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Roselien Buys,1,2,* Kimberly Dockx,1,* Marc Gewillig,3 Tony Reybrouck1,21Department of Rehabilitation Sciences, 2Department of Cardiovascular Rehabilitation, University of Leuven, Leuven, Belgium; 3Department of Pediatric Cardiology, University Hospital Gasthuisberg, Leuven, Belgium*These authors contributed equally to this paperBackground: The oxygen pulse equals stroke volume times arterial–venous oxygen difference and is calculated by dividing oxygen uptake (VO2) by heart rate (HR). In children with a Senning repair for the transposition of the great arteries (TGA), the response of both HR and VO2 to exercise is impaired. Our aim was to assess the oxygen pulse response during exercise in patients who underwent a Senning operation, comparing it with healthy controls.Methods: Twenty-one children with a Senning repair (mean age 12.5 ± 1.7 years) and a control group of 31 healthy children (mean age 13.2 ± 2.0 years) performed a graded maximal exercise test on a treadmill, during which HR and VO2 were measured. Oxygen pulse was calculated by dividing VO2 by HR. Right ventricular function was quantitatively assessed by cardiac ultrasound.Results: Senning patients had a lower peak oxygen pulse than the control (P = 0.0024) (8.45 ± 1.90 mL • beats-1 versus 11.7 ± 3.93 mL • beats-1), as with the peak VO2 (P < 0.001) (35.8 ± 5.67 mL • min-1 • kg-1 versus 46.6 ± 8.02 mL • min-1 • kg-1) and peak HR (171 ± 14 beats • min-1 versus 188 ± 11 beats • min-1). During submaximal exercise, oxygen pulse and VO2 were also significantly lower in Senning patients when compared to the control group (P = 0.027). In seven Senning patients (33%), the oxygen pulse did not increase any further after the first exercise levels. These patients had lower right ventricular function compared to the control group (P = 0.04).Conclusion: Children with a Senning repair for TGA have a reduced peak VO2, peak HR, and peak oxygen pulse. Their oxygen pulse starts off at a lower level, reaches its plateau earlier, and is related to right ventricular function. This variable can be considered a complementary parameter to assess cardiovascular exercise performance.Keywords: transposition of the great arteries, Senning repair, oxygen pulse, cardiopulmonary exercise testing

Research on liver-related conditions requires a robust and efficient method to purify viable hepatocytes, lymphocytes and all other liver resident cells, such as Kupffer or liver sinusoidal endothelial cells. Here we describe a novel purification method using liver enzymatic digestion, followed by a downstream optimized purification. Using this enzymatic digestion protocol, the resident liver cells as well as viable hepatocytes could be captured, compared to the classical mechanical liver disruption method. Moreover, single-cell RNA-sequencing demonstrated higher quality lymphocyte data in downstream analyses after the liver enzymatic digestion, allowing for studying of immunological responses or changes. In order to also understand the peripheral immune landscape, a protocol for lymphocyte purification from mouse systemic whole blood was optimized, allowing for efficient removal of red blood cells. The combination of microbeads and mRNA blockers allowed for a clean blood sample, enabling robust single-cell RNA-sequencing data. These two protocols for blood and liver provide important new methodologies for liver-related studies such as NASH, hepatitis virus infections or cancer research but also for immunology where high-quality cells are indispensable for further downstream assays., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: D.DP, B.DC, S.S, P.D, M.B, I.B, I.N, E.VG, N.CN and W.P were employed by Janssen Research and Development at the time of the research and may be Johnson and Johnson stockholders. All other authors declare no conflicts of interest. This does not alter our adherence to the PLOS ONE policies on sharing data and materials, restrictions do apply to the sharing of any further data on the CAM-A compound and to the sharing of CAM material., (Copyright: © 2024 De Pooter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We present the electrical characterization of wafer-scale graphene devices fabricated with an industrially-relevant, contact-first integration scheme combined with Al 2 O 3 encapsulation via atomic layer deposition. All the devices show a statistically significant reduction in the Dirac point position,Vcnp, from around +47 V to between -5 and 5 V (on 285 nm SiO 2 ), while maintaining the mobility values. The data and methods presented are relevant for further integration of graphene devices, specifically sensors, at the back-end-of-line of a standard CMOS flow., (© 2024 IOP Publishing Ltd.)

