Immunosurveillance associated with upper respiratory symptoms in elite swimmers: 8-month period leading into Commonwealth Games

Most research suggests that a greater degree of immune suppression and subsequent increased illness risk occurs during winter and the heaviest training periods. Monitoring an individual’s change in salivary Immunoglobulin A (sIgA) throughout a training programme, could help identify athletes at risk of illness; promoting the use of individual athlete monitoring. Epstein Barr Virus (EBV) has been identified as one of the most likely causes of illness symptoms (Reid et al., 2004). An association has been found between short sleep duration (< 7 hours) and increased number of illnesses, including cold and flu (Orzech et al., 2014). These findings are empirical because athletes do not obtain enough sleep, regularly sleeping less than the NR of 7-9hours of sleep per night.Peer reviewe

Changes to Physical Activity, Sitting Time, Eating Behaviours and Barriers to Exercise during the First COVID-19 ‘Lockdown’ in an English Cohort

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)This study aimed to determine the effect of the first English national COVID-19 lockdown on physical activity (PA), sitting time, eating behaviours and body mass in an adult cohort. This was further examined to determine whether conforming to recommended guidelines on PA and sedentary behaviour was improved. Based on an online survey (n = 818) incorporating the International Physical Activity Questionnaire Short Form (IPAQ-SF), self-reported body mass change showed that in 32.2% of participants body mass increased, with 39.1% reporting an increase in food intake. Never exercising at the gym or undertaking an exercise class (online or live), increased by 50.8% during lockdown, with 53.5% changing from exercising frequently to never exercising, suggesting a lack of engagement with online and home workouts. However, outdoor running and cycling >2 times/week increased by 38% during lockdown. Walking at least 30 min continuously on >2 occasions/week increased by 70% during lockdown with minimum 10-min walks on 7 days per week increasing by 23%. The lockdown had a negative impact on sitting time (>8 h a day), which increased by 43.6% on weekdays and 121% at weekends. Furthermore, sitting 4 h/day decreased during lockdown (46.5% and 25.6% for weekdays and weekends, respectively). Those citing tiredness or lack of time as a barrier to exercise reduced by 16% and 60%, respectively, from pre-lockdown to during lockdown. More of the sedentary group met the Public Health England PA recommendations, however most participants still did not meet the UK Government guidelines for PA. Improvements in health per additional minutes of physical activity will be proportionately greater in those previously doing 30 min/week, the area where most improvements were found although, conversely sitting time was greatly increased. This study may assist in informing whether future lifestyle changes could improve the health of the population.Peer reviewedFinal Published versio

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG)

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged \u3c22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions

Defining the critical limit of oxygen extraction in the human small intestine

AbstractAlthough animal models have been used to characterize the relation between oxygen consumption and blood flow, reliable data have not been generated in the human small intestine. We perfused segments of human small intestine by using an ex vivo perfusion circuit that allowed precise manipulation of blood flow and perfusion pressure. Our goal was to define the critical level of intestinal blood flow necessary to maintain the metabolic needs of the tissue. Human small intestine (n = 5) tissue obtained at transplantation harvest was transported on ice to the laboratory. A 40-cm mid-jejunal segment was selected for perfusion, and appropriate inflow and outflow vessels were identified and cannulated. Perfusion with an autologous blood solution was initiated through an extracorporeal membrane oxygenation circuit. After a 30-minute equilibration period, arterial and venous blood gases were measured at varying flow rates while maintaining a constant hematocrit level. Arterial and venous oxygen content, arteriovenous oxygen difference (A-VO2 diff), and oxygen consumption (O 2 ) were then calculated. Our results demonstrated that at blood flows >30 ml/min/100 g, O 2 is independent of blood flow (1.6 ± 0.06 ml/min/100 g), and oxygen extraction is inversely related to flow. Below this blood flow rate of 30 ml/min/100 g, oxygen extraction does not increase further (6.3 ± 0.3 vol%), and O 2 becomes flow dependent. This ex vivo preparation defines for the first time a threshold value of blood flow for small intestine below which oxygen consumption decreases (30 ml/min/100 g). Previous animal studies have correlated such a decrease in oxygen consumption with functional and histologic evidence of tissue injury. This “critical” flow rate in human intestine is similar to that found previously in canine and feline intestine, but lower than that of rodent species. (J Vasc Surg 1996;23:832-8.

