Factors Affecting Best-Tolerated Dose of Pirfenidone in Patients with Fibrosing Interstitial Lung Disease.

The aim of the study was to examine the best-tolerated dose of pirfenidone, the adverse effects profile, and potential factors other than drug dose influencing the tolerability of pirfenidone in patients with fibrosing interstitial lung diseases (ILDs). We performed an observational retrospective study of 113 patients with IPF and other fibrosing ILDs treated with pirfenidone. Baseline liver function tests (LFTs) and dose escalation of pirfenidone were recorded for all patients. The best-tolerated dose was continued if the patient did not tolerate full dose (2400 mg) despite repeated dose escalation attempts. Potential risk factors such as age, height, weight, body mass index (BMI), body surface area (BSA), gender, smoking, and presence of comorbidities were analyzed between 3 groups of best-tolerated pirfenidone doses: 2400 mg/day vs. <2400 mg/day, 2400 mg/day vs. 1800 mg/day, and 2400 mg/day vs. 1200 mg/day. A total of 24 patients tolerated 2400 mg/day, and 89 patients tolerated <2400 mg/day (43 tolerated 1800 mg/day, 45 tolerated 1200 mg/day and 1 tolerated 600 mg/day). Patients who tolerated 2400 mg/day were taller and had a larger BSA as compared to those tolerating <2400 mg/day. Overall, males tolerated the drug better. Presence of comorbidities or smoking did not affect the tolerance of pirfenidone, except for the presence of cerebrovascular diseases. Various adverse effects did not have any significantly different frequencies between the compared groups. Moreover, 71.7% of patients experienced at least one side effect. 1200 mg/day was the best-tolerated dose in the majority of the patients. Male patients with a larger BSA and greater height showed better tolerability of pirfenidone overall.

Self-assembly of ionic and non-ionic surfactants in type IV cerium nitrate and urea based deep eutectic solvent.

Understanding and manipulating micelle morphology are key to exploiting surfactants in various applications. Recent studies have shown surfactant self-assembly in a variety of Deep Eutectic Solvents (DESs) where both the nature of surfactants and the interaction of the surfactant molecule with the solvent components influence the size, shape, and morphology of the micelles formed. So far, micelle formation has only been reported in type III DESs, consisting solely of organic species. In this work, we have explored the self-assembly of cationic surfactant dodecyl trimethylammonium nitrate/bromide (C12TANO3/C12TAB), anionic surfactant sodium dodecyl sulfate (SDS), and non-ionic surfactants hexaethylene glycol monododecyl ether (C12EO6) and octaethylene glycol monohexadecyl ether (C16EO8) in a type IV DES comprising metal salt, cerium (III) nitrate hexahydrate, and a hydrogen bond donor, urea, in the molar ratio 1:3.5. C12TANO3, C12TAB, C12EO6, and C16EO8 form spherical micelles in the DES with the micelle size dependent on both the surfactant alkyl chain length and the head group, whereas SDS forms cylindrical micelles. We hypothesize that the difference in the micelle shape can be explained by counterion stabilization of the SDS headgroup by polycations in the DES compared to the nitrate/bromide anion interaction in the case of cationic surfactants or molecular interaction of the urea and the salting out effect of (CeNO3)3 in the DES on the alkyl chains/polyethoxy headgroup for non-ionic surfactants. These studies deepen our understanding of amphiphile self-assembly in this novel, ionic, and hydrogen-bonding solvent, raising the opportunity to use these structures as liquid crystalline templates to generate porosity in metal oxides (ceria) that can be synthesized using these DESs.

Structural evolution of iron forming iron oxide in a deep eutectic-solvothermal reaction.

