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Purpose: Measuring persistent imbalance after mTBI is challenging and may include subjective symptom-reporting as well as clinical scales. Clinical assessments for quantifying balance following mTBI have focused on sensory orientation. It is theorized that balance control goes beyond sensory orientation and also includes subdomains of anticipatory postural adjustments, reactive postural control, and dynamic gait. The Mini Balance Evaluation Systems Test (Mini-BESTest) is a validated balance test that measures balance according to these subdomains for a more comprehensive assessment. The purpose of this study was to compare Mini-BESTest total and subdomain scores after subacute mTBI with healthy controls., Methods: Symptomatic mTBI (n = 90, 20 % male, age=36.0 ± 12.0, 46.3.4 ± 22.1 days since injury) and healthy control (n = 45, 20 % male, age=35.4 ± 12.5) participants completed the Mini-BESTest for balance. Mini-BESTest between-group differences were evaluated using Wilcoxon rank-sum tests., Results: The mTBI group (Median[minimum,maximum]) had a significantly worse Mini-BESTest total score than the healthy controls (24[18,28] vs 27[23-28], p < 0.001). The mTBI group performed significantly worse in 3 of the 4 subdomains compared to the healthy controls: reactive postural control: 5[2-6] vs 6[3-6], p = 0.003; sensory orientation: 6[5,6] vs 6[6], p = 0.005; dynamic gait: 8[5-10] vs 9[8-10], p < 0.001. There was no significance difference between groups in the anticipatory postural adjustments domain (5[3-6] vs 5[3-6], p = 0.12)., Conclusions: The Mini-BESTest identified deficits in people with subacute mTBI in the total score and 3 out of 4 subdomains, suggesting it may be helpful to use in the clinic to identify balance subdomain deficits in the subacute mTBI population. In combination with self-reported assessments, the mini-BESTest may identify balance domain deficits in the subacute mTBI population and help guide treatment for this population., Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Humanised antibodies targeting Crimean-Congo Haemorrhagic virus (CCHFV) are needed for the development and standardisation of serological assays. These assays are needed to address a shortfall in available tests that meet regulatory diagnostic standards and to aid surveillance activities to extend knowledge on the distribution of CCHFV. To generate a humanised monoclonal antibody against CCHFV, we have compared two methods: the traditional mouse hybridoma approach with subsequent sequencing and humanisation of antibodies versus a non-animal alternative using a human combinatorial antibody library (HuCAL). Our results demonstrated that the mouse hybridoma followed by humanisation protocol gave higher affinity antibodies. Whilst not yet able to demonstrate the generation of equivalent humanised antibodies without the use of animals, sequencing data enables the subsequent production of recombinant antibodies, thus providing a reduction in future animal usage for this application. Ultimately, our report provides information on development of a humanised standardised control, which can form an important positive control component of serological assays against CCHFV., Competing Interests: Declaration of Competing Interest No potential conflict of interests are declared by any of the authors., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Imbalance is common following mild Traumatic Brain Injury (mTBI) and can persist months after the initial injury. To determine if mTBI subjects with chronic imbalance differed from healthy age- and sex-matched controls (HCs) we used both the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation properties and the standard Sensory Organization Test (SOT). Four CSMI conditions evoked center-of-mass sway in response to: surface tilts with eyes closed (SS/EC), surface tilts with eyes open viewing a fixed visual surround (SS/EO), visual surround tilts with eyes open standing on a fixed surface (VS/EO), and combined surface and visual tilts with eyes open (SS+VS/EO). The mTBI participants relied significantly more on visual cues during the VS/EO condition compared to HCs but had similar reliance on combinations of vestibular, visual, and proprioceptive cues for balance during SS/EC, SS/EO, and SS+VS/EO conditions. The mTBI participants had significantly longer time delays across all conditions and significantly decreased motor activation relative to HCs across conditions that included surface-tilt stimuli with a sizeable subgroup having a prominent increase in time delay coupled with reduced motor activation while demonstrating no vestibular sensory weighting deficits. Decreased motor activation compensates for increased time delay to maintain stability of the balance system but has the adverse consequence that sensitivity to both internal (e.g., sensory noise) and external disturbances is increased. Consistent with this increased sensitivity, SOT results for mTBI subjects showed increased sway across all SOT conditions relative to HCs with about 45% of mTBI subjects classified as having an "Aphysiologic" pattern based on published criteria. Thus, CSMI results provided a plausible physiological explanation for the aphysiologic SOT pattern. Overall results suggest that rehabilitation that focuses solely on sensory systems may be incomplete and may benefit from therapy aimed at enhancing rapid and vigorous responses to balance perturbations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campbell, King, Parrington, Fino, Antonellis and Peterka.)

