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We present electrical resistivity (ρ) and AC magnetic susceptibility measurements on Ge-doped single crystals of the NFL compound YbRh2Si2. Upon producing the volume expansion (ΔV≃+0.3%) necessary to tune this material to its QCP, the low-temperature ρ(T) data of YbRh2(Si0.95Ge0.05)2 are found to follow ρ(T)=ρ0+bT over three decades in temperature. We compare the effect of ΔV to that produced by the application of hydrostatic pressure, and show that the linear temperature dependence is intrinsic to the proximity to the QCP and not due to disorder induced by Ge-alloying. [Copyright &y& Elsevier]

Abstract Background In many countries, the need for physical therapists to use standardised measures has been recognised and is recommended in clinical practice guidelines. Research has shown a lack of clinimetric knowledge and clinical application of measurement instruments in daily practice may hamper implementation of these guidelines. Objectives The aims of our study were a) to investigate the current use of measurement instruments by Dutch physical therapists; b) to investigate the facilitators and barriers in using measurement instruments. Methods To get a complete and valid overview of relevant barriers and facilitators, different methods of data collection were used. We conducted a literature search, semi-structured interviews with 20 physical therapists and an online survey. Results Facilitators are the fact that most therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. The most important barriers to the use of measurement instruments included physical therapists' competence and problems in changing behaviour, practice organisation (no room; no time) and the unavailability and feasibility of measurement instruments. Furthermore, physical therapists indicated the need to have a core set of measurement instruments with a short user's instruction on application, scoring and interpretation. Conclusions The main barriers are on the level of the physical therapist (lack of knowledge; not focusing on the use of outcome measures) and organisation (lack of time; availability; lack of management support). There seems to be a disparity between what physical therapists say and what they do. The majority of participating physical therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. However, the main problem for physical therapists is when to use which instrument for what patient (lack of knowledge). Furthermore, physical therapists indicated a need to compile a core set of measurement instruments with instructions concerning application, scoring and interpretation. Based on the identified factors, a number of strategies will be developed and evaluated in future studies.

Many current research efforts in strongly correlated systems focus on the interplay between magnetism and superconductivity. Here we report on coexistence of both cooperative ordered states in recently discovered stoichiometric and fully inversion symmetric heavy fermion compound Ce3PdIn11 at ambient pressure. Thermodynamic and transport measurements reveal two successive magnetic transitions at T1 = 1.67 K and TN = 1.53 K into antiferromagnetic type of ordered states. Below Tc = 0.42 K the compound enters a superconducting state. The large initial slope of dBc2/dT ≈ - 8.6 T/K indicates that heavy quasiparticles form the Cooper pairs. The origin of the two magnetic transitions and the coexistence of magnetism and superconductivity is briefly discussed in the context of the coexistence of the two inequivalent Ce-sublattices in the unit cell of Ce3PdIn11 with different Kondo couplings to the conduction electrons. [ABSTRACT FROM AUTHOR]

Abstract Background Clinical guidelines are considered important instruments to improve quality in health care. Since 1998 the Royal Dutch Society for Physical Therapy (KNGF) produced evidence-based clinical guidelines, based on a standardized program. New developments in the field of guideline research raised the need to evaluate and update the KNGF guideline program. Purpose of this study is to compare different guideline development programs and review the KNGF guideline program for physical therapy in the Netherlands, in order to update the program. Method Six international guideline development programs were selected, and the 23 criteria of the AGREE Instrument were used to evaluate the guideline programs. Information about the programs was retrieved from published handbooks of the organizations. Also, the Dutch program for guideline development in physical therapy was evaluated using the AGREE criteria. Further comparison the six guideline programs was carried out using the following elements of the guideline development processes: Structure and organization; Preparation and initiation; Development; Validation; Dissemination and implementation; Evaluation and update. Results Compliance with the AGREE criteria of the guideline programs was high. Four programs addressed 22 AGREE criteria, and two programs addressed 20 AGREE criteria. The previous Dutch program for guideline development in physical therapy lacked in compliance with the AGREE criteria, meeting only 13 criteria. Further comparison showed that all guideline programs perform systematic literature searches to identify the available evidence. Recommendations are formulated and graded, based on evidence and other relevant factors. It is not clear how decisions in the development process are made. In particular, the process of translating evidence into practice recommendations can be improved. Conclusion As a result of international developments and consensus, the described processes for developing clinical practice guidelines have much in common. The AGREE criteria are common basis for the development of guidelines, although it is not clear how final decisions are made. Detailed comparison of the different guideline programs was used for updating the Dutch program. As a result the updated KNGF program complied with 22 AGREE criteria. International discussion is continuing and will be used for further improvement of the program.

Introduction: Neointima formation and vascular remodelling through vascular smooth muscle cell (VSMC) migration and proliferation can limit the long term success of coronary interventions, for example in coronary artery bypass grafting (CABG). Gene therapy may provide a novel treatment strategy to improve long-term patency rates and reduce the need for repeat surgery. CABG surgery is potentially suitable for gene therapy as it allows ex vivo treatment of the vein before grafting. Therapeutic gene delivery to endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) using recombinant adenovirus (Ad) 5 can successfully reduce pathological remodelling in experimental animal models. However, the Ad5 receptor coxsackie adenovirus receptor (CAR) is only expressed at low levels on vascular cells. Additionally, the common prevalence of neutralising antibodies against Ad5 in humans may limit the efficacy of Ad5 based gene therapy, although this requires testing in the clinical setting. Thus, alternative Ad serotypes may provide more efficient vascular gene transfer with lower neutralising antibody titer, thereby improving the prospect of effective gene therapy. Here we investigate the potential of Ad49, a novel species D adenovirus, as a vector for vascular gene delivery.Methods and Results: Transduction of primary human VSMCs and ECs with Ad49 was 4 fold higher than Ad5 (p<0.001) and 30 fold higher than Ad35 (p<0.0001) when infected with 1000 viral particles per cell. Ad49 could also transduce HVSMCs more efficiently than Ad5 following a short exposure time <60 minutes. Ex vivo incubation of whole mouse aorta with Ad49GFP resulted in transduction of endothelial cells seen by co-localisation of GFP and CD31 immunohistochemistry. Similarly, luminal infusion of Ad49GFP into intact human saphenous vein ex vivo also resulted in endothelial cell transduction. The Ad49 receptor is unidentified however, blocking CAR, CD46 and removal of sialic acid, classical candidate adenovirus receptors, did not alter Ad49 transduction. Importantly serum neutralisation studies in 103 patient serum samples from Glasgow cardiovascular clinics found Ad5 neutralisation rates were high (40/103) but no pre-existing immunity to Ad49 was observed.In conclusion, we demonstrate that Ad49 efficiently transduces vascular cells in vitro and ex vivo in intact tissue and may provide a new vector for vascular gene therapy. [ABSTRACT FROM PUBLISHER]

