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Anticonvulsant effects of novel and repurposed drugs on docetaxel-induced neuropathy in <i>C. elegans</i>

by Paola Ximena Gonzalez-Lerma, Crystal Lloyd, Scarlet J. Park, Ken Dawson-Scully

Chemotherapeutic agents used for most common cancers are frequently associated with neurotoxicity, which often include debilitating side effects such as seizures. Docetaxel, one of the most widely and effectively used chemotherapeutic drugs, is associated with an array of symptoms referred to as Docetaxel-Induced Peripheral Neuropathies (DIPNs), including motor neuropathy, tingling, muscle weakness, and numbness. In this study, we use the electroconvulsive assay to model DIPN-related muscle weakness in C. elegans, via shock induction. We show that acutely or chronically exposing nematodes to docetaxel increases time to recovery from shock-induced seizure-like behaviors. Additionally, we find that sildenafil citrate, a PDE-5 inhibitor, and a novel bicyclic bridge compound, Resveramorph-3 (RVM-3), are both effective at rescuing the animals from prolonged seizure-like movement duration following acute and chronic exposure to docetaxel. The results demonstrate that sildenafil citrate and RVM-3 are potential candidates for mitigating the neurological deficits resulting from DIPNs.

Determining the burden of falls amongst community-dwelling older people in Ireland to inform falls care delivery: secondary data analysis from the Irish longitudinal study on ageing - the defined study

Por: Briggs · R. · Ward · M. · Scarlett · S. · van der Velde · N. · Hernandez · B. · Romero-Ortuno · R. · Tysinger · B. · May · P. · Ahern · E. · Kenny · R. A.
Objective

Falls represent the most frequent reason older people are admitted to hospital and significantly increase the likelihood of functional decline, healthcare utilisation and early mortality. The aim of this study is to comprehensively delineate the burden of falls amongst community-dwelling older people in Ireland.

Design

Population-representative analysis of Wave 6 of the Irish Longitudinal Study on Ageing (TILDA) estimating incidence of falls requiring medical attention and emergency department (ED) attendance, fractures and fear of falling over 12 months. Additional data detailing falls-risk increasing drugs (FRIDs) and prior falls were also analysed.

Using Central Statistics Office Census 2022, the population of older people in Ireland was multiplied by the proportion of TILDA participants with each outcome of interest to yield population-level estimates.

Participants/Setting

Population-representative sample of 2299 (55% female) community-dwelling people in Ireland aged ≥70 years.

Results

Almost 12% (proportion 0.12 (95% CI 0.10 to 0.13)) of participants, corresponding to almost 62 000 older people in Ireland, reported a fall requiring medical attention in 12 months, with 6% (proportion 0.06 (95% CI 0.05 to 0.07)), or over 32 000 people, attending ED due to a fall. Over 3% (proportion 0.03 (95% CI 0.03 to 0.04)) reported sustaining a fracture. Almost half of participants reporting a fall requiring medical attention were prescribed FRIDs, and over half had also reported a fall when assessed at the prior wave of the study (ie, 2 years ago).

Conclusions

The burden of falls amongst community-dwelling older people is considerable; 1 in 8 required medical attention for a fall and 1 in 16 attended the ED with falls over 12 months.

Currently, there is no national falls strategy in Ireland. These findings, alongside our ageing population, underscore the need for strengthened falls-prevention strategies to reduce avoidable morbidity and healthcare utilisation.

High flow oxygen for vaso-occlusive crisis: a multicentre, prospective, randomised, multi-arm, multi-stage clinical trial (OSONE)

Por: Mekontso Dessap · A. · Habibi · A. · Guillaud · C. · Kassasseya · C. · Larrat · C. · Agbakou · M. · Tchoubou · T. · Candille · C. · Carpentier · B. · Landais · M. · Arlet · J.-B. · Fartoukh · M. · Desclaux · A. · Masseau · A. · Oziel · J. · Bouharaoua · S. · Affo · C. · Viglino · D. · Bouk
Introduction

Sickle cell disease (SCD) is due to the mutation of haemoglobin (Hb), from HbA to HbS and characterised by recurrent vaso-occlusive crises (VOC), which can progress to acute chest syndrome (ACS), a leading cause of death in adults with SCD. Hypoxia is a key modifiable factor in the polymerisation of HbS and the pathogenesis of VOC. High-flow nasal oxygen (HFNO) delivers humidified gas at high oxygen concentrations and flow rates: the former may reverse sickling (metabolic effect) to accelerate VOC resolution and prevent ACS, while the latter may reduce the risk of ACS by mitigating hypercapnia and generating positive airway pressure that limits hypoventilation and atelectasis (pulmonary effect). The study hypothesises that HFNO is a safe and effective strategy for treating VOC and preventing secondary ACS, and will assess this using a multi-arm multi-stage (MAMS) trial design.