Complaints of non-resolving imbalance are common in individuals with chronic mild traumatic brain injury (mTBI). Vestibular rehabilitation therapy may be beneficial for this population. Additionally, wearable sensors can enable biofeedback, specifically audio biofeedback (ABF), and aid in retraining balance control mechanisms in people with balance impairments. In this study, we described the effectiveness of vestibular rehabilitation therapy with and without ABF to improve balance in people with chronic mTBI. Participants ( n = 31; females = 22; mean age = 40.9 ± 11 y) with chronic (>3 months) mTBI symptoms of self-reported imbalance were randomized into vestibular rehabilitation with ABF ( n = 16) or without ABF ( n = 15). The intervention was a standard vestibular rehabilitation, with or without ABF, for 45 min biweekly for 6 weeks. The ABF intervention involved a smartphone that provided auditory feedback when postural sway was outside of predetermined equilibrium parameters. Participant's completed the Post-Concussion Symptom Scale (PCSS). Balance was assessed with the sensory organization test (SOT) and the Central Sensorimotor Integration test which measured sensory weighting, motor activation, and time delay with sway evoked by surface and/or visual surround tilts. Effect sizes (Hedge's G) were calculated on the change between pre-and post-rehabilitation scores. Both groups demonstrated similar medium effect-sized decreases in PCSS and large increases in SOT composite scores after rehabilitation. Effect sizes were minimal for increasing sensory weighting for both groups. The with ABF group showed a trend of larger effect sizes in increasing motor activation (with ABF = 0.75, without ABF = 0.22) and in decreasing time delay (with ABF = -0.77, without ABF = -0.52) relative to the without ABF group. Current clinical practice focuses primarily on sensory weighting. However, the evaluation and utilization of motor activation factors in vestibular rehabilitation, potentially with ABF, may provide a more complete assessment of recovery and improve outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campbell, Peterka, Fino, Parrington, Wilhelm, Pettigrew and King.)

Background and Purpose: Multimodal physical therapy for mild traumatic brain injury (mTBI) has been shown to improve recovery. Due to the coronavirus disease-2019 (COVID-19) pandemic, a clinical trial assessing the timing of multimodal intervention was adapted for telerehabilitation. This pilot study explored feasibility and adoption of an in-person rehabilitation program for subacute mTBI delivered through telerehabilitation., Methods: Fifty-six in-person participants-9 males; mean (SD) age 34.3 (12.2); 67 (31) days post-injury-and 17 telerehabilitation participants-8 males; age 38.3 (12.7); 61 (37) days post-injury-with subacute mTBI (between 2 and 12 weeks from injury) were enrolled. Intervention included 8, 60-minute visits over 6 weeks and included subcategories that targeted cervical spine, cardiovascular, static balance, and dynamic balance impairments. Telerehabilitation was modified to be safely performed at home with minimal equipment. Outcome measures included feasibility (the number that withdrew from the study, session attendance, home exercise program adherence, adverse events, telerehabilitation satisfaction, and progression of exercises performed), and changes in mTBI symptoms pre- and post-rehabilitation were estimated with Hedges' g effect sizes., Results: In-person and telerehabilitation had a similar study withdrawal rate (13% vs 12%), high session attendance (92% vs 97%), and no adverse events. The telerehabilitation group found the program easy to use (4.2/5), were satisfied with care (4.7/5), and thought it helped recovery (4.7/5). The telerehabilitation intervention was adapted by removing manual therapy and cardiovascular portions and decreasing dynamic balance exercises compared with the in-person group. The in-person group had a large effect size (-0.94) in decreases in symptoms following rehabilitation, while the telerehabilitation group had a moderate effect size (-0.73)., Discussion and Conclusions: Telerehabilitation may be feasible for subacute mTBI. Limited ability to address cervical spine, cardiovascular, and dynamic balance domains along with underdosage of exercise progression may explain group differences in symptom resolution.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A392 )., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Academy of Neurologic Physical Therapy, APTA.)

