Long-term sustainability of response to upadacitinib among patients with active rheumatoid arthritis refractory to biological treatments: results up to 5 years from SELECT-BEYOND.

OBJECTIVE: To evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR) in the SELECT-BEYOND phase 3 trial. METHODS: Patients on background conventional synthetic DMARDs (csDMARDs) were treated once daily with upadacitinib 15 mg or placebo. Patients who completed the week 24 visit could enter a long-term extension of up to 5 years. The sustainability of response was assessed based on achievement of Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and Disease Activity Score 28-joint count using C-reactive protein (DAS28 (CRP)) targets and evaluated up to week 260 in all patients receiving the approved upadacitinib 15 mg dose, including those randomised to upadacitinib 15 mg and those who switched from placebo to upadacitinib 15 mg at week 12. RESULTS: In this bDMARD-IR population, 45% (n=104/229) and 79% (n=172/219) of patients treated with upadacitinib 15 mg plus background csDMARD(s) achieved CDAI remission or CDAI low disease activity (LDA) at any point during the 5-year study, respectively. Of those who achieved CDAI remission/LDA, 25%/43% maintained their initial response through 240 weeks of follow-up after first achieving response. Most patients who lost remission or LDA were able to recapture that response by the cut-off date. Similar overall results were observed for SDAI and DAS28 (CRP). No strong predictors of response were identified. CONCLUSIONS: Over three-quarters of bDMARD-IR patients achieved CDAI LDA with upadacitinib, and almost half of those maintained LDA through 240 weeks of follow-up. Remission was achieved by nearly half of all patients and maintained in approximately a quarter of those achieving remission. TRIAL REGISTRATION NUMBER: NCT02706847.

Efficacy and safety of upadacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to biological treatments: results through 5 years from the SELECT-BEYOND study.

OBJECTIVE: To evaluate the efficacy and safety of upadacitinib over 5 years among patients with rheumatoid arthritis (RA) in a long-term extension (LTE) of the SELECT-BEYOND phase 3 trial. METHODS: Patients refractory to ≥1 biological disease-modifying antirheumatic drug (DMARD) received upadacitinib 15 mg or 30 mg once daily or placebo, in combination with background conventional synthetic DMARD(s). At week 12, patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg. All patients who completed the week 24 visit could enter the LTE for up to 5 years. Efficacy was analysed as observed and by non-responder imputation through week 260. Treatment-emergent adverse events per 100 patient-years were summarised over 5 years. RESULTS: Of the 498 patients randomised, 418 (84%) completed week 24 and entered the LTE. Of those who remained in the trial (n=80, upadacitinib 15 mg; n=81, upadacitinib 30 mg), 36%/36% and 81%/77% randomised to upadacitinib 15/30 mg were in Clinical Disease Activity Index (CDAI) remission or low disease activity at week 260, respectively (as observed). Approximately 47% of all patients who began in high disease activity demonstrated a CDAI improvement >12 at week 260 with upadacitinib 15/30 mg. Functional and pain-related outcomes also showed comparable improvements with both doses. Numerically higher rates of anaemia, herpes zoster and creatine phosphokinase elevation were observed with upadacitinib 30 mg vs 15 mg. No new safety issues were identified. CONCLUSIONS: Upadacitinib 15/30 mg continued to be effective in treating clinical and functional outcomes in patients with RA. The safety profile observed over 5 years was consistent with earlier study-specific and integrated assessments of upadacitinib treatment.

Structural determinants of collapse by a monomolecular mimic of pulmonary surfactant at the physiological temperature.

Pulmonary surfactant forms a thin film on the liquid that lines the alveolar air-sacks. When compressed by the decreasing alveolar surface area during exhalation, the films avoid collapse from the air/water interface and reduce surface tension to exceptionally low levels. To define better the structure of compressed films that determines their susceptibility to collapse, we measured how cholesterol affects the structure and collapse of dipalmitoyl phosphatidylcholine (DPPC) monolayers at physiological temperatures. Grazing incidence X-ray diffraction (GIXD) and grazing incidence X-ray off-specular scattering (GIXOS) established the lateral and transverse structures of films on a Langmuir trough at a surface pressure of 45 mN m-1, just below the equilibrium spreading pressure at which collapse begins. Experiments with captive bubbles at a surface pressure of 51 mN m-1 measured how the steroid affects isobaric collapse. Mol fractions of the steroid (Xchol) at 0.05 removed the tilt by the acyl chains of DPPC, shifted the unit cell from centered rectangular to hexagonal, and dramatically decreased the long-range order. Higher Xchol produced no further change in diffraction, suggesting that cholesterol partitions into a coexisting disordered phase. Cholesterol had minimal effect on rates of collapse until Xchol reached 0.20. Our results demonstrate that the decreased coherence length, indicating conversion of positional order to short-range, is insufficient to make a condensed monolayer susceptible to collapse. Our findings suggest a two-step process by which cholesterol induces disorder. The steroid would first convert the film with crystalline chains to a hexatic phase before generating a fully disordered structure that is susceptible to collapse. These results lead to far-reaching consequences for formulation of animal-derived therapeutic surfactants. Our results suggest that removal of cholesterol from these preparations should be unnecessary below Xchol = 0.20.

