight unloading is a novel technology that may provide superior training stimuli and continued functional improvements in individuals with residual impairments in the chronic phase after the ischemic insult. The aim of the present study is to investigate the effect of dynamic robot-assisted versus standard training, initiated 6 months post-stroke, on motor function, physical function, fatigue, and quality of life in stroke-affected individuals still suffering from moderate-to-severe disabilities after subacute rehabilitation. Methods Stroke-affected individuals with moderate to severe disabilities will be recruited into a prospective cohort with measurements at 3-, 6-, 12- and 18-months post-stroke. A randomised controlled trial (RCT) will be nested in the prospective cohort with measurements pre-intervention (Pre), post-intervention (Post) and at follow-up 6 months following post-intervention testing. The present RCT will be conducted as a multicentre parallel-group superiority of intervention study with assessor-blinding and a stratified block randomisation design. Following pre-intervention testing, participants in the RCT study will be randomised into robot-assisted training (intervention) or standard training (active control). Participants in both groups will train 1:1 with a physiotherapist two times a week for 6 months (groups are matched for time allocated to training). The primary outcome is the between-group difference in change score of Fugl-Meyer Lower Extremity Assessment from pre-post intervention on the intention-to-treat population. A per-protocol analysis will be conducted analysing the differences in change scores of the participants demonstrating acceptable adherence. A priori sample size calculation allowing the detection of the minimally clinically important between-group difference of 6 points in the primary outcome (standard deviation 6 point, α = 5% and β = 80%) resulted in 34 study participants. Allowing for dropout the study will include 40 participants in total. Discussion For stroke-affected individuals still suffering from moderate to severe disabilities following subacute standard rehabilitation, training interventions based on dynamic robot-assisted body weight unloading may facilitate an appropriate intensity, volume and task-specificity in training leading to superior functional recovery compared to training without the use of body weight unloading. Trial Registration ClinicalTrials.gov. NCT06273475. Trial status: Recruiting. Trial identifier: NCT06273475. Registry name: ClinicalTrials.gov. Date of registration on ClinicalTrials.gov: 22/02/2024.

Compact millimeter-wave arrays demand novel packaging solutions that feature low-cost dielectric materials with significant thermal conductivity ($\sim$100 W/m ⋅ K). To characterize the permittivity and loss tangent of the dielectric materials above 100 GHz, free-space characterization is proposed to avoid de-embedding conductor losses. We review current approaches for characterization to investigate the properties of ultradense diamond composite materials at D-band. We compare free-space calibration multiple methods to extract the permittivity and loss tangent. Time-domain gating is employed to reduce the uncertainty in the free space characterization. Material characterizations of the dielectric constant and loss tangent include pure polymer TMPTA, PDMS, TMPTA-based, PDMS-based diamond composites as well as quartz and sapphire wafers for calibration from 120–160 GHz. To the author's knowledge, this is the first characterization of diamond composites for thermally conductive dielectric packaging requirements at D-band.

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1α (IL1α), and complement component 1q (C1q), together “TIC.” This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

BackgroundMotor impairment after stroke is due not only to direct tissue loss but also to disrupted connectivity within the motor network. Mixed results from studies attempting to enhance motor recovery with Transcranial Magnetic Stimulation (TMS) highlight the need for a better understanding of both connectivity after stroke and the impact of TMS on this connectivity. This study used TMS-EEG to map the causal information flow in the motor network of healthy adult subjects and define how stroke alters these circuits.MethodsFourteen stroke patients and 12 controls received TMS to two sites (bilateral primary motor cortices) during two motor tasks (paretic/dominant hand movement vs. rest) while EEG measured the cortical response to TMS pulses. TMS-EEG based connectivity measurements were derived for each hemisphere and the change in connectivity (ΔC) between the two motor tasks was calculated. We analyzed if ΔC for each hemisphere differed between the stroke and control groups or across TMS sites, and whether ΔC correlated with arm function in stroke patients.ResultsRight hand movement increased connectivity in the left compared to the right hemisphere in controls, while hand movement did not significantly change connectivity in either hemisphere in stroke. Stroke patients with the largest increase in healthy hemisphere connectivity during paretic hand movement had the best arm function.ConclusionsTMS-EEG measurements are sensitive to movement-induced changes in brain connectivity. These measurements may characterize clinically meaningful changes in circuit dynamics after stroke, thus providing specific targets for trials of TMS in post-stroke rehabilitation.

