Improving the Decay Resistance of Wood through the Fixation of Different Nanoparticles Using Silica Aerogel.

Nowadays, the protection of wood is becoming more important with the increasing demand for durable wood, in addition to its limited accessibility. One possible way to increase the durability is the use of nanoparticles, which can be effective even with a low intake of active ingredients. However, avoiding their leaching is a challenge. A possible solution to leaching is the use of silica aerogel as a fixative. This study investigated the use of mesoporous silica aerogel against the leaching of different nanoparticles under laboratory conditions. Tests were performed involving beech (Fagus sylvatica) and Scots pine (Pinus sylvestris) sapwood, using Trametes versicolor as a white rot and Coniophora puteana as a brown rot fungus. The results show that the subsequent treatment of the wood with mesoporous silica aerogel effectively fixed the nanoparticles in wood. The durability of the samples without aerogel significantly decreased as a result of leaching, whereas the resistance of the samples treated with aerogel decreased only slightly. However, the silica aerogel modification itself caused the leaching of silver nanoparticles, which is a limitation in the use of this method for the fixation of nanoparticles.

The Meteoritics Trial: efficacy of methotrexate after remission-induction with tocilizumab and glucocorticoids in giant cell arteritis-study protocol for a randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Glucocorticoids (GC) are the standard treatment for giant cell arteritis (GCA), even though they are associated with adverse side effects and high relapse rates. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, has shown promise in sustaining remission and reducing the cumulative GC dosage, but it increases the risk of infections and is expensive. After discontinuation of TCZ, only about half of patients remain in remission. Additionally, only few studies have been conducted looking at remission maintenance, highlighting the need for alternative strategies to maintain remission in GCA. Methotrexate (MTX) has been shown to significantly decrease the risk of relapse in new-onset GCA and is already a proven safe drug in many rheumatologic diseases. METHODS: This study aims to evaluate the efficacy and safety of MTX in maintaining remission in patients with GCA who have previously been treated with GC and at least 6 months with TCZ. We hypothesize that MTX can maintain remission in GCA patients, who have achieved stable remission after treatment with GC and TCZ, and prevent the occurrence of relapses. The study design is a monocentric, randomized, double-blind, placebo-controlled, parallel-group phase II trial randomizing 40 GCA patients 1:1 into a MTX or placebo arm. Patients will receive 17.5 mg MTX/matching placebo weekly by subcutaneous injection for 12 months, with the possibility of dose reduction if clinically needed. A 6-month follow-up will take place. The primary endpoint is the time to first relapse in the MTX group versus placebo during the 12-month treatment period. Secondary outcomes include patient- and investigator-reported outcomes and laboratory findings, as well as the prevalence of aortitis, number of vasculitic vessels, and change in intima-media thickness during the study. DISCUSSION: This is the first clinical trial evaluating remission maintenance of GCA with MTX after a previous treatment cycle with TCZ. Following the discontinuation of TCZ in GCA, MTX could be a safe and inexpensive drug. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05623592. Registered on 21 November 2022. EU Clinical Trials Register, 2022-501058-12-00. German Clinical Trials Register DRKS00030571.

Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial: Study protocol for a randomized controlled trial.

RATIONALE: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. While the primary injury results from the initial bleeding cannot currently be influenced, secondary injury through vasospasm and delayed cerebral ischemia worsens outcome and might be a target for interventions to improve outcome. To date, beside the aneurysm treatment to prevent re-bleeding and the administration of oral nimodipine, there is no therapy available, so novel treatment concepts are needed. Evidence suggests that inflammation contributes to delayed cerebral ischemia and poor outcome in SAH. Some studies suggest a beneficial effect of anti-inflammatory glucocorticoids, but there are no data from randomized controlled trials examining the efficacy of glucocorticoids. Therefore, current guidelines do not recommend the use of glucocorticoids in SAH. AIM: The Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial aims to determine whether dexamethasone improves outcome in a clinically relevant endpoint in SAH patients. METHODS AND DESIGN: FINISHER is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical phase III trial which is testing the outcome and safety of anti-inflammatory treatment with dexamethasone in SAH patients. SAMPLE SIZE ESTIMATES: In all, 334 patients will be randomized to either dexamethasone or placebo within 48 h after SAH. The dexamethasone dose is 8 mg tds for days 1-7 and then 8 mg od for days 8-21. STUDY OUTCOME: The primary outcome is the modified Rankin Scale (mRS) at 6 months, which is dichotomized to favorable (mRS 0-3) versus unfavorable (mRS 4-6). DISCUSSION: The results of this study will provide the first phase III evidence as to whether dexamethasone improves outcome in SAH.

PrImary decompressive Craniectomy in AneurySmal Subarachnoid hemOrrhage (PICASSO) trial: study protocol for a randomized controlled trial.