The Impact of Annealing Methods on the Encapsulating Structure and Storage-Stability of Freeze-Dried Pellets of Probiotic Bacteria.

OBJECTIVE: This paper investigates the critical role of material thickness in freeze-dried pellets for enhancing the storage stability of encapsulated bacteria. Freeze dried material of varying thicknesses obtained from different annealing durations is quantified using Scanning Electron Microscopy (SEM) and X-ray microtomography (µCT), the material thickness is then correlated to the storage stability of the encapsulated cells. METHODS: A formulation comprising of sucrose, maltodextrin, and probiotic cells is quenched in liquid nitrogen to form pellets. The pellets undergo different durations of annealing before undergoing freeze-drying. The material thickness is quantified using SEM and µCT. Storage stability in both oxygen-rich and oxygen-poor environments is evaluated by measuring CFU counts and correlated with the pellet structure. RESULTS: The varying annealing protocols produce a range of material thicknesses, with more extensive annealing resulting in thicker materials. Storage stability exhibits a positive correlation with material thickness, indicating improved stability with thicker materials. Non-annealed pellets exhibit structural irregularities and inconsistent storage stability, highlighting the impracticality of avoiding annealing in the freeze-drying process. CONCLUSIONS: Extensive annealing not only enhances the storage stability of probiotic products but also provides greater control over the freeze-drying process, ensuring homogeneous and reproducible products. This study underscores the importance of material thickness in freeze-dried pellets for optimizing storage stability for probiotic formulations, and emphasize the necessity of annealing as a critical step in freeze-drying quenched pellets to achieve desired structural and stability outcomes.

New opportunities for time-resolved imaging using diffraction-limited storage rings.

The advent of diffraction-limited storage rings (DLSRs) has boosted the brilliance or coherent flux by one to two orders of magnitude with respect to the previous generation. One consequence of this brilliance enhancement is an increase in the flux density or number of photons per unit of area and time, which opens new possibilities for the spatiotemporal resolution of X-ray imaging techniques. This paper studies the time-resolved microscopy capabilities of such facilities by benchmarking the ForMAX beamline at the MAX IV storage ring. It is demonstrated that this enhanced flux density using a single harmonic of the source allows micrometre-resolution time-resolved imaging at 2000 tomograms per second and 1.1 MHz 2D acquisition rates using the full dynamic range of the detector system.

Identification of a Safe and Tolerable Carbamazepine Dosing Paradigm that Facilitates Effective Evaluation of CYP3A4 Induction.

Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b.i.d. alone (100 mg Days 2-4; 200 mg Days 5-7; 300 mg Days 8-10 and 12-13), and 300 mg CBZ b.i.d. plus 1.2 mg MDZ (Days 11 and 14). One participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11. One participant (6.7%) experienced urticaria (Days 12-13), and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300 mg CBZ b.i.d. alone. All AEs were mild. For MDZ, the geometric mean (90% CI) ratio (vs. Day 1) of the area under the curve (AUC 0-∞) was 0.28 (0.24-0.31) on Day 11 and 0.26 (0.23-0.29) on Day 14. The AUC (0-12 hours) of CBZ was 114,000 ng∙h/mL on Day 11 and 105,000 ng∙h/mL on Day 14. Steady-state concentrations of CBZ and induction of CYP3A4 were achieved on Day 11. The data are consistent with predictions of physiologically-based pharmacokinetic models in Simcyp. The 9-day dosing regimen for CBZ induction was well-tolerated by healthy participants, supporting the use of a shorter CBZ regimen for CYP3A4 induction studies.

Scanning WAXS microscopy of regenerated cellulose fibers at mesoscopic resolution.