One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44-96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.

The number of older adults living with functional decline and serious illness is growing exponentially at a time when availability of both family and professional caregivers is strained. Achieving optimal outcomes for this vulnerable population involves advancing the knowledge needed to improve the quality of care delivered by families, health professionals, and community programs. Recent reports from National Institute of Health and the National Academy of Science, Engineering and Medicine have called for the identification of gaps in key areas of family caregiving intervention research. In March 2018, the Family Caregiving Institute at UC Davis convened an invitational meeting of over 50 thought leaders in family caregiving-representing service agencies, funding organizations, and academia-to participate in the Research Priorities in Caregiving Summit: Advancing Family-Centered Care across the Trajectory of Serious Illness. Using an iterative process, attendees identified the top 10 research priorities and created research priority statements that incorporated a definition of the priority topic, rationale for the priority; problem(s) to address; priority population(s); and example research topics. The research priority statements serve as a roadmap for research development that will address the most significant gaps in the caregiving field.

This article presents a set of measured benchmarks for the noise and gain performance of six different millimeter-wave (mm-wave) gallium nitride (GaN) high electron mobility transistor (HEMT) technologies fabricated at four different foundries in the United States. Measurements of the GaN transistors were collected on two independent noise parameter (NP) systems from 8–50 GHz and 75–110 GHz. The resulting raw NPs were stitched together to yield ultra broadband 8–110 GHz smoothed NPs. Several comparisons and summaries of the minimum noise figure and associated gain are reported for the six different GaN technologies. This work seeks to provide an initial database for noise and gain of GaN HEMTs at mm-wave frequencies to quantify progress on technology in the future.

The analysis, design, and measurement of two Indium Phosphide (InP) heterojunction bipolar transistor (HBT) power amplifier (PA) designs are presented at G-band with record efficiency. A pseudo-differential common-base (CB) stage with neutralization capacitors and low-loss coupled-line balun (CLB) improve the gain and reduce matching loss. A single-stage design achieves 8.3 to 12.7-dBm output power and 7.7 to 17.3% power-added efficiency (PAE) over 180 to 220 GHz. The use of compact baluns allows the design to occupy only 0.011mm2 with power density of 1.69 W/mm2. A 3-stage, 4-way power-combined PA delivers 16.6 to 19.7-dBm output power and 6.5 to 13% PAE over 185 to 210 GHz.

An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.

Highlights It is widely recognized among hand surgeons that female patients present at a younger age for basal thumb osteoarthritis, with more severe degeneration. The little-known menstrual hormone relaxin, which peaks every ovulatory cycle, may be responsible for the female predominance of this pathology. The soft tissue support structures for the thumb are known to express relaxin receptors which, when activated, trigger lysis of collagen and other extracellular matrix components. Laxity in soft tissues supporting the thumb, such as the deep anterior oblique ligament, would result in joint instability and microtrauma. If women cyclically experience thumb instability and cumulative cartilage microtrauma from menarche through menopause, the female propensity to develop TMC arthritis is aptly justified.

Abstract Background The important contribution of glia to mechanisms of injury and repair of the nervous system is increasingly recognized. In stark contrast to the central nervous system (CNS), the peripheral nervous system (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors to PNS regeneration, but the molecular underpinnings of the Schwann cell response to injury and how they interact with the inflammatory response remain incompletely understood. Methods We completed bulk RNA-sequencing of Schwann cells purified acutely using immunopanning from the naïve and injured rodent sciatic nerve at 3, 5, and 7 days post-injury. We used qRT-PCR and in situ hybridization to assess cell purity and probe dataset integrity. Finally, we used bioinformatic analysis to probe Schwann cell-specific injury-induced modulation of cellular pathways. Results Our data confirm Schwann cell purity and validate RNAseq dataset integrity. Bioinformatic analysis identifies discrete modules of genes that follow distinct patterns of regulation in the 1st days after injury and their corresponding molecular pathways. These findings enable improved differentiation of myeloid and glial components of neuroinflammation after peripheral nerve injury and highlight novel molecular aspects of the Schwann cell injury response such as acute downregulation of the AGE/RAGE pathway and of secreted molecules Sparcl1 and Sema5a. Conclusions We provide a helpful resource for further deciphering the Schwann cell injury response and a depth of transcriptional data that can complement the findings of recent single cell sequencing approaches. As more data become available on the response of CNS glia to injury, we anticipate that this dataset will provide a valuable platform for understanding key differences in the PNS and CNS glial responses to injury and for designing approaches to ameliorate CNS regeneration.