Background: The Ad26.COV2.S vaccine was highly effective against severe-critical coronavirus disease 2019 (Covid-19), hospitalization, and death in the primary phase 3 efficacy analysis.Methods: We conducted the final analysis in the double-blind phase of our multinational, randomized, placebo-controlled trial, in which adults were assigned in a 1:1 ratio to receive single-dose Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Safety and key secondary and exploratory end points were also assessed.Results: Median follow-up in this analysis was 4 months; 8940 participants had at least 6 months of follow-up. In the per-protocol population (39,185 participants), vaccine efficacy against moderate to severe-critical Covid-19 at least 14 days after administration was 56.3% (95% confidence interval [CI], 51.3 to 60.8; 484 cases in the vaccine group vs. 1067 in the placebo group); at least 28 days after administration, vaccine efficacy was 52.9% (95% CI, 47.1 to 58.1; 433 cases in the vaccine group vs. 883 in the placebo group). Efficacy in the United States, primarily against the reference strain (B.1.D614G) and the B.1.1.7 (alpha) variant, was 69.7% (95% CI, 60.7 to 76.9); efficacy was reduced elsewhere against the P.1 (gamma), C.37 (lambda), and B.1.621 (mu) variants. Efficacy was 74.6% (95% CI, 64.7 to 82.1) against severe-critical Covid-19 (with only 4 severe-critical cases caused by the B.1.617.2 [delta] variant), 75.6% (95% CI, 54.3 to 88.0) against Covid-19 leading to medical intervention (including hospitalization), and 82.8% (95% CI, 40.5 to 96.8) against Covid-19-related death, with protection lasting 6 months or longer. Efficacy against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was 41.7% (95% CI, 36.3 to 46.7). Ad26.COV2.S was associated with mainly mild-to-moderate adverse events, and no new safety concerns were identified.Conclusions: A single dose of Ad26.COV2.S provided 52.9% protection against moderate to severe-critical Covid-19. Protection varied according to variant; higher protection was observed against severe Covid-19, medical intervention, and death than against other end points and lasted for 6 months or longer. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.). [ABSTRACT FROM AUTHOR]

Background: Bowel dysfunction after rectal cancer surgery is common, with some experiencing low anterior resection syndrome (LARS) is common after rectal cancer surgery. This study examined if transanal total mesorectal excision (TaTME) has a similar risk of LARS and altered quality of life (QoL) as patients who undergo low anterior resection (LAR). Methods: Patients who underwent TaTME or traditionally approached total mesorectal excision in a prospective colorectal cancer cohort study (2014-2019) were propensity score matched in a 1 : 1 ratio. LARS and QoL scores were assessed before and after surgery with a primary endpoint of major LARS at 12 months analysed for possible association between factors by logistic regression. Results: Of 61 TaTME and 317 LAR patients eligible, 55 from each group were propensity score matched. Higher LARS scores (30.6 versus 25.4, P=0.010) and more major LARS (65 versus 42 per cent, P=0.013; OR 2.64, 95 per cent c.i. 1.22 to 5.71) were reported after TaTME. Additionally, QoL score differences (body image, bowel frequency, and embarrassment) were worse in the TaTME group. Conclusions: TaTME may be associated with more severe bowel dysfunction than traditional approaches to rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial disease is a rare, hereditary disease with a heterogeneous clinical presentation. However, fatigue is a common and burdensome complaint in children and adolescents with mitochondrial disease. No psychological intervention targeting fatigue exists for paediatric patients with a mitochondrial disease. We designed the PowerMe intervention, a blended cognitive behaviour therapy targeting fatigue in children and adolescents with mitochondrial disease. The aim of the intervention is to reduce perceived fatigue by targeting fatigue-related cognitions and behaviours.Methods: A multiple baseline single case experiment will be conducted in five children (8-12 years old) and 5 adolescents (12-18 years old) with mitochondrial disease and severe fatigue. Patients will be included in the study for 33 weeks, answering weekly questions about the fatigue. Patients will be randomly assigned a baseline period of 5 to 9 weeks before starting the PowerMe intervention. The intervention consists of face-to-face and online sessions with a therapist and a website with information and assignments. The treatment will be tailored to the individual. Each patient will work on their personalized treatment plan focusing on personally relevant goals. The primary outcome is perceived fatigue. Secondary outcomes are quality of life, school presence and physical functioning.Discussion: The results of the PowerMe study will provide information on the efficacy of a blended cognitive behaviour therapy on reducing perceived fatigue and its impact on daily life in children and adolescents with mitochondrial disease. Strengths and limitations of the study design are discussed.Trial Registration: Dutch Trial Register NTR 7675. Registered on 17 December 2018. Identifier https://www.trialregister.nl/trial/7433. [ABSTRACT FROM AUTHOR]