Chronic infection with hepatitis B virus (HBV) develops in millions of patients per year, despite the availability of effective prophylactic vaccines. Patients who resolve acute HBV infection develop HBV-specific polyfunctional T cells accompanied by neutralizing antibodies, while in patients with chronic hepatitis B (CHB), immune cells are dysfunctional and impaired. We describe a lipid nanoparticle (LNP)-formulated mRNA vaccine, optimized for the expression of HBV core, polymerase, and surface (preS2-S) antigens with the aim of inducing an effective immune response in patients with CHB. Prime and prime/boost vaccination with LNP-formulated mRNA encoding for core, pol, and/or preS2-S dosing strategies were compared in naive C57BL/6 and BALB/c mice. Immune responses were assessed by IFN-γ ELISpot, intracellular cytokine staining (ICS), and ELISA for antibody production, whereas anti-viral efficacy was evaluated in the AAV-HBV mouse model. The mRNA vaccine induced strong antigen-specific polyfunctional T cell responses in these mouse models, accompanied by the emergence of anti-HBs and anti-HBe antibodies. After three immunizations, the antigen-specific immune stimulation resulted in up to 1.7 log 10 IU/mL reduction in systemic HBV surface antigen (HBsAg), accompanied by a transient drop in systemic HBeAg, and this was observed in 50% of the AAV-HBV-transduced mice in the absence of additional modalities such as adjuvants, HBsAg reducing agents, or checkpoint inhibitors. However, no treatment-related effect on viremia was observed in the liver. These results warrant further optimization and evaluation of this mRNA vaccine as a candidate in a multimodal therapeutic regimen for the treatment of chronic HBV infection.

Background: Suppression of HBV DNA, inhibition of HBV surface (HBsAg) production and therapeutic vaccination to reverse HBV-specific T-cell exhaustion in chronic HBV patients are likely required to achieve a functional cure. In the AAV-HBV mouse model, therapeutic vaccination can be effective in clearing HBV when HBsAg levels are low. Using a single-cell approach, we investigated the liver immune environment with different levels of HBsAg and sustained HBsAg loss through treatment with a GalNAc-HBV-siRNA followed by therapeutic vaccination., Methods: AAV-HBV-transduced C57BL/6 mice were treated with GalNAc-HBV-siRNA to lower HBsAg levels and then vaccinated using a DNA vaccine. We used single-cell RNA and V(D)J sequencing to understand liver immune microenvironment changes., Results: GalNAc-HBV-siRNA, followed by therapeutic vaccination, achieved sustained HBsAg loss in all mice. This was accompanied by CD4 follicular helper T-cell induction, polyclonal activation of CD8 T cells and clonal expansion of plasma cells that were responsible for antibody production., Conclusions: This study provides novel insights into liver immune changes at the single-cell level, highlighting the correlation between induced reduction of HBsAg levels and clonal expansion of CD4, CD8 T cells and plasma cells in the liver upon HBV siRNA and subsequent therapeutic vaccination.

A major barrier to HIV-1 cure is caused by the pool of latently infected CD4 T-cells that persist under combination antiretroviral therapy (cART). This latent reservoir is capable of producing replication-competent infectious viruses once prolonged suppressive cART is withdrawn. Inducing the reactivation of HIV-1 gene expression in T-cells harboring a latent provirus in people living with HIV-1 under cART may result in depletion of this latent reservoir due to cytopathic effects or immune clearance. Studies have investigated molecules that reactivate HIV-1 gene expression, but to date, no latency reversal agent has been identified to eliminate latently infected cells harboring replication-competent HIV in cART-treated individuals. Stochastic fluctuations in HIV-1 tat gene expression have been described and hypothesized to allow the progression into proviral latency. We hypothesized that exposing latently infected CD4+ T-cells to Tat would result in effective latency reversal. Our results indicate the capacity of a truncated Tat protein and mRNA to reactivate HIV-1 in latently infected T-cells ex vivo to a similar degree as the protein kinase C agonist: phorbol 12-myristate 13-acetate, without T-cell activation or any significant transcriptome perturbation., Competing Interests: E.V.G., E.N., N.V., C.V.D.E., I.V.D.W., F.E., E.B., and D.B. are employees of Johnson & Johnson and may be Johnson & Johnson stockholders. J.V. was an employee of Arcturus and may be an Arcturus stockholder.