Deep eutectic solvents (DES) and their hydrated mixtures are used for solvothermal routes towards greener functional nanomaterials. Here we present the first static structural and in situ studies of the formation of iron oxide (hematite) nanoparticles in a DES of choline chloride : urea where xurea = 0.67 (aka. reline) as an exemplar solvothermal reaction, and observe the effects of water on the reaction. The initial speciation of Fe3+ in DES solutions was measured using extended X-ray absorption fine structure (EXAFS), while the atomistic structure of the mixture was resolved from neutron and X-ray diffraction and empirical potential structure refinement (EPSR) modelling. The reaction was monitored using in situ small-angle neutron scattering (SANS), to determine mesoscale changes, and EXAFS, to determine local rearrangements of order around iron ions. It is shown that iron salts form an octahedral [Fe(L)3(Cl)3] complex where (L) represents various O-containing ligands. Solubilised Fe3+ induced subtle structural rearrangements in the DES due to abstraction of chloride into complexes and distortion of H-bonding around complexes. EXAFS suggests the complex forms [-O-Fe-O-] oligomers by reaction with the products of thermal hydrolysis of urea, and is thus pseudo-zero-order in iron. In the hydrated DES, the reaction, nucleation and growth proceeds rapidly, whereas in the pure DES, the reaction initially proceeds quickly, but suddenly slows after 5000 s. In situ SANS and static small-angle X-ray scattering (SAXS) experiments reveal that nanoparticles spontaneously nucleate after 5000 s of reaction time in the pure DES before slow growth. Contrast effects observed in SANS measurements suggest that hydrated DES preferentially form 1D particle morphologies because of choline selectively capping surface crystal facets to direct growth along certain axes, whereas capping is restricted by the solvent structure in the pure DES.

Morphology Modulation of Ionic Surfactant Micelles in Ternary Deep Eutectic Solvents.

Deep eutectic solvents (DES) are potentially greener solvents obtained through the complexation of simple precursors which, among other applications, have been investigated in recent years for their ability to support the self-assembly of amphiphilic molecules. It is crucial to understand the factors which influence surfactant solubility and self-assembly with respect to the interaction of the surfactant molecule with the DES components. In this work, small-angle neutron scattering (SANS) has been used to investigate the micellization of cationic (CnTAB) and anionic (SDS) surfactants in a ternary DES comprising choline chloride, urea, and glycerol, where the hydrogen bond donors are mixed in varying molar ratios. The results show that in each case either globular or rodlike micelles are formed with the degree of elongation being directly dependent on the composition of the DES. It is hypothesized that this composition dependence arises largely from the poor solubility of the counterions in the DES, especially at low glycerol content, leading to a tighter binding of the counterion to the micelle surface and giving rise to micelles with a high aspect ratio. This potential for accurate control over micelle morphology presents unique opportunities for rheology control or to develop templated syntheses of porous materials in DES, utilizing the solvent composition to tailor micelle shape and size, and hence the pore structure of the resulting material.

Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway.

Reactive oxygen species (ROS) play critical roles in metabolism and disease, yet a comprehensive analysis of the cellular response to oxidative stress is lacking. To systematically identify regulators of oxidative stress, we conducted genome-wide Cas9/CRISPR and shRNA screens. This revealed a detailed picture of diverse pathways that control oxidative stress response, ranging from the TCA cycle and DNA repair machineries to iron transport, trafficking, and metabolism. Paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, disruption of peroxisomal import unexpectedly increases resistance to oxidative stress by altering the localization of catalase. Together, these studies provide insights into the roles of peroxisomal matrix import and the PPP in redox biology and represent a rich resource for understanding the cellular response to oxidative stress.

Applying for regulatory approval of a clinical trial of a medical device in the UK - A practical guide.

Seeking regulatory and ethical approval is a significant task that must be completed before conducting a clinical trial of a medical device. Currently in the UK, the Integrated Research Application System (IRAS) is a unified system for preparing regulatory, ethical and governance applications for the relevant bodies that must approve health and social research. This article outlines key aspects in planning a clinical trial of a medical device and how applications for approval can be prepared using IRAS.

Silencing a phloretin-specific glycosyltransferase perturbs both general phenylpropanoid biosynthesis and plant development.

The polyphenol profile of apple (Malus × domestica) is dominated by the dihydrochalcone glycoside phloridzin, but its physiological role is yet to be elucidated. Biosynthesis of phloridzin occurs as a side branch of the main phenylpropanoid pathway, with the final step mediated by the phloretin-specific glycosyltransferase UGT88F1. Unexpectedly, given that UGTs are sometimes viewed as 'decorating enzymes', UGT88F1 knockdown lines were severely dwarfed, with greatly reduced internode lengths, narrow lanceolate leaves, and changes in leaf and fruit cellular morphology. These changes suggested that auxin transport had been altered in the knockdown lines, which was confirmed in assays showing that auxin flux from the shoot apex was increased in the transgenic lines. Metabolite analysis revealed no accumulation of the phloretin aglycone, as well as decreases in many non-target phenylpropanoid compounds. This decreased accumulation of metabolites appeared to be mediated by the repression of the phenylpropanoid pathway via a reduction in key transcript levels (e.g. phenylalanine ammonia lyase, PAL) and enzyme activities (PAL and chalcone synthase). Application of exogenous phloridzin to the UGT88F1 knockdown lines in tissue culture enhanced axial leaf growth and partially restored some aspects of 'normal' apple leaf growth. Together, our results strongly implicate dihydrochalcones as critical compounds in modulating phenylpropanoid pathway flux and establishing auxin patterning early in apple development.

