Dysanapsis is not associated with exertional dyspnoea in healthy male and female never-smokers aged 40 years and older.

In healthy adults, airway-to-lung (i.e., dysanapsis) ratio is lower and dyspnoea during exercise at a given minute ventilation (V̇E) is higher in females than in males. We investigated the relationship between dysanapsis and sex on exertional dyspnoea in healthy adults. We hypothesized that females would have a smaller airway-to-lung ratio than males and that exertional dyspnoea would be associated with airway-to-lung ratio in males and females. We analyzed data from n = 100 healthy never-smokers aged ≥40 years enrolled in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study who underwent pulmonary function testing, a chest computed tomography scan, and cardiopulmonary exercise testing. The luminal area of the trachea, right main bronchus, left main bronchus, right upper lobe, bronchus intermedius, left upper lobe, and left lower lobe were 22%-37% smaller (all p < 0.001) and the airway-to-lung ratio (i.e., average large conducting airway diameter relative to total lung capacity) was lower in females than in males (0.609 ± 0.070 vs. 0.674 ± 0.082; p < 0.001). During exercise, there was a significant effect of V̇E, sex, and their interaction on dyspnoea (all p < 0.05), indicating that dyspnoea increased as a function of V̇E to a greater extent in females than in males. However, after adjusting for age and total lung capacity, there were no significant associations between airway-to-lung ratio and measures of exertional dyspnoea, regardless of sex (all r < 0.34; all p > 0.05). Our findings suggest that sex differences in airway size do not contribute to sex differences in exertional dyspnoea.

Understanding repertoire sequencing data through a multiscale computational model of the germinal center.

Sequencing of B-cell and T-cell immune receptor repertoires helps us to understand the adaptive immune response, although it only provides information about the clonotypes (lineages) and their frequencies and not about, for example, their affinity or antigen (Ag) specificity. To further characterize the identified clones, usually with special attention to the particularly abundant ones (dominant), additional time-consuming or expensive experiments are generally required. Here, we present an extension of a multiscale model of the germinal center (GC) that we previously developed to gain more insight in B-cell repertoires. We compare the extent that these simulated repertoires deviate from experimental repertoires established from single GCs, blood, or tissue. Our simulations show that there is a limited correlation between clonal abundance and affinity and that there is large affinity variability among same-ancestor (same-clone) subclones. Our simulations suggest that low-abundance clones and subclones, might also be of interest since they may have high affinity for the Ag. We show that the fraction of plasma cells (PCs) with high B-cell receptor (BcR) mRNA content in the GC does not significantly affect the number of dominant clones derived from single GCs by sequencing BcR mRNAs. Results from these simulations guide data interpretation and the design of follow-up experiments.

Thermal tolerance of two Diptera that pollinate thermogenic plants.

Pollinating insects can be exposed to temperatures far from ambient air when visiting flowers, reducing their warming tolerance. Typically, such scenario occurs when flowers are exposed to solar radiation. The case of thermogenic flowers is particular because they warm up even when they are not exposed to solar energy. The flowers of Arum attract their pollinators with a deceptive method and trap them for a whole day, thereby imposing elevated temperature to visiting insects. Therefore, we predict a relatively high basal thermal tolerance in those insects. The aim of this study was to assess the thermal tolerance and warming tolerance of females of two fly species (genus Psychoda) pollinating Arum sp. (thermogenic plant). We measured their critical temperature (CTmax) and its response to rate of temperature increase as well as acclimation period to moderate temperature of 25 °C. We found relatively low CTmax (33.7 °C on average) for both species, and a weak response to acclimation period and ramping rate. In general, the thermal tolerance increased with a rapid ramping in temperature. To evaluate the warming tolerance, we compared thermal tolerance limits to flower temperatures measured in the field. We highlighted that the temperature of the thermogenic floral organ could reach values close to the thermal tolerance threshold of pollinators. This discovery raises questions about the sustainability of the interaction between these thermogenic plants and their pollinators.

From affinity selection to kinetic selection in Germinal Centre modelling.