[Formula: see text]Ac is a radio-isotope that can be linked to biological vector molecules to treat certain distributed cancers using targeted alpha therapy. However, developing [Formula: see text]Ac-labelled radiopharmaceuticals remains a challenge due to the supply shortage of pure [Formula: see text]Ac itself. Several techniques to obtain pure [Formula: see text]Ac are being investigated, amongst which is the high-energy proton spallation of thorium or uranium combined with resonant laser ionization and mass separation. As a proof-of-principle, we perform off-line resonant ionization mass spectrometry on two samples of [Formula: see text]Ac, each with a known activity, in different chemical environments. We report overall operational collection efficiencies of 10.1(2)% and 9.9(8)% for the cases in which the [Formula: see text]Ac was deposited on a rhenium surface and a ThO[Formula: see text] mimic target matrix respectively. The bottleneck of the technique was the laser ionization efficiency, which was deduced to be 15.1(6)%., (© 2023. The Author(s).)

Background&nbsp; Despite high prevalence of psychopathology, the use of mental health services by asylum seekers seems low. Barriers to care may play an important role in this. Aim&nbsp; To explore the barriers in mental health care for adult and adolescent asylum seekers and their care providers in high-income countries. Method&nbsp; A narrative literature review, based on a systematic evaluation of the current scientific literature. Results&nbsp; In a narrative synthesis of the results, we identified the following six categories of barriers: lack of knowledge of the healthcare system, language barriers, discrepant beliefs and expectations of mental healthcare, lack of trust towards authority, and structural difficulties. Conclusion&nbsp; Six thematic barriers were retained. Different interventions are possible to address these barriers. Further research into needs and interventions is recommended, with specific attention to the Belgian and Dutch context.

This work reports the production cross-section data for seventy-one radionuclides produced by 0.3 GeV-1.7 GeV protons impinging on thin tantalum targets. For that purpose, activation experiments were performed using the COSY synchrotron at FZ Jülich utilizing the stacked-foils technique and γ-ray spectrometry with high-purity germanium detectors. The Al-27(p,x)Na-24 reaction has been used as monitor reaction. All experimental data have been systematically compared with the existing literature. The excitation functions of Te-116, I-123, Dy-153 and Er-158 are reported for the first time., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Public health strategies in the context of respiratory droplet-transmissible diseases (such as influenza or COVID-19) include intensified hand hygiene promotion, but a review on the effectiveness of different ways of promoting hand hygiene in the community, specifically for this type of infections, has not been performed. This rapid systematic review aims to summarize the effectiveness of community-based hand hygiene promotion programs on infection transmission, health outcomes and behavioral outcomes during epidemic periods in the context of respiratory droplet-transmissible diseases. We also included laboratory-confirmed health outcomes for epidemic-prone disease during interepidemic periods., Methods: We searched for controlled experimental studies. A rapid systematic review was performed in three databases and a COVID-19 resource. Following study selection (in which studies performed in the (pre-)hospital/health care setting were excluded), study characteristics and effect measures were synthesized, using meta-analyses of cluster-RCTs where possible. Risk of bias of each study was assessed and the certainty of evidence was appraised according to the GRADE methodology., Results: Out of 2050 unique references, 12 cluster-RCTs, all in the context of influenza, were selected. There were no controlled experimental studies evaluating the effectiveness of hand hygiene promotion programs in the context of COVID-19 that met the in-/exclusion criteria. There was evidence that preventive hand hygiene promotion interventions in interepidemic periods significantly decreased influenza positive cases in the school setting. However, no improvement could be demonstrated for programs implemented in households to prevent secondary influenza transmission from previously identified cases (epidemic and interepidemic periods)., Conclusions: The data suggest that proactive hand hygiene promotion interventions, i.e. regardless of the identification of infected cases, can improve health outcomes upon implementation of such a program, in contrast to reactive interventions in which the program is implemented after (household) index cases are identified., (© 2021. The Author(s).)