Methods and analysis

This is a prospective, multicentre, randomised, open-label controlled trial following an MAMS design with three phases and four arms: one control (low-flow oxygen) and three HFNO intervention arms with varying fraction of inspired oxygen levels (low, intermediate, high). The pilot stage will assess safety and feasibility, using the rate of cardiac and neurological events as the primary endpoint. In the activity stage, arms demonstrating acceptable safety will be compared for efficacy based on the rate of VOC resolution without complications by day 5, allowing selection of the most promising arm. The final efficacy stage will compare the selected HFNO strategy to control, with prevention of secondary ACS by day 14 as the primary endpoint. The study aims to enrol up to 350 VOC episodes in total.

Ethics and dissemination

The study has been granted ethical approval (CPP SUD MEDITERRANEE IV). Following the provision of informed consent, patients will be included in the study. The results will be submitted for publication in peer-reviewed journals.

Trial registration number

NCT03976180.

The INfectious DIsease REgistry BIObank (INDI-REBIO): protocol for the design and implementation of a single-centre, prospective registry and biobank in a tertiary care centre in Italy for advancing infectious disease research

Por: Ripa · M. · Galli · L. · Cinque · P. · Nozza · S. · Spagnuolo · V. · Tassan Din · C. · Guffanti · M. · Lolatto · R. · Piromalli · G. · Carletti · S. · Locatelli · M. · Sanvito · F. · Ponzoni · M. · Cantarelli · E. · Tresoldi · C. · Castagna · A. · on behalf of the INDI-REBIO Study Grou
Introduction

Infectious diseases are a major global health concern, responsible for significant morbidity and mortality. To advance the understanding and treatment of these diseases, biobanks and biorepositories play a crucial role in guaranteeing sample traceability through their entire life cycle (collection, acquisition and registration, processing, storage, distribution) and future analysis of clinical and biological data.

Methods and analysis

The INfectious DIsease REgistry BIObank (INDI-REBIO) is an observational, prospective, monocentric, open-ended registry with ad hoc procedures and a systematic collection of uniform clinical, laboratory, imaging and therapeutic data of patients with suspected or microbiologically documented bacterial, viral, fungal and parasitic infectious diseases from the IRCCS San Raffaele Hospital (Milan, Italy). The study aims to collect both uniform data and biological samples such as blood and other relevant specimens. The registry aims to include significant patient numbers across various conditions (among others: bloodstream infections, endovascular infections as infective endocarditis, central nervous system infections, bone and joint infections, multidrug-resistant organisms (MDROs) colonisation, sexually transmitted infections, HIV infection, emerging and re-emerging infectious diseases), enabling comprehensive research on disease evolution, treatment outcomes and the identification of biomarkers.

Ethics and dissemination

The study adheres to ethical principles outlined by the Helsinki Declaration and Good Clinical Practice guidelines. It has received ethical approval (Comitato Etico CET Lombardia 1, CET 138–2023) and is registered on clinicaltrials.gov (NCT06418048). Participants will provide informed consent and can withdraw at any time. The study results will be disseminated through major international conferences and submitted to peer-reviewed research journals.

Trial registration number

ClinicalTrials.gov, NCT06418048.

Prototyping Process and Usability Testing of a Serious Game for Brazilian Children With Type 1 Diabetes

imageThis study aims to describe the prototype development and testing of a serious game designed for Brazilian children with diabetes. Following an approach of user-centered design, the researchers assessed game's preferences and diabetes learning needs to develop a Paper Prototype. The gameplay strategies included diabetes pathophysiology, self-care tasks, glycemic management, and food group learning. Diabetes and technology experts (n = 12) tested the prototype during audio-recorded sessions. Next, they answered a survey to evaluate the content, organization, presentation, and educational game aspects. The prototype showed a high content validity ratio (0.80), with three items not achieving the critical values (0.66). Experts recommended improving the game content and food illustrations. This evaluation contributed to the medium-fidelity prototype version, which after testing with diabetes experts (n = 12) achieved high content validity values (0.88). One item did not meet the critical values. Experts suggested increasing the options of outdoor activities and meals. Researchers also observed and video-recorded children with diabetes (n = 5) playing the game with satisfactory interaction. They considered the game enjoyable. The interdisciplinary team plays an important role guiding the designers in the use of theories and real needs of children. Prototypes are a low-cost usability and a successful method for evaluating games.
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