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Avacopan is currently approved in several regions of the world as an oral treatment in combination with standard therapy, including glucocorticoids, for adult patients with severe active antineutrophil cytoplasmic autoantibody‐associated vasculitis. In vitro and clinical studies have established that avacopan is primarily eliminated through cytochrome P450 3A4 metabolism. This Phase 1, open‐label, single‐dose study (ClinicalTrials.gov identifier: NCT06004934) was conducted to evaluate the effect of mild (n = 8) or moderate (n = 8) hepatic impairment compared with normal hepatic function (n = 8) on the pharmacokinetics, safety, and tolerability of a single oral dose of 30 mg of avacopan in patients without active antineutrophil cytoplasmic autoantibody‐associated vasculitis. Relative to participants with normal hepatic function, in participants with mild or moderate hepatic impairment, the avacopan area under the plasma concentration‐time curve from time 0 to infinity geometric mean ratios (90% confidence intervals) were 1.3 (0.9‐2.0) and 1.1 (0.6‐2.0), respectively, and the avacopan maximum plasma concentration geometric mean ratios (90% CIs) were 1.0 (0.8‐1.3) and 0.8 (0.6‐1.1), respectively. The geometric mean ratios of metabolite M1 also revealed no pharmacokinetically relevant increase in the peak exposure of M1 in participants with mild or moderate hepatic impairment. Thus, no avacopan dosage adjustment is necessary for patients with mild or moderate hepatic impairment.

Electroactive microbes that can release or take up electrons are essential components of nearly every ecological niche and are powerful tools for the development of alternative energy technologies. Small-molecule mediators are critical for this electron transfer but remain difficult to study and engineer because they perform concerted two-electron transfer in native systems but only individual, one-electron transfers in electrochemical studies. Here, we report that electrode modification with ion- and electron-conductive polymers yields biosimilar, concerted two-electron transfer from Shewanella oneidensisvia flavin mediators. S. oneidensisbiofilms on these polymers show significantly improved per-microbe current generation and morphologies that more closely resemble native systems, setting a new paradigm for the study and optimization of these electron transfer processes. The unprecedented concerted electron transfer was found to be due to altered mediator electron transfer thermodynamics, enabling biologically relevant studies of electroactive biofilms in the lab for the first time. These important findings pave the way for a complete understanding of the ecological role of electroactive microbes and their broad application in sustainable technologies.

Physical-product firms (manufacturers) face a number of major challenges when they adopt agile for new-product development. Typically, manufacturers embed agile methods into the stages of their stage-and-gate process to yield a hybrid model; they also modify agile methods to suit their company and industry. But major questions and challenges still remain. For example, where and when to use Agile–Stage-Gate—for which projects and which stages? A tougher issue is how to make investment decisions—the go/no go decisions at gates—when everything from the product definition to the project plan is changing. Solutions from leading firms are offered. Other challenges highlighted include how to get the product right when requirements are constantly changing; how to organize for agile, which demands dedicated collocated teams, which are not practical for most manufacturers; the inconsistency between the traditional longer term project planning versus agile's two-week sprint plans; and how to scale up agile to larger programs. Actions for implementation suggested by leading firms are outlined.

Proteins are exposed to hydrostatic pressure (HP) in a variety of ecosystems as well as in processing steps such as freeze–thaw, cell disruption, sterilization, and homogenization, yet pressure effects on protein–protein interactions (PPIs) remain underexplored. With the goal of contributing toward the expanded use of HP as a fundamental control parameter in protein research, processing, and engineering, small-angle X-ray scattering was used to examine the effects of HP and ionic strength on ovalbumin, a model protein. Based on an extensive data set, we develop an empirical method for scaling PPIs to a master curve by combining HP and osmotic effects. We define an effective pressure parameter that has been shown to successfully apply to other model protein data available in the literature, with deviations evident for proteins that do not follow the apparent Hofmeister series. The limitations of the empirical scaling are discussed in the context of the hypothesized underlying mechanisms.