Background and Aim: Individuals with Parkinson's disease (PD) with and without freezing of Gait (FoG) may respond differently to exercise interventions for several reasons, including disease duration. This study aimed to determine whether both people with and without FoG benefit from the Agility Boot Camp with Cognitive Challenges (ABC-C) program., Methods: This secondary analysis of our ABC-C trial included 86 PD subjects: 44 without FoG (PD-FoG) and 42 with FoG (PD + FoG). We collected measures of standing sway balance, anticipatory postural adjustments, postural responses, and a 2-minute walk with and without a cognitive task. Two-way repeated analysis of variance, with disease duration as covariate, was used to investigate the effects of ABC-C program. Effect sizes were calculated using standardized response mean (SRM) for PD-FoG and PD + FoG, separately., Results: The ABC-C program was effective in improving gait performance in both PD-FoG and PD + FoG, even after controlling for disease duration. Specifically, dual-task gait speed ( P  < .0001), dual-cost stride length ( P  = .012), and these single-task measures: arm range of motion ( P  < .0001), toe-off angle ( P  = .005), gait cycle duration variability ( P  = .019), trunk coronal range of motion ( P  = .042), and stance time ( P  = .046) improved in both PD-FoG and PD + FoG. There was no interaction effect between time (before and after exercise) and group (PD-FoG/PD + FoG) in all 24 objective measures of balance and gait. Dual-task gait speed improved the most in PD + FoG (SRM = 1.01), whereas single-task arm range of motion improved the most in PD-FoG (SRM = 1.01)., Conclusion: The ABC-C program was similarly effective in improving gait (and not balance) performance in both PD-FoG and PD + FoG.

Objective: The purpose of this study was to (1) explore differences in vestibular ocular motor screening (VOMS) symptoms between healthy adults and adults with persistent symptoms after mild traumatic brain injury (mTBI), and (2) explore the relationships between VOMS symptoms and other measures (self-reported vestibular symptoms, clinical measures of balance and gait, and higher-level motor ability tasks)., Setting: Research laboratory setting., Participants: Fifty-three persons with persistent symptoms (>3 weeks) following mTBI and 57 healthy controls were recruited. Eligibility for participation included being 18 to 50 years of age and free of medical conditions that may affect balance, with the exception of recent mTBI for the mTBI group., Design: Cross-sectional., Main Measures: The primary outcomes were the VOMS symptom scores and near point of convergence (NPC) distance. Secondary outcomes included the Dizziness Handicap Inventory (DHI) total and subdomain scores, sway area, Functional Gait Analysis total score, gait speed, and modified Illinois Agility Task completion time, and Revised High-Level Mobility Assessment Tool total score., Results: The mTBI group reported more VOMS symptoms ( z range, -7.28 to -7.89) and a further NPC ( t = -4.16) than healthy controls (all P s < .001). DHI self-reported symptoms (total and all subdomain scores) were strongly associated with the VOMS symptom scores (rho range, 0.53-0.68; all P s < .001). No significant relationships existed between VOMS symptoms and other measures., Conclusion: Significant group differences support the relevance of the VOMS for mTBI in an age-diverse sample with persistent symptoms. Furthermore, strong association with DHI symptoms supports the ability of the VOMS to capture vestibular complaints in this population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Background: Up to 40% of mild traumatic brain injuries (mTBI) can result in chronic unresolved symptoms, such as balance impairment, that persist beyond three months. Sensorimotor control, the collective coordination and regulation of both sensory and motor components of the postural control system, may underlie balance deficits in chronic mTBI. The aim of this study was to determine if the relationship between severity of impairment in chronic (> 3 months) mTBI and poorer balance performance was mediated by sensorimotor integration measures., Methods: Data were collected from 61 healthy controls and 58 mTBI participants suffering persistent balance problems. Participants completed questionnaires (Dizziness Handicap Inventory (DHI), Neurobehavioral Symptom Inventory (NSI), and Sports Concussion Assessment Tool Symptom Questionnaire (SCAT2)) and performed instrumented postural sway assessments and a test of Central Sensory Motor Integration (CSMI). Exploratory Factor Analysis was used to reduce the variables used within the mediation models to constructs of impairment (Impairment Severity - based on questionnaires), balance (Sway Dispersion - based on instrumented postural sway measures), and sensorimotor control (Sensory Weighting, Motor Activation and Time Delay - based on parameters from CSMI tests). Mediation analyses used path analysis to estimate the direct effect (between impairment and balance) and indirect (mediating) effects (from sensorimotor control)., Results: Two out of three sensorimotor integration factors (Motor Activation and Time Delay) mediated the relationship between Impairment Severity and Sway Dispersion, however, there was no mediating effect of Sensory Weighting., Significance: These findings have clinical implications since rehabilitation of balance commonly focuses on sensory cues. Our findings indicate the importance of Motor Activation and Time Delay, and thus a focus on strategies to improve factors related to these constructs throughout the rehabilitative process (i.e., level of muscular contractions to control joint torques; response time to stimuli/perturbations) may improve a patient's balance control., (Copyright © 2022 Elsevier B.V. All rights reserved.)

γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors ( i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3 + T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results., Competing Interests: JS-E, MJ and LK are funded by Lava therapeutics. HV, PP, EE, BW are employed by and hold stock of LAVA Therapeutics. TG holds stock of LAVA Therapeutics., (Copyright © 2022 Saura-Esteller, de Jong, King, Ensing, Winograd, de Gruijl, Parren and van der Vliet.)

Background: Each year, approximately one million older adults die in American intensive care units (ICUs) or survive with significant functional impairment. Inadequate symptom management, surrogates' psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated., Design: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) vs. usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania., Intervention: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care., Outcomes: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care scale. Secondary outcomes include surrogates' psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction scale., Conclusions: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes., Competing Interests: Conflicts of Interests See relevant ICMJE forms., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Physical function remains a crucial component of mild traumatic brain injury (mTBI) assessment and recovery. Traditional approaches to assess mTBI lack sensitivity to detect subtle deficits post-injury, which can impact a patient's quality of life, daily function and can lead to chronic issues. Inertial measurement units (IMU) provide an opportunity for objective assessment of physical function and can be used in any environment. A single waist worn IMU has the potential to provide broad/macro quantity characteristics to estimate gait mobility, as well as more high-resolution micro spatial or temporal gait characteristics (herein, we refer to these as measures of quality). Our recent work showed that quantity measures of mobility were less sensitive than measures of turning quality when comparing the free-living physical function of chronic mTBI patients and healthy controls. However, no studies have examined whether measures of gait quality in free-living conditions can differentiate chronic mTBI patients and healthy controls. This study aimed to determine whether measures of free-living gait quality can differentiate chronic mTBI patients from controls., Methods: Thirty-two patients with chronic self-reported balance symptoms after mTBI (age: 40.88 ± 11.78 years, median days post-injury: 440.68 days) and 23 healthy controls (age: 48.56 ± 22.56 years) were assessed for ~ 7 days using a single IMU at the waist on a belt. Free-living gait quality metrics were evaluated for chronic mTBI patients and controls using multi-variate analysis. Receiver operating characteristics (ROC) and Area Under the Curve (AUC) analysis were used to determine outcome sensitivity to chronic mTBI., Results: Free-living gait quality metrics were not different between chronic mTBI patients and controls (all p > 0.05) whilst controlling for age and sex. ROC and AUC analysis showed stride length (0.63) was the most sensitive measure for differentiating chronic mTBI patients from controls., Conclusions: Our results show that gait quality metrics determined through a free-living assessment were not significantly different between chronic mTBI patients and controls. These results suggest that measures of free-living gait quality were not impaired in our chronic mTBI patients, and/or, that the metrics chosen were not sensitive enough to detect subtle impairments in our sample., (© 2022. The Author(s).)

GaInP 2 has shown promise as the wide bandgap top junction in tandem absorber photoelectrochemical (PEC) water splitting devices. Among previously reported dual-junction PEC devices with a GaInP 2 top cell, those with the highest performance incorporate an AlInP 2 window layer (WL) to reduce surface recombination and a thin GaInP 2 capping layer (CL) to protect the WL from corrosion in electrolytes. However, the stability of these III-V systems is limited, and durability continues to be a major challenge broadly in the field of PEC water splitting. This work provides a systematic investigation into the durability of GaInP 2 systems, examining the impacts of the window layer and capping layer among single junction pn-GaInP 2 photocathodes coated with an MoS 2 catalytic and protective layer. The photocathode with both a CL and WL demonstrates the highest PEC performance and longest lifetime, producing a significant current for >125 h. In situ optical imaging and post-test characterization illustrate the progression of macroscopic degradation and chemical state. The surface architecture combining an MoS 2 catalyst, CL, and WL can be translated to dual-junction PEC devices with GaInP 2 or other III-V top junctions to enable more efficient and stable PEC systems.

Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8 + memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically 'record' the replicative history of different CD8 + T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (T CM ) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the T CM compartment. Specifically, we demonstrate that lowly divided T CM cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8 + T cell effector pool upon reinfection is marked by prior quiescence., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Two studies examined the relationship between right-wing authoritarianism (RWA) and religious fundamentalism (RF), and tested their unique contributions to meaning in life (MIL)., Method: We recruited Amazon Mechanical Turk Participants located in the United States. Studies 1 (N = 827) included measures of RWA, RF, and global MIL. Study 2 (N = 809) additionally included measures of the facets of global MIL (existential significance, purpose, and coherence), and intrinsic religiosity., Results: In both studies, RWA, RF, and MIL were positively correlated. Partial correlations and structural equation modeling showed that, when modeled together, RF significantly contributes to MIL and RWA facets were either unrelated or negatively related. Study 2 extended these results to show that RF primarily contributed positively to global MIL through existential significance, rather than purpose or coherence. When modeled jointly with intrinsic religiosity, religious fundamentalism no longer contributed to MIL., Conclusions: These studies demonstrate that RF positively contributes to the experience of MIL, and that the link between RWA and MIL arises from their mutual overlap with RF. The link between RF and MIL is about religiosity, rather than fundamentalism. Implications are discussed., (© 2021 Wiley Periodicals, Inc.)

Background: Associations between benign gynecologic pathologies and circulating inflammatory markers are unknown. Our goal was to evaluate self-reported history of benign gynecologic pathology and subsequent alterations in systemic inflammation., Methods: Using nested case-control studies from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, study-specific associations between self-reported history of benign ovarian cysts, uterine fibroids, and endometriosis with inflammatory marker concentrations were evaluated using logistic regression and combined using meta-analysis. Inflammatory markers associated with individual benign pathologies were mutually adjusted for one another to evaluate independent associations., Results: Compared to women without a self-reported history of the pathology evaluated, benign ovarian cysts were associated with increased PAI-1 (OR [95% CI] 6.24 [2.53-15.39], P <.001) and TGF-β1 (3.79 [1.62-8.86], P =.002) and decreased BCA-1 (0.38 [0.19-0.73], P =.004). Uterine fibroids were associated with decreased CXCL11 (0.37 [0.22-0.63], P <.001) and VEGFR3 (0.40 [0.24-0.65], P <.001). Endometriosis was associated with increased SIL-4R (4.75 [1.84-12.26], P =.001)., Conclusions: Self-reported history of benign gynecologic pathologies were associated with alterations in inflammatory markers that have been previously linked to cancer risk. Understanding interactions between benign gynecologic pathologies and the systemic immune system may help inform disease risk later in life., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To explore patterns of postconcussion care at a level 1 trauma center., Design: Retrospective cohort study., Setting: U.S. level 1 trauma center and local satellite units., Participants: Patients of any age with a concussion diagnosis that reported to level 1 trauma center and local satellite units between 2016 and 2018 (N=2417)., Intervention: Not applicable., Main Outcome Measures: Age, sex, point of entry, rehabilitation referrals, and pre-existing comorbidity diagnosis., Results: Patient age (mean [SD]) significantly differed among points of entry, from youngest to oldest: 26.0 (14.0) years in sports medicine, 29.3 (23.0) years in the emergency department, 34.6 (23.6) years at primary care providers, and 46.0 (19.7) years at specialty care departments. Sex also significantly differed among points of entry; emergency departments reported more men (55.6%), whereas the other points of entry reported more women (59.3%-65.6%). Patients were more likely to receive a referral from sports medicine (odds ratio [OR] unadjusted =75.05, P <.001), primary care providers (OR unadjusted =7.98, P <.001), and specialty care departments (OR unadjusted =7.62, P <.001) than from the emergency department. Women were more likely to receive a referral (OR unadjusted =1.92, P <.0001), regardless of point of entry. Lastly, patients with a preexisting comorbidity were more likely (OR adjusted =2.12, P <.001) to get a rehabilitation referral than patients without a comorbidity., Conclusions: Point of entry, age, sex, and preexisting comorbidities are associated with postconcussion care rehabilitation referral patterns. Improving concussion education dissemination across all entry points of a level 1 trauma center may standardize the postconcussion rehabilitation referral patterns, potentially improving the time to recovery from a concussion., (© 2022 The Authors.)

