Study protocol for two stepped-wedge interventional trials evaluating the effects of holistic information technology-based patient-oriented management in older multimorbid patients with cancer: The GERONTE trials.

INTRODUCTION: Current hospital-based care pathways are generally single-disease centred. As a result, coexisting morbidities are often suboptimally evaluated and managed, a deficiency becoming increasingly apparent among older patients who exhibit heterogeneity in health status, functional abilities, frailty, and other geriatric impairments. To address this issue, our study aims to assess a newly developed patient-centred care pathway for older patients with multimorbidity and cancer. The new care pathway was based on currently available evidence and co-designed by end-users including health care professionals, patients, and informal caregivers. Within this care pathway, all healthcare professionals involved in the care of older patients with multimorbidity and cancer will form a Health Professional Consortium (HPC). The role of the HPC will be to centralise oncologic and non-oncologic treatment recommendations in accordance with the patient's priorities. Moreover, an Advanced Practice Nurse will act as case-manager by being the primary point of contact for the patient, thus improving coordination between specialists, and by organising and leading the consortium. Patient monitoring and the HPC collaboration will be facilitated by digital communication tools designed specifically for this purpose, with the added benefit of being customisable for each patient. MATERIALS AND METHODS: The GERONTE study is a prospective international, multicentric study consisting of two stepped-wedge trials performed at 16 clinical sites across three European countries. Each trial will include 720 patients aged 70 years and over with a new or progressive cancer (breast, lung, colorectal, prostate) and at least one moderate or severe multimorbidity. The patients in the intervention group will receive the new care pathway whereas patients in the control group will receive usual oncologic care. DISCUSSION: GERONTE will evaluate whether this kind of holistic, patient-oriented healthcare management can improve quality of life (primary outcome) and other valuable endpoints in older patients with multimorbidity and cancer. An ancillary study will assess in depth the socio-economic impact of the intervention and deliver concrete implementation guidelines for the GERONTE intervention care pathway. TRIAL REGISTRATION: FRONE: NCT05720910 TWOBE: NCT05423808.

Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC).

The molecular basis for the signal transduction through the classical Cys-loop receptors (CLRs) has been delineated in great detail. The Zinc-Activated Channel (ZAC) constitutes a so far poorly elucidated fifth branch of the CLR superfamily, and in this study we explore the molecular mechanisms underlying ZAC signaling in Xenopus oocytes by two-electrode voltage clamp electrophysiology. In studies of chimeric receptors fusing either the extracellular domain (ECD) or the transmembrane/intracellular domain (TMD-ICD) of ZAC with the complementary domains of 5-HT3A serotonin or α1 glycine receptors, serotonin and Zn2+/H+ evoked robust concentration-dependent currents in 5-HT3A/ZAC- and ZAC/α1-Gly-expressing oocytes, respectively, suggesting that Zn2+ and protons activate ZAC predominantly through its ECD. The molecular basis for Zn2+-mediated ZAC signaling was probed further by introduction of mutations of His, Cys, Glu and Asp residues in this domain, but as none of the mutants tested displayed substantially impaired Zn2+ functionality compared to wild-type ZAC, the location of the putative Zn2+ binding site(s) in the ECD was not identified. Finally, the functional importance of Leu246 (Leu9') in the transmembrane M2 α-helix of ZAC was investigated by Ala, Val, Ile and Thr substitutions. In concordance with findings for this highly conserved residue in classical CLRs, the ZACL9'X mutants exhibited left-shifted agonist concentration-response relationships, markedly higher degrees of spontaneous activity and slower desensitization kinetics compared to wild-type ZAC. In conclusion, while ZAC is an atypical CLR in terms of its (identified) agonists and channel characteristics, its signal transduction seems to undergo similar conformational transitions as those in the classical CLR.

A touch of awe: crafting meaning from the wonder of the cosmos.