Abstract: The cage compound Ce3Pd20Si6 has recently been shown to undergo two successive low-temperature phase transitions which are strongly affected by an applied magnetic field. Here we show that, as the lower, probably antiferromagnetic transition is suppressed to zero in a field slightly above 1T, the electrical resistivity shows a non-Fermi-liquid-like linear-in-T temperature dependence while it follows the usual Fermi liquid temperature dependence both at smaller and larger fields. This suggests that a field-induced quantum critical point exists in Ce3Pd20Si6. [Copyright &y& Elsevier]

We report on single crystal growth and crystallographic parameters results of Ce2PdIn8, Ce3PdIn11, Ce2PtIn8 and Ce3PtIn11. The Pt-systems Ce2PtIn8 and Ce3PtIn11 are synthesized for the first time. All these compounds are member of Ce n T m In3n+2m (n=1, 2,..; m=1, 2,.. and T= transition metal) to which the extensively studied heavy fermion superconductor CeCoIn5 belongs. Single crystals have been grown by an In self-flux method. Differential scanning calorimetry studies were used to derive optimal growth conditions. Evidently, the maximum growth conditions for these materials should not exceed 750°C. Single crystal x-ray data show that Ce2 TIn8 compounds crystallize in the tetragonal Ho2CoGa8 phase (space group P4/mmm) with lattice parameters a=4.6898(3)Å and c=12.1490(8)Å for Pt-based one (Pd: a=4.6881(4)Å and c=12.2031(8)Å). Ce3 TIn11 compounds adopt Ce3PdIn11 structure with a=4.6874(4)Å and c=16.8422(12)Å for Pt-based one (Pd: a=4.6896Å and c=16.891Å). Specific heat experiments on Ce3PtIn11 and Ce3PdIn11 have revealed that both compounds undergo two successive magnetic transitions at T 1 ~2.2K followed by T N ~2.0K and T 1 ~1.7K and T N ~1.5K, respectively. In addition, both compounds exhibit enhanced Sommerfeld coefficients yielding γ Pt=0.300J/molK2 Ce (γ Pd=0.29J/molK2 Ce), hence qualifying them as heavy fermion materials. [ABSTRACT FROM AUTHOR]

Ex vivo gene therapy during coronary artery bypass grafting (CABG) holds great potential to prevent excessive smooth muscle cell (SMC) proliferation, neointima formation and graft failure. The most successful preclinical strategies to date have utilised vectors based on the species C adenovirus, Ad5, which engages the Coxsackie and Adenovirus receptor (CAR) as its primary attachment receptor. Profiling receptors on human SMCs demonstrated the absence of CAR but substantial expression of the species B receptor CD46. We performed transduction experiments using Ad5 and the CD46-utilising adenovirus Ad35, and found Ad35 significantly more efficient at transducing SMCs. To evaluate whether transduction could be further augmented, we evaluated chimeric CD46-utilising Ad5/Ad35 vectors comprising the Ad5 capsid pseudotyped with the Ad35 fibre alone (Ad5/F35) or in combination with the Ad35 penton (Ad5/F35/P35). In human smooth muscle cells (hSMCs), Ad5/F35/P35 mediated significantly higher levels of transduction than either parental vector or Ad5/F35. Ex vivo transduction experiments using mouse aortas from CD46 transgenics demonstrated that Ad5/F35/P35 was significantly more efficient at transducing SMCs than the other vectors tested. Finally, ex vivo transduction and immunofluorescent colocalisation experiments using human tissue from CABG procedures confirmed the preclinical potential of Ad5/F35/P35 as an efficient vector for vascular transduction during CABG. [ABSTRACT FROM AUTHOR]

We present a combined experimental and theoretical study of the structure and the lattice dynamics in the complex metallic alloy Mg2Zn11, by means of neutron and x-ray scattering, as well as ab initio and empirical potential calculations. Mg2Zn11 can be seen as an intermediate step in structural complexity between the simple Laves-phase MgZn2 on one side, and the complex 1/1 approximants and quasicrystals ZnMgAl and Zn(Mg)Sc on the other. The structure can be described as a cubic packing of a triacontahedron whose center is partially occupied by a Zn atom. This partially occupied site turned out to play a major role in understanding the lattice dynamics. Data from inelastic neutron scattering evidence a Van Hove singularity in the vibrational spectrum of Mg2Zn11 for an energy as low as 4.5 meV, which is a unique feature for a nearly-close-packed metallic alloy. This corresponds to a gap opening at the Brillouin zone boundary and an interaction between a low-lying optical branch and an acoustic one, as could be deduced from the dispersion relation measured by inelastic x-ray scattering. Second, the measured phonon density of states exhibits many maxima, indicating strong mode interactions across the whole energy range. The origin of the low-energy modes in Mg2Zn11 and other features of the vibrational spectra are studied, using both ab initio and empirical potential calculations. A detailed analysis of vibrational eigenmodes is presented, linking features in the vibrational spectrum to atomic motions within structural building blocks. [ABSTRACT FROM AUTHOR]

Abstract: Reverse genetics, the generation of influenza viruses from cDNA, presents a rapid method for creating vaccine strains. The technique necessitates the use of cultured cells. Due to technical and regulatory requirements, the choice of cell lines for production of human influenza vaccines is limited. PER.C6® cells, among the most extensively characterized and documented cells, support growth of all influenza viruses tested to date, and can be grown to high densities in large bioreactors in the absence of serum or micro carriers. Here, the suitability of these cells for the generation of influenza viruses by reverse genetics was investigated. A range of viruses reflective of vaccine strains was rescued exclusively using PER.C6 cells by various transfection methods, including an animal component-free procedure. Furthermore, a whole inactivated vaccine carrying the HA and NA segments of A/HK/156/97 (H5N1) that was both rescued from and propagated on PER.C6 cells, conferred protection in a mouse model. Thus PER.C6 cells provide an attractive platform for generation of influenza vaccine strains via reverse genetics. [Copyright &y& Elsevier]