This work demonstrates new circuit techniques in distributed-stacked-complimentary (DiSCo) switches that enable picosecond switching speed in RF CMOS SOI switches. By using seriesstacked devices with optimized gate impedance and voltage swing, both high linearity and fast switching are possible. A theoretical analysis and design framework has been developed and verified through simulation and measurement through two broadband, high-linearity passive mixer designs, one optimized for linearity and the other for bandwidth, using a 45-nm SOI CMOS process. The mixers achieve $P_{1dB}{s}$ of 16-22 dBm with $IIP3s$ of 25-34 dBm across a bandwidth from 1 GHz up to 30 GHz. This performance exceeds prior SOI RF and microwave mixer performance by more than an order of magnitude and is comparable to III-V device technologies. The mixers include integrated local oscillator (LO) driving amplifiers for high efficiency operation and low total power consumption. DC power consumption ranges from 250 mW to 1 W for the LO driver. The integrated LO drivers demonstrate a pathway to on-chip LO generation with simplified matching to maximize LO power delivered to the input of the switch.

This paper describes the energy-efficient realization of a QPSK optical receiver (CoRX) for short-reach intra-datacenter interconnects based on analog coherent detection. The CoRX comprises inphase and quadrature channels for each polarization and a high-speed phase-frequency detector (PFD) that provides feedback to stabilize an optical local oscillator (LO) and maintain coherence with the received optical signal. Each receive (RX) channel consists of a transimpedance amplifier (TIA) based on a Cherry-Hooper emitter follower (CHEF). The electronic RX is implemented in a 130-nm SiGe HBT technology ( $f_{T} = 300$ GHz), consumes 534 mW of DC power for a total electrical RX energy efficiency of 5.34 pJ/bit, and occupies 2.8 $mm^{2}$ . Electrical characterization of the CoRX on an FR-4 PCB assembly demonstrates operation up to 60 GBaud with a bit error rate (BER) of less than 10−12. A co-packaged optical/electrical CoRX assembly with a silicon photonic receiver is characterized using a commercial-off-the-shelf quadrature phase-shift keying (QPSK) transmitter for constellations up to 50 GBaud (100 Gbps) at BER below KP4-FEC ( $2.2\times 10^{-4}$ ).

We propose a coupled embedding network (CEN) as a portable, robust design technique to simultaneously introduce gain boosting and loadline matching in millimeter-wave power (mm-wave) amplifiers (PAs). The approach uses directional couplers as an abstraction for the embedding network and produces straightforward design equations to achieve optimal input-stability margins for any specified gain. We demonstrate the design process and implementation using a 40-nm Gallium Nitride (GaN) process technology through simulated and measured performance of the PA with and without the embedding network. The output power is greater than 20 dBm and remains above 18 dBm over an 8 GHz bandwidth. Peak power added efficiency (PAE) is 6.5%. The 3-stage PA achieves 21 dB of gain at 137 GHz offering 7.1-dB gain per device. The measured gain is 8 dB higher than the common-emitter design with the same number of stages. To our knowledge, this is the highest gain per stage for a GaN PA in D-band.

