BackgroundLong COVID is a rapidly evolving global health crisis requiring interdisciplinary support strategies that incorporate the lived experience of patients. Currently, there is a paucity of research documenting the day-to-day experiences of patients living with Long COVID.ObjectiveTo explore the lived experience of Long COVID patients.Study designLongitudinal, observation study.SettingAn inductive, data-driven, qualitative approach was used to evaluate hand-written diaries obtained from individuals who had been referred to a Derbyshire Long COVID clinic.Participants12 participants (11 females, age 49±10 years, 11 Caucasians) were recruited. Participants were included if they had a previous confirmed or suspected COVID-19 infection with ongoing recovery, >18 years old, understood the study requirements and provided informed consent.MethodParticipants were directed to complete self-report diaries over 16 weeks. Responses were transcribed verbatim and analysed using thematic analysis.ResultsThree key themes were highlighted: (1) understanding who helps patients manage symptoms, (2) daily activities and the impact on quality of life and health status and (3) the effect of turbulent and episodic symptom profiles on personal identity and recovery.ConclusionsThe novel challenges presented by Long COVID are complex with varying inter-related factors that are broadly impacting functional status and quality of life. Support mechanisms must incorporate the lived experiences and foster true collaborations between health professionals, patients and researchers to improve patient outcomes.Trial registration numberNCT04649957.

Despite some indicators of a localized curtailing of cardiovascular disease (CVD) prevalence, CVD remains one of the largest contributors to global morbidity and mortality. While the magnitude and impact of the coronavirus disease 2019 (COVID-19) pandemic have yet to be realized in its entirety, an unquestionable impact on global health and well-being is already clear. At a time when the global state of CVD is perilous, we provide a continental overview of prevalence data and initiatives that have positively influenced CVD outcomes. What is clear is that despite attempts to address the global burden of CVD, there remains a lack of collective thinking and approaches. Moving forward, a coordinated global infrastructure that, if developed with appropriate and relevant key stakeholders, could provide significant and longstanding benefits to public health and yield prominent and consistent policy resulting in impactful change. To achieve global impact, research priorities that address multi-disciplinary social, environmental, and clinical perspectives must be underpinned by unified approaches that maximize public health.

PURPOSE:The complexity of long COVID and its diverse symptom profile contributes to unprecedented challenges for patients, clinicians, and healthcare services. The threat of long COVID remains ignored by Governments, the media and public health messaging, and patients' experiences must be heard through understanding of the lived experience. This study aimed to understand the lived experience of those living with long COVID.METHODS:An online web-based survey was designed using Patient and Public Involvement and Engagement (PPIE) to increase understanding of the lived experiences of long COVID, and was distributed through PPIE groups, social media, and word of mouth. The survey used closed and open questions relating to demographics, pre- and post-COVID-19 health quality of life, daily activities and long COVID experiences.RESULTS:Within our sample of 132 people living with long COVID, the findings highlight that individuals are being severely impacted by their symptoms and are unable to or limited in participating in their daily activities, reducing quality of life. Long COVID places strain on relationships, the ability to live life fully and is detrimental to mental health. Varying health care experiences are described by participants, with reports of medical gaslighting and inadequate support received.CONCLUSIONS:Long COVID has a severe impact on the ability to live life fully, and strains mental health. The appropriate mechanisms and support services are needed to support those living with long COVID and manage symptoms.

The rapid development and deployment of coronavirus disease 2019 (COVID-19) vaccines should be heralded as a feat of true scientific collaboration that saved millions of lives [1]. Despite the success, vaccines do not offer complete protection against infection, mild, and severe disease [2-5] and the de-velopment of a long-term complex symptom profile, commonly referred to as long COVID [5,6]. Long CO-VID results from a positive infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. It used ribonucleic acid (RNA), which is prone to replication and proliferation, leading to the transmission of variants that are a threat to global health. SARS-CoV-2 is known to evolve at an approximate rate of 1.1 x 10-3 substitutions per site per year, equivalent to a single substitution every 11 days [7]. Whilst not all mutations pose a threat to public and global health, previous variants including Omicron (B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4, and BA.5 lineages) and Delta (B.1.617.2 and AY lineages) are widely regarded as variants of concern [8]. Data highlights that there is no difference in risk level between Delta and Omicron BA.1 variant among those that are triple-vaccinated [9]. These variants are characterised by several mutations that affect the spike protein and increase transmissibility [10], leading to the sustained and widespread transmission of acute infection which will inevitably result in increased pro-gression of long COVID. The latest data highlight that vaccines only offer a 15% reduction against developing long COVID and a 34% reduction in the risk of mortality [1]. Furthermore, clinical features are indistinguishable in those that were vaccinated and subsequently contracted SARS-CoV-2 compared with those with long COVID that were unvac-cinated [5]. While data sets remain infrequent, > 144 million people globally are living with multi -dimension-al and episodic symptoms that broadly impact functional status and quality of life [11]. This is compounded by economic and societal drivers contributing to an increasing burden of Long COVID in the global popula-sustained transmission of SARS-CoV-2, future variants of concern and confirmed projection of increas-Long COVID prevalence, pose a significant risk to public health.