The CERN-MEDICIS (MEDical Isotopes Collected from ISolde) facility has delivered its first radioactive ion beam at CERN (Switzerland) in December 2017 to support the research and development in nuclear medicine using non-conventional radionuclides. Since then, fourteen institutes, including CERN, have joined the collaboration to drive the scientific program of this unique installation and evaluate the needs of the community to improve the research in imaging, diagnostics, radiation therapy and personalized medicine. The facility has been built as an extension of the ISOLDE (Isotope Separator On Line DEvice) facility at CERN. Handling of open radioisotope sources is made possible thanks to its Radiological Controlled Area and laboratory. Targets are being irradiated by the 1.4 GeV proton beam delivered by the CERN Proton Synchrotron Booster (PSB) on a station placed between the High Resolution Separator (HRS) ISOLDE target station and its beam dump. Irradiated target materials are also received from external institutes to undergo mass separation at CERN-MEDICIS. All targets are handled via a remote handling system and exploited on a dedicated isotope separator beamline. To allow for the release and collection of a specific radionuclide of medical interest, each target is heated to temperatures of up to 2,300°C. The created ions are extracted and accelerated to an energy up to 60 kV, and the beam steered through an off-line sector field magnet mass separator. This is followed by the extraction of the radionuclide of interest through mass separation and its subsequent implantation into a collection foil. In addition, the MELISSA (MEDICIS Laser Ion Source Setup At CERN) laser laboratory, in service since April 2019, helps to increase the separation efficiency and the selectivity. After collection, the implanted radionuclides are dispatched to the biomedical research centers, participating in the CERN-MEDICIS collaboration, for Research & Development in imaging or treatment. Since its commissioning, the CERN-MEDICIS facility has provided its partner institutes with non-conventional medical radionuclides such as Tb-149, Tb-152, Tb-155, Sm-153, Tm-165, Tm-167, Er-169, Yb-175, and Ac-225 with a high specific activity. This article provides a review of the achievements and milestones of CERN-MEDICIS since it has produced its first radioactive isotope in December 2017, with a special focus on its most recent operation in 2020., 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 Duchemin, Ramos, Stora, Ahmed, Aubert, Audouin, Barbero, Barozier, Bernardes, Bertreix, Boscher, Bruchertseifer, Catherall, Chevallay, Christodoulou, Chrysalidis, Cocolios, Comte, Crepieux, Deschamps, Dockx, Dorsival, Fedosseev, Fernier, Formento-Cavaier, El Idrissi, Ivanov, Gadelshin, Gilardoni, Grenard, Haddad, Heinke, Juif, Khalid, Khan, Köster, Lambert, Lilli, Lunghi, Marsh, Palenzuela, Martins, Marzari, Menaa, Michel, Munos, Pozzi, Riccardi, Riegert, Riggaz, Rinchet, Rothe, Russell, Saury, Schneider, Stegemann, Talip, Theis, Thiboud, van der Meulen, van Stenis, Vincke, Vollaire, Vuong, Webster, Wendt, Wilkins and the CERN-MEDICIS collaboration.)

Trauma-exposed individuals are at risk of developing mental health problems, including posttraumatic stress disorder (PTSD). As an exposed individual's friend or family member may be the first person to provide posttrauma relief, informing and training laypeople in psychosocial first aid may benefit mental health outcomes of trauma-exposed individuals. We aimed to (a) collect the best available evidence on communication as a first aid intervention in assisting individuals following traumatic events and (b) formulate practical recommendations. Systematic literature searches were conducted in three databases (March 2019). Following study selection, the extracted data were tabulated and synthesized narratively. The evidence was appraised according to the GRADE methodology and evaluated by a multidisciplinary expert panel to formulate recommendations for practice. Out of 1,724 articles, no experimental studies were identified, showing a complete lack of high-quality controlled studies on the efficacy of communicative practices. However, when lower-quality study designs were included, nine cross-sectional studies constituted the best available evidence. The studies suggested that positive communication by family members, r = -.38, aOR = 0.26, β = -.22, p < .001-p < .05, and expressive coping by the victim, β = -.62, p < .001, were associated with PTSD diagnosis and/or symptom severity; however, the evidence was of very low certainty. The expert panel took the methodological limitations into account when formulating weak practical recommendations. Cross-sectional studies currently provide the best possible evidence for developing guidelines on psychosocial first aid. High-quality controlled studies are needed to establish casual associations and identify the most effective interventions., (© 2020 International Society for Traumatic Stress Studies.)