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC. To investigate the GC selection bias towards rapid and tight binding, we developed an agent-based model of GC and compared the evolution of founder B cells with initially identical low affinities but with different association/dissociation rates for Ag presented by follicular dendritic cells in three Ag collection mechanisms. We compared an Ag collection mechanism based on association/dissociation rates of B-cell interaction with presented Ag, which includes a probabilistic rupture of bonds between the B-cell and Ag (Scenario-1) with a reference scenario based on an affinity-based Ag collection mechanism (Scenario-0). Simulations showed that the mechanism of Ag collection affects the GC dynamics and the GC outputs concerning fast/slow (un)binding of B cells to FDC-presented Ags. In particular, clones with lower dissociation rates outcompete clones with higher association rates in Scenario-1, while remaining B cells from clones with higher association rates reach higher affinities. Accordingly, plasma cell and memory B cell populations were biased towards B-cell clones with lower dissociation rates. Without such probabilistic ruptures during the Ag extraction process (Scenario-2), the selective advantage for clones with very low dissociation rates diminished, and the affinity maturation level of all clones decreased to the reference level.

Decreased Passive Immunity to Respiratory Viruses through Human Milk during the COVID-19 Pandemic.

Infants may develop severe viral respiratory tract infections because their immune system is still developing in the first months after birth. Human milk provides passive humoral immunity during the first months of life. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to the preventative measures resulting in reduced maternal exposure. Therefore, we hypothesized that this might result in lower antibody levels in human milk during the pandemic and, subsequently, decreased protection of infants against viral respiratory tract infections. We assessed antibody levels against respiratory syncytial virus (RSV), Influenza virus, and several seasonal coronaviruses in different periods of the COVID-19 pandemic in serum and human milk using a Luminex assay. IgG levels against RSV, Influenza, HCoV-OC43, HCoV-HKU1, and HCoV-NL63 in human milk were reduced with a factor of 1.7 (P < 0.001), 2.2 (P < 0.01), 2.6 (P < 0.05), 1.4 (P < 0.01), and 2.1 (P < 0.001), respectively, since the introduction of the COVID-19 restrictions. Furthermore, we observed that human milk of mothers that experienced COVID-19 contained increased levels of IgG and IgA binding to other respiratory viruses. Passive immunity via human milk against common respiratory viruses was reduced during the COVID-19 pandemic, which may have consequences for the protection of breastfed infants against respiratory infections. IMPORTANCE Passive immunity derived from antibodies in human milk is important for protecting young infants against invading viruses. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to preventative measures. In this study, we observed a decrease in human milk antibody levels against common respiratory viruses several months into the COVID-19 pandemic. This waning of antibody levels might partially explain the previously observed surge of hospitalizations of infants, mostly due to RSV, when preventative hygiene measures were lifted. Knowledge of the association between preventative measures, antibody levels in human milk and subsequent passive immunity in infants might help predict infant hospital admissions and thereby enables anticipation to prevent capacity issues. Additionally, it is important in the consideration for strategies for future lockdowns to best prevent possible consequences for vulnerable infants.

A self-portrait: Design opportunities for a tool that supports children's involvement in brain-related health care.

INTRODUCTION: Paediatric patients with disorders that involve brain functioning are particularly vulnerable with respect to including them in shared decision-making. Current tools are mostly paper or digital patient information. We lay the groundwork for improving engagement with a concept that we coined 'the Self-Portrait'. The main goals were to identify (1) obstacles and (2) design parameters that enable patient participation. METHODS: A research-through-design approach was utilized in nine patients with brain-related disorders (4-12 years), 15 parents and 15 medical professionals, involving contextual research (interviews and observations) within the paediatric hospital and patients' homes and codesign. Sensitizing materials and early instances of design solutions were deployed as catalysts for communication. Five rounds of enriched interviews and design reviews were thematically analysed to answer the research questions. RESULTS: Obstacles to child involvement were related to children's level of understanding, the time and energy necessary for information processing and lack of perceived relevance of the information. Patients' engagement is supported by design features that extend the time frame of interaction beyond the consultation, transfer information interactively and give control and influence during the consultation. CONCLUSION: Obstacles were detected that complicate child engagement, which differ between stakeholders. Promising design features were identified that have the potential to play an important role in enabling active child involvement. These findings show that applying principles of human-centred design research and codesign can bring together patients, parents and medical professionals around a tool that provides a shared language and focus, which are prerequisites to increase child engagement. PATIENT OR PUBLIC CONTRIBUTION: Patients, parents and clinicians contributed as design informants during contextual research and design reviews. Clinicians provided feedback on the initial outcomes of thematic analysis. Two researchers assisted in consensus sessions during the thematic analysis.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing.