Heart Rate Recovery Assessed by Cardiopulmonary Exercise Testing in Patients with Cardiovascular Disease: Relationship with Prognosis

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Background: The use of exercise testing has expanded in recent decades and there is a wealth of information examining the prognostic significance of exercise variables, such as peak oxygen consumption or ventilatory measures whilst exercising. However, a paucity of research has investigated the use of recovery-derived parameters after exercise cessation. Heart rate recovery (HRR) has been considered a measure of the function of the autonomic nervous system and its dysfunction is associated with cardiovascular risk. Objectives: We aim to provide an overview of the literature surrounding HRR and its prognostic significance in patients with cardiovascular disease undertaking an exercise test. Data Sources: In December 2020, searches of PubMed, Scopus, and ScienceDirect were performed using key search terms and Boolean operators. Study Selection: Articles were manually screened and selected as per the inclusion criteria. Results: Nineteen articles met inclusion criteria and were reviewed. Disagreement exists in methodologies used for measuring and assessing HRR. However, HRR provides prognostic mortality information for use in clinical practice. Conclusions: HRR is a simple, non-invasive measure which independently predicts mortality in patients with heart failure and coronary artery disease; HRR should be routinely incorporated into clinical exercise testing.Peer reviewe

Supporting patient-clinician interaction in chronic HIV care: Design and development of a patient-reported outcomes software application

Background: The consideration of health-related quality of life (HRQL) is a hallmark of best practice in HIV care. Information technology offers an opportunity to more closely engage patients with chronic HIV infection in their long-term management and support a focus on HRQL. However, the implementation of patient-reported outcome (PRO) measures, such as HRQL in routine care, is challenged by the need to synthesize data generated by questionnaires, the complexity of collecting data between patient visits, and the integration of results into clinical decision-making processes. Objective: Our aim is to design and pilot-test a multimedia software platform to overcome these challenges and provide a vehicle to increase focus on HRQL issues in HIV management. Methods: A multidisciplinary team in France and Australia conducted the study with 120 patients and 16 doctors contributing to the design and development of the software. We used agile development principles, user-centered design, and qualitative research methods to develop and pilot the software platform. We developed a prototype application to determine the acceptability of the software and piloted the final version with 41 Australian and 19 French residents using 2 validated electronic questionnaires, the Depression, Anxiety and Stress Scale-21 Items, and the Patient Reported Outcomes Quality of Life-HIV. Results: Testing of the prototype demonstrated that patients wanted an application that was intuitive and without excessive instruction, so it felt effortless to use, as well as secure and discreet. Clinicians wanted the PRO data synthesized, presented clearly and succinctly, and clinically actionable. Safety concerns for patients and clinicians included confidentiality, and the potential for breakdown in communication if insufficient user training was not provided. The final product, piloted with patients from both countries, showed that most respondents found the application easy to use and comprehend. The usability testing survey administered found that older Australians had reduced scores for understanding the visual interface (P=.004) and finding the buttons organized (P=.02). Three-fourths of the respondents were concerned with confidentiality (P=.007), and this result was more prevalent in participants with higher anxiety and stress scores (P=.01), as measured by the Depression, Anxiety and Stress Scale-21 Items. These statistical associations were not observed in 15 French patients who completed the same questionnaire. Conclusions: Digital applications in health care should be safe and fit for purpose. Our software was acceptable to patients and shows potential to overcome some barriers to the implementation of PROs in routine care. The design of the clinicians’ interface presents a solution to the problem of voluminous data, both synthesizing and providing a snapshot of longitudinal data. The next stage is to conduct a randomized controlled trial to determine whether patients experience increased satisfaction with care and whether doctors perceive that they deliver better clinical care without compromising efficiency

A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0511-2) contains supplementary material, which is available to authorized users