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (SAH) is associated with poor neurological outcome and high mortality. A major factor influencing morbidity and mortality is brain swelling in the acute phase. Decompressive craniectomy (DC) is currently used as an option in order to reduce intractably elevated intracranial pressure (ICP). However, execution and optimal timing of DC remain unclear. METHODS: PICASSO resembles a multicentric, prospective, 1:1 randomized standard treatment-controlled trial which analyzes whether primary DC (pDC) performed within 24 h combined with the best medical treatment in patients with poor-grade SAH reduces mortality and severe disability in comparison to best medical treatment alone and secondary craniectomy as ultima ratio therapy for elevated ICP. Consecutive patients presenting with poor-grade SAH, defined as grade 4-5 according to the World Federation of Neurosurgical Societies (WFNS), will be screened for eligibility. Two hundred sixteen patients will be randomized to receive either pDC additional to best medical treatment or best medical treatment alone. The primary outcome is the clinical outcome according to the modified Rankin Scale (mRS) at 12 months, which is dichotomized to favorable (mRS 0-4) and unfavorable (mRS 5-6). Secondary outcomes include morbidity and mortality, time to death, length of intensive care unit (ICU) stay and hospital stay, quality of life, rate of secondary DC due to intractably elevated ICP, effect of size of DC on outcome, use of duraplasty, and complications of DC. DISCUSSION: This multicenter trial aims to generate the first confirmatory data in a controlled randomized fashion that pDC improves the outcome in a clinically relevant endpoint in poor-grade SAH patients. TRIAL REGISTRATION: DRKS DRKS00017650. Registered on 09 June 2019.

Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial.

BACKGROUND: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology. METHODS: In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6-12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint. DISCUSSION: This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality. TRIAL REGISTRATION: EudraCT 2021-000708-39 . Registered on 08 February 2021.

Evaluation of the effect of naltrexone coadministration on the pharmacokinetics of oxycodone in a randomized phase 1 clinical trial
.

OBJECTIVE: Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid receptor antagonist -naltrexone is often coadministered to healthy subjects in clinical trials evaluating the pharmacokinetics (PK) of oxycodone to minimize its pharmacodynamic opioid effects. One objective of this relative bioavailability trial in healthy subjects was to investigate the effect of naltrexone on the PK of oxycodone. MATERIALS AND METHODS: A randomized, single-dose, parallel-group, within-groups crossover, clinical trial was conducted in 24 healthy subjects. 12 subjects were to receive a new oxycodone prolonged-release (PR) tablet (test) with naltrexone (T+) and without naltrexone (T) in the fasted state. Additionally, 12 subjects were to receive an Oxygesic PR tablet (reference) with naltrexone (R+) and without naltrexone (R) in the fasted state. Naltrexone was given orally 1.5 hours prior to each oxycodone administration. Pharmacokinetics, safety, and tolerability were assessed. RESULTS: The PK parameters of either oxycodone formulation were not changed with naltrexone administration under fasted conditions (point estimate T+/T (corresponding 90% confidence interval): Cmax: 103% (88 - 119%), AUC0-t: 97% (87 - 108%), AUC: 97% (88 - 108%); point estimate R+/R (corresponding 90% confidence interval): Cmax: 104% (97 - 112%), AUC0-t: 95% (88 - 102%), AUC: 94% (87 - 100%)). The safety and tolerability of both formulations was not qualitatively affected by naltrexone coadministration; however, treatment with naltrexone coadministration showed lower frequencies of adverse events. CONCLUSION: Oral naltrexone does not affect the PK of oral oxycodone under fasted conditions. A naltrexone block can be applied in oxycodone PK trials to minimize adverse opioid effects.

Allelic variation in candidate genes associated with wood properties of cultivated poplars (Populus).

INTRODUCTION: Since Populus has veritable value as timber, plywood, pulp, and paper, genomic research should create the sound basis for further breeding toward desirable wood quality attributes. MATERIALS AND METHODS: In this study, we addressed the need for a research methodology that initially identifies and then characterize candidate genes encoding enzymes with wood property phenotypic traits, toward the aim of developing a genomics-based breeding technology. RESULTS: On 23 different poplar species/hybrid samples, we successfully amplified 55 primers designed on Populus trichocarpa L. Considering the number of polymorphic sites, out of 73,206 bp, 51 SNPs and 31 indel events were found. Non-synonymous single base mutations could be detected in number of 30, 21 out of 164 sequences were the number of minimum recombination events and 41 significant pairwise comparisons between loci could be detected. DISCUSSION AND CONCLUSION: Our results provide a roadmap for a future association genetic study between nucleotide diversity and precise evaluation of phenotype.

Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study.

BACKGROUND: Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure µ-opioid peptide receptor agonists. METHODS: We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 µg; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. RESULTS: Forty-two subjects completed the study. Cebranopadol 200 and 400 µg did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 µg were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. CONCLUSIONS: These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure µ-opioid peptide agonist.

