Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study.

OBJECTIVES: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER: NCT01500551.

ACT To Sustain: Adoptive Cell Therapy To Sustain Access to Non-Commercialized Genetically Modified Cell Therapies.

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products.

Ca-Based Layered Double Hydroxides for Environmentally Sustainable Carbon Capture.

The process of carbon dioxide capture typically requires a large amount of energy for the separation of carbon dioxide from other gases, which has been a major barrier to the widespread deployment of carbon capture technologies. Innovation of carbon dioxide adsorbents is herein vital for the attainment of a sustainable carbon capture process. In this study, we investigated the electrified synthesis and rejuvenation of calcium-based layered double hydroxides (Ca-based LDHs) as solid adsorbents for CO2. We discovered that the particle morphology and phase purity of the LDHs, along with the presence of secondary phases, can be controlled by tuning the current density during electrodeposition on a porous carbon substrate. The change in phase composition during carbonation and calcination was investigated to unveil the effect of different intercalated anions on the surface basicity and thermal stability of Ca-based LDHs. By decoupling the adsorption of water and CO2, we showed that the adsorbed water largely promoted CO2 adsorption, most likely through a sequential dissolution and reaction pathway. A carbon capture capacity of 4.3 ± 0.5 mmol/g was measured at 30 °C and relative humidity of 40% using 10 vol % CO2 in nitrogen as the feed stream. After CO2 capture occurred, the thermal regeneration step was carried out by directly passing an electric current through the conductive carbon substrate, known as the Joule-heating effect. CO2 was found to start desorbing from the Ca-based LDHs at a temperature as low as 220 °C as opposed to the temperature above 700 °C required for calcium carbonate that forms as part of the Ca-looping capture process. Finally, we evaluated the cumulative energy demand and environmental impact of the LDH-based capture process using a life cycle assessment. We identified the most environmentally concerning step in the process and concluded that the postcombustion CO2 capture using LDH could be advantageous compared with existing technologies.

Formulation and Scale-up of Delamanid Nanoparticles via Emulsification for Oral Tuberculosis Treatment.

Delamanid (DLM) is a hydrophobic small molecule therapeutic used to treat drug-resistant tuberculosis (DR-TB). Due to its hydrophobicity and resulting poor aqueous solubility, formulation strategies such as amorphous solid dispersions (ASDs) have been investigated to enhance its aqueous dissolution kinetics and thereby improve oral bioavailability. However, ASD formulations are susceptible to temperature- and humidity-induced phase separation and recrystallization under harsh storage conditions typically encountered in areas with high tuberculosis incidence. Nanoencapsulation represents an alternative formulation strategy to increase aqueous dissolution kinetics while remaining stable at elevated temperature and humidity. The stabilizer layer coating the nanoparticle drug core limits the formation of large drug domains by diffusion during storage, representing an advantage over ASDs. Initial attempts to form DLM-loaded nanoparticles via precipitation-driven self-assembly were unsuccessful, as the trifluoromethyl and nitro functional groups present on DLM were thought to interfere with surface stabilizer attachment. Therefore, in this work, we investigated the nanoencapsulation of DLM via emulsification, avoiding the formation of a solid drug core and instead keeping DLM dissolved in a dichloromethane dispersed phase during nanoparticle formation. Initial emulsion formulation screening by probe-tip ultrasonication revealed that a 1:1 mass ratio of lecithin and HPMC stabilizers formed 250 nm size-stable emulsion droplets with 40% DLM loading. Scale-up studies were performed to produce nearly identical droplet size distribution at larger scale using high-pressure homogenization, a continuous and industrially scalable technique. The resulting emulsions were spray-dried to form a dried powder, and in vitro dissolution studies showed dramatically enhanced dissolution kinetics compared to both as-received crystalline DLM and micronized crystalline DLM, owing to the increased specific surface area and partially amorphous character of the DLM-loaded nanoparticles. Solid-state NMR and dissolution studies showed good physical stability of the emulsion powders during accelerated stability testing (50 °C/75% RH, open vial).

The Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D) at the Spallation Neutron Source (invited).