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine-chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self-optimization tools.

Applying an Oleophobic/Hydrophobic Fluorinated Polymer Monolayer Coating from Aqueous Solutions.

Despite major advancements in the fabrication of low-surface-energy surfaces, the environmental consequences of their fabrication can be a serious issue, particularly in an industrial context. This is especially the case for fluorine-based coatings, which often require fluorinated solvents for their processing and applications. These solvents are not only detrimental to the ozone layer but also represent a potential workplace hazard because they tend to bioaccumulate. We describe the design, synthesis, and characterization of a new fluorinated-polymer coating that can be simply applied to surfaces from an aqueous environment using a dip-coating technique. This was made possible by copolymerizing three different methacrylate monomers, each serving a specific function. Namely, fluorinated methacrylate providing oleo/hydrophobicity, photocleavable polyethylene glycol (PEG) methacrylate promoting water solubility of the copolymer, and thioether-based methacrylate serving as an anchoring unit to a number of different substrates. This copolymer is initially grafted to the surface as a monolayer from an aqueous solvent, after which the system is treated with ultraviolet (UV) light, cleaving away the protecting PEG moieties to yield an oleo/hydrophobic surface.

Deprescribing Statins and Proton Pump Inhibitors in Nursing Home Residents; a Pragmatic Exploratory Study.

INTRODUCTION: Polypharmacy is common in the frail nursing home population and associated with an increased risk of adverse events, unplanned hospitalizations, and increased all-cause mortality. Deprescribing using a deprescribing algorithm might reduce unnecessary polypharmacy. This exploratory study was performed to determine the effect of this implicit deprescribing algorithm in deprescribing statins and proton pump inhibitors (PPIs) in nursing home residents. METHOD: Multicenter, longitudinal, single-arm exploratory study. All participants received the same deprescribing intervention to identify and deprescribe potentially inappropriate statins and/or PPIs. Residents across 10 nursing homes in the Netherlands were included if they used a statin and/or PPI. Residents in hospices or short-stay wards were excluded. The intervention involved a deprescribing algorithm in which nursing home physicians identified and, if possible, deprescribed potentially inappropriate statins and/or PPIs. RESULTS: Sixty-seven residents participated in the study. At 3 months, deprescribing was successful in 52% of the residents. Six months after the intervention, all these residents still had their medication sustainably deprescribed. CONCLUSION: Based on this study, deprescribing statins and PPIs using an implicit deprescribing algorithm is possible in a considerable number of nursing home residents.

Atmospheric modeling and source reconstruction of radioactive ruthenium from an undeclared major release in 2017.

In October 2017 unusual 106Ru detections across most of Europe prompted the Institut de Radioprotection et de Sûreté Nucléaire (IRSN) to analyze the event in order to locate the origin and identify the magnitude of the release. This paper presents the inverse modeling techniques used during the event to achieve this goal. The method is based on a variational approach and consists of using air concentration measurements with the ldX long-range dispersion model included in the IRSN's C3X operational platform. The method made it possible to quickly identify the southern Urals as the most likely geographical origin of the release. Despite uncertainties regarding the starting date of the release, calculations show that it potentially began on 23 September, while most of the release was emitted on 26 September. Among the nuclear plants identified in the southern Urals, the Mayak complex is that from which the dispersion of the 106Ru plume is most consistent with observations. The reconstructed 106Ru source term from Mayak is ∼250 TBq. In total, it was found that for 72% of the measurements simulated and observed air concentration agreed within a factor of 5. In addition, the simulated deposition of 106Ru agrees with the observed deposition. Outside the southern Urals, the simulations indicate that areas with highest deposition values are located in southern Scandinavia and southeastern Bulgaria and are explained by rainfall events occurring while the plume was passing over.