The purpose of this paper is to put forward some evidence-based lessons that can be learned from how to respond to a Pandemic that relate to healthy living behaviours (HLB). A 4-step methodology was followed to conduct a narrative review of the literature and to present a professional practice vignette. The narrative review identified 8 lessons: 1) peer review; 2) historical perspectives; 3) investing in resilience and protection; 4) unintended consequences; 5) protecting physical activity; 6) school closures; 7) mental health; and 8) obesity. As in all probability there will be another Pandemic, it is important that the lessons learned over the last three years in relation to HLB are acted upon. Whilst there will not always be a consensus on what to emphasise, it is important that many evidence-based positions are presented. The authors of this paper recognise that this work is a starting point and that the lessons presented here will need to be revisited as new evidence becomes available.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in homologous recombination deficient (HRD) tumours, such as those with BRCA mutations (BRCAm). In this setting PARPi treatments lead to accumulation of DNA damage and cancer cell death. PARPi currently in clinical use inhibit both PARP1 and PARP2, as well as other members of the PARP family. Here, we report for the first time in vivo profiling of AZD5305, a potent and highly selective PARP1 inhibitor and trapper, currently in Ph1 clinical trials. Dose response efficacy of AZD5305 was evaluated in the BRCA1m triple-negative breast cancer (TNBC) xenograft model MDA-MB-436. AZD5305 dosed at 0.1mg/kg QD or higher for 35 days delivered about 90% regression, compared with 83% regression caused by treatment with 100mg/kg QD olaparib. Anti-tumour effects of AZD5305 continued after cessation of treatment and complete responses were achieved which were sustained for the whole duration of the study, over 100 days after treatment withdrawal, in contrast to the olaparib-treated group where regrowth of tumours was observed from day 63 after treatment withdrawal. Investigation of the PK/PD/efficacy relationship in MDA-MB-436 showed that maximum efficacy of AZD5305 was achieved when unbound plasma concentrations were maintained above the IC95 estimated from an in vitro DLD-1 BRCA2-/- cell growth assay. Similar results were obtained in a BRCA1m patient-derived explant (PDX) model, HBCx-17. Anti-tumour efficacy of AZD5305 was also tested in the DLD-1 BRCA2-/- and wild-type (WT) isogenic xenograft models. In the DLD-1 BRCA2-/- model, AZD5305 dosed at 10mg/kg QD and 1mg/kg QD delivered 78% and 63% tumour regression, respectively. AZD5305 at 0.1mg/kg QD resulted in responses similar to those observed in the olaparib 100mg/kg QD group (40-54% tumour growth inhibition, TGI). As expected, AZD5305 and olaparib showed no anti-tumour efficacy in the DLD-1 WT tumour model. Due to improved PARP1 selectivity, AZD5305 has the potential to show improved efficacy and tolerability in combination with standard of care chemotherapy when compared to non-selective PARPi. Hence, we investigated the anti-tumour effects of AZD5305 in combination with carboplatin or paclitaxel in a BRCA1m TNBC xenograft, SUM149PT, and BRCA WT TNBC PDX model, HBCx-9. In both models, combination of AZD5305 with carboplatin was well tolerated and demonstrated clear benefit compared to each monotherapy treatment. The effects of adjusted dosing and scheduling of the combination on the anti-tumour efficacy will be presented. Citation Format: Anna D. Staniszewska, James W. Yates JWT, Andy Pike, Christine Fazenbaker, Kimberly Cook, Emily Bosco, Aaron Smith, Joanne Wilson, Elisabetta Leo. The novel PARP1-selective inhibitor, AZD5305, is efficacious as monotherapy and in combination with standard of care chemotherapy in the in vivo preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1270.

