DE-AFO: A Robotic Ankle Foot Orthosis for Children with Cerebral Palsy Powered by Dielectric Elastomer Artificial Muscle.

Conventional passive ankle foot orthoses (AFOs) have not seen substantial advances or functional improvements for decades, failing to meet the demands of many stakeholders, especially the pediatric population with neurological disorders. Our objective is to develop the first comfortable and unobtrusive powered AFO for children with cerebral palsy (CP), the DE-AFO. CP is the most diagnosed neuromotor disorder in the pediatric population. The standard of care for ankle control dysfunction associated with CP, however, is an unmechanized, bulky, and uncomfortable L-shaped conventional AFO. These passive orthoses constrain the ankle's motion and often cause muscle disuse atrophy, skin damage, and adverse neural adaptations. While powered orthoses could enhance natural ankle motion, their reliance on bulky, noisy, and rigid actuators like DC motors limits their acceptability. Our innovation, the DE-AFO, emerged from insights gathered during customer discovery interviews with 185 stakeholders within the AFO ecosystem as part of the NSF I-Corps program. The DE-AFO is a biomimetic robot that employs artificial muscles made from an electro-active polymer called dielectric elastomers (DEs) to assist ankle movements in the sagittal planes. It incorporates a gait phase detection controller to synchronize the artificial muscles with natural gait cycles, mimicking the function of natural ankle muscles. This device is the first of its kind to utilize lightweight, compact, soft, and silent artificial muscles that contract longitudinally, addressing traditional actuated AFOs' limitations by enhancing the orthosis's natural feel, comfort, and acceptability. In this paper, we outline our design approach and describe the three main components of the DE-AFO: the artificial muscle technology, the finite state machine (the gait phase detection system), and its mechanical structure. To verify the feasibility of our design, we theoretically calculated if DE-AFO can provide the necessary ankle moment assistance for children with CP-aligning with moments observed in typically developing children. To this end, we calculated the ankle moment deficit in a child with CP when compared with the normative moment of seven typically developing children. Our results demonstrated that the DE-AFO can provide meaningful ankle moment assistance, providing up to 69% and 100% of the required assistive force during the pre-swing phase and swing period of gait, respectively.

Characterizing the structure of mouse behavior using Motion Sequencing.

Spontaneous mouse behavior is composed from repeatedly used modules of movement (e.g., rearing, running or grooming) that are flexibly placed into sequences whose content evolves over time. By identifying behavioral modules and the order in which they are expressed, researchers can gain insight into the effect of drugs, genes, context, sensory stimuli and neural activity on natural behavior. Here we present a protocol for performing Motion Sequencing (MoSeq), an ethologically inspired method that uses three-dimensional machine vision and unsupervised machine learning to decompose spontaneous mouse behavior into a series of elemental modules called 'syllables'. This protocol is based upon a MoSeq pipeline that includes modules for depth video acquisition, data preprocessing and modeling, as well as a standardized set of visualization tools. Users are provided with instructions and code for building a MoSeq imaging rig and acquiring three-dimensional video of spontaneous mouse behavior for submission to the modeling framework; the outputs of this protocol include syllable labels for each frame of the video data as well as summary plots describing how often each syllable was used and how syllables transitioned from one to the other. In addition, we provide instructions for analyzing and visualizing the outputs of keypoint-MoSeq, a recently developed variant of MoSeq that can identify behavioral motifs from keypoints identified from standard (rather than depth) video. This protocol and the accompanying pipeline significantly lower the bar for users without extensive computational ethology experience to adopt this unsupervised, data-driven approach to characterize mouse behavior.

Nonoperative Versus Operative Treatment of Z-Type Comminuted Clavicle Fractures in Adolescents: A Prospective Substratified Cohort Analysis.