Natural Genetic Transformation: A Direct Route to Easy Insertion of Chimeric Genes into the Pneumococcal Chromosome.

The ability of Streptococcus pneumoniae (the pneumococcus) to transform is particularly convenient for genome engineering. Several protocols relying on sequential positive and negative selection strategies have been described to create directed markerless modifications, including deletions, insertions, or point mutations. Transformation with DNA fragments carrying long flanking homology sequences is also used to generate mutations without selection but it requires high transformability. Here, we present an optimized version of this method. As an example, we construct a strain harboring a translational fusion ftsZ-mTurquoise at the ftsZ locus. We provide instructions to produce a linear DNA fragment containing the chimeric construction and give details of the conditions to obtain optimal pneumococcal transformation efficiencies.

Increased Cell Traction-Induced Prestress in Dynamically Cultured Microtissues.

Prestress is a phenomenon present in many cardiovascular tissues and has profound implications on their in vivo functionality. For instance, the in vivo mechanical properties are altered by the presence of prestress, and prestress also influences tissue growth and remodeling processes. The development of tissue prestress typically originates from complex growth and remodeling phenomena which yet remain to be elucidated. One particularly interesting mechanism in which prestress develops is by active traction forces generated by cells embedded in the tissue by means of their actin stress fibers. In order to understand how these traction forces influence tissue prestress, many have used microfabricated, high-throughput, micrometer scale setups to culture microtissues which actively generate prestress to specially designed cantilevers. By measuring the displacement of these cantilevers, the prestress response to all kinds of perturbations can be monitored. In the present study, such a microfabricated tissue gauge platform was combined with the commercially available Flexcell system to facilitate dynamic cyclic stretching of microtissues. First, the setup was validated to quantify the dynamic microtissue stretch applied during the experiments. Next, the microtissues were subjected to a dynamic loading regime for 24 h. After this interval, the prestress increased to levels over twice as high compared to static controls. The prestress in these tissues was completely abated when a ROCK-inhibitor was added, showing that the development of this prestress can be completely attributed to the cell-generated traction forces. Finally, after switching the microtissues back to static loading conditions, or when removing the ROCK-inhibitor, prestress magnitudes were restored to original values. These findings show that intrinsic cell-generated prestress is a highly controlled parameter, where the actin stress fibers serve as a mechanostat to regulate this prestress. Since almost all cardiovascular tissues are exposed to a dynamic loading regime, these findings have important implications for the mechanical testing of these tissues, or when designing cardiovascular tissue engineering therapies.

Peripheral nervous system involvement in systemic lupus erythematosus: a retrospective study on prevalence, associated factors and outcome.

BACKGROUND: Despite its potentially significant impact on disease outcome, peripheral nervous system involvement in systemic lupus erythematosus has received little attention. OBJECTIVE: The objective of this study was to assess the prevalence and clinical features of peripheral nervous system involvement in a large cohort of systemic lupus erythematosus patients. METHODS: The records of systemic lupus erythematosus patients examined at two tertiary referral centres over a period of 14 years (from 2000 to 2014) were analyzed. Peripheral nervous system events were ascertained according to the 1999 American College of Rheumatology case definitions and by using an attribution algorithm for neuropsychiatric events. Prevalence of peripheral nervous system in systemic lupus erythematosus and demographic, clinical and laboratory features were assessed. Patients with peripheral nervous system events were compared with a control group of systemic lupus erythematosus patients without peripheral nervous system involvement. RESULTS: In a retrospective cohort of 1224 patients, the overall prevalence of peripheral nervous system involvement was 6.9% (85 patients, 95% confidence interval 0.06-0.08), with 68% of peripheral nervous system events attributable to systemic lupus erythematosus. Polyneuropathy was the most common manifestation observed (38 events, 39.2%), followed by cranial neuropathy in 30 cases (30.9%) and 12 cases of single (12.4%) or multiple (eight events, 8.2%) mononeuritis. The average age of systemic lupus erythematosus onset was significantly higher in patients with peripheral nervous system events than in controls (mean ± standard deviation: 45.9 ± 14.8 vs. 37.1 ± 14.0) and they were more likely to have higher SLEDAI-2K and SLICC/ACR Damage Index scores, as well as hypertension and livedo reticularis. A subgroup analysis of events deemed to be systemic lupus erythematosus-related provided similar results. CONCLUSION: Peripheral nervous system manifestations are a potential complication of systemic lupus erythematosus. Careful neurological assessment should therefore be included in the diagnostic workup of patients with systemic lupus erythematosus, especially in those with later onset and greater damage and disease activity.