In this work, regenerated cellulose textile fibers, Ioncell-F, dry-wet spun with different draw ratios, have been investigated by scanning wide-angle X-ray scattering (WAXS) using a mesoscopic X-ray beam. The fibers were found to be homogeneous on the 500 nm length scale. Analysis of the azimuthal angular dependence of a crystalline Bragg spot intensity revealed a radial dependence of the degree of orientation of crystallites that was found to increase with the distance from the center of the fiber. We attribute this to radial velocity gradients during the extrusion of the spin dope and the early stage of drawing. On the other hand, the fiber crystallinity was found to be essentially homogeneous over the fiber cross section.

Distance tuneable integral membrane protein containing floating bilayers via in situ directed self-assembly.

Model membranes allow for structural and biophysical studies on membrane biochemistry at the molecular level, albeit on systems of reduced complexity which can limit biological accuracy. Floating supported bilayers offer a means of producing planar lipid membrane models not adhered to a surface, which allows for improved accuracy compared to other model membranes. Here we communicate the incorporation of an integral membrane protein complex, the multidomain ß-barrel assembly machinery (Bam), into our recently developed in situ self-assembled floating supported bilayers. Using neutron reflectometry and quartz crystal microbalance measurements we show this sample system can be fabricated using a two-step self-assembly process. We then demonstrate the complexity of the model membrane and tuneability of the membrane-to-surface distance using changes in the salt concentration of the bulk solution. Results demonstrate an easily fabricated, biologically accurate and tuneable membrane assay system which can be utilized for studies on integral membrane proteins within their native lipid matrix.

Novel non-helical antimicrobial peptides insert into and fuse lipid model membranes.

This research addresses the growing menace of antibiotic resistance by exploring antimicrobial peptides (AMPs) as alternatives to conventional antibiotics. Specifically, we investigate two linear amphipathic AMPs, LE-53 (12-mer) and LE-55 (16-mer), finding that the shorter LE-53 exhibits greater bactericidal activity against both Gram-negative (G(-)) and Gram-positive (G(+)) bacteria. Remarkably, both AMPs are non-toxic to eukaryotic cells. The heightened effectiveness of LE-53 is attributed to its increased hydrophobicity (H) compared to LE-55. Circular dichroism (CD) reveals that LE-53 and LE-55 both adopt ß-sheet and random coil structures in lipid model membranes (LMMs) mimicking G(-) and G(+) bacteria, so secondary structure is not the cause of the potency difference. X-ray diffuse scattering (XDS) reveals increased lipid chain order in LE-53, a potential key distinction. Additionally, XDS study uncovers a significant link between LE-53's upper hydrocarbon location in G(-) and G(+) LMMs and its efficacy. Neutron reflectometry (NR) confirms the AMP locations determined using XDS. Solution small angle X-ray scattering (SAXS) demonstrates LE-53's ability to induce vesicle fusion in bacterial LMMs without affecting eukaryotic LMMs, offering a promising strategy to combat antibiotic-resistant strains while preserving human cell integrity, whereas LE-55 has a smaller ability to induce fusion.

The biophysical function of pulmonary surfactant.

The type II pneumocytes of the lungs secrete a mixture of lipids and proteins that together acts as a surfactant. The material forms a thin film on the surface of the liquid layer that lines the alveolar air sacks. When compressed by the decreasing alveolar surface area during exhalation, the films reduce surface tension to exceptionally low levels. Pulmonary surfactant is essential for preserving the integrity of the barrier between alveolar air and capillary blood during normal breathing. This review focuses on the major biophysical processes by which endogenous pulmonary surfactant achieves its function and the mechanisms involved in those processes. Vesicles of pulmonary surfactant adsorb rapidly from the alveolar liquid to form the interfacial film. Interfacial insertion, which requires the hydrophobic surfactant protein SP-B, proceeds by a process analogous to the fusion of two vesicles. When compressed, the adsorbed film desorbs slowly. Constituents remain at the surface at high interfacial concentrations that reduce surface tensions well below equilibrium levels. We review the models proposed to explain how pulmonary surfactant achieves both the rapid adsorption and slow desorption characteristic of a functional film.

Promoting diverse perspectives: Addressing health disparities related to Alzheimer's and all dementias.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's-related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14-16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

Development towards high-resolution kHz-speed rotation-free volumetric imaging.

X-ray multi-projection imaging (XMPI) has the potential to provide rotation-free 3D movies of optically opaque samples. The absence of rotation enables superior imaging speed and preserves fragile sample dynamics by avoiding the centrifugal forces introduced by conventional rotary tomography. Here, we present our XMPI observations at the ID19 beamline (ESRF, France) of 3D dynamics in melted aluminum with 1000 frames per second and 8 µm resolution per projection using the full dynamical range of our detectors. Since XMPI is a method under development, we also provide different tests for the instrumentation of up to 3000 frames per second. As the high-brilliance of 4th generation light-sources becomes more available, XMPI is a promising technique for current and future X-ray imaging instruments.