Rapid detection of Mycobacterium tuberculosis complex directly from clinical specimens is critical for patient care. Mycobacterial culture requires days to weeks for results and therefore many laboratories employ rapid molecular methods for the diagnosis of tuberculosis. There are two FDA-cleared molecular assays for the detection of M. tuberculosis complex in the United States and both are cleared for testing of respiratory specimens only. The detection of M. tuberculosis complex in extrapulmonary specimens is often done using laboratory-developed PCR methods. In this work, the verification and subsequent validation of test performance over a decade is detailed for a laboratory-developed PCR assay (MTBRP) that detects M. tuberculosis complex from respiratory and non-respiratory specimens. The assay also provides information about potential isoniazid resistance. The performance of the MTBRP PCR assay was compared to the Cepheid Xpert MTB/RIF assay in acid-fast smear positive and smear negative specimens and mycobacterial culture for acid-fast smear positive specimens. The MTBRP assay demonstrated 99% correlation with the Xpert MTB/RIF assay using 499 respiratory specimens. The performance of the MTBRP PCR assay compared with mycobacterial culture for 867 AFB smear positive respiratory and non-respiratory specimens demonstrated a sensitivity of 100% and a specificity of 99.1%. This work provides longitudinal evidence using real-world clinical laboratory conditions and specimens to demonstrate that laboratory-developed PCR assays such as the MTBRP can provide a rapid and sensitive method for detection of pulmonary and extra-pulmonary tuberculosis from a wide-variety of smear positive specimen sources.

Category: Ankle; Hindfoot Introduction/Purpose: Somatic neuropathy is a common complication following foot and ankle surgery, trauma, or compression due to entrapment. Symptoms can be intense and debilitating. The Sural nerve is commonly affected and is at risk due to the location and proximity to frequently used surgical approaches. The purpose of this study is to investigate the outcomes of sural nerve neurolysis and neurectomy with intramuscular burial for sural neuritis. Methods: IRB approval was obtained, and patients were identified who underwent operative treatment by two foot and ankle specialists for sural nerve related pain. Exclusion criteria included patients under the age of 18, prisoners, those who underwent concomitant osseous procedures, and less than 6-week follow-up. Demographics and preoperative outcomes including FFI, SF-36, FAAM, and VAS were recorded. Final follow-up questionnaires using PROMIS measures and FAAM were administered using REDCap. Results: The 25 patients meeting inclusion criteria for this study had a median age of 47 (interquartile range [IQR], 43 to 49) and had median follow-up of 33.7 months (IQR, 4.5 -73.2). Median FAAM ADL improved from 40.8 (IQR 38.1-51.3) preoperatively to 59.5 (IQR 47.6-76.2) postoperatively, p=0.032. FAAM Sports scores improved from 15.6 (IQR 9.4-21.9) to 31.3 (IQR 25.0-56.3) postoperatively, p=0.002. VAS scores improved from a median of 9.0 (IQR 7.0-9.0) to 4.5 (3.0-6.0), p

Category: Ankle; Midfoot/Forefoot; Trauma; Other Introduction/Purpose: Peripheral nerve injury or entrapment is a common complication following surgery in the foot and ankle region. The superficial peroneal nerve is particularly at risk following ankle arthroscopy and lateral approaches to the ankle or fibula. Symptoms can result in intense pain and significant disability for patients. The purpose of this study is to investigate the outcomes of superficial peroneal nerve neurolysis and neurectomy. Methods: All patients were identified who underwent operative treatment by two foot and ankle specialists for superficial peroneal nerve related pain. Exclusion criteria included patients under the age of 18, prisoners, those who underwent concomitant osseous procedures, and less than 6-week follow-up. Demographic data, baseline outcomes including FFI, SF-36, FAAM, and VAS were recorded. Final follow-up questionnaires using PROMIS measures and FAAM were administered using REDCap. Results: 55 patients were included in this study with a mean age of 43.0 years (IQR, 33.0-48.0). At a median follow-upof 6.8 months (IQR 1.2-20.2 months), VAS improved from a median of 9.0 (IQR 6.0-9.0) preoperatively to 2.0 (IQR 0.00-5.0) after surgery, p < 0.05. Patients reported a median VAS improvement of 4.0 (IQR 2.0-7.0). At final follow-up patients reported PROMIS lower extremity function score median of 58.6 (IQR 45.2-58.6), PROMIS neuropathic pain quality score of 42.9 (IQR 37.2-55.5), and PROMIS pain interference of 50.5 (IQR 41.1-57.0). Worker's compensation claims were independently associated with significantly poorer post-operative function measured using FAAM ADL (58.58 WC vs 74.86 non-WC, p