Abstract: The presence of replication-competent adenovirus (RCA) is a safety concern for biologics based on recombinant adenoviruses and RCA testing is therefore mandatory for release of clinical material. RCA, which arises from homologous recombination between Ad5 vectors and HEK-293 cells, can be eliminated by the use of PER.C6 cells in combination with a matched vector. However, little is known on RCA formation with vectors based on adenovirus serotypes other than Ad5 and reliable RCA assays to test them are generally lacking. Here we report on the development and qualification of a sensitive RCA assay for Ad35, a promising alternative to Ad5 vectors. The assay is able to detect 1 RCA in 3×1010 vector particles with 95% confidence, thus meeting current FDA requirements, and can discriminate between RCA and other rare CPE-causing entities, including helper dependent E1 positive particles (HDEP). Using this assay, the first batches of Ad35 vectors produced in PER.C6 cells were analysed and found to be free of RCA and HDEP. Based on the statistical model used, we anticipate that our approach to RCA assay development can be broadly applicable to other adenoviral vectors. [Copyright &y& Elsevier]

A new U-based compound of the U 2 Rh 2 Pb, a new compound of the U 2 T 2 X series (T – transition metal, X – Sn, In, Pb), was prepared in a single-crystal form. Its structure was determined as belonging to the tetragonal Mo 2 FeB 2 structure type with the shortest U–U spacing along the c -axis. The crystals were subjected to study of magnetic, specific heat, and electrical resistivity in various magnetic fields. U 2 Rh 2 Pb undergoes an antiferromagnetic transition at a Néel temperature T N of 20 K and exhibits an enhanced Sommerfeld coefficient γ ≈ 150 mJ/molK2. In contrast to the two rhodium analogues U 2 Rh 2 In and U 2 Rh 2 Sn, the easy-magnetization direction is the c- axis with rather low value of the critical field H c = 4.3 T of the metamagnetic transition of a spin-flip type. The observed dependences of T N and H c on temperature and magnetic field have been used for constructing a magnetic phase diagram. The experimental observations are mostly supported by first-principles calculations. We have prepared single crystals of a new compound U2Rh2Pb. Our research represents first single crystals study of lead compound in the U2T2X series. Figure shows the magnetic phase diagram of U2Rh2Pb. Antiferromagnet U2Rh2Pb is unique by unusual easy magnetization direction, the lowest value of the magnetic field inducing metamagnetic transition combined with very simple magnetic phase diagram. Image 1 [ABSTRACT FROM AUTHOR]

Many current research efforts in strongly correlated systems focus on the interplay between magnetism and superconductivity. Here we report on coexistence of both cooperative ordered states in recently discovered stoichiometric and fully inversion symmetric heavy fermion compound Ce3PdIn11 at ambient pressure. Thermodynamic and transport measurements reveal two successive magnetic transitions at T1 = 1.67 K and TN = 1.53 K into antiferromagnetic type of ordered states. Below Tc = 0.42 K the compound enters a superconducting state. The large initial slope of dBc2/dT ≈ - 8.6 T/K indicates that heavy quasiparticles form the Cooper pairs. The origin of the two magnetic transitions and the coexistence of magnetism and superconductivity is briefly discussed in the context of the coexistence of the two inequivalent Ce-sublattices in the unit cell of Ce3PdIn11 with different Kondo couplings to the conduction electrons. [ABSTRACT FROM AUTHOR]

The properties of the heavy-fermion superconductor Ce3PtIn11 are investigated by thermodynamic and transport measurements at ambient and under hydrostatic pressure. At ambient pressure the compound exhibits two successive magnetic transitions at T1≃2.2 K and TN≃2 K into antiferromagnetically ordered states and enters into a heavy-fermion superconducting phase below Tc≃0.32 K. The coexistence of long-range magnetic order and superconductivity is discussed in the context of the existence of the two crystallographically inequivalent Ce sites in the unit cell of Ce3PtIn11. The experimental data allow us to construct the pressure-temperature phase diagram. [ABSTRACT FROM AUTHOR]