An octameric PqiC toroid stabilises the outer-membrane interaction of the PqiABC transport system.

The E. coli Paraquat Inducible (Pqi) Pathway is a putative Gram-negative phospholipid transport system. The pathway comprises three components: an integral inner membrane protein (PqiA), a periplasmic spanning MCE family protein (PqiB) and an outer membrane lipoprotein (PqiC). Interactions between all complex components, including stoichiometry, remain uncharacterised; nevertheless, once assembled into their quaternary complex, the trio of Pqi proteins are anticipated to provide a continuous channel between the inner and outer membranes of diderms. Here, we present X-ray structures of both the native and a truncated, soluble construct of the PqiC lipoprotein, providing insight into its biological assembly, and utilise neutron reflectometry to characterise the nature of the PqiB-PqiC-membrane interaction. Finally, we employ phenotypic complementation assays to probe specific PqiC residues, which imply the interaction between PqiB and PqiC is less intimate than previously anticipated.

Hierarchically Porous 3D Freestanding Holey-MXene Framework via Mild Oxidation of Self-Assembled MXene Hydrogel for Ultrafast Pseudocapacitive Energy Storage.

The true promise of MXene as a practical supercapacitor electrode hinges on the simultaneous advancement of its three-dimensional (3D) assembly and the engineering of its nanoscopic architecture, two critical factors for facilitating mass transport and enhancing an electrode's charge-storage performance. Herein, we present a straightforward strategy to engineer robust 3D freestanding MXene (Ti3C2Tx) hydrogels with hierarchically porous structures. The tetraamminezinc(II) complex cation ([Zn(NH3)4]2+) is selected to electrostatically assemble colloidal MXene nanosheets into a 3D interconnected hydrogel framework, followed by a mild oxidative acid-etching process to create nanoholes on the MXene surface. These hierarchically porous, conductive holey-MXene frameworks facilitate 3D transport of both electrons and electrolyte ions to deliver an excellent specific capacitance of 359.2 F g-1 at 10 mV s-1 and superb capacitance retention of 79% at 5000 mV s-1, representing a 42.2% and 15.3% improvement over pristine MXene hydrogel, respectively. Even at a commercial-standard mass loading of 10.1 mg cm-2, it maintains an impressive capacitance retention of 52% at 1000 mV s-1. This rational design of an electrode by engineering nanoholes on MXene nanosheets within a 3D porous framework dictates a significant step forward toward the practical use of MXene and other 2D materials in electrochemical energy storage systems.

Impact of higher-income countries on child health in lower-income countries from a climate change perspective. A case study of the UK and Malawi.

Climate change is the number one threat to child health according to the World Health Organisation. It increases existing inequalities, and lower-income countries are disproportionately affected. This is unjust. Higher-income countries have contributed and continue to contribute more to climate change than lower-income countries. This has been recognised by the United Nations Committee on the Rights of the Child, which has ruled that states can be held responsible if their carbon emissions harm child rights both within and outside their jurisdiction. Nevertheless, there are few analyses of the bilateral relationship between higher- and lower-income countries concerning climate change. This article uses the UK and Malawi as a case study to illustrate higher-income countries' impact on child health in lower-income countries. It aims to assist higher-income countries in developing more targeted policies. Children in Malawi can expect more food insecurity and reduced access to clean water, sanitation, and education. They will be more exposed to heat stress, droughts, floods, air pollution and life-threatening diseases, such as malaria. In 2019, 5,000 Malawian children died from air pollution (17% of under-five deaths). The UK needs to pay its 'fair share' of climate finance and ensure adaptation is prioritised for lower-income countries. It can advocate for more equitable and transparent allocation of climate finance to support the most vulnerable countries. Additionally, the UK can act domestically to curtail revenue losses in Malawi and other lower-income countries, which would free up resources for adaptation. In terms of mitigation, the UK must increase its nationally determined commitments by 58% to reach net zero and include overseas emissions. Land use, heating systems and renewable energy must be reviewed. It must mandate comprehensive scope three emission reporting for companies to include impacts along their value chain, and support businesses, multinational corporations, and banks to reach net zero.

Proof-of-concept solution to create an interoperable timeline of healthcare data.