OBJECTIVES: To compare the clinical, radiographic, and patient-reported outcomes of nonoperative and operative treatment of adolescents with comminuted "Z-type" midshaft clavicle fractures. DESIGN: Prospective observational cohort. SETTING: Eight tertiary care pediatric centers. PATIENT SELECTION CRITERIA: Patients aged 10-18 years who were treated either operatively or nonoperatively for a diaphyseal clavicle fracture between 2013 and 2017 were screened/enrolled at the time of injury. The current subcohort analysis was derived from a larger adolescent clavicle study population of 907 patients. OUTCOME MEASUREMENTS AND COMPARISONS: Complications and validated patient-reported outcome measures (PROs):(ASES, QuickDASH, Marx Shoulder Activity Score, EQ-5D, EQ-VAS, and patient satisfaction score) were compared between operative and nonoperative cohorts. RESULTS: Eighty-one patients (69 male [85.2%], 12 female; average age 15 years [11.1-18.7]; 78 with sports participation [96.2%]) were followed through bony healing and return to sports, while 59 patients (73%) completed 2-year follow-up with PROs, 26 of whom were treated nonoperatively and 33 treated operatively. All demographic and fracture characteristics were similar (P > 0.05) between the 2-year follow-up cohorts except for fracture shortening, which was greater in the operative cohort (23 vs. 29 mm, P = 0.01). After controlling for this potential confounder through both regression and propensity matched subgroup analysis, nonoperative versus operative cohorts showed no difference in rates of nonunion (0%), delayed union (0% vs. 2.3%, P = 1.0), symptomatic malunion (2.7% vs. 0%, P = 0.4), refracture (2.7% vs. 2.2%, P = 1.0), unexpected subsequent surgery (5.4% vs. 11.4%, P = 0.45), or clinically significant complications (5.4% vs. 16%, P = 0.17). There were no differences in any PROs between cohorts, both before and after controlling for the difference in fracture shortening (all P-values >0.05). CONCLUSIONS: In this prospective comparison of complications and 2-year PROs in adolescents with comminuted Z-type clavicle fractures, nonoperative and operative treatment yielded similar outcomes. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Propensity score matched analysis of laparoscopic revisional and conversional sleeve gastrectomy with concurrent hiatal hernia repair.

INTRODUCTION: The primary aim of this study was to evaluate outcomes associated with concurrent hiatal hernia repair (CHHR) when performing a conversional or revisional vertical sleeve gastrectomy (VSG). CHHR is often necessary during VSG due to potential gastroesophageal reflux disease (GERD) development or obstructive symptoms. METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement (MBSAQIP) participant use file was assessed for the years 2015-2020 for revisional/conversional VSG procedures. The presence of CHHR was used to create two groups. Propensity score matching (PSM) was performed with E-analysis. RESULTS: There were 33,909 patients available, with 5986 undergoing the VSG procedure with CHHR. In the unmatched analysis, there was an increased frequency of patients being female (85.72 vs 83.30%; p < 0.001), having a history of GERD (38.01 vs 31.25%; p < 0.001), and being of older age (49.59 ± 10.97 vs 48.70 ± 10.83; p < 0.001). Patients undergoing VSG with CHHR experienced decreased sleep apnea (25.00 vs 28.84%; p < 0.001) and diabetes (14.27 vs 17.80%; p < 0.001). PSM yielded 5986 patient pairs. Matched patients with CHHR experienced increased operative time (115 min ± 53 vs 103 min ± 51; p < 0.001), increased risk of postoperative pneumonia (0.45 vs 0.15%; p = 0.005) and readmission (4.69 vs 3.58%; p = 0.002) within thirty days. However, patients undergoing CHHR with revisional or conversional VSG did not experience increased risk of death, postoperative bleeding, postoperative leak, or reoperations. CONCLUSION: Despite a small association with increased postoperative pneumonia, the rate of complications in patients undergoing laparoscopic revisional/conversional VSG and CHHR are low. CHHR is a safe option when combined with the laparoscopic revisional/conversional VSG procedure in the early postoperative period.

Double Stiletto Flap for Soft Tissue Cover as a Firebreak Following Contracture Release of Digits and Full-Thickness Grafting: A Surgical Technique.

Contracture release followed by full-thickness skin grafting is often performed while releasing severe contracture of the digits. We report a technique for flexion contracture of the finger, by using two triangular flaps from either side of the digit as a firebreak over the proximal interphalangeal (PIP) joint while using a skin graft following contracture release. We reviewed the medical records of patients who underwent contracture release at our institution from January 2018 to July 2021, and this technique was used for the release of flexion contracture of the five digits belonging to four patients. Our technique used triangular flaps from either side of the digit, which were rotated and brought over the PIP region, and hence, a single sheet of graft spanning the PIP joint is avoided. We believe that this acts as a firebreak and thus reduces the recurrence of contracture at the PIP joint.

Impact of pathologic re-review on grade, clinical stage, and risk stratification for patients with nonmuscle invasive bladder cancer.