This work presents the production cross-sections of Ce, Tb and Dy radionuclides produced by 300 MeV to 1.7 GeV proton-induced spallation reactions in thin tantalum targets as well as the related Thick Target production Yield (TTY) values and ratios. The motivation is to optimise the production of terbium radionuclides for medical applications and to find out at which energy the purity of the collection by mass separation would be highest. For that purpose, activation experiments were performed using the COSY synchrotron at FZ Jülich utilising the stacked-foils technique and γ spectrometry with high-purity germanium detectors. The Al-27(p,x)Na-24 reaction has been used as monitor reaction. All experimental data have been systematically compared with the existing literature., Competing Interests: RF-C was employed by AdAcAp during his PhD thesis under the MEDICIS-promed agreement, when the experiments presented in this work have been conducted. The research has been perform within the framework of the MEDICIS-promed Horizon 2020 Marie Sklodowska-Curie Innovative Training Network. OF, RG, BN, BS, IS, and SS were employed by Forschungszentrum Julich GmbH when the experiments presented in this work have been conducted. The remaining 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 Duchemin, Cocolios, Dockx, Farooq-Smith, Felden, Formento-Cavaier, Gebel, Köster, Neumaier, Scholten, Spahn, Spellerberg, Stamati, Stegemann and Verhoeven.)

Background: First aid training is a cost-effective way to decrease the burden of disease and injury in low- and middle-income countries (LMIC). Since evidence from Western countries has shown that children are able to learn first aid, first aid training of children in LMIC may be a promising way forward. Hence, our project aim was to develop contextualized materials to train sub-Saharan African children in first aid, based on the best available evidence., Methods: Systematic literature searches were conducted to identify studies on first aid education to children up to 18 years old (research question one), and studies investigating different teaching approaches (broader than first aid) in LMIC (research question two). A multidisciplinary expert panel translated the evidence to the context of sub-Saharan Africa, and evidence and expert input were used to develop teaching materials., Results: For question one, we identified 58 studies, measuring the effect of training children in resuscitation, first aid for skin wounds, poisoning etc. For question two, two systematic reviews were included from which we selected 36 studies, revealing the effectiveness of several pedagogical methods, such as problem-solving instruction and small-group instruction. However, the certainty of the evidence was low to very low. Hence expert input was necessary to formulate training objectives and age ranges based on "good practice" whenever the quantity or quality of the evidence was limited. The experts also placed the available evidence against the African context., Conclusions: The above approach resulted in an educational pathway (i.e. a scheme with educational goals concerning first aid for different age groups), a list of recommended educational approaches, and first aid teaching materials for children, based on the best available evidence and adapted to the African context.

Background and Objectives: The deferral policy for blood donation after dental care is based on the precautionary principle. The aim of this systematic review is to give an overview of the scientific evidence concerning the risk of transfusion transmissible infections (TTIs) after dental care., Materials and Methods: Four databases were searched: Medline, the Cochrane Library, Embase and Web of Science. Screening was independently performed by two reviewers. The quality of evidence was evaluated using the Grades of Recommendation, Assessment, Development and Evaluation principle. A meta-analysis was performed to assess the association between dental treatment and TTI markers., Results: A total of 22 studies were included. Meta-analysis of 16 studies showed an increased association of TTIs with dental treatment, however with large heterogeneity. Subgroup analysis revealed a significant increased association of hepatitis B virus (HBV) with dental treatment [odds ratio 1.79, 95% confidence interval (1.48; 2.18)]. There was conflicting evidence concerning the risk of hepatitis C virus (HCV). One study could not demonstrate a statistically significant increased association of human T-lymphotropic virus type I with dental treatment. Three studies showed a significant increased association of HCV with tooth extraction [odds ratio 1.48, 95% confidence interval (1.11; 1.97)]. Finally, there is conflicting evidence concerning the risk of HBV or HCV after dental cleaning. One study could not demonstrate an association between HIV and dental cleaning. All evidence is of very low certainty and results cannot be considered precise., Conclusion: Studies of high quality concerning the risk of TTI after dental care in blood donors are scarce. An association of HBV after dental treatment and HCV after tooth extraction was demonstrated but evidence is of very low certainty. The currently identified studies are of too low certainty to make any suggestions regarding the value of deferral or deferral times.