The Oak Ridge National Laboratory is planning to build the Second Target Station (STS) at the Spallation Neutron Source (SNS). STS will host a suite of novel instruments that complement the First Target Station's beamline capabilities by offering an increased flux for cold neutrons and a broader wavelength bandwidth. A novel neutron imaging beamline, named the Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D), is among the first eight instruments that will be commissioned at STS as part of the construction project. CUPI2D is designed for a broad range of neutron imaging scientific applications, such as energy storage and conversion (batteries and fuel cells), materials science and engineering (additive manufacturing, superalloys, and archaeometry), nuclear materials (novel cladding materials, nuclear fuel, and moderators), cementitious materials, biology/medical/dental applications (regenerative medicine and cancer), and life sciences (plant-soil interactions and nutrient dynamics). The innovation of this instrument lies in the utilization of a high flux of wavelength-separated cold neutrons to perform real time in situ neutron grating interferometry and Bragg edge imaging-with a wavelength resolution of δλ/λ ≈ 0.3%-simultaneously when required, across a broad range of length and time scales. This manuscript briefly describes the science enabled at CUPI2D based on its unique capabilities. The preliminary beamline performance, a design concept, and future development requirements are also presented.

Algae Pyrolysis in Molten NaOH-Na2CO3 for Hydrogen Production.

Biomass pyrolysis within the alkaline molten salt is attractive due to its ability to achieve high hydrogen yield under relatively mild conditions. However, poor contact between biomass, especially the biomass pellet, and hydroxide during the slow heating process, as well as low reaction temperatures, become key factors limiting the hydrogen production. To address these challenges, fast pyrolysis of the algae pellet in molten NaOH-Na2CO3 was conducted at 550, 650, and 750 °C. Algae were chosen as feedstock for their high photosynthetic efficiency and growth rate, and the concept of coupling molten salt with concentrated solar energy was proposed to address the issue of high energy consumption at high temperatures. At 750 °C, the pollutant gases containing Cl and S were completely removed, and the HCN removal rate reached 44.92%. During the continuous pyrolysis process, after a slight increase, the hydrogen yield remained stable at 71.48 mmol/g-algae and constituted 86.10% of the gas products, and a minimum theoretical hydrogen production efficiency of algae can reach 84.86%. Most importantly, the evolution of physicochemical properties of molten NaOH-Na2CO3 was revealed for the first time. Combined with the conversion characteristics of feedstock and gas products, this study provides practical guidance for large-scale application of molten salt including feedstock, operation parameters, and post-treatment process.

Predictors of quality of life in patients within the first year of commencing haemodialysis based on baseline data from the PIVOTAL trial and associations with the study outcomes.

BACKGROUND: Impaired quality of life is common in patients with end-stage kidney disease. We report the baseline quality of life measures in participants from the PIVOTAL randomized controlled trial and the potential relationship with the primary outcome (all-cause mortality, myocardial infarction, stroke, and heart failure hospitalisation), and associations with key baseline characteristics. METHODS: This was a post hoc analysis of 2141 patients enrolled in the PIVOTAL trial. Quality of life was measured using EQ5D index, Visual Analogue Scale, and the KD-QoL [Physical Component Score and Mental Component Score]. RESULTS: Mean baseline EQ5D index and visual analogue scale scores were 0.68 and 60.7 and 33.7 (Physical Component Score) and 46.0 (Mental Component Score), respectively. Female sex, higher Body Mass Index, diabetes mellitus, history of myocardial infarction, stroke or heart failure were associated with significantly worse EQ5D index and visual analogue scale. Higher C-reactive protein levels and lower transferrin saturation were associated with worse quality of life. Haemoglobin was not an independent predictor of quality of life. A lower transferrin saturation was an independent predictor of worse physical component score. A higher C-reactive protein level was associated with most aspects of worse quality of life. Impaired functional status was associated with mortality. CONCLUSION: Quality of life was impaired in patients starting haemodialysis. A higher C-reactive protein level level was a consistent independent predictor of the majority of worse quality of life. Transferrin saturation ≤ 20% was associated with worse physical component score of quality of life. Baseline quality of life was predictive of all-cause mortality and the primary outcome measure. EUDRACT REGISTRATION NUMBER: 2013-002267-25.

Synthesis and Growth of Green Graphene from Biochar Revealed by Magnetic Properties of Iron Catalyst.