From the birth of galaxies to the self-organizing dynamics of our planet to the ongoing expansion of the universe, the more we discover about the evolution of the cosmos, the more acutely we realize the enormity of what remains to be known. Just this year astrophysicists at the University of Nottingham confirmed that there are at least two trillion galaxies in the cosmos, 10 times more than had been previously thought. What guidance or wisdom can the study of cosmology and astrophysics offer us in our search for meaning and purpose? In conversation with Steve Paulson, executive producer and host of To the Best of Our Knowledge, theoretical physicists Paul Davies and Ard Louis, and astrophysicist Lucianne Walkowicz share their perceptions based on years of gazing upward and beyond our own intimate planet.

Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors.

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors.

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.

The structure of lipid bilayers adsorbed on activated carboxy-terminated monolayers investigated by sum frequency generation spectroscopy.

The formation and structure of isotopically asymmetric supported bilayer membranes (SBMs) has been investigated using sum frequency generation (SFG) vibrational spectroscopy supplemented by reflection absorption infrared spectroscopy (RAIRS). The bilayers were composed of a proximal and distal leaflet of the phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) supported on a gold surface. The proximal leaflet was chemically tethered to the gold via an 11-mercapto-undecanoic acid (MUA) self-assembled monolayer (SAM) that had been chemically modified to produce an activated succinimidyl ester headgroup using N-hydroxysuccinimide (NHS) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). The activation of the MUA and the tethering of the DPPE were monitored and confirmed using SFG and RAIRS. The distal leaflet of the bilayer was added using either vesicle fusion (VF) or Langmuir-Blodgett (LB) deposition. To gain insight into the structure of each layer of the SBM perdeuterated DPPE (d-DPPE) and MUA (d-MUA) were used to create SBMs with a layer that was isotopically distinguishable from the rest. The polar orientation and conformational ordering of the lipids was determined using SFG. It was found that the tethering of the proximal lipid leaflet resulted in an increase in the conformational order of the MUA SAM. Furthermore, by careful analysis and comparison of spectra recorded in both the C-H (2800-3000 cm(-1)) and C-D (2000-2300 cm(-1)) stretching regions it was concluded that a better ordered and more biologically relevant lipid bilayer was formed when the distal leaflet was added using LB deposition. On the other hand the SFG spectra of the SBMs in which the distal leaflet was added by VF showed little evidence of conformational ordering on the time scale of minutes, suggesting the presence of an incomplete monolayer or of multilayer formation.

Partial replacement of an artificial nectar diet with native browse for feather-tail gliders (Acrobates pygmaeus) in captivity.

Captive-bred feather-tail gliders (Acrobates pygmaeus) housed at Taronga Zoo have had a long history of eye cholesterol plaques that may be associated with a largely sugar-based diet such as artificial nectar. The gliders also have prolonged periods of reduced activity when they are not visible in exhibits. This may be due to the ad libitum supply of an energy rich feed and reduced need to forage. This study examined behavioral and physiological changes associated with supplementing the high sugar-based diet with two species of native browse. The experiment was conducted over two consecutive periods of 3 weeks and consisted of two treatment groups: one group was offered the artificial nectar only, while the other group was offered the artificial nectar supplemented with a variety of native flowers. Live weight was recorded weekly. There was no change (P > 0.10) in artificial nectar intake with the supplementation of native browse in the diet. Blood metabolites (cholesterol, triglycerides, glucose) tested for the two groups had no differences (P > 0.10) between treatments. Upon examination, there were no signs of tooth decay or cholesterol plaques in all animals throughout the experiment. Feed intake and behavior were recorded via sensor cameras. There was an increase (P < 0.05) in the daily foraging activity of gliders supplemented with native flowers compared to gliders fed the artificial nectar alone. In conclusion, supplementing to provide a more native diet to A. pygmaeus enhanced their natural foraging behavior, suggesting that it may result in long-term improvements in their health.

Adsorption of 1- and 2-butylimidazoles at the copper/air and steel/air interfaces studied by sum frequency generation vibrational spectroscopy.