Abstract Background Patients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed. Methods Because intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy. Results We observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression. Conclusions Our results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

Abstract Background Motor impairment after stroke is due not only to direct tissue loss but also to disrupted connectivity within the motor network. Mixed results from studies attempting to enhance motor recovery with Transcranial Magnetic Stimulation (TMS) highlight the need for a better understanding of both connectivity after stroke and the impact of TMS on this connectivity. This study used TMS-EEG to map the causal information flow in the motor network of healthy adult subjects and define how stroke alters these circuits. Methods Fourteen stroke patients and 12 controls received TMS to two sites (bilateral primary motor cortices) during two motor tasks (paretic/dominant hand movement vs. rest) while EEG measured the cortical response to TMS pulses. TMS-EEG based connectivity measurements were derived for each hemisphere and the change in connectivity (ΔC) between the two motor tasks was calculated. We analyzed if ΔC for each hemisphere differed between the stroke and control groups or across TMS sites, and whether ΔC correlated with arm function in stroke patients. Results Right hand movement increased connectivity in the left compared to the right hemisphere in controls, while hand movement did not significantly change connectivity in either hemisphere in stroke. Stroke patients with the largest increase in healthy hemisphere connectivity during paretic hand movement had the best arm function. Conclusions TMS-EEG measurements are sensitive to movement-induced changes in brain connectivity. These measurements may characterize clinically meaningful changes in circuit dynamics after stroke, thus providing specific targets for trials of TMS in post-stroke rehabilitation.

For the vast majority of geostationary satellites currently in orbit, station keeping activities including orbit determination and maneuver planning and execution are ground-directed and dependent on the availability of ground-based satellite control personnel and facilities. However, a requirement linked to satellite autonomy and survivability in cases of interrupted ground support is often one of the stipulated provisions on the satellite platform design. It is especially important for a geostationary military-purposed satellite to remain within its designated orbital window, in order to provide reliable uninterrupted telecommunications services, in the absence of ground-based resources due to warfare or other disasters. In this paper we investigate factors affecting the robustness of a geostationary satellite’s orbit in terms of the maximum duration the satellite’s station keeping window can be maintained without ground intervention. By comparing simulations of orbit evolution, given different initial conditions and operations strategies, a variation of parameters study has been performed and we have analyzed which factors the duration is most sensitive to. This also provides valuable insights into which factors may be worth controlling by a military or civilian geostationary satellite operator. Our simulations show that the most beneficial factor for maximizing the time a satellite will remain in the station keeping window is the operational practice of pre-emptively loading East-West station keeping maneuvers for automatic execution on board the satellite should ground control capability be lost. The second most beneficial factor is using short station keeping maneuver cycle durations.

Wireless communication above 100 GHz offers the potential for massive data rates and has attracted considerable attention for Beyond 5G and 6G systems. A key challenge in the receiver design in these bands is power consumption, particularly for mobile and portable devices. This paper provides a general methodology for understanding the trade-offs of power consumption and end-to-end performance of a large class of potential receivers for these frequencies. The framework is applied to the design of a fully digital 140 GHz receiver with a 2 GHz sample rate, targeted for likely 6G cellular applications. Design options are developed for key RF components including the low noise amplifier (LNA), mixer, local oscillator (LO) and analog-digital converter (ADC) in 90 nm SiGe BiCMOS. The proposed framework, combined with detailed circuit and system simulations, is then used to select among the design options for the overall optimal end-to-end performance and power tradeoff. The analysis reveals critical design choices and bottlenecks. It is shown that optimizing these critical components can enable a dramatic 70 to 80% power reduction relative to a standard baseline design enabling fully-digital 140 GHz receivers with RF power consumption less than 2 W.