Understanding the mechanism of iron-catalyzed graphitization of biomass is an important step for the large-scale synthesis of green graphene. Although iron is known to be the most active transition metal for the catalytic graphitization of cellulose-derived biochar, the direct effect of the iron molecular structure on the formation of highly graphitic carbon remains elusive. Here, biochar was produced from pyrolysis of iron-impregnated cellulose at three different temperatures (1000, 1400, and 1800 °C). X-ray diffraction, X-ray photoelectron spectroscopy, and magnetic measurements were used to probe changes in biochar nanostructure catalyzed by the inclusion of iron. An increase of pyrolysis temperature led to an increase in the iron particle size and the degree of iron reduction, as well as the formation of larger graphitic carbon crystallite sizes, and these two attributes of iron were seen to positively affect the biochar graphitization usually challenging under 2000 °C.

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.

Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P = .334) or neighborhood opportunity (P = .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P = .006; adjusted hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.3-4.1). There was no difference in hazard of death (P = .545; adjusted HR, 1.2; 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted.

Nano- to Global-Scale Uncertainties in Terrestrial Enhanced Weathering.

Enhanced weathering (EW) is one of the most promising negative emissions technologies urgently needed to limit global warming to at least below 2 °C, a goal recently reaffirmed at the UN Global Climate Change conference (i.e., COP26). EW relies on the accelerated dissolution of crushed silicate rocks applied to soils and is considered a sustainable solution requiring limited technology. While EW has a high theoretical potential of sequestering CO2, research is still needed to provide accurate estimates of carbon (C) sequestration when applying different silicate materials across distinct climates and major soil types in combination with a variety of plants. Here we elaborate on fundamental advances that must be addressed before EW can be extensively adopted. These include identifying the most suitable environmental conditions, improving estimates of field dissolution rates and efficacy of CO2 removal, and identifying alternative sources of silicate materials to meet future EW demands. We conclude with considerations on the necessity of integrated modeling-experimental approaches to better coordinate future field experiments and measurements of CO2 removal, as well as on the importance of seamlessly coordinating EW with cropland and forest management.

An Analysis of Vascular Access Thrombosis Events From the Proactive IV irOn Therapy in hemodiALysis Patients Trial.

Introduction: Treatment of anemia in dialysis patients has been associated with increased risk of vascular access thrombosis (VAT). Proactive IV irOn Therapy in hemodiALysis Patients (PIVOTAL) was a clinical trial of proactive compared with reactive i.v. iron therapy in patients requiring hemodialysis. We analyzed the trial data to determine whether randomized treatment arm, alongside other clinical and laboratory variables, independently associated with VAT. Methods: In PIVOTAL, 2141 adult patients were randomized. The type of vascular access (arteriovenous fistula [AVF], arteriovenous graft [AVG], or central venous catheter [CVC]) was recorded at baseline and every month after randomization. The associations between clinical and laboratory data and first VAT were evaluated in a multivariate analysis. Results: A total of 480 (22.4%) participants experienced VAT in a median of 2.1 years of follow-up. In multivariable analyses, treatment arm (proactive vs. reactive) was not an independent predictor of VAT (hazard ratio [HR] 1.13, P = 0.18). Diabetic kidney disease (HR 1.45, P < 0.001), AVG use (HR 2.29, P < 0.001), digoxin use (HR 2.48, P < 0.001), diuretic use (HR 1.25, P = 0.02), female sex (HR 1.33, P = 0.002), and previous/current smoker (HR 1.47, P = 0.004) were independently associated with a higher risk of VAT. Angiotensin receptor blocker (ARB) use (HR 0.66, P = 0.01) was independently associated with a lower risk of VAT. Conclusion: In PIVOTAL, VAT occurred in nearly 1 quarter of participants in a median of just >2 years. In this post hoc analysis, randomization to proactive i.v. iron treatment arms did not increase the risk of VAT.

Postpartum management of perineal injury - A critical narrative review of level 1 evidence.