Thermoreversible hyaluronan-hydrogel and autologous nucleus pulposus cell delivery regenerates human intervertebral discs in an ex vivo, physiological organ culture model.

Numerous studies show promise for cell-based tissue engineering strategies aiming to repair painful intervertebral disc (IVD) degeneration. However, clinical translation to human IVD repair is slow. In the present study, the regenerative potential of an autologous nucleus pulposus (NP)-cell-seeded thermoresponsive hyaluronic acid hydrogel in human lumbar IVDs was assessed under physiological conditions. First, agarose-encased in vitro constructs were developed, showing greater than 90 % NP cell viability and high proteoglycan deposition within HA-pNIPAM hydrogels following 3 weeks of dynamic loading. Second, a bovine-induced IVD degeneration model was used to optimise and validate T1ρ magnetic resonance imaging (MRI) for detection of changes in proteoglycan content in isolated intact IVDs. Finally, isolated intact human lumbar IVDs were pre-scanned using the established MRI sequence. Then, IVDs were injected with HA-pNIPAM hydrogel alone or autologous NP-cell-seeded. Next, the treated IVDs were cultured under cyclic dynamic loading for 5 weeks. Post-treatment T1ρ values were significantly higher as compared to pre-treatment scans within the same IVD and region of interest. Histological evaluation of treated human IVDs showed that the implanted hydrogel alone accumulated proteoglycans, while those that contained NP cells also displayed neo-matrix-surrounded cells within the gel. The study indicated a clinical potential for repairing early degenerative human IVDs using autologous cells/hydrogel suspensions. This unique IVD culture set-up, combined with the long-term physiological culture of intact human IVDs, allowed for a more clinically relevant evaluation of human tissue repair and regeneration, which otherwise could not be replicated using the available in vitro and in vivo models.

Gene expression polymorphism underpins evasion of host immunity in an asexual lineage of the Irish potato famine pathogen.