OBJECTIVES: To overcome the barriers of interoperability by sharing simulated patient data from different electronic health records systems and presenting them in an intuitive timeline of events. METHODS: The 'Patient Story' software comprising database and blockchain, PS Timeline Windows interface, PS Timeline Web interface and network relays on Azure cloud was customised for Epic and Lorenzo electonic patient record (EPR) systems used at different hospitals, using site-specific adapters. RESULTS: Each site could view their own clinical documents and view each other's site specific, fully coded test sets of (Care Connect) medications, conditions and allergies, in an aggregated single view. DISCUSSION: This work has shown that clinical data from different EPR systems can be successfully integrated and visualised on a single timeline, accessible by clinicians and patients. CONCLUSION: The Patient Story system combined the timeline visualisation with successful interoperability across healthcare settings, as well giving patients the ability to directly interact with their timeline.

Financing child rights in Malawi.

BACKGROUND: Nearly all countries have ratified the United Nations Convention on the Rights of the Child and, therefore, support children having access to their rights. However, only a small minority of children worldwide have access to their environmental, economic, and social rights. The most recent global effort to address these deficits came in 2015, when the United Nations General Assembly agreed to a plan for a fairer and more sustainable future by 2030 and outlined the Sustainable Development Goals (SDGs). One remediable cause is the lack of revenue in many countries, which affects all SDGs. However, illicit financial flows from low-income to high-income countries, including international tax abuse, continue unabated. METHODS: Using the most recent estimates of tax abuse perpetuated by multinational companies and tax evasion through offshore wealth, and precise econometric modelling, we illustrate the potential regarding child rights (or progress towards the SDGs) if there was an increase in revenue equivalent to tax abuse in Malawi, a low-income country particularly vulnerable to climate change. The Government Revenue and Development Estimations model provides realistic estimates of government revenue changes in developmental outcomes. Using panel data on government revenue per capita, it models the impact of increased revenue on governance and SDG progress. RESULTS: If cross-border tax abuse and tax evasion were curtailed, the equivalent increase in government revenue in one country, Malawi, would be associated with 12,000 and 20,000 people having access to basic water and sanitation respectively each year. Each year, an additional 5000 children would attend school, 150 additional children would survive, and 10 mothers would survive childbirth. CONCLUSIONS: More children would access their economic and social rights if actions were taken to close the gap in global governance regarding taxation. We discuss the responsibility of duty bearers, the need for a global body to arbitrate and monitor international tax matters, and how the Government of Malawi could take further domestic action to mitigate the gaps in global governance and protect itself against illicit financial flows, including tax abuse.

Anchor Group Bottlebrush Polymers as Oil Additive Friction Modifiers.

Surface-tethered polymers have been shown to be an efficient lubrication strategy for boundary and mixed lubrication by providing a solvated film between solid surfaces. We have assessed the performance of various graft copolymers as friction modifier additives in oil and revealed important structure-property relationships for this application. The polymers consisted of an oil-soluble, grafted poly(lauryl acrylate) segment and a polar, linear poly(4-acryloylmorpholine) anchor group. Reversible addition-fragmentation chain transfer polymerization was used to access various architectures with control of the grafting density and position of the anchor group. Macrotribological studies displayed promising results with ≈50% reduction in friction coefficient at low polymer treatment rates. QCM-D experiments, neutron reflectometry, small-angle neutron scattering, and atomic force microscopy were used to gather detailed information on these polymers' surface adsorption characteristics, film structure, and solution behavior.

Structural formation during bread baking in a combined microwave-convective oven determined by sub-second in-situ synchrotron X-ray microtomography.

A new concept has been developed for characterizing the real-time evolution of the three-dimensional pore and lamella microstructure of bread during baking using synchrotron X-ray microtomography (SRµCT). A commercial, combined microwave-convective oven was modified and installed at the TOMCAT synchrotron tomography beamline at the Swiss Light Source (SLS), to capture the 3D dough-to-bread structural development in-situ at the micrometer scale with an acquisition time of 400 ms. This allowed characterization and quantitative comparison of three baking technologies: (1) convective heating, (2) microwave heating, and (3) a combination of convective and microwave heating. A workflow for automatic batchwise image processing and analysis of 3D bread structures (1530 analyzed volumes in total) was established for porosity, individual pore volume, elongation, coordination number and local wall thickness, which allowed for evaluation of the impact of baking technology on the bread structure evolution. The results showed that the porosity, mean pore volume and mean coordination number increase with time and that the mean local cell wall thickness decreases with time. Small and more isolated pores are connecting with larger and already more connected pores as function of time. Clear dependencies are established during the whole baking process between the mean pore volume and porosity, and between the mean local wall thickness and the mean coordination number. This technique opens new opportunities for understanding the mechanisms governing the structural changes during baking and discern the parameters controlling the final bread quality.