OBJECTIVES: Pathologic re-review of transurethral resection of bladder tumor (TURBT) specimen is a common practice at our tertiary care center, but its impact on disease risk stratification remains unknown. We sought to determine how pathologic re-review of specimen initially read at an outside institution changed grade, clinical T (cT) stage, and AUA non-muscle-invasive bladder cancer (NMIBC) risk stratification. METHODS AND MATERIALS: The laboratory information system was searched for patients who underwent TURBT from 2021 to 2022, yielding 561 records. 173 patients met inclusion criteria: 113 with

Body morphometry may predict parastomal hernia following radical cystectomy with ileal conduit.

OBJECTIVE: To investigate whether preoperative body morphometry analysis can identify patients at risk of parastomal hernia (PH), which is a common complication after radical cystectomy (RC). PATIENTS AND METHODS: All patients who underwent RC between 2010 and 2020 with available cross-sectional imaging preoperatively and at 1 and 2 years postoperatively were included. Skeletal muscle mass and total fat mass (FM) were determined from preoperative axial computed tomography images obtained at the level of the L3 vertebral body using Aquarius Intuition software. Sarcopenia and obesity were assigned based on consensus definitions of skeletal muscle index (SMI) and FM index (FMI). PH were graded using both the Moreno-Matias and European Hernia Society criteria. Binary logistic regression and recursive partitioning were used to identify patients at risk of PH. The Kaplan-Meier method with log-rank and Cox proportional hazards models included clinical and image-based parameters to identify predictors of PH-free survival. RESULTS: A total of 367 patients were included in the final analysis, with 159 (43%) developing a PH. When utilising binary logistic regression, high FMI (odds ratio [OR] 1.63, P < 0.001) and low SMI (OR 0.96, P = 0.039) were primary drivers of risk of PH. A simplified model that only relied upon FMI, SMI, and preoperative albumin improved the classification of patients at risk of PH. On Kaplan-Meier analysis, patients who were obese or obese and sarcopenic had significantly worse PH-free survival (P < 0.001). CONCLUSION: Body morphometry analysis identified FMI and SMI to be the most consistent predictors of PH after RC.

Clinical upstaging after neoadjuvant chemotherapy impacting eligibility for vaginal-sparing cystectomy: identifying bladder cancer patients who may benefit from interim imaging.

INTRODUCTION AND OBJECTIVES: Limited data exists on the frequency with which clinical progression during neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) impacts eligibility for a vaginal-sparing surgical approach or on the utility of interim imaging assessment. We sought to evaluate the incidence of clinical upstaging following NAC that would render a patient ineligible for a vaginal-sparing cystectomy. METHODS: 89 female patients with non-metastatic MIBC treated with NAC and radical cystectomy (RC) (2012-2023) were retrospectively reviewed. Tumor location(s) was determined from transurethral resection of bladder tumor operative reports. Pre- and post-NAC clinical staging was determined from imaging. Outcomes of interest included clinical upstaging and upstaging to vaginal invasion after NAC. RESULTS: 75/89 patients had pre- and post-NAC imaging. 55 had no change in clinical staging, six patients were upstaged (4 cT2→cT3, 2 cT3→cT4), and 14 patients were downstaged (13 cT3→cT2, 1 cT4→cT2). Of the 75 patients with pre- and post-NAC imaging, 39 had trigone tumors. Of these, 28 had no change in clinical staging, two were upstaged (1 cT2→cT3, 1 cT3→cT4) and nine were downstaged (8 cT3→cT2, 1 cT4→cT2). Overall, 6/75 (8%) of patients demonstrated clinical upstaging after NAC. 2/39 (5%) of patients with trigone tumors clinically progressed after NAC and both had vaginal invasion (pT4) on final pathology. CONCLUSIONS: Although clinical upstaging after NAC was infrequent, 5% of patients with trigonal MIBC were rendered ineligible for vaginal-sparing cystectomy following NAC due to progression. Interim imaging assessment may identify non-responders and preserve eligibility for vaginal-sparing RC.

Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial.

Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ≥3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

Association between job lost and mental health outcomes during the COVID-19 pandemic and the role of food insecurity as mediator of this relationship.

This study aimed to evaluate the association between employment status and mental health, considering food insecurity as a mediator of this relation. A cross-sectional population-based study was conducted with adults (≥ 18 and < 60 years) during the COVID-19 outbreak in two cities from Southern Brazil. Employment status was categorized into working, not working, and lost job. The mental health outcomes evaluated were depressive symptoms, perceived stress, and sadness. Food insecurity was identified by the short-form version of the Brazilian Food Insecurity Scale. Adjusted analyses using Poisson regression were performed to assess the association between employment status and mental health. Mediation analysis was performed to investigate the direct and indirect effects of employment status on mental health outcomes. In total, 1,492 adults were analyzed. The not working status was associated with 53% and 74% higher odds of perceived stress and of sadness, respectively. Being dismissed during the pandemic increased the odds of depressive symptoms, perceived stress, and sadness by 68%, 123%, and 128%, respectively. Mediation analyses showed that food insecurity was an important mediator of the association between employment status and depressive symptoms and sadness, but not of perceived stress. The complexity of these results highlights economic and nutritional aspects involved in mental health outcomes.