Nearly 90% of diarrhea-related mortalities are the result of unsafe drinking water, poor sanitation, and insufficient hygiene. Although "Water, Sanitation, and Hygiene" (WASH) interventions may significantly reduce the risk of diarrheal disease, it is currently unclear which interventions are the most effective. In this study, we aim to determine the importance of contextualizing a WASH intervention to the local context and the needs for increasing impact (Clinicaltrials.gov NCT03709368). A total of 1500 households in rural Tanzania will participate in this cluster randomized controlled trial. Households will be randomized into one of three cohorts: (1) a control group receiving a basic intervention and 1 placebo household visit, (2) an intervention group receiving a basic intervention + 9 additional household visits which are contextualized to the setting using the RANAS approach, and (3) an intervention group receiving a basic intervention + 9 additional household visits, which are not contextualized, i.e., a general intervention. Assessments will take place at a baseline, 1 and 2 years after the start of the intervention, and 1 year after the completion of the intervention. Measurements involve questionnaires and spot checks. The primary outcome is hand-washing behavior, secondary objectives include, the impact on latrine use, health, WASH infrastructure, quality of life, and cost-effectiveness.

Aims: To summarize the best available evidence on the effectiveness of physical counterpressure manoeuvers (PCM) for vasovagal syncope management compared to a control intervention. Control interventions included either a PCM, no intervention, or other interventions feasible in a lay setting., Methods: A systematic literature search (March 21st 2018) was performed in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. PCM were subdivided into 1) PCM decreasing orthostatic load (PCMOL), 2) PCM shortening the hydrostatic column between heart and brain (PCMHC), 3) PCM using mechanical compression of the veins (PCMMC). The primary outcome was syncope, secondary outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR). When possible, a random effects meta-analysis was performed. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for dichotomous outcomes, and mean differences (MD) or standardized mean differences (SMD) were calculated for continuous outcomes. Heterogeneity was assessed by means of the I2 statistic. The total body of evidence was evaluated by means of the GRADE methodology., Results: Eleven trials involving 688 people with vasovagal syncope were included. Risk of bias was high in all included studies. The total body of evidence (GRADE) was considered to be low or very low. PCM were found to improve syncope as compared to control (OR: 0.52, 95% CI [0.33;0.81], p = 0.004). Similarly, before-and-after studies without a control group showed a significant reduction in syncope following PCM (OR: 0.01, 95%CI [0.00;0.01], p<0.001). No studies investigated PCMOL. PCMHC increased SBP, DBP, MAP, SV, and CO, and decreased HR. PCMMC increased SBP, DBP, and MAP., Conclusion: PCM may reduce syncope and increase SBP, DBP, and MAP. The effects on other outcomes are less clear. Additional high-quality studies are needed., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Freezing of gait (FOG) is a powerful determinant of falls in Parkinson's disease (PD). Automatic postural reactions serve as a protective strategy to prevent falling after perturbations. However, differences in automatic postural reactions between patients with and without FOG in response to perturbation are at present unclear. Therefore, the present study aimed to compare the response patterns and neuromuscular control between PD patients with and without FOG and healthy controls (HCs) after postural perturbations. Methods: 28 PD patients (15 FOG+, 13 FOG-) and 22 HCs were included. Participants stood on a moveable platform while random perturbations were imposed. The first anterior platform translation was retained for analysis. Center of pressure (CoP) and center of mass (CoM) trajectories and trunk, knee and ankle angles were compared between the three groups using the Statistical Parametric Mapping technique, allowing to capture changes in time. In addition, muscle activation of lower leg muscles was measured using EMG. Results: At baseline, FOG+ stood with more trunk flexion than HCs ( p = 0.005), a result not found in FOG-. Following a perturbation, FOG+ reacted with increased trunk extension ( p = 0.004) in comparison to HCs, a pattern not observed in FOG-. The CoM showed greater backward displacement in FOG- and FOG+ ( p = 0.008, p = 0.027). Both FOG+ and FOG- showed increased co-activation of agonist and antagonist muscles compared to HCs ( p = 0.010), with no differences between FOG+ and FOG-. Conclusions: Automatic postural reactions after a sudden perturbation are similar between PD subgroups with and without FOG but different from HCs. Reactive postural control, largely regulated by brain stem centers, seems to be modulated by different mechanisms than those governing freezing of gait. Greater differences in initial stance position, enhanced by joint stiffening, could however underlie maladaptive postural responses and increase susceptibility for balance loss in FOG+ compared to FOG-.

Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser 422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cell-based immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG + memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated V H 5-51/V L 4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of V H 5-51 and V L 4-1 recognizes a common Pro-X n -Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

Background: Postural instability and freezing of gait (FOG) are major problems in patients with Parkinson's disease (PD), and both contribute to falls. However, the interrelationship between these 2 deficits is still unclear., Objective: This study investigated whether dual-tasking influenced postural control differently in freezers (FOG+) and nonfreezers (FOG-)., Methods: Thirty-three patients with PD (19 FOG+, 14 FOG-, well-matched) and 28 healthy controls underwent 4 postural control tasks, consisting of standing on either stable or unstable surfaces with eyes open or closed. Each condition was performed with and without a cognitive dual-task (DT). Center of pressure and center of mass variables and cognitive DT performance outcomes were investigated., Results: Postural stability decreased to a larger extent in FOG+ under DT conditions compared with the other groups, although overall most differences were found between FOG+ and controls. FOG+ exhibited worse postural control compared with FOG- under stable surface DT conditions, shown by higher medial-lateral sway measures (group × surface × task, P < .05). Also, postural DT cost (%) was higher in FOG+ than in FOG- in unstable surface conditions without vision. Controls performed better on the cognitive DT when balancing compared with sitting, whereas this improvement was absent in both PD subgroups and more so in FOG+., Conclusions: Postural stability in FOG+ deteriorated more than in FOG- and controls upon cognitive load. Our results extend earlier findings on gait that the compensatory mechanisms to cope with DT stance are insufficient in FOG+. The findings highlight the need for adapted rehabilitation programs for this subgroup, comprising motor-cognitive balance training.

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstrated to be isoform-selective (PT18 and hTau56) or phospho-selective (PT84). Evaluation of the antibodies in cellular- and in vivo seeding assays revealed clear differences in maximal efficacy. Limited proteolysis experiments support the hypothesis that some epitopes are more exposed than others in the tau seeds. Moreover, antibody efficacy seems to depend on the structural properties of fibrils purified from tau Tg mice- and postmortem human AD brain.

Postural instability and freezing of gait (FOG) are key features of Parkinson's disease (PD) that are closely related to falls. Uncovering the postural control differences between individuals with and without FOG contributes to our understanding of the relationship between these phenomena. The objective of this meta-analysis was to investigate whether postural control deficits, as detected by clinical balance scales, were more apparent in FOG+ compared to FOG-. Furthermore, we aimed to identify whether different scales were equally sensitive to detect postural control deficits and whether medication affected postural control differentially in each subgroup. Relevant articles were identified via five electronic databases. We performed a meta-analysis on nine studies which reported clinical balance scale scores in 249 freezers and 321 non-freezers. Methodological analysis showed that in 5/9 studies disease duration differed between subgroups. Despite this drawback, postural control was found to be significantly worse in FOG+ compared to FOG-. All included clinical balance scales were found to be sufficiently sensitive to detect the postural control differences. Levodopa did not differentially affect postural control (p=0.21), as in both medication states FOG+ had worse postural stability than FOG-. However, this finding warrants a cautious interpretation given the limitations of the studies included. From subscore analysis, we found that reactive and dynamic postural control were the most affected postural control systems in FOG+. We conclude that our findings provide important evidence for pronounced postural instability in individuals with FOG, which can be easily picked up with clinical evaluation tools. Posturographic measures in well-matched subgroups are needed to highlight the exact nature of these deficits., (Copyright © 2017 Elsevier B.V. All rights reserved.)