The structure of thin films of 1- and 2-butylimidazoles adsorbed on copper and steel surfaces under air was examined using sum frequency generation (SFG) vibrational spectroscopy in the ppp and ssp polarizations. Additionally, the SFG spectra of both isomers were recorded at 55 °C at the liquid imidazole/air interface for reference. Complementary bulk infrared, reflection-absorption infrared spectroscopy (RAIRS), and Raman spectra of both imidazoles were recorded for assignment purposes. The SFG spectra in the C-H stretching region at the liquid/air interface are dominated by resonances from the methyl end group of the butyl side chain of the imidazoles, indicating that they are aligned parallel or closely parallel to the surface normal. These are also the most prominent features in the SFG spectra on copper and steel. In addition, both the ppp and ssp spectra on copper show resonances from the C-H stretching modes of the imidazole ring for both isomers. The ring C-H resonances are completely absent from the spectra on steel and at the liquid/air interface. The relative intensities of the SFG spectra can be interpreted as showing that, on copper, under air, both butylimidazoles are adsorbed with their butyl side chains perpendicular to the interface and with the ring significantly inclined away from the surface plane and toward the surface normal. The SFG spectra of both imidazoles on steel indicate an orientation where the imidazole rings are parallel or nearly parallel to the surface. The weak C-H resonances from the ring at the liquid/air interface suggest that the tilt angle of the ring from the surface normal at this interface is significantly greater than it is on copper.

The role of Broca's area in regular past-tense morphology: an event-related potential study.

It has been suggested that damage to anterior regions of the left hemisphere results in a dissociation in the perception and lexical activation of past-tense forms. Specifically, in a lexical-decision task in which past-tense primes immediately precede present-tense targets, such patients demonstrate significant priming for irregular verbs (spoke-speak), but, unlike control participants, fail to do so for regular verbs (looked-look). Here, this behavioral dissociation was first confirmed in a group of eleven patients with damage to the pars opercularis (BA 44) and pars triangularis (BA 45) of the left inferior frontal gyrus (i.e., Broca's area). Two conditions containing word-onset orthographic-phonological overlap (bead-bee, barge-bar) demonstrated that the disrupted regular-verb priming was accompanied by, and covaried with, disrupted ortho-phonological priming, regardless of whether prime stimuli contained the regular inflectional rhyme pattern. Further, the dissociation between impaired regular-verb and preserved irregular-verb priming was shown to be continuous rather than categorical; priming for weak-irregular verbs (spent-spend) was intermediate in size between that of regular verbs and strong verbs. Such continuous dissociations grounded in ortho-phonological relationships between present- and past-tense forms are predicted by single-system, connectionist approaches to inflectional morphology and not predicted by current dual-system, rule-based models. Event-related potential data demonstrated that N400 priming effects were intact for both regular and irregular verbs, suggesting that the absence of significant regular-verb priming in the response time data did not result from a disruption of lexical access, and may have stemmed instead from post-lexical events such as covert articulation, segmentation strategies, and/or cognitive control.

A bacterium that can grow by using arsenic instead of phosphorus.

Life is mostly composed of the elements carbon, hydrogen, nitrogen, oxygen, sulfur, and phosphorus. Although these six elements make up nucleic acids, proteins, and lipids and thus the bulk of living matter, it is theoretically possible that some other elements in the periodic table could serve the same functions. Here, we describe a bacterium, strain GFAJ-1 of the Halomonadaceae, isolated from Mono Lake, California, that is able to substitute arsenic for phosphorus to sustain its growth. Our data show evidence for arsenate in macromolecules that normally contain phosphate, most notably nucleic acids and proteins. Exchange of one of the major bio-elements may have profound evolutionary and geochemical importance.

Interpreting dissociations between regular and irregular past-tense morphology: evidence from event-related potentials.

Neuropsychological dissociations between regular and irregular English past-tense morphology have been reported using a lexical decision task in which past-tense primes immediately precede present-tense targets. We present N400 event-related potential data from healthy participants using the same design. Both regular and irregular past-tense forms primed corresponding present-tense forms, but with a longer duration for irregular verbs. Phonological control conditions suggested that differences in formal overlap between prime and target contribute to, but do not account for, this difference, suggesting a link between irregular morphology and semantics. Further analysis dividing the irregular verbs into two categories (weak irregular and strong) revealed that priming for strong verbs was reliably stronger than that for weak irregular and regular verbs, which were statistically indistinguishable from one another. We argue that, although we observe a regular-irregular dissociation, the nature of this dissociation is more consistent with single- than with dual-system models of inflectional morphology.