The outcome of patients with COVID‐19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID‐19 over several waves. Patients with both SSc and COVID‐19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID‐19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc‐specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied. A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID‐19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P< 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P< 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P =0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P =0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment. The outcome of patients with both SSc and COVID‐19 improved significantly over time because of intrinsic and extrinsic factors.

A lack of knowledge of the heating systems used by electricity consumers impedes distribution system operators in developing a sound grid upgrade plan and estimating potential demand flexibility from these consumers. The large-scale rollout of smart meters for electricity consumers provides an excellent opportunity to identify end users’ heating types. This paper proposed a hierarchically structured deep-learning framework for identifying heating types of individual electricity consumers. The main contributions of the paper are: (a) We propose an effective framework based on long short-term memory (LSTM) that offers an effective automatic feature learning from sequential electricity consumption data and weather conditions. (b) We apply the proposed deep-learning architecture for household heating type classification which is among the first few successful reports on this application. We evaluate the performance using hourly measurement data collected over four years from one and two-family dwellings with either district heating, exhaust air heat pumps or direct electric heating as the heating type. Good performance was shown from the test results using the proposed framework, with an average test accuracy of 94.2%. Comparisons with four existing machine learning algorithms using hand-crafted features and a single-layer LSTM-based deep-learning algorithm have shown marked improvement of the proposed method.

Introduction: Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. Methods: Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30 mg once daily (QD), adalimumab (ADA) 40 mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. Results: A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30 mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5 years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1–4.3 and 1.7–5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15 mg and UPA 30 mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30 mg QD, respectively. Conclusions: The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Juvenile systemic sclerosis (SSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed, but clearly defining appropriate outcomes is necessary if successful therapies are to be developed. Our objective here was to propose such outcomes. This proposal is the result of 4 face‐to‐face consensus meetings with a 27‐member multidisciplinary team of pediatric rheumatologists, adult rheumatologists, dermatologists, pediatric cardiologists, pulmonologists, gastroenterologists, a statistician, and patients. Throughout the process, we reviewed the existing adult data in this field, the more limited pediatric literature for juvenile SSc outcomes, and data from 2 juvenile SSc patient cohorts to assist in making informed, data‐driven decisions. The use of items for each domain as an outcome measure in an open label 12‐month clinical trial of juvenile SSc was voted and agreed upon using a nominal group technique. After voting, the domains agreed on were global disease activity, skin, Raynaud's phenomenon, digital ulcers, musculoskeletal, cardiac, pulmonary, renal, and gastrointestinal involvement, and quality of life. Fourteen outcome measures had 100% agreement, 1 item had 91% agreement, and 1 item had 86% agreement. The domains of biomarkers and growth/development were moved to the research agenda. We reached consensus on multiple domains and items that should be assessed in an open label, 12‐month clinical juvenile SSc trial as well as a research agenda for future development.

Phononic materials exhibit mechanical properties that alter the propagation of acoustic waves and are widely useful for metamaterials. To fabricate acoustic materials with phononic bandgaps, colloidal nanoparticles and their assemblies allow access to various crystallinities in the submicrometer scale. We fabricated anisotropic crystals with dumbbell-shaped nanoparticles via field-directed self-assembly. Brillouin light spectroscopy detected the formation of direction-dependent hypersonic phononic bandgaps that scale with the lattice parameters. In addition, the local resonances of the constituent nanoparticles enable metamaterial behavior by opening hybridization gaps in disordered structures. Unexpectedly, this bandgap frequency is robust to changes in the dumbbell aspect ratio. Overall, this study provides a structure–property relationship for designing anisotropic phononic materials with targeted phononic bandgaps.