Molecular mechanism of BMP signal control by Twisted gastrulation.

Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1.

Efficacy and safety of tesamorelin in people with hiv on integrase inhibitors.

OBJECTIVE: Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy. DESIGN: We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily versus identical placebo among participants on INSTI-based regimens at baseline. METHODS: In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms. RESULTS: Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm2, P = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P = 0.03). Tesamorelin was well-tolerated with a similar frequency of adverse events including hyperglycemia between groups. CONCLUSIONS: The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.

Persistent Luminescence Nanosensors: A Generalized Optode-Based Platform for Autofluorescence-Free Sensing in Biological Systems.

Fluorescent nanosensors have revolutionized diagnostics and our ability to monitor cellular dynamics. Yet, distinguishing sensor signals from autofluorescence remains a challenge. Here, we merged optode-based sensing with near-infrared-emitting ZnGa2O4:Cr3+ persistent luminescence nanoparticles (PLNPs) to create nanocomposites for autofluorescence-free "glow-in-the-dark" sensing. Hydrophobic modification and incorporation of the persistent luminescence nanoparticles into an optode-based nanoparticle core yielded persistent luminescence nanosensors (PLNs) for five analytes (K+, Na+, Ca2+, pH, and O2) via two distinct mechanisms. We demonstrated the viability of the PLNs by quantifying K+ in fetal bovine serum, calibrating the pH PLNs in the same, and ratiometrically monitoring O2 metabolism in cultures of Saccharomyces cerevisiae, all the while overcoming their respective autofluorescence signatures. This highly modular platform allows for facile tuning of the sensing functionality, optical properties, and surface chemistry and promises high signal-to-noise ratios in complex optical environments.

Macrophage interleukin-1ß mediates atrial fibrillation risk in diabetic mice.

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high fat diet to induce type II DM and were subjected to IL-1ß antibodies, macrophage depletion by Clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1ß levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1ß neutralization, macrophage depletion, mitoTEMPO, and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1ß contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.

Cardiac Development Long Non-Coding RNA (CARDEL) Is Activated during Human Heart Development and Contributes to Cardiac Specification and Homeostasis.

Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

A gH/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge.

Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH/gL, gH/gL/gp42 or gp350 delivered by a cationic nanocarrier termed LION™. The lead candidate, encoding full-length gH/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8+ T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION/repRNA-gH/gL is an ideal candidate vaccine for preventing EBV infection and/or related malignancies in humans.

In Utero Exposure to Maternal SARS-CoV-2 Infection Is Associated With Higher Left Ventricular Mass in Toddlers.

The intrauterine environment plays a critical role in shaping chronic disease risk over the life course. We prospectively evaluated cardiometabolic outcomes in toddlers born to mothers with versus without prenatal severe acute respiratory syndrome coronavirus 2 infection. Children with in utero severe acute respiratory syndrome coronavirus 2 exposure had higher left ventricular mass in association with altered maternal immunologic indices.

Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.

The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.

Ebola Virus-Specific Neutralizing Antibody Persists at High Levels in Survivors 2 Years After Resolution of Disease in a Sierra Leonean Cohort.

Ebola virus (EBOV) infection results in Ebola virus disease (EVD), an often severe disease with a nonspecific presentation. Since its recognition, periodic outbreaks of EVD continue to occur in sub-Saharan Africa. The 2013-2016 West African EVD outbreak was the largest recorded, resulting in a substantial cohort of EVD survivors with persistent health complaints and variable immune responses. In this study, we characterize humoral immune responses in EVD survivors and their contacts in Eastern Sierra Leone. We found high levels of EBOV IgG in EVD survivors and lower yet substantial antibody levels in household contacts, suggesting subclinical transmission. Neutralizing antibody function was prevalent but variable in EVD survivors, raising questions about the durability of immune responses from natural infection with EBOV. Additionally, we found that certain discrete symptoms-ophthalmologic and auditory-are associated with EBOV IgG seropositivity, while an array of symptoms are associated with the presence of neutralizing antibody.