BACKGROUND: Injury to the perineum is a common sequalae of vaginal birth. Lack of appropriateperineal wound care in the postnatal period is associated with increased pain and morbidity in theshort, medium, and long term. Women and maternity healthcare providers require high-levelevidence-based information to inform postnatal perineal wound care. OBJECTIVES: To review the high-level evidence informing postpartum management of perineal trauma. DESIGN: A systematic search of the literature regarding the postnatal management of perineal injury to produce a critical narrative review of the available level I evidence regarding the postnatal management of perineal trauma up to six months postpartum was undertaken. Systematic reviews were identified from searching the following databases: CINAHL, Cochrane Library, MEDLINE, PUBMED, and SCOPUS. Papers were selected if they met the following criteria: systematic reviews/level I evidence related to postnatal management of any form of perineal injury up to six months post birth, written in English, and published from January 2010 to 30th May 2021. A synthesis of the results was developed. FINDINGS: Nineteen systematic reviews met criteria for inclusion. The systematic reviews fell into one of the following categories of perineal trauma management: use of medication for pain relief, the decision to suture, suture techniques/materials, cryotherapy, use of antibiotics, ultrasound, physiotherapy treatment and complementary therapies. CONCLUSION: There is an overall lack of focused high-quality research to inform management of perineal injuries beyond the acute postnatal period. Clinical trials that include women's satisfaction and wellbeing as outcome measures are limited. IMPLICATIONS FOR PRACTICE: It is vital that women are provided with evidence-based postnatal care strategies to enhance perineal healing and resumption of normal activities. Future clinical trials for the management of perineal trauma should incorporate women's satisfaction as an outcome measure.Further research examining the follow-up care for the medium-long term for women experiencing ongoing sequalae of symptoms in the community setting is required to support clinical practice recommendations.

Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer's disease.

The brain microcirculation is increasingly viewed as a potential target for disease-modifying drugs in the treatment of Alzheimer's disease patients, reflecting a growing appreciation of evidence that cerebral blood flow is compromised in such patients. However, the pathogenic mechanisms in brain resistance arteries underlying blood flow defects have not yet been elucidated. Here we probed the roles of principal vasodilatory pathways in cerebral arteries using the APP23 mouse model of Alzheimer's disease, in which amyloid precursor protein is increased approximately sevenfold, leading to neuritic plaques and cerebrovascular accumulation of amyloid-ß similar to those in patients with Alzheimer's disease. Pial arteries from APP23 mice (18 mo old) exhibited enhanced pressure-induced (myogenic) constriction because of a profound reduction in ryanodine receptor-mediated, local calcium-release events ("Ca2+ sparks") in arterial smooth muscle cells and a consequent decrease in the activity of large-conductance Ca2+-activated K+ (BK) channels. The ability of the endothelial cell inward rectifier K+ (Kir2.1) channel to cause dilation was also compromised. Acute application of amyloid-ß 1-40 peptide to cerebral arteries from wild-type mice partially recapitulated the BK dysfunction seen in APP23 mice but had no effect on Kir2.1 function. If mirrored in human Alzheimer's disease, these tandem defects in K+ channel-mediated vasodilation could account for the clinical cerebrovascular presentation seen in patients: reduced blood flow and crippled functional hyperemia. These data direct future research toward approaches that reverse this dual vascular channel dysfunction, with the ultimate aim of restoring healthy cerebral blood flow and improving clinical outcomes.

Upscaling 3D Engineered Trees for Off-Grid Desalination.

More than 70% of the population without access to safe drinking water lives in remote and off-grid areas. Inspired by natural plant transpiration, we designed and tested in this study an array of scalable three-dimensional (3D) engineered trees made of natural wood for continuous water desalination to provide affordable and clean drinking water. The trees took advantage of capillary action in the wood xylems and lifted water more than 1 foot off the ground with or without solar irradiation. This process overcame some major challenges of popular solar-driven water evaporation and water harvesting, such as intermittent operation, low water production rate, and system scaling. The trade-off between energy transfer and system footprint was tackled by optimizing the interspacing between the trees. The scaled system has a ratio of surface area (vapor generation) to project area (water transport) up to 118, significantly higher than the prevailing flat-sheet design. The extensive surface area evaporated water at a temperature cooler than the surrounding air, drawing on multiple environmental energy sources including solar, wind, or ambient heat in the air and realized continuous operation. The total energy for evaporation reached over 300% of the one-sun irradiance, enabling a freshwater production rate of 4.8 L m-2 h-1 from an array of 16 trees in an enclosed room and 14 L m-2 h-1 under a 3 m/s airflow. Furthermore, we found that the ambient heat in the air contributed 60%-70% of the total latent heat of vaporization when energy sources were decoupled. During long-term desalination tests, the engineered trees demonstrated a self-cleaning mechanism with daily cycles of salt accumulation and dissolution. Combining the quantification from an evaporation model and meteorology data covering the globe, we also demonstrated that the 3D engineered trees can be of particular interest for sustainable desalination in the Middle East and North Africa (MENA) regions.