ABSTRACTObjectiveThe purpose of the current study was to develop and evaluate a brief screening instrument for ME/CFS. The current study identified 4 symptom items that identify those positive for the IOM ME/CFS case definition.Study DesignA data set of over 2,000 patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and over 350 controls were assessed for the 4-item DePaul Symptom Questionnaire-Brief (DSQ-Brief). All respondents also completed the longer 54-item DePaul Symptom Questionnaire (DSQ-1) as well as the 14-item DePaul Symptom Questionnaire-Short Form (DSQ-SF). These data sets were collected from multiple countries. We also examined the DSQ-Brief, DSQ-1, and DSQ-SF with other chronic illness groups [Multiple Sclerosis (MS) and Post-Polio Syndrome (PPS)] and those with Long COVID. Random Forest comparisons were employed in these analyses.ResultsWhen contrasting ME/CFS from controls, high levels of accuracy occurred using the DSQ-1, DSQ-SF, and DSQ-Brief. High accuracy again occurred for differentiating those with ME/CFS from MS, PPS, and Long COVID using the DSQ-1 and DSQ-SF, but accuracy was less for the DSQ-Brief.ConclusionsThe DSQ-Brief had high sensitivity, meaning it could identify those with ME/CFS versus controls, whereas accuracy dropped with other chronic illnesses. However, it was possible to achieve better accuracy and identify those cases where misidentification occurred by administering the DSQ-SF or DSQ-1 following the DSQ-Brief. It is now possible to screen individuals for ME/CFS using the DSQ-Brief and in so doing, identify those who are most likely to have ME/CFS.

Introduction: Heart involvement is a common problem in systemic sclerosis. Recently, a definition of systemic sclerosis primary heart involvement had been proposed. Our aim was to establish consensus guidance on the screening, diagnosis and follow-up of systemic sclerosis primary heart involvement patients.Methods: A systematic literature review was performed to investigate the tests used to evaluate heart involvement in systemic sclerosis. The extracted data were categorized into relevant domains (conventional radiology, electrocardiography, echocardiography, cardiac magnetic resonance imaging, laboratory, and others) and presented to experts and one patient research partner, who discussed the data and added their opinion. This led to the formulation of overarching principles and guidance statements, then reviewed and voted on for agreement. Consensus was attained when the mean agreement was ⩾7/10 and of ⩾70% of voters.Results: Among 2650 publications, 168 met eligibility criteria; the data extracted were discussed over three meetings. Seven overarching principles and 10 guidance points were created, revised and voted on. The consensus highlighted the importance of patient counseling, differential diagnosis and multidisciplinary team management, as well as defining screening and diagnostic approaches. The initial core evaluation should integrate history, physical examination, rest electrocardiography, trans-thoracic echocardiography and standard serum cardiac biomarkers. Further investigations should be individually tailored and decided through a multidisciplinary management. The overall mean agreement was 9.1/10, with mean 93% of experts voting above 7/10.Conclusion: This consensus-based guidance on screening, diagnosis and follow-up of systemic sclerosis primary heart involvement provides a foundation for standard of care and future feasibility studies that are ongoing to support its application in clinical practice.

Here we highlight 35 (+1) global researchers approximately under the age of 35. The annual cohort was self-generated by initial seed invitations sent by the editorial team, with each contributor inviting the next in a self-selecting unrestricted (nominally supervised) manner. The final collection is an inspiring look at the challenges the current generation of materials researchers are tackling, demonstrating the interdisciplinarity of materials science.

•High-resolution typing at HLA-A, -B, -C, and -DRB1 should be standard practice when selecting units for double UCBT.•UCB units with a maximum of 3 allele mismatches should be selected for double UCBT adult candidates with hematologic malignancies.