The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches.

Background: Turning is a component of gait that requires planning for movement of multiple body segments and the sophisticated integration of sensory information from the vestibular, visual, and somatosensory systems. These aspects of turning have led to growing interest to quantify turning in clinical populations to characterize deficits or identify disease progression. However, turning may be affected by environmental differences, and the degree to which turning assessments are comparable across research or clinical sites has not yet been evaluated., Research Question: The aim of this study was to determine the extent to which peak turning speeds are equivalent between two sites for a variety of mobility tasks., Methods: Data were collected at two different sites using separate healthy young adult participants (n = 47 participants total), but recruited using identical inclusion and exclusion criteria. Participants at each site completed three turning tasks: a one-minute walk (1 MW) along a six-meter walkway, a modified Illinois Agility Test (mIAT), and a custom clinical turning course (CCTC). Peak yaw turning speeds were extracted from wearable inertial sensors on the head, trunk, and pelvis. Between-site differences and two one-sided tests (TOST) were used to determine equivalence between sites, based on a minimum effect size reported between individuals with mild traumatic brain injury and healthy control subjects., Results: No outcomes were different between sites, and equivalence was determined for 6/21 of the outcomes. These findings suggest that some turning tasks and outcome measures may be better suited for multi-site studies. The equivalence results are also dependent on the minimum effect size of interest; nearly all outcomes were equivalent across sites when larger minimum effect sizes of interest were used., Significance: Together, these results suggest some tasks and outcome measures may be better suited for multi-site studies and literature-based comparisons., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Five studies tested the effect of exposure to authoritarian values on positive affect (PA), negative affect (NA), and meaning in life (MIL). Study 1 (N = 1,053) showed that simply completing a measure of right-wing authoritarianism (vs. not) prior to rating MIL led to higher MIL. Preregistered Study 2 (N = 1,904) showed that reading speeches by real-world authoritarians (e.g., Adolf Hitler) led to lower PA, higher NA, and higher MIL than a control passage. In preregistered Studies 3 (N = 1,573) and 4 (N = 1,512), Americans read authoritarian, egalitarian, or control messages and rated mood, MIL, and evaluated the passages. Both studies showed that egalitarian messages led to better mood and authoritarian messages led to higher MIL. Study 5 (N = 148) directly replicated these results with Canadians. Aggregating across studies (N = 3,401), moderational analyses showed that meaning in life, post manipulation, was associated with more favorable evaluations of the authoritarian passage. In addition, PA was a stronger predictor of MIL in the egalitarian and control conditions than in the authoritarian condition. Further results showed no evidence that negative mood (or disagreement) spurred the boost in MIL. Implications and future directions are discussed., Competing Interests: The authors have declared that no competing interests exist.