Older adults consistently prefer aging in place, which requires a high level of community support and services that are currently lacking. With a rapidly aging population, the present infrastructure for healthcare will prove even more inadequate to meet seniors' physical and mental health needs. A paradigm shift away from the sole focus on delivery of interventions at an individual level to more prevention-focused, community-based approaches will become essential. Recent initiatives have been proposed to promote healthy lifestyles and preventive care to enable older adults to age in place. Prominent among these are the World Health Organization's Global Age-Friendly Communities (AFC) Network, with 287 communities in 33 countries, and AARP's Network of AFCs with 77 communities in the United States. In an AFC, older adults are actively involved, valued, and supported with necessary infrastructure and services. Specific criteria include affordable housing, safe outdoor spaces and built environments conducive to active living, inexpensive and convenient transportation options, opportunities for social participation and community leadership, and accessible health and wellness services. Active, culture-based approaches, supported and developed by local communities, and including an intergenerational component are important. This article provides a brief historical background, discusses the conceptualization of the AFC, offers a list of criteria, narrates case studies of AFCs in various stages of development, and suggests solutions to common challenges to becoming age-friendly. Academic geriatric psychiatry needs to play a major role in the evolving AFC movement to ensure that mental healthcare is considered and delivered on par with physical care.

Abstract Background B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE). Methods Female C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1–125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted. Results Radiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/μmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry—providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice. Conclusion CD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.

Abstract Background Stroke increases the risk of cognitive impairment even several years after the stroke event. The exact mechanisms of post-stroke cognitive decline are unclear, but the immunological response to stroke might play a role. The aims of the StrokeCog study are to examine the associations between immunological responses and long-term post-stroke cognitive trajectories in individuals with ischemic stroke. Methods StrokeCog is a single-center, prospective, observational, cohort study. Starting 6–12 months after stroke, comprehensive neuropsychological assessment, plasma and serum, and psychosocial variables will be collected at up to 4 annual visits. Single cell sequencing of peripheral blood monocytes and plasma proteomics will be conducted. The primary outcome will be the change in global and domain-specific neuropsychological performance across annual evaluations. To explain the differences in cognitive change amongst participants, we will examine the relationships between comprehensive immunological measures and these cognitive trajectories. It is anticipated that 210 participants will be enrolled during the first 3 years of this 4-year study. Accounting for attrition, an anticipated final sample size of 158 participants with an average of 3 annual study visits will be available at the completion of the study. Power analyses indicate that this sample size will provide 90% power to detect an average cognitive change of at least 0.23 standard deviations in either direction. Discussion StrokeCog will provide novel insight into the relationships between immune events and cognitive change late after stroke.

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.

Abstract Background Ischemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on β2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in β2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM β2-adrenergic receptors to post-stroke neuroinflammation. Methods To investigate the effects of β2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the β2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the β2-adrenergic receptor from microglia and monocyte-lineage cells. Results We report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the β2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of β2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of β2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression. Conclusions We identified β2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased β2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished β2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The β2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.

Needle aponeurotomy (NA) and collagenase injections (CI) for treatment of Dupuytren disease are practical and clinically efficient techniques. The purpose of this report is to review the comparative literature and present postprocedure survey data on NA. We reviewed the current literature on treatment of Dupuytren disease with NA and report on direct and indirect comparisons of the 2 treatment options. We also retrospectively identified patients treated with NA for Dupuytren disease, reviewed the demographic details of treatment in the medical records, and solicited patients’ feedback on satisfaction, recurrence, and complications using a phone survey. The results of the survey are discussed in the context of current literature. A total of 250 completed the survey an average of 34 months after treatment. Of those, 178 (71%) were very satisfied or satisfied, 187 (75%) reported some recurrence, and 5% reported a complication. Patients less than 2 years from the procedure were statistically significantly more likely to be satisfied with the procedure and more likely to have it again, and reported less recurrence of disease. Current literature does not clearly suggest a best treatment option for Dupuytren disease. Recent analyses suggest that there is a cost difference, with NA presenting as a more cost-effective option. Survey results demonstrated a low complication rate although the rate of recurrence was high, which was consistent with other studies. Needle aponeurotomy is safe and effective, and results in high patient satisfaction despite a high recurrence rate. Key words: complications, Dupuytren disease, hand surgery, needle aponeurotomy, patient-reported satisfaction, recurrence

One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44–96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.