Objectives: Systemic sclerosis often has a significant impact on an individual’s quality of life. Life satisfaction is a subjective expression of well-being and a key component of quality of life. We examined the associations between functional limitations, social support, and spiritual well-being with life satisfaction and investigated the moderating roles of social support and spiritual well-being on the relationship between functional limitations and life satisfaction in people with systemic sclerosis.Methods: Data were drawn from the baseline University of California Los Angeles Scleroderma Quality of Life Study. Participants completed questionnaires that included demographics, depressive symptoms, functional limitations, social support, and spiritual well-being. The Satisfaction with Life Scale was used to evaluate overall life satisfaction. Data were analyzed using a hierarchical linear regression.Results: Of 206 participants (84% female, 74% White, 52% limited cutaneous subtype, 51% early disease), 38% reported being dissatisfied with their lives. Functional limitations (β = −0.19, p= 0.006), social support (β = 0.18, p= 0.006), and spiritual well-being (β = 0.40, p< 0.001) were associated with life satisfaction, with spiritual well-being emerging as the strongest statistical contributor. However, social support and spiritual well-being did not significantly moderate the relationship between functional limitations and life satisfaction (p= 0.882 and p= 0.339, respectively).Conclusion: Spiritual well-being is particularly important in understanding life satisfaction in people with systemic sclerosis. Future longitudinal research is needed to assess and examine spiritual well-being and its impact on life satisfaction in a larger and more diverse systemic sclerosis sample.

The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to update the current guidelines, and the objective here was to produce this document to guide clinicians managing children with juvenile idiopathic arthritis–associated uveitis (JIAU) and idiopathic chronic anterior uveitis (CAU). The group analyzed the literature published between December 2014 and June 2020 after a systematic literature review conducted by 2 clinicians. Pediatric rheumatologists were paired with ophthalmologists to review the eligible 37 publications. The search criteria were selected to reflect those used for the 2018 Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, in order to provide an update, rather than a replacement for that publication. The summary of the current evidence for each SHARE recommendation was presented to the expert committee. These recommendations were then discussed and revised during a video consensus meeting on January 22, 2021, with 14 voting participants, using a nominal group technique to reach consensus. JIAU treatment was extended to include CAU. Fourteen recommendations regarding treatment of JIAU und CAU with >90% agreement were accepted. An update to the previous 2018 SHARE recommendations for the treatment of children with JIAU with the addition of CAU was created using an evidence‐based consensus process. This guideline should help support clinicians to care for children and young people with CAU.

Modification of electrodes with biomolecules is an essential first step for the development of bioelectrochemical systems, which are used in a variety of applications ranging from sensors to fuel cells. Gold is often used because of its ease of modification with thiolated biomolecules, but carbon screen-printed electrodes (SPEs) are gaining popularity due to their low cost and fabrication from abundant resources. However, their effective modification with biomolecules remains a challenge; the majority of work to-date relies on nonspecific adhesion or broad amide bond formation to chemical handles on the electrode surface. By combining facile electrochemical modification to add an aniline handle to electrodes with a specific and biocompatible oxidative coupling reaction, we can readily modify carbon electrodes with a variety of biomolecules. Importantly, both proteins and DNA maintain bioactive conformations following coupling. We have then used biomolecule-modified electrodes to generate microbial monolayers through DNA-directed immobilization. This work provides an easy, general strategy to modify inexpensive carbon electrodes, significantly expanding their potential as bioelectrochemical systems.

Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons. Assuming that data were missing at random, mixed‐effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal‐like, inflammatory, and fibroproliferative signatures) were also studied. Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by –3.70/year for CYC (P= 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long‐term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal‐like subset (n = 22), superiority of HSCT was less apparent. Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term.

Surgical simulators are safe and evolving educational tools for developing surgical skills. In particular, virtual and hybrid simulators are preferred due to their detailedness, customization and evaluation capabilities. To accelerate the revolution of a novel class of hybrid simulators, a Smart Artificial Soft Tissue is presented here, that determines the relative position of conductive surgical instruments in artificial soft tissue by inverse resistance mappings without the need for a fixed reference point. This is particularly beneficial for highly deformable structures when specific target regions need to be reached or avoided. The carbon-black-silicone composite used can be shaped almost arbitrarily and its elasticity can be tuned by modifying the silicone base material. Thus, objective positional feedback for haptically correct artificial soft tissue can be ensured. This is demonstrated by the development of a laryngeal phantom to simulate the implantation of laryngeal pacemaker electrodes. Apart from the position-detecting larynx phantom, the simulator uses a tablet computer for the virtual representation of the vocal folds' movements, in accordance with the electrical stimulation by the inserted electrodes. The possibility of displaying additional information about target regions and anatomy is intended to optimize the learning progress and illustrates the extensibility of hybrid surgical simulators.