The validity of the International Physical Activity Questionnaire (IPAQ) for adults with progressive muscle diseases.

PURPOSE: Measuring the physical activity of adults with progressive muscle diseases is important to inform clinical practice, for activity recommendations and for outcomes meaningful to participants in clinical trials. Despite its wide use, the measurement properties of the International Physical Activity Questionnaire (IPAQ) have not been established in a muscle disease population. MATERIALS AND METHODS: The sample of 103 adults with progressive muscle diseases included independently mobile participants and wheelchair users. Their home-based activity measured by the IPAQ was compared to simultaneous weeks of accelerometer activity data collected remotely in a longitudinal, measure evaluation study. Validity, reliability, and responsiveness were evaluated for the IPAQ alone, and for the IPAQ used in conjunction with a smart activity monitor. RESULTS: The IPAQ did not demonstrate satisfactory criterion validity, reliability or responsiveness and it systematically overestimated moderate and vigorous physical activity time by 161 minutes per week. Measurement properties of the IPAQ were improved when it was used in combination with a smart activity monitor. CONCLUSIONS: The IPAQ did not have satisfactory measurement properties compared to accelerometry in adults with progressive muscle disease. Combining self-report and objective activity measures might improve the accuracy of physical activity assessment in this and other comparable populations.Implications for RehabilitationPhysical activity is a meaningful health outcome for adults with progressive muscle diseases, for whom precise activity quantification is important because of the potential for activity-related disease exacerbation.The International Physical Activity Questionnaire (IPAQ) had unsatisfactory measurement properties compared to accelerometry; however, these were improved by adjunctive smart activity monitoring.Objective or combined physical activity measurement is recommended over self-report alone for clinical assessment of physical activity as part of rehabilitation and self-management programmes.

Validity of Fitbit activity monitoring for adults with progressive muscle diseases.

PURPOSE: Measuring physical activity informs activity recommendations in clinical practice and provides outcomes in clinical trials that are meaningful to patients. Activity assessment in muscle disease is challenging and there is insufficient evidence to support any single activity measure; however, multi-modal activity measurement might have potential. MATERIALS AND METHODS: This two-part study included 20 and 95 adults with progressive muscle diseases with mobility ranging from independent to assisted, including wheelchair users. Their activity was measured using a multi-sensor Fitbit activity monitor, for which criterion validity and acceptability were tested in study 1 and validity, reliability, and responsiveness were tested in the longitudinal, home-based study 2. RESULTS: Study 1: Fitbit was acceptable and had strong criterion validity (rho/kappa ≥0.90), although up to 15% measurement error. Study 2: Fitbit had satisfactory concurrent and construct validity, reliability, and responsiveness. However, Fitbit active minutes registered 75 min more activity per week than gold standard moderate and vigorous physical activity (MVPA) time. CONCLUSIONS: Fitbit had satisfactory measurement properties for monitoring physical activity in adults with progressive muscle diseases. However, Fitbit should not be considered an exact step counter, heart rate monitor or calorimeter and Fitbit active minutes are not synonymous with MVPA time.Implications for rehabilitationPeople with progressive muscle diseases mobilise independently, with walking aids and with wheelchairs; physical activity measurement can be challenging in this population.Multisensor smart activity monitoring by Fitbit had satisfactory validity, reliability, responsiveness, and acceptability for the estimation of physical activity in adults with progressive muscle diseases.Fitbit active minutes are not synonymous with moderate and vigorous physical activity (MVPA) time measured using a research grade accelerometer.

Selective Fluoride Transport in Subnanometer TiO2 Pores.