Objective: We aimed to report a community outbreak of an uncommon methicillin-resistant Staphylococcus aureus (MRSA) originating in a maternity ward., Patients and Methods: Cases were defined by epidemiological, clinical, and microbiological investigations. Microbiological investigations included phenotypic analysis, molecular typing, and whole-genome sequencing. To control the outbreak, we applied both national recommendations to prevent in-hospital transmission and the French High Council for Public Health guidelines on the management of community-acquired MRSA infections., Results: Between March and July 2016, seven patients with MRSA infections were identified: six skin and soft tissue infections and one pulmonary infection, including six microbiologically confirmed infections. Infections occurred in community settings, but a link with the same maternity ward was found for all patients. All MRSA strains had a t690 spa type, were tetracycline-resistant, and produced Panton-Valentine leukocidin. All isolates belonged to the sequence type 88 (ST88)., Conclusion: This outbreak highlights the largely underestimated risk of healthcare-associated infections in maternity wards. Healthcare workers should be aware of the importance of standard hygiene precautions and use of alcohol-based hand sanitizers for neonates and mothers., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Purpose: Since the 1960s, increasing oral contraceptive (OC) use has mirrored decreasing ovarian cancer incidence. The impact of intrauterine devices (IUDs) on cancer risk is less well established. With improved access and increased options, we must consider how changing usage can affect cancer risks., Methods: Nationally representative data from the National Health and Nutrition Examination Survey (NHANES, 1999-2016) and the National Survey for Family Growth (NSFG, 2006-2017) were used to evaluate contraceptive use over time in premenopausal women (NHANES n = 13,179; NSFG n = 26,262). Trends were assessed overall and by race, age, pregnancy history, education, and body mass index., Results: The average annual absolute increase in self-reported IUD use was 0.81% (NSFG), while OC use decreased 0.49% in NSFG and 0.47% in NHANES. This represents a significant decrease in OC use in NSFG [annual percent change (APC) - 2.2% (95% CI - 3.4, - 1.0%), p < 0.01]. Trends in OC use varied somewhat by pregnancy history in NHANES (p-interaction = 0.054). In contrast, IUD use increased 6.2% annually [(1.4, 11.2%), p = 0.03] and varied significantly by pregnancy history (p-interaction < 0.01). Nulligravid women increased IUD use 11.0% annually [(2.6, 20.1%), p = 0.02] compared to women with prior pregnancy at 5.2% [(0.4, 10.2%), p = 0.04]. In 2015-2017, IUD use was 76.5% hormonal (71.1, 81.8%) and 22.9% copper (17.4, 28.3%) with greater hormonal IUD use in obese women [89.4%, (82.9, 95.9%)]., Conclusion: Increasing IUD use outpaced declining OC use in premenopausal US women. There may be a resulting decreased gynecologic cancer risk as more women gain access to potentially risk-reducing contraceptives.

Purpose: Although considerable progress has been made with autologous T cell-based therapy in B-cell malignancies, application in chronic lymphocytic leukemia (CLL) lags behind due to disappointing response rates as well as substantial toxicity that is of particular concern in the elderly CLL population. Vγ9Vδ2-T cells form a conserved T-cell subset with strong intrinsic immunotherapeutic potential, largely because of their capacity to be triggered by phosphoantigens that can be overproduced by CLL and other malignant cells. Specific activation of Vγ9Vδ2-T cells by a bispecific antibody may improve the efficacy and toxicity of autologous T-cell-based therapy in CLL., Experimental Design: We evaluated CD1d expression in a cohort of 78 untreated patients with CLL and generated and functionally characterized a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies (VHH)., Results: CD1d was expressed by CLL in the majority of patients, particularly in patients with advanced disease. The CD1d-specific Vγ9Vδ2-T cell engager induced robust activation and degranulation of Vγ9Vδ2-T cells, enabling Vγ9Vδ2-T cells from patients with CLL to lyse autologous leukemic cells at low effector-to-target ratios. Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis. Furthermore, we provide evidence that the Vγ9Vδ2-T cell receptor retains responsiveness to phosphoantigens when the bispecific VHH is bound, and aminobisphosphonates can therefore enhance bispecific Vγ9Vδ2-T cell engager-mediated tumor-specific killing., Conclusions: Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vγ9Vδ2-T cell engager in CLL., (©2021 American Association for Cancer Research.)