Pollen proteolytic enzymes degrade tight junctions.

BACKGROUND AND OBJECTIVE: Asthma and allergic rhinitis are significant, increasing causes of morbidity worldwide. Pollen, a major cause of seasonal rhinitis/conjunctivitis, carries proteolytic enzymes on its surface. We showed previously that peptidase allergens from house dust mites compromise epithelial barrier function by degrading the extracellular domains of the tight junction proteins, occludin and claudin, thus facilitating allergen delivery across epithelial layers. In this study, we aimed to determine whether peptidases from allergenic pollens should similarly be considered to have a role in disrupting tight junctions. METHODS: Diffusates from stored pollen of Giant Ragweed, White Birch and Kentucky Blue Grass, and fresh pollen from Easter Lily were applied to confluent monolayers of Madin-Darby canine kidney (MDCK) and Calu-3 cells in serum-free medium. Immunofluorescence was performed for the tight junction proteins, occludin, claudin-1 and ZO-1. The effect of pollen diffusate on occludin was studied by Western blotting, and enzymatic activity in the diffusates was demonstrated by zymography. The ability of protease inhibitors to block the action of the diffusate on tight junctions was investigated. RESULTS: Diffusates from all four allergenic pollens caused loss of immunofluorescence labelling for tight junction proteins on MDCK and Calu-3 cells. The effect was blocked by inhibitors of serine and cysteine proteases. Degradation of occludin was demonstrated by Western blotting and zymography indicated that diffusates contain proteolytic activity. CONCLUSIONS: Pollen peptidases directly or indirectly disrupt epithelial tight junctions, and this activity should be considered as a possible mechanism for facilitating allergen delivery across epithelia.

Introducing an integrated care pathway for the last days of life.

Integrated care pathways (ICPs) are multiprofessional documents designed to enable the implementation of evidence-based care and support the practical delivery of clinical governance. However, the implementation of care pathways is resource intensive and few evaluations have been conducted with respect to these areas or to the efficacy of care pathways to change practice and improve outcomes in care. This project sought to address these issues and the report outlines the approach taken by a palliative care team in South Wales, UK, to implement a care pathway for the dying throughout a district general hospital and six community hospitals. Dying can be a complex area of care and changing practice can be challenging, therefore a PRINCE Project management approach was taken and a full-time project nurse employed for the life of the project. This paper describes the strategies used to approach implementing a care pathway and provides a template for other teams who may embark on similar projects. At the end of the project, the care pathway was successfully implemented and provided demonstrable outcomes of care for those dying from cancer and nonmalignant diseases. Strikingly, a large number of patients dying from nonmalignant disease were cared for via the pathway, which was not expected.

A survey of a novel epilepsy clinic.

The management of a group of epilepsy patients from primary care, in a geographical area with clear epilepsy management guidelines and secondary care clinics is surveyed. Suggestions are made to improve liaison between primary and secondary care as well as epilepsy management in primary care. All 42 local primary care practices were invited to take part in this project. A study day providing a broad overview of epilepsy management was held. Those attending were expected to identify all patients in their practice with epilepsy using diagnostic codes and prescribing data. Nine of the invited 42 practices took part in the project, and identified 506 patients prescribed anti-epilepsy drugs (AEDs). Three hundred and three patients were invited for review by their practice nurse, following exclusion of those prescribed AEDs for other conditions, children and those already under specialist review. One hundred and sixteen patients attended for review. Seventy-one patients were identified as requiring specialist review and a consultant neurologist, epilepsy nurse specialist and clinical assistant completed them. Of the 71 patients 31 had experienced no seizures for 5 years, 40 had experienced seizures in the past 5 years, of whom 32 had experienced seizures in the last year. Sixteen were suffering at least one seizure per month, and a few had poorly controlled epilepsy. Patients were taking mainly Phenytoin, Carbamazepine and Sodium valproate. Twenty were taking polytherapy and one no treatment.Fifty-two patients reported side effects and 15 poor compliance. Many patients reviewed were considered to be taking unnecessary medication and suffering unnecessary side effects. There is a need for improved epilepsy management in primary care and better liaison between primary and secondary care.