BACKGROUND: Outbreaks caused by asexual lineages of fungal and oomycete pathogens are a continuing threat to crops, wild animals and natural ecosystems (Fisher MC, Henk DA, Briggs CJ, Brownstein JS, Madoff LC, McCraw SL, Gurr SJ, Nature 484:186-194, 2012; Kupferschmidt K, Science 337:636-638, 2012). However, the mechanisms underlying genome evolution and phenotypic plasticity in asexual eukaryotic microbes remain poorly understood (Seidl MF, Thomma BP, BioEssays 36:335-345, 2014). Ever since the 19th century Irish famine, the oomycete Phytophthora infestans has caused recurrent outbreaks on potato and tomato crops that have been primarily caused by the successive rise and migration of pandemic asexual lineages (Goodwin SB, Cohen BA, Fry WE, Proc Natl Acad Sci USA 91:11591-11595, 1994; Yoshida K, Burbano HA, Krause J, Thines M, Weigel D, Kamoun S, PLoS Pathog 10:e1004028, 2014; Yoshida K, Schuenemann VJ, Cano LM, Pais M, Mishra B, Sharma R, Lanz C, Martin FN, Kamoun S, Krause J, et al. eLife 2:e00731, 2013; Cooke DEL, Cano LM, Raffaele S, Bain RA, Cooke LR, Etherington GJ, Deahl KL, Farrer RA, Gilroy EM, Goss EM, et al. PLoS Pathog 8:e1002940, 2012). However, the dynamics of genome evolution within these clonal lineages have not been determined. The objective of this study was to use a comparative genomics and transcriptomics approach to determine the molecular mechanisms that underpin phenotypic variation within a clonal lineage of P. infestans. RESULTS: Here, we reveal patterns of genomic and gene expression variation within a P. infestans asexual lineage by comparing strains belonging to the South American EC-1 clone that has dominated Andean populations since the 1990s (Yoshida K, Burbano HA, Krause J, Thines M, Weigel D, Kamoun S, PLoS Pathog 10e1004028, 2014; Yoshida K, Schuenemann VJ, Cano LM, Pais M, Mishra B, Sharma R, Lanz C, Martin FN, Kamoun S, Krause J, et al. eLife 2:e00731, 2013; Delgado RA, Monteros-Altamirano AR, Li Y, Visser RGF, van der Lee TAJ, Vosman B, Plant Pathol 62:1081-1088, 2013; Forbes GA, Escobar XC, Ayala CC, Revelo J, Ordonez ME, Fry BA, Doucett K, Fry WE, Phytopathology 87:375-380, 1997; Oyarzun PJ, Pozo A, Ordonez ME, Doucett K, Forbes GA, Phytopathology 88:265-271, 1998). We detected numerous examples of structural variation, nucleotide polymorphisms and loss of heterozygosity within the EC-1 clone. Remarkably, 17 genes are not expressed in one of the two EC-1 isolates despite apparent absence of sequence polymorphisms. Among these, silencing of an effector gene was associated with evasion of disease resistance conferred by a potato immune receptor. CONCLUSIONS: Our findings highlight the molecular changes underpinning the exceptional genetic and phenotypic plasticity associated with host adaptation in a pandemic clonal lineage of a eukaryotic plant pathogen. We observed that the asexual P. infestans lineage EC-1 can exhibit phenotypic plasticity in the absence of apparent genetic mutations resulting in virulence on a potato carrying the Rpi-vnt1.1 gene. Such variant alleles may be epialleles that arose through epigenetic changes in the underlying genes.

Triggered Metal Ion Release and Oxidation: Ferrocene as a Mechanophore in Polymers.

The introduction of mechanophores into polymers makes it possible to transduce mechanical forces into chemical reactions that can be used to impart functions such as self-healing, catalytic activity, and mechanochromic response. Here, an example of mechanically induced metal ion release from a polymer is reported. Ferrocene (Fc) was incorporated as an iron ion releasing mechanophore into poly(methyl acrylate)s (PMAs) and polyurethanes (PUs). Sonication triggered the preferential cleavage of the polymers at the Fc units over other bonds, as shown by a kinetic study of the molar mass distribution of the cleaved Fc-containing and Fc-free reference polymers. The released and oxidized iron ions can be detected with KSCN to generate the red-colored [Fe(SCN)n (H2 O)6-n )](3-n)+ complex or reacted with K4 [Fe(CN)6 ] to afford Prussian blue.

Decoupling the Effect of Shear Stress and Stretch on Tissue Growth and Remodeling in a Vascular Graft.