Newly approved subunit and mRNA vaccines for respiratory syncytial virus (RSV) demonstrate effectiveness in preventing severe disease, with protection exceeding 80% primarily through the generation of antibodies. An alternative vaccine platform called self-amplifying RNA (saRNA) holds promise in eliciting humoral and cellular immune responses. We evaluate the immunogenicity of a lipid nanoparticle (LNP)-formulated saRNA vaccine called SMARRT.RSV.preF, encoding a stabilized form of the RSV fusion protein, in female mice and in non-human primates (NHPs) that are either RSV-naïve or previously infected. Intramuscular vaccination with SMARRT.RSV.preF vaccine induces RSV neutralizing antibodies and cellular responses in naïve mice and NHPs. Importantly, a single dose of the vaccine in RSV pre-exposed NHPs elicits a dose-dependent anamnestic humoral immune response comparable to a subunit RSV preF vaccine. Notably, SMARRT.RSV.preF immunization significantly increases polyfunctional RSV.F specific memory CD4 + and CD8 + T-cells compared to RSV.preF protein vaccine. Twenty-four hours post immunization with SMARRT.RSV.preF, there is a dose-dependent increase in the systemic levels of inflammatory and chemotactic cytokines associated with the type I interferon response in NHPs, which is not observed with the protein vaccine. We identify a cluster of analytes including IL-15, TNFα, CCL4, and CXCL10, whose levels are significantly correlated with each other after SMARRT.RSV.preF immunization. These findings suggest saRNA vaccines have the potential to be developed as a prophylactic RSV vaccine based on innate, cellular, and humoral immune profiles they elicit., Competing Interests: Competing interests The authors declare the following competing interests: A.V., R.V., R.G., Y.J., S.K., M.V.K., S.J., S.B., M.B., H.V.D., H.K., J.R.V., A.B., L.N., S.R., B.J., J.A., J.S., T.R.G., H.S., J.C., and R.Z., are or were employees of Janssen Vaccines & Prevention B.V. or of Johnson & Johnson Innovative Medicine while engaged in the research project. These authors held or still hold stock in Johnson & Johnson. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: COVID-19 vaccines have been widely used to control the SARS-CoV-2 pandemic. In individuals receiving replication-incompetent, adenovirus vector-based COVID-19 vaccines (eg, ChAdOx1 nCoV-19 [AstraZeneca] or Ad26.COV2.S [Johnson & Johnson/Janssen] vaccines), a very rare but serious adverse reaction has been reported and described as vaccine-induced immune thrombotic thrombocytopenia (VITT). The exact mechanism of VITT following Ad26.COV2.S vaccination is under investigation. Antibodies directed against human platelet factor 4 (PF4) are considered critical in the pathogenesis of VITT, suggesting similarities with heparin-induced thrombocytopenia. It has been postulated that components of these vaccines mimic the role of heparin by binding to PF4, triggering production of these anti-PF4 antibodies., Objectives: This study aimed to investigate the potential interaction between human PF4 and Ad26.COV2.S vaccine using several biophysical techniques., Methods: Direct interaction of PF4 with Ad26.COV2.S vaccine was investigated using dynamic light scattering, biolayer interferometry, and surface plasmon resonance. For both biosensing methods, the Ad26.COV2.S vaccine was immobilized to the sensor surface and PF4 was used as analyte., Results: No direct interactions between PF4 and Ad26.COV2.S vaccine could be detected using dynamic light scattering and biolayer interferometry. Surface plasmon resonance technology was shown to be unsuitable to investigate these types of interactions., Conclusion: Our findings make it very unlikely that direct binding of PF4 to Ad26.COV2.S vaccine or components thereof is driving the onset of VITT, although the occurrence of such interactions after immunization (potentially facilitated by unknown plasma or cellular factors) cannot be excluded. Further research is warranted to improve the understanding of the full mechanism of this adverse reaction., Competing Interests: Declaration of competing interests R.B. is a co-inventor on related vaccine patents. M.v.d.N.K., H.I., J.M.M., N.v.D., M.P., E.K., D.v.M., J.C., and R.B. are employees of Janssen Vaccines & Prevention B.V. M.v.d.N.K., N.v.D., D.v.M., J.V., J.C., and R.B. hold stock of Johnson & Johnson. C.P.-P., J.C.d.S.F., and J.V. are former employees of Janssen Vaccines & Prevention B.V., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the psychosocial outcomes of facial weakness in facioscapulohumeral muscular dystrophy (FSHD)., Materials and Methods: A cross-sectional survey study. The severity of facial weakness was assessed by patients (self-reported degree of facial weakness) and by physicians (part I FSHD clinical score). Questionnaires on facial function, psychosocial well-being, functioning, pain, and fatigue were completed. Regression analyses were performed to explain variance in psychosocial outcomes by demographic and disease variables., Results: One hundred and thirty-eight patients participated. They reported mild to moderate psychological distress, no to mild fear of negative evaluation, and moderate to good social functioning. However, patients with severe self-reported facial weakness scored lower in social functioning. Patients with more facial dysfunction experienced more fear of negative evaluation and lower social functioning. Furthermore, younger age, presence of pain, fatigue, walking difficulty, and current or previous psychological support were associated with lower psychosocial outcomes. Overall, patients report moderate to good psychosocial functioning in this study. The factors contributing to lower psychosocial functioning are diverse., Conclusions: A multidisciplinary, personalized approach, focusing on coping with physical, emotional, and social consequences of FSHD is supposed to be helpful. Further research is needed to assess the psychosocial outcomes of facial weakness in younger patients.Implications for rehabilitationResearch on the psychosocial consequences of facial weakness in facioscapulohumeral muscular dystrophy (FSHD) is limited.Patients with FSHD experience mild to moderate psychosocial distress, partly due to overall disease severity, such as reduced mobility, and partly due to facial weakness and reduced facial function.Self-reported degree of facial weakness and facial dysfunction were related to lower psychosocial outcomes (social functioning, fear of negative evaluation, and psychological distress).Physician-reported degree of facial weakness was not related to psychosocial outcomes, suggesting an absence of a strong correlation between observed facial weakness and experienced disease burden in this study.This calls for a multidisciplinary, personalized approach with a focus on coping with physical, emotional, and social consequences of FSHD.

Since the original outbreak of the SARS-CoV-2 virus, several rapidly spreading SARS-CoV-2 variants of concern (VOC) have emerged. Here, we show that a single dose of Ad26.COV2.S (based on the Wuhan-Hu-1 spike variant) protects against the Gamma and Delta variants in naive hamsters, supporting the observed maintained vaccine efficacy in humans against these VOC. Adapted spike-based booster vaccines targeting Omicron variants have now been authorized in the absence of human efficacy data. We evaluated the immunogenicity and efficacy of Ad26.COV2.S.529 (encoding a stabilized Omicron BA.1 spike) in naive mice and in hamsters with pre-existing immunity to the Wuhan-Hu-1 spike. In naive mice, Ad26.COV2.S.529 elicited higher neutralizing antibody titers against SARS-CoV-2 Omicron BA.1 and BA.2, compared with Ad26.COV2.S. However, neutralizing titers against the SARS-CoV-2 B.1 (D614G) and Delta variants were lower after primary vaccination with Ad26.COV2.S.529 compared with Ad26.COV2.S. In contrast, we found comparable Omicron BA.1 and BA.2 neutralizing titers in hamsters with pre-existing Wuhan-Hu-1 spike immunity after vaccination with Ad26.COV2.S, Ad26.COV2.S.529 or a combination of the two vaccines. Moreover, all three vaccine modalities induced equivalent protection against Omicron BA.2 challenge in these animals. Overall, our data suggest that an Omicron BA.1-based booster in rodents does not improve immunogenicity and efficacy against Omicron BA.2 over an Ad26.COV2.S booster in a setting of pre-existing immunity to SARS-CoV-2., (© 2023. The Author(s).)