An assessment of silver copper sulfides for photovoltaic applications: theoretical and experimental insights.

As the worldwide demand for energy increases, low-cost solar cells are being looked to as a solution for the future. To attain this, non-toxic earth-abundant materials are crucial, however cell efficiencies for current materials are limited in many cases. In this article, we examine the two silver copper sulfides AgCuS and Ag3CuS2 as possible solar absorbers using hybrid density functional theory, diffuse reflectance spectroscopy, XPS and Hall effect measurements. We show that both compounds demonstrate promising electronic structures and band gaps for high theoretical efficiency solar cells, based on Shockley-Queisser limits. Detailed analysis of their optical properties, however, indicates that only AgCuS should be of interest for PV applications, with a high theoretical efficiency. From this, we also calculate the band alignment of AgCuS against various buffer layers to aid in future device construction.

Predictors and outcomes of early adherence to the use of a home telehealth device by older veterans with heart failure.

OBJECTIVES: The present study examined home telehealth (HT) adherence, and its potential predictors and outcomes, in older Veterans with heart failure (HF) using the Health Buddy (Bosch Healthcare, Palo Alto, CA) device. SUBJECTS AND METHODS: This was a retrospective study using secondary data from the Department of Veterans Affairs (VA) databases, describing adherence rates and patterns in the first 90 days after enrollment in 248 older Veterans with HF enrolled in the VA HT Programs using the Health Buddy at five medical centers in Southern California and Nevada, between June 1, 2006 and June 1, 2008. Adherence to the use of Health Buddy was defined as the number of days the patient completed an HT session over different time frames during the study period. RESULTS: Significant differences occurred between average adherence across all three 30-day time frame increments, with adherence decreasing over time. Despite the use of standardized VA HT protocols and equipment, the department in which the HT program was embedded was a consistent significant predictor of patient adherence in all time frames, with odds ratios of 2.2-4.0 for the department with the consistent best adherence versus that with the worse adherence (confidence intervals varying with the time frame, p<0.03). Increased co-morbidity burden was associated with decreased adherence only in the first 30 days after enrollment. In this short-term study, no relationship was found between adherence to the use of the Health Buddy and outcomes. CONCLUSIONS: Program and patient characteristics warrant further study as potential predictors of HT device adherence. Additional research is also needed to further examine the relationships between HT device adherence and various outcomes.

Barriers in the management of glucocorticoid-induced osteoporosis.

OBJECTIVE: To determine present practice for the management of glucocorticoid-induced osteoporosis (GIOP) in veterans; to characterize provider knowledge, beliefs, and practice behaviors regarding management of GIOP; and to identify potential barriers and interventions in the management of GIOP. METHODS: To characterize current management of GIOP in an academic veterans administration medical center, we conducted a retrospective chart review of 100 patients who were prescribed a 90-day supply of prednisone. To assess clinicians' knowledge of GIOP clinical guidelines and perceptions of GIOP management, primary care clinicians and subspecialists completed a questionnaire and participated in focus groups. RESULTS: Chart review revealed that only 32 of 100 patients receiving long-term glucocorticoid treatment underwent bone mineral density testing, and only 32 patients were prescribed the recommended calcium supplements. Of the 23 providers who completed the questionnaire and participated in the focus groups, 4 correctly identified both the dose and duration of glucocorticoid use at which GIOP prevention measures should be instituted. Common GIOP management barriers cited by participants were lack of knowledge, having limited time during the clinic visit to address all problems, patient nonadherence, and system problems. The most commonly mentioned potential interventions were the use of computerized clinical reminders and patient education. CONCLUSION: Clinicians frequently do not follow recommended guidelines for the management of GIOP. Improving the management of GIOP will likely require a fundamental redesigning of care processes for this disorder in order to overcome provider, patient-related, and system barriers.