Synthesizing nanopores which mimic the functionality of ion-selective biological channels has been a challenging yet promising approach to advance technologies for precise ion-ion separations. Inspired by the facilitated fluoride (F-) permeation in the biological fluoride channel, we designed a highly fluoride-selective TiO2 film using the atomic layer deposition (ALD) technique. The subnanometer voids within the fabricated TiO2 film (4 Å < d < 12 Å, with two distinct peaks at 5.5 and 6.5 Å), created by the hindered diffusion of ALD precursors (d = 7 Å), resulted in more than eight times faster permeation of sodium fluoride compared to other sodium halides. We show that the specific Ti-F interactions compensate for the energy penalty of F- dehydration during the partitioning of F- ions into the pore and allow for an intrapore accumulation of F- ions. Concomitantly, the accumulation of F- ions on the pore walls also enhances the transport of sodium (Na+) cations due to electrostatic interactions. Molecular dynamics simulations probing the ion concentration and mobility within the TiO2 pore further support our proposed mechanisms for the selective F- transport and enhanced Na+ permeation in the TiO2 film. Overall, our work provides insights toward the design of ion-selective nanopores using the ALD technique.

Randomized Trial-PrEscription of intraDialytic exercise to improve quAlity of Life in Patients Receiving Hemodialysis.

INTRODUCTION: Whether clinically implementable exercise interventions in people receiving hemodialysis (HD) therapy improve health-related quality of life (HRQoL) remains unknown. The PrEscription of intraDialytic exercise to improve quAlity of Life (PEDAL) study evaluated the clinical benefit and cost-effectiveness of a 6-month intradialytic exercise program. METHODS: In a multicenter, single-blinded, randomized, controlled trial, people receiving HD were randomly assigned to (i) intradialytic exercise training (exercise intervention group [EX]) and (ii) usual care (control group [CON]). Primary outcome was change in Kidney Disease Quality of Life Short-Form Physical Component Summary (KDQOL-SF 1.3 PCS) from baseline to 6 months. Cost-effectiveness was determined using health economic analysis; physiological impairment was evaluated by peak oxygen uptake; and harms were recorded. RESULTS: We randomized 379 participants; 335 and 243 patients (EX n = 127; CON n = 116) completed baseline and 6-month assessments, respectively. Mean difference in change PCS from baseline to 6 months between EX and CON was 2.4 (95% confidence interval [CI]: -0.1 to 4.8) arbitrary units (P = 0.055); no improvements were observed in peak oxygen uptake or secondary outcome measures. Participants in the intervention group had poor compliance (47%) and poor adherence (18%) to the exercise prescription. Cost of delivering intervention ranged from US$598 to US$1092 per participant per year. The number of participants with harms was similar between EX (n = 69) and CON (n = 56). A primary limitation was the lack of an attention CON. Many patients also withdrew from the study or were too unwell to complete all physiological outcome assessments. CONCLUSIONS: A 6-month intradialytic aerobic exercise program was not clinically beneficial in improving HRQoL as delivered to this cohort of deconditioned patients on HD.

Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT.

BACKGROUND: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown. OBJECTIVES: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients. DESIGN: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis. SETTING: The setting was five dialysis units across the UK from 2015 to 2019. PARTICIPANTS: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year. INTERVENTIONS: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training. MAIN OUTCOME MEASURES: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted. RESULTS: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention, n = 127; control, n = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval -0.1 to 4.8 arbitrary units; p = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention (n = 69) and control (n = 56) groups. LIMITATIONS: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation. CONCLUSIONS: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis. FUTURE WORK: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83508514. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.

Although the benefits of exercise in the general population are well recognised, we do not know if offering cycling exercise during haemodialysis is an effective way to improve quality of life, and if this would be a cost-effective way to provide exercise training for this patient population. To determine whether or not this type of exercise training is effective, and provides value for money, this study compared cycling during haemodialysis treatment, three times per week for 6 months, with usual care that does not include routine delivery of any exercise training. Five regions of the UK were included in the study. We compared the results from the two groups at the start of the study and at 6 months, after correcting for age and diabetes status. We also assessed the economic impact of delivering the cycling during haemodialysis programme and interviewed people from different regions of the UK in both groups. The baseline assessments revealed a deconditioned population in the study. There was no difference in quality of life or any physical function measures between the group that performed cycling during haemodialysis and the usual-care group. Compliance with the exercise intervention was very poor. Interviews with patients showed that patient engagement with the exercise training was linked to the presence of an exercise culture, and leadership to provide this, in the renal unit. An economic evaluation showed that delivering cycling during haemodialysis would not be value for money when delivered to a deconditioned haemodialysis population. Ways to engage patients with exercise training during their haemodialysis treatment should be explored further.