Correction to: Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic.

For each simulation, PK profiles from 1000 subjects were simulated based on a titration scheme.

Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic.

BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials. RESULTS: After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (4-6 h), a long half-value duration [HVD] (14-15 h), and a terminal phase half-life in the range of 62-96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70-80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200-1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration. CONCLUSIONS: Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4-6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.

Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials.

A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.

Photodegradation of wood at elevated temperature: infrared spectroscopic study.

The purpose of this investigation was to evaluate the effect of elevated temperature on the photodegradation of solid wood. The work presented here, deals with the changes of infrared spectrum generated by the photodegradation process. Wood samples were irradiated with a mercury vapour lamp. The photodegradation behaviours of conifers and deciduous species were studied at elevated (80 °C) and at ambient (30 °C) temperatures. The infrared data were analysed using the difference spectrum method. The properly calculated difference spectrum gave much more information about the chemical changes than the visual comparison of the absorption spectra measured before and after the irradiation. The results showed considerably greater degradation at 80 °C than at 30 °C. The difference spectra revealed the absorption increase of tree different types of carbonyl groups. Remarkable differences were found between the photodegradation behaviours of softwoods and hardwoods. Poplar belongs anatomically to the hardwoods but its photodegradation properties were between that of hardwoods and softwoods.

[Reconstruction of soft tissue defect of the sole using an ALT flap]. / Talpi lágyrész-hiány pótlása ALT lebennyel.

Soft tissue defect of the sole is usually a quite challenging problem. In this case report the most frequently used reconstructive options of this problem are reviewed paying particular attention for the well applicable and reliable types. An ALT graft as a free flap to the sole offers a good possibility for coverage, which is resistant enough to mechanic strains.

Characterization of Au-Rh/TiO2 bimetallic nanocatalysts by CO and CH3CN adsorption: XPS, TEM and FTIR measurements.

On X-ray photoelectron spectra of the Au-Rh/TiO2 catalysts the position of Au4f peak was practically unaffected by the presence of rhodium, the peak position of Rh3d, however, shifted to lower binding energy with the increase of gold content of the catalysts. Rh enrichment in the outer layers of the bimetallic crystallites was experienced. The bands due to Au0-CO, Rh0-CO and (Rh0)2-CO were observed on the IR spectra of bimetallic samples, no signs for Rh+-(CO)2 were detected on these catalysts. The band due to CH3CN on Lewis acid centers shifted to lower wavenumbers with the increase of Rh content, which shows that the strength of Lewis acid sites weakens with the increase of Rh content of the catalysts. CH3CN, on the other hand, dissociates producing CN(a) species even at this temperature. From the shift to higher wavenumbers of the band due to CN(a) the strengthening of the C-N bond with increasing Rh content has been established. The results were interpreted by electron donation from titania through gold to rhodium and by the higher particle size of bimetallic crystallites. The effects of catalyst composition, reaction temperature and composition of the reacting gas mixtures have been studied on the oxidation of CO in the presence of hydrogen (PROX process). The presence of both O2 and H2 reduced the surface concentration of CO adsorbed on metallic sites. Mass spectroscopic analysis of the gas phase showed that gaseous CO2 formed in the highest amount in CO+O2 mixture, the presence of H2 suppressed the amount of CO2 produced. This negative effect of hydrogen was the lowest on 1% Rh/TiO2, the highest inhibition was observed on Au/TiO2 systems.

Juror reactions to jury duty: perceptions of the system and potential stressors.

Jurors were surveyed on their general perceptions of the court system and factors that may cause stress immediately after trial, after participating in a post-trial debriefing, and a month after trial. Jurors had an overall positive view of the court system but did report some perceived inequities. The two most stressful elements of jury duty were related to the complexity of the trial and the decision-making involved in the trial, although jurors reported low levels of stress overall. Women reported more stress than men, and trial characteristics such as trial length also affected stress levels. The debriefing intervention was perceived as helpful, but jurors' stress levels were similar at pre- and post-debriefing. Finally, although stress on some measures was lower at the 1 month follow-up, this reduction was not moderated by whether or not jurors received the debriefing.

Pretrial publicity and civil cases: a two-way street?

Published pretrial publicity (PTP) research has been conducted almost exclusively with criminal cases and has focused on PTP that is detrimental to the defense. The current research examined the effects of PTP in a civil case to determine if PTP can have a biasing effect against either the defendant or the plaintiff in civil litigation. In Experiment 1, participants exposed to PTP biased against the defendant were more likely to reach a liable verdict than participants who read a control article or PTP biased against the plaintiff Experiment 2 demonstrated that a judicial admonition did not reduce the biasing effect of PTP about a civil defendant. However, participants given the admonition both before and after the trial evidence viewed the defendant as less culpable than participants given the admonition after the trial only or not at all. The implications for the legal system are discussed.