Objectives: Objectives were to evaluate the sociodemographic and disease-related factors, and coping style associated with social interaction and social appearance anxiety in people with unilateral facial palsy., Methods: Medical data were extracted from electronic health records, and participants completed the Social Interaction Anxiety Scale (SIAS), Social Appearance Anxiety Scale (SAAS), and Coping Orientation to Problems Experienced inventory. Associations of SIAS and SAAS scores with sociodemographic and disease variables, and coping were assessed with multiple linear regression., Results: Among 111 participants (mean age 58.6 years; 59% women), higher age and greater use of emotion-focused coping were associated with lower SIAS scores, whereas greater use of avoidant coping was associated with higher SIAS scores. Higher age, male sex, and greater use of emotion-focused coping were associated with lower SAAS scores, whereas greater use of avoidant coping was associated with higher SAAS scores., Conclusions: Healthcare providers should understand that women and younger people are more likely to have social appearance concerns and that this is not predicted by the objective severity of facial palsy., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Human adenovirus type 26 (HAdV26) has been recognized as a promising platform for vaccine vector development, and very recently vaccine against COVID-19 based on HAdV26 was authorized for emergency use. Nevertheless, basic biology of this virus, namely, pathway which HAdV26 uses to enter the cell, is still insufficiently known. We have shown here that HAdV26 infection of human epithelial cells expressing low amount of αvβ3 integrin involves clathrin and is caveolin-1-independent, while HAdV26 infection of cells with high amount of αvβ3 integrin does not involve clathrin but is caveolin-1-dependent. Thus, this study demonstrates that caveolin-1 is limiting factor in αvβ3 integrin-mediated HAdV26 infection. Regardless of αvβ3 integrin expression, HAdV26 infection involves dynamin-2. Our data provide for the first-time description of HAdV26 cell entry pathway, hence increase our knowledge of HAdV26 infection. Knowing that functionality of adenovirus vector is influenced by its cell entry pathway and intracellular trafficking, our results will contribute to better understanding of HAdV26 immunogenicity and antigen presentation when used as vaccine vector. IMPORTANCE In order to fulfill its role as a vector, adenovirus needs to successfully deliver its DNA genome to the host nucleus, a process highly influenced by adenovirus intracellular translocation. Thus, cell entry pathway and intracellular trafficking determine functionality of human adenovirus-based vectors. Endocytosis of HAdV26, currently extensively studied as a vaccine vector, has not been described so far. We present here that HAdV26 infection of human epithelial cells with high expression of αvβ3 integrin, one of the putative HAdV26 receptors, is caveolin-1- and partially dynamin-2-dependent. Since caveolin containing domains provide a unique environment for specific signaling events and participate in inflammatory signaling one can imagine that directing HAdV26 cell entry toward caveolin-1-mediate pathway might play role in immunogenicity of this virus. Therefore, our results contribute to better understanding of HAdV26 infection pathway, hence, can be helpful in explaining induction of immune response and antigen presentation by HAdV26-based vaccine vector.

The low seroprevalent human adenovirus type 26 (HAdV26)-based vaccine vector was the first adenovirus-based vector to receive marketing authorization from European Commission. HAdV26-based vaccine vectors induce durable humoral and cellular immune responses and, as such, represent a highly valuable tool for fighting infectious diseases. Despite well-described immunogenicity in vivo, the basic biology of HAdV26 still needs some refinement. The aim of this study was to determine the pro-inflammatory cytokine profile of epithelial cells infected with HAdV26 and then investigate the underlying molecular mechanism. The expression of studied genes and proteins was assessed by quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Confocal microscopy was used to visualize HAdV26 cell uptake. We found that HAdV26 infection in human epithelial cells triggers the expression of pro-inflammatory cytokines and chemokines, namely IL-6, IL-8, IL-1β, and TNF-α, with the most pronounced difference shown for IL-6. We investigated the underlying molecular mechanism and observed that HAdV26-induced IL-6 gene expression is αvβ3 integrin dependent and NF-κB mediated. Our findings provide new data regarding pro-inflammatory cytokine and chemokine expression in HAdV26-infected epithelial cells, as well as details concerning HAdV26-induced host signaling pathways. Information obtained within this research increases our current knowledge of HAdV26 basic biology and, as such, can contribute to further development of HAdV26-based vaccine vectors.

Objective: To evaluate the short-term psychological consequences of gestational trophoblastic disease (GTD)., Design: A prospective observational multicentre cohort study., Setting: Nationwide in the Netherlands., Population: GTD patients., Methods: Online questionnaires directly after diagnosis., Main Outcome Measures: Hospital Anxiety and Depression Scale (HADS), Distress Thermometer (DT), Impact of Event Scale (IES) and Reproductive Concerns Scale (RCS)., Results: Sixty GTD patients were included between 2017 and 2020. Anxious feelings (47%) were more commonly expressed than depressive feelings (27%). Patients experienced moderate to severe adaptation problems in 88%. Patients who already had children were less concerned about their reproductivity than were patients without children (mean score 10.4 versus 15.0, P = 0.031), and patients with children experienced lower distress levels (IES mean score 25.7 versus 34.7, P = 0.020). In addition, patients with previous pregnancy loss scored lower for distress compared with patients without pregnancy loss (IES mean score 21.1 versus 34.2, P = 0.002)., Discussion: We recommend that physicians monitor physical complaints and the course of psychological wellbeing over time in order to provide personalised supportive care in time for patients who have high levels of distress at baseline., Conclusions: GTD patients experience increased levels of distress, anxiety and depression, suggesting the diagnosis has a substantial effect on the psychological wellbeing of patients. The impact of GTD diagnosis on intrusion and avoidance seems to be ameliorated in patients who have children or who have experienced previous pregnancy loss., Tweetable Abstract: Patients with gestational trophoblastic disease (GTD) experience short-term psychological consequences such as distress, anxiety and depression, suggesting that the diagnosis GTD has a substantial effect on the psychological wellbeing of patients. Various patient characteristics affect the impact of GTD diagnosis., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose: To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors., Methods: Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors., Results: The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3-8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1-0.8)., Conclusion: Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment., (© 2021. The Author(s).)