Determining readiness for duty after mild traumatic brain injury (mTBI) is essential for the safety of service members and their unit. Currently, these decisions are primarily based on self-reported symptoms, objective measures that assess a single system, or standardized physical or cognitive tests that may be insensitive or lack ecological validity for warrior tasks. While significant technological advancements have been made in a variety of assessments of these individual systems, assessments of isolated tasks are neither diagnostically accurate nor representative of the demands imposed by daily life and military activities. Emerging evidence suggests that complex tasks, such as dual-task paradigms or turning, have utility in probing functional deficits after mTBI. Objective measures from turning tasks in single- or dual-task conditions, therefore, may be highly valuable for clinical assessments and return-to-duty decisions after mTBI. The goals of this study are to assess the diagnostic accuracy, predictive capacity, and responsiveness to rehabilitation of objective, dual-task turning measures within an mTBI population. These goals will be accomplished over two phases. Phase 1 will enroll civilians at three sites and active-duty service members at one site to examine the diagnostic accuracy and predictive capacity of dual-task turning outcomes. Phase 1 participants will complete a series of turning tasks while wearing inertial sensors and a battery of clinical questionnaires, neurocognitive testing, and standard clinical assessments of function. Phase 2 will enroll active-duty service members referred for rehabilitation from two military medical treatment facilities to investigate the responsiveness to rehabilitation of objective dual-task turning measures. Phase 2 participants will complete two assessments of turning while wearing inertial sensors: a baseline assessment prior to the first rehabilitation session and a post-rehabilitation assessment after the physical therapist determines the participant has completed his/her rehabilitation course. A variable selection procedure will then be implemented to determine the best task and outcome measure for return-to-duty decisions based on diagnostic accuracy, predictive capacity, and responsiveness to rehabilitation. Overall, the results of this study will provide guidance and potential new tools for clinical decisions in individuals with mTBI. Clinical Trial Registration : clinicaltrials.gov, Identifier NCT03892291., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fino, Weightman, Dibble, Lester, Hoppes, Parrington, Arango, Souvignier, Roberts and King.)

There is a dearth of knowledge about how symptom severity affects gait in the chronic (>3 months) mild traumatic brain injury (mTBI) population despite up to 53% of people reporting persisting symptoms after mTBI. The aim of this investigation was to determine whether gait is affected in a symptomatic, chronic mTBI group and to assess the relationship between gait performance and symptom severity on the Neurobehavioral Symptom Inventory (NSI). Gait was assessed under single- and dual-task conditions using five inertial sensors in 57 control subjects and 65 persons with chronic mTBI (1.0 year from mTBI). The single- and dual-task gait domains of Pace, Rhythm, Variability, and Turning were calculated from individual gait characteristics. Dual-task cost (DTC) was calculated for each domain. The mTBI group walked (domain z-score mean difference, single-task = 0.70; dual-task = 0.71) and turned (z-score mean difference, single-task = 0.69; dual-task = 0.70) slower ( p  < 0.001) under both gait conditions, with less rhythm under dual-task gait (z-score difference = 0.21; p  = 0.001). DTC was not different between groups. Higher NSI somatic subscore was related to higher single- and dual-task gait variability as well as slower dual-task pace and turning ( p  < 0.01). Persons with chronic mTBI and persistent symptoms exhibited altered gait, particularly under dual-task, and worse gait performance related to greater symptom severity. Future gait research in chronic mTBI should assess the possible underlying physiological mechanisms for persistent symptoms and gait deficits.

Meaning in life has long been a mystery of human existence. In this review, we seek to demystify this construct. Focusing on the subjective experience of meaning in life, we review how it has been measured and briefly describe its correlates. Then we review evidence that meaning in life, for all its mystery, is a rather commonplace experience. We then define the construct and review its constituent facets: comprehension/coherence, purpose, and existential mattering/significance. We review the many experiences that have been shown to enhance meaning in life and close by considering important remaining research questions about this fascinating topic.

Background: Little is known on the peripheral and central sensory contributions to persistent dizziness and imbalance following mild traumatic brain injury (mTBI)., Objective: To identify peripheral vestibular, central integrative, and oculomotor causes for chronic symptoms following mTBI., Methods: Individuals with chronic mTBI symptoms and healthy controls (HC) completed a battery of oculomotor, peripheral vestibular and instrumented posturography evaluations and rated subjective symptoms on validated questionnaires. We defined abnormal oculomotor, peripheral vestibular, and central sensory integration for balance measures among mTBI participants as falling outside a 10-percentile cutoff determined from HC data. A X-squared test associated the proportion of normal and abnormal responses in each group. Partial Spearman's rank correlations evaluated the relationships between chronic symptoms and measures of oculomotor, peripheral vestibular, and central function for balance control., Results: The mTBI group (n = 58) had more abnormal measures of central sensory integration for balance than the HC (n = 61) group (mTBI: 41% -61%; HC: 10%, p's < 0.001), but no differences on oculomotor and peripheral vestibular function (p > 0.113). Symptom severities were negatively correlated with central sensory integration for balance scores (p's < 0.048)., Conclusions: Ongoing balance complaints in people with chronic mTBI are explained more by central sensory integration dysfunction rather than peripheral vestibular or oculomotor dysfunction.