The success of cardiovascular tissue engineering (TE) strategies largely depends on the mechanical environment in which cells develop a neotissue through growth and remodeling processes. This mechanical environment is defined by the local scaffold architecture to which cells adhere, that is, the microenvironment, and by external mechanical cues to which cells respond, that is, hemodynamic loading. The hemodynamic environment of early developing blood vessels consists of both shear stress (due to blood flow) and circumferential stretch (due to blood pressure). Experimental platforms that recapitulate this mechanical environment in a controlled and tunable manner are thus critical for investigating cardiovascular TE. In traditional perfusion bioreactors, however, shear stress and stretch are coupled, hampering a clear delineation of their effects on cell and tissue response. In this study, we uniquely designed a bioreactor that independently combines these two types of mechanical cues in eight parallel vascular grafts. The system is computationally and experimentally validated, through finite element analysis and culture of tissue constructs, respectively, to distinguish various levels of shear stress (up to 5 Pa) and cyclic stretch (up to 1.10). To illustrate the usefulness of the system, we investigated the relative contribution of cyclic stretch (1.05 at 0.5 Hz) and shear stress (1 Pa) to tissue development. Both types of hemodynamic loading contributed to cell alignment, but the contribution of shear stress overruled stretch-induced cell proliferation and matrix (i.e., collagen and glycosaminoglycan) production. At a macroscopic level, cyclic stretching led to the most linear stress-stretch response, which was not related to the presence of shear stress. In conclusion, we have developed a bioreactor that is particularly suited to further unravel the interplay between hemodynamics and in situ TE processes. Using the new system, this work highlights the importance of hemodynamic loading to the study of developing vascular tissues.

Early Lupus Project: one-year follow-up of an Italian cohort of patients with systemic lupus erythematosus of recent onset.

Objective To describe the clinical and serological features of a prospectively followed cohort of early diagnosed systemic lupus erythematosus (SLE) patients during a one-year follow-up period. Methods SLE patients with disease duration less than 12 months were consecutively enrolled in a multicentre, prospective study. At study entry and then every 6 months, a large panel of data was recorded. Results Of 260 patients enrolled, 185 had at least 12 months of follow-up; of these, 84.3% were female, 92.4% were Caucasians. Mean diagnostic delay was about 20 months; higher values of European Consensus Lupus Activity Measurement (ECLAM) and of organs/systems involved were both associated with shorter diagnostic delay. Clinical and serological parameters improved after study entry. However, patients' quality of life deteriorated and cardiovascular risk factors significantly increased. About one-third of patients with active disease at study entry went into remission (ECLAM = 0). Negative predictors for remission were: oral ulcers, arthritis, low C4, anti-SSB (Ro) antibodies and therapy with mycophenolate. There was a widespread use of glucocorticoids both at baseline and during follow-up. Conclusion Clinical symptoms and serological parameters improve during the first period after diagnosis. However, patients' quality of life deteriorates. The widespread use of glucocorticoids is probably the reason for the early significant increase of some cardiovascular risk factors.

Musculoskeletal manifestations as determinants of quality of life impairment in patients with systemic lupus erythematosus.

Objective The objective of this study was to identify determinants of health-related quality of life (HRQoL) impairment in patients with systemic lupus erythematosus (SLE). Methods Overall, 101 SLE patients were recruited; 37 healthy subjects and 35 rheumatoid arthritis (RA) patients served as controls. HRQoL was evaluated using three patient reported outcomes (PROs): the Short Form-36 version 2 (SF-36v2) health survey, the fatigue scale version 4 (FACITv4) and the Heath Assessment Questionnaire (HAQ). A large set of demographic and clinical variables, including SLE arthritis subtypes, was evaluated searching for factors independently associated with worse QoL. Multivariate models were applied to identify factors independently associated with outcomes. Bonferroni's corrected p values < 0.05 were considered significant. Results SLE patients showed worse results than healthy controls ( p < 0.01) in all SF-36v2 domains and, with reference to the mental QoL, also than RA patients ( p < 0.01). Jaccoud's deformities, active arthritis, and fibromyalgia were the only factors independently associated with worse results in both physical and mental components summary of the SF-36v2 ( p < 0.01) and FACITv4 fatigue scale ( p < 0.01). Fragility fractures, deformities, and active arthritis negatively affected disability perception measured by the HAQ ( p < 0.01). No statistically significant differences in perceived HRQoL were highlighted between patients with deforming and erosive arthritis. However, they had significantly worse results than patients with non-deforming non-erosive arthritis across all investigated PROs ( p < 0.01). Conclusion In order to limit musculoskeletal manifestations as a source of impaired QoL in SLE patients, therapeutic strategies targeted to successfully manage active arthritis and fibromyalgia and to prevent deforming damage are needed.