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Introduction Home-based, virtually-supported care models may represent the most efficient and scalable approach to delivering prehabilitation services. However, virtual approaches to prehabilitation are understudied. This manuscript describes the protocol for an internal pilot randomised controlled trial of a virtually-delivered, multimodal prehabilitation intervention.Methods and analysis We will conduct a pragmatic, individual patient, internal pilot randomised controlled trial of home-based, virtually supported, multimodal prehabilitation compared with standard perioperative care in adults undergoing elective, inpatient thoracic, abdominal, pelvic and vascular surgery at five Canadian hospitals. Participants will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of 3–12 weeks of a home-based, multimodal (exercise, nutrition and psychosocial support) prehabilitation programme supported through an online platform. The primary feasibility outcomes and their progression targets are (1) monthly recruitment of>6 participants at each centre, (2) intervention adherence of>75%, (3) retention of>90% of participants at the patient-reported primary outcome point of 30-days after surgery and (4) elicitation of patient, clinician and researcher-identified barriers to our pragmatic trial. A sample size of 144 participants will be adequate to estimate recruitment, adherence and retention rates with acceptable precision. All participants will be followed to either death or up to 1 year. As an internal pilot, if no substantive changes to the trial or intervention design are required, pilot participant outcome data will migrate, unanalysed by allocation, to the future full-scale trial.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 4479) and our ethics review board (Protocol Approval #20230399–01T). Results will be disseminated through presentations at scientific conferences, peer-reviewed publications, partner organisations and engagement of social and traditional media.Trial registration number ClinicalTrials.gov identifier NCT06042491. Protocol, V.1.2, dated 6 June 2024.

Microbiomes, populations of microscopic organisms, have been found to be related to human health and it is expected further investigations will lead to novel perspectives of disease. The data used to analyze microbiomes is one of the newest types (the result of high-throughput technology) and the means to analyze these data is still rapidly evolving. One of the distributions that have been introduced into the microbiome literature, the Dirichlet-Multinomial, has received considerable attention. We extend this distribution's use uncover compositional relationships between organisms at a taxonomic level. We apply our new method in two real microbiome data sets: one from human nasal passages and another from human stool samples. [ABSTRACT FROM AUTHOR]

Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the combination of pembrolizumab with the antibody-drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients.

A significant problem in high-throughput drug screening is the disproportionate number of false hits associated with drug candidates that form colloidal aggregates. Such molecules, referred to as promiscuous inhibitors, nonspecifically inhibit multiple enzymes and are thus not useful as potential drugs. Here, we report a printable hydrogel-based drug-screening platform capable of non-ambiguously differentiating true enzyme inhibitors from promiscuous aggregating inhibitors, critical for accelerating the drug discovery process. The printed hydrogels can both immobilize as well as support the activity of entrapped enzymes against drying or treatment with a protease or chemical denaturant. Furthermore, the printed hydrogel can be applied in a high-throughput microarray-based screening platform (consistent with current practice) to rapidly ( <25 min) and inexpensively identify only clinically promising lead compounds with true inhibitory potential as well as to accurately quantify the dose-response relationships of those inhibitors, all while using 95% less sample than required for a solution assay.

Cyclodextrins (CDs) are typically functionalized to increase their solubility or provide reactive functional groups suitable for grafting onto polymer supports designed for controlled release applications. In this work, a systematic investigation was performed on the binding behaviour of the model drug dexamethasone with βCD derivatives functionalized with a small, negatively charged moiety (carboxyl groups, CM) and a large, neutral, reactive moiety (hydrazide groups, Hzd), both free and grafted to dextran. Solubilization capacities and thermodynamic parameters were examined through phase solubility analysis, the method of continuous variation, and isothermal titration calorimetry. Alternate mechanisms of solubilization were also investigated by probing aggregation of both free and complexed βCD derivatives using nanoparticle tracking analysis. CM/βCD and Hzd/βCD derivatives exhibited similar complexation behaviours with dexamethasone: 1:1 stoichiometry, linear phase solubility profiles, and consistent binding enthalpies. Increased functionalization reduced the complex stability constant as well as the complexation efficiency, while polymer grafting resulted in no significant change in binding properties. CM/βCD derivatives complexed with dexamethasone formed more and larger aggregates, while Hzd/βCD derivatives formed significantly fewer, smaller aggregates and dextran-grafted βCD did not aggregate. Such characterization of βCD derivatives provides a framework for designing βCDs as pharmaceutical excipients or drug binding sites in drug delivery vehicles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Injectable, degradable hydrogels based on cross-linking between aldehyde-functionalized dextran, hydrazide-functionalized dextran, and hydrazide-functionalized beta-cyclodextrin (βCD) were developed for hydrophobic drug delivery. βCD functions as both the in situ-gelling agent driving hydrogel formation as well as the binding site for the hydrophobic model drug, dexamethasone. In hydrogel systems where βCD is primarily covalently attached to the polymer network through cross-linking, the amount of drug release per sampling point is independent of the time between samples, the solubility of drug in the release medium, and the cross-link density of the hydrogel; instead, drug release is controlled primarily by partitioning of free (water-solubilized) drug between the hydrogel and the release medium. When the concentration of the hydrazide-functionalized dextran polymer was increased and more hydrazide groups were available to compete with βCD reactive sites for cross-linking the polymers, greater than ten-fold more drug was released from the hydrogel during the 20 day sampling period. Mobile, non-cross-linked βCD increases the solubility of the drug and facilitates rapid drug release by diffusion, as confirmed by quenching βCD-bound hydrazide groups. In this way, via a very subtle change in the composition of the injectable hydrogel, both the kinetics of drug release as well as the mechanism of drug release can be tuned over a wide range. Together with the low cytotoxicity of the materials, these results suggest that injectable βCD-based hydrogels have potential for facilitating controlled release of hydrophobic drugs over multiple time scales by controlling the mobility of βCD within the hydrogel network.