Preexisting immune responses toward adenoviral vectors limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest in vectorizing novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full-genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton base, which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor-binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver, and spleen and triggered robust inflammatory immune responses. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination. IMPORTANCE Adenoviral vectors are under investigation for a broad range of therapeutic indications in diverse fields, such as oncology and gene therapy, as well as for vaccination both for human and veterinary use. A wealth of data shows that preexisting immune responses may limit the use of a vector. Particularly in the current climate of global pandemic, there is a need to expand the toolbox with novel adenoviral vectors for vaccine development. Our data demonstrate that we have successfully vectorized a novel adenovirus type candidate with low seroprevalence. The cell transduction data and antigen-specific immune responses induced in vivo demonstrate that this vector is highly promising for the development of gene therapy and vaccine products.

Safe and effective coronavirus disease-19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged nonhuman primates (NHPs). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared with a single dose. In one-dose regimens, neutralizing antibody responses were stable for at least 14 wk, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and T helper cell (Th cell) 1-skewed cellular responses in aged NHPs that were comparable to those in adult animals. Aged Ad26.COV2.S-vaccinated animals challenged 3 mo after dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. Neutralization of variants of concern by NHP sera was reduced for B.1.351 lineages while maintained for the B.1.1.7 lineage independent of Ad26.COV2.S vaccine regimen., Competing Interests: Disclosures: M.R.M. Baert, Y. Choi, J. Custers, D.N. Czapska-Casey, A.H. de Wilde, J. Drijver, J. Huizingh, M. Jongeneelen, K. Kaszas, E. Kourkouta, H. Kuipers, L. Muchene, R. Roozendaal, S.K. Rosendahl Huber, L. Solforosi, J.T.B.M. Tolboom, J.E.M. van der Lubbe, R. van der Vlugt, M. van Heerden, E. van Huizen, J. Vaneman, D. Veldman, J. Vreugdenhil, and R. Zahn are employees of Janssen Pharmaceutical Companies of Johnson & Johnson. D.H. Barouch reports grants from Janssen during the conduct of the study; grants from NIH, HJF/WRAIR, BMGF, DARPA, Gilead, Intima, Alkermes, CureVac, South Africa MRC, amfAR, Ragon Institute, MassCPR, Sanofi, Legend, and Zentalis; and personal fees from SQZ Biotech outside the submitted work. In addition, D.H. Barouch has a patent to COVID-19 vaccines licensed (Janssen). H. Schuitemaker reports "other" from Department of Health and Human Services BARDA (HHS0100201700018C) during the conduct of the study; and personal fees from Johnson & Johnson and Janssen Vaccines & Prevention B.V. outside the submitted work. F. Wegmann reports a patent to company pending and is an employee of Janssen Pharmaceutical Companies of Johnson & Johnson. No other disclosures were reported., (© 2021 Solforosi et al.)

Replication-incompetent adenoviral vectors have been under investigation as a platform to carry a variety of transgenes, and express them as a basis for vaccine development. A replication-incompetent adenoviral vector based on human adenovirus type 26 (Ad26) has been evaluated in several clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and features of recombinant viral vector vaccines. This paper reviews features of the Ad26 vectors, including tabulation of safety and risk assessment characteristics of Ad26-based vaccines. In the Ad26 vector, deletion of E1 gene rendering the vector replication incompetent is combined with additional genetic engineering for vaccine manufacturability and transgene expression optimization. These vaccines can be manufactured in mammalian cell lines at scale providing an effective, flexible system for high-yield manufacturing. Ad26 vector vaccines have favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the Ad26 vaccine safety database version 4.0, with unblinded data from 23 ongoing and completed clinical studies for 3912 participants in five different Ad26-based vaccine programs. Overall, Ad26-based vaccines have been well tolerated, with no significant safety issues identified. Evaluation of Ad26-based vaccines is continuing, with >114,000 participants vaccinated as of 4th September 2020. Extensive evaluation of immunogenicity in humans shows strong, durable humoral and cellular immune responses. Clinical trials have not revealed impact of pre-existing immunity to Ad26 on vaccine immunogenicity, even in the presence of Ad26 neutralizing antibody titers or Ad26-targeting T cell responses at baseline. The first Ad26-based vaccine, against Ebola virus, received marketing authorization from EC on 1st July 2020, as part of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. New developments based on Ad26 vectors are underway, including a COVID-19 vaccine, which is currently in phase 3 of clinical evaluation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Brighton Collaboration V3SWG authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Jerome Custers, Maarten Leyssen, Frank Tomaka, Esther Heijnen, Georgi Shukarev, Dirk Heerwegh, Roy van Heesbeen, Hanneke Schuitemaker, and Macaya Douoguih, are current employees of Janssen Pharmaceuticals and potentially hold stock in J&J., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death 1-4 . Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters 5-7 and nonhuman primates 8-10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates 11-13 . Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.