A challenging opportunity in structural health monitoring of composite materials is using machine learning (ML) methods to classify acoustic emissions according to the damage mechanism that emitted the signal. A wide variety of ML frameworks have been developed; however, lack of ground truth datasets in addition to limited overlap between experimental configurations has precluded any direct, quantitative benchmarking of their accuracy. Here, we generate a ground truth dataset comprised of pencil lead breaks with known angles of incidence, θ. Each angle generates a unique frequency spectrum that changes continuously with θ, which could be analogous to attributes of acoustic emission signals generated from failure processes, such as those that occur in composites. Five frameworks are then applied to the ground truth dataset and benchmarked according to their ability to discriminate between two sets of signals with a fixed Δθ. A discussion of their performance as related to choice of features is given, and a set of guidelines for best-practices for feature selection and standardized practices are proposed.

Seeking to get the best of both worlds, leading manufacturers have borrowed agile development from the software world and integrated it with their Stage-Gate method. Typically, physical-product firms adopt some but not all elements of agile and embed them into the stages of their familiar gating process to replace the traditional product management methods. The resulting hybrid Agile–Stage-Gate (A-SG) model delivers very positive performance results: faster response to change, higher customer satisfaction, and increased team motivation. Based on the input from leading firms, the article describes a consensus A-SG model that physical-product firms have crafted, including a number of major differences from the “pure agile” model. Observations and suggestions from experienced A-SG users are summarized. Agile is a new way of working based on a unique mindset; thus, a physical-product version of the agile principles is also presented. But no system is perfect, and pitfalls to watch out for are identified and summarized for manufacturers.

Donor selection may contribute to improve clinical outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy). Impact of second-degree related donor (SRD) was not fully elucidated in this platform. We retrospectively compared the outcome of patients receiving Haplo-SCT either from a SRD (n= 31) or a first-degree related donor (FRD, n= 957). Median time to neutrophil and platelet recovery did not differ between a SRD and a FRD transplant (p= 0.599 and 0.587). Cumulative incidence of grade II–IV acute graft-versus host disease (GVHD) and moderate-severe chronic GVHD was 13% and 19% after SRD vs 24% (p= 0.126) and 13% (p= 0.395) after FRD transplant. One-year cumulative incidence of non-relapse mortality (NRM) was 19% for SRD and 20% for FRD (p= 0.435) cohort. The 3-year probability of overall survival (OS) and progression-free survival (PFS) was 42% vs 55% (p= 0.273) and 49% vs 35% (p= 0.280) after SRD and FRD transplant, respectively. After propensity score adjustment or matched pair analysis, the outcome of patients receiving Haplo-SCT from a SRD or a FRD did not differ in terms of NRM, OS, PFS, acute and chronic GVHD. Our results suggest that a SRD is a viable option for Haplo-SCT with PT-Cy when a FRD is not available.

Aquatic athletes not only face common headache etiologies similar to the general population and land-based athletes but also experience their own unique pathology. Posture, aquatic pressure, equipment, and even marine animals pose as unique causes to head pain in the aquatic athlete. Common head pain pathologies seen in the aquatic athlete include tension-type headaches, migraines, cluster headaches, and compressive headaches, including supraorbital neuralgia. Creating a thorough but focused differential diagnosis for head pain in the aquatic athlete can be a difficult and overwhelming task for some. We review both the common and not-so-common etiologies of head pain in the aquatic athlete and suggest a simple framework for assessment and treatment to diagnose and treat head pain in this specific population.