Follow-up after curative treatment for colorectal cancer (CRC) puts pressure on outpatient services due to the growing number of CRC survivors. The aim of this state-of-the-art review was to evaluate setting, manner and provider of follow-up. Moreover, perceptions of CRC survivors and health care providers regarding standard and alternative follow-up were examined. After a comprehensive literature search of the PubMed database, 69 articles were included reporting on CRC follow-up in the hospital, primary care and home setting. Hospital-based follow-up is most common and has been provided by surgeons, medical oncologists, and gastroenterologists, as well as nurses. Primary care-based follow-up has been provided by general practitioners or nurses. Even though most hospital- or primary care-based follow-up care requires patients to visit the clinic, telephone-based care has proven to be a feasible alternative. Most patients perceived follow-up as positive; valuing screening and detection for disease recurrence and appreciating support for physical and psychosocial symptoms. Hospital-based follow-up performed by the medical specialist or nurse is highly preferred by patients and health care providers. However, willingness of both patients and health care providers for alternative, primary care or remote follow-up exists. Nurse-led and GP-led follow-up have proven to be cost-effective alternatives compared to specialist-led follow-up. If proven safe and acceptable, remote follow-up can become a cost-effective alternative. To decrease the personal and financial burden of follow-up for a growing number of colorectal cancer survivors, a more acceptable, flexible and dynamic care follow-up mode consisting of enhanced communication and role definitions among clinicians is warranted., Competing Interests: Declaration of competing interest No potential conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic 1-8 . For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes 9,10 . The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

Development of effective preventative interventions against SARS-CoV-2, the etiologic agent of COVID-19 is urgently needed. The viral surface spike (S) protein of SARS-CoV-2 is a key target for prophylactic measures as it is critical for the viral replication cycle and the primary target of neutralizing antibodies. We evaluated design elements previously shown for other coronavirus S protein-based vaccines to be successful, e.g., prefusion-stabilizing substitutions and heterologous signal peptides, for selection of a S-based SARS-CoV-2 vaccine candidate. In vitro characterization demonstrated that the introduction of stabilizing substitutions (i.e., furin cleavage site mutations and two consecutive prolines in the hinge region of S2) increased the ratio of neutralizing versus non-neutralizing antibody binding, suggestive for a prefusion conformation of the S protein. Furthermore, the wild-type signal peptide was best suited for the correct cleavage needed for a natively folded protein. These observations translated into superior immunogenicity in mice where the Ad26 vector encoding for a membrane-bound stabilized S protein with a wild-type signal peptide elicited potent neutralizing humoral immunity and cellular immunity that was polarized towards Th1 IFN-γ. This optimized Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in a phase I clinical trial (ClinicalTrials.gov Identifier: NCT04436276)., Competing Interests: Competing interestsThe authors declare no competing financial interests. R.B., L.R., M.J.G.B., F.W., D.Z., and J.P.L. are co-inventors on related vaccine patents. R.B., L.R., J.E.M.vd.L., M.J.G.B., G.H., F.W., D.Z., A.H.d.W., A.K., A.V., D.v.M., T.K., R.V., J.V., J.P.M.L., R.C.Z, J.C., and H.S. are employees of Janssen Vaccines & Prevention BV. R.B., L.R., F.W., D.Z., D.v.M., T.K., R.V., J.V., J.P.M.L., R.C.Z, J.C., and H.S. hold stock of Johnson & Johnson., (© The Author(s) 2020.)

A loss of physical functioning (i.e., a low physical capacity and/or a low physical activity) is a common feature in patients with chronic obstructive pulmonary disease (COPD). To date, the primary care physiotherapy and specialized pulmonary rehabilitation are clearly underused, and limited to patients with a moderate to very severe degree of airflow limitation (GOLD stage 2 or higher). However, improved referral rates are a necessity to lower the burden for patients with COPD and for society. Therefore, a multidisciplinary group of healthcare professionals and scientists proposes a new model for referral of patients with COPD to the right type of exercise-based care, irrespective of the degree of airflow limitation. Indeed, disease instability (recent hospitalization, yes/no), the burden of disease (no/low, mild/moderate or high), physical capacity (low or preserved) and physical activity (low or preserved) need to be used to allocate patients to one of the six distinct patient profiles. Patients with profile 1 or 2 will not be referred for physiotherapy; patients with profiles 3-5 will be referred for primary care physiotherapy; and patients with profile 6 will be referred for screening for specialized pulmonary rehabilitation. The proposed Dutch model has the intention to get the right patient with COPD allocated to the right type of exercise-based care and at the right moment.

There is an ongoing dispute in the community about the absence of a magnetic quantum critical point (QCP) in the noncentrosymmetric heavy fermion compound CeRhSi 3 . In order to explore this question we prepared single crystals of CeRh(Si 1- x Ge x ) 3 with x = 0.05 and 0.15 and determined the temperature-pressure ( T - p ) phase diagram by means of measurements of the electrical resistivity. The substitution of isoelectronic but large Ge enforces a lattice volume increase resulting in a weakening of the Kondo interaction. As a result, the x = 0.05 and x = 0.15 compound exhibit a transition into the antiferromagnetic (AFM) at higher temperatures being T N = 4.7 K and T N1 = 19.7 K, respectively. Application of pressure suppresses T N ( T N1 ) monotonically and pressure induced superconductivity is observed in both Ge-substituted compounds above p ⩾ 2.16 GPa ( x = 0.05) and p ⩾ 2.93 GPa ( x = 0.15). Extrapolation of T N ( p ) → 0 of CeRh(Si 0.95 Ge 0.05 ) 3 yields a critical pressure of p c ≈ 3.4 GPa (in CeRh(Si 0.85 Ge 0.15 ) 3   p c ≈ 3.5 GPa) pointing to the presence of an AFM QCP located deep inside the superconducting state., (© 2020 IOP Publishing Ltd.)