Exon 20 insertions (Ex20Ins) have been identified in approximately 5% of epidermal growth factor receptor (EGFR)-mutated lung tumours in patients presenting with non-small cell lung cancer (NSCLC). Several small molecule tyrosine kinase inhibitors (TKIs) have been reported to have pre-clinical activity against such insertions including afatinib, poziotinib, osimertinib, nazartinib, AP32788/TAK-788 and TAS6417. However, there remains a lack of approved treatments for patients with Ex20Ins with early approved EGFR agents appearing to be ineffective in this setting. Poziotinib, osimertinib and AP32788/TAK-788 are undergoing clinical evaluation in patients whose tumours carry Ex20Ins and in some cases clinical responses have been reported giving hope that such insertions can be targeted by small molecules. There is however a need for comparable data across such compounds that would enable understanding of the relative activity of these compounds between Ex20Ins and the wild-type form of EGFR. As many of the Exon 20 insertions are not part of the ATP binding pocket achieving selectivity over wild type EGFR is highly challenging and may limit the clinical utility of agents due to dose limiting EGFR wild-type driven toxicity.A selection of TKIs were profiled for Ex20Ins and wild-type EGFR activity using biochemical, in vitro cellular phosphorylation and proliferation assays. This has enabled us to differentiate the Ex20Ins versus wild-type EGFR selectivity profiles of a range of pre-clinical, clinical and proprietary compounds. As part of this evaluation we utilized a CRISPR CAS9 approach in H2073 EGFR wild-type NSCLC cell line, where we have established cellular disease models against the most prevalent insertions including D770-N771insSVD (22%). Finally, we will show anti-tumour efficacy data for a selection of these inhibitors along with a potential combination approach of osimertinib and cetuximab.EGFR D770-N771InsSVD cell phospho IC50 (µM)EGFR WT (H2073) cell phospho IC50 (µM)Fold-EGFR WT margin (cell)afatinib0.0060.00330.5osimertinib0.0940.414.4poziotinib0.00340.00351TAS64170.0230.0672.9AZ62810.0972.223Citation Format: Richard A. Ward, Ambra Bianco, Nicola Colclough, Darren Cross, Emanuela M. Cuomo, M. Raymond V. Finlay, Martina Fitzek, Nicolas Floc’h, Sladjana Gagrica, Beverley Hammond, Matthew J. Martin, Darren McKerrecher, Daniel J. O’Neill, Jonathan P. Orme, Paul D. Smith, Anna D. Staniszewska, Jelena Urosevic, Nicky Whalley, James W. Yates. Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4813.

OBJECTIVE:Evaluate the effect of aerobic exercise using arm crank ergometry (ACE) in high motor complete (ISNCSCI A/B) spinal cord injury (SCI) as primarily related to cardiovascular disease (CVD) risk factors and functional mobility and secondarily to body composition and metabolic profiles. DESIGN:Longitudinal interventional study at an academic medical center. METHODS:Ten previously untrained participants (M8/F2, Age 36.7 y ± 10.1, BMI 24.5 ± 6.0) with high motor complete SCI (C7-T5) underwent ACE exercise training 30 minutes/day × 3 days/week for 10 weeks at 70% VO2Peak. OUTCOME MEASURES:Primary outcome measures were pre- and post-intervention changes in markers of cardiovascular fitness (graded exercise testing (GXT): VO2, VO2Peak, respiratory quotient [RQ], GXT time, peak power, and energy expenditure [EE]) and community mobility (time to traverse a 100ft-5° ramp, and 12-minute WC propulsion test). Secondary outcome measures were changes in body composition and metabolic profiles (fasting and area under the curve for glucose and insulin, homeostasis model assessment [HOMA] for %β-cell activity [%β], %insulin sensitivity [%S], and insulin resistance [IR], and Matsuda Index [ISIMatsuda]). RESULTS:Resting VO2, relative VO2Peak, absolute VO2Peak, peak power, RQ, 12-minute WC propulsion, fasting insulin, fasting G:I ratio, HOMA-%S, and HOMA-IR all significantly improved following intervention (P < 0.05). There were no changes in body composition (P>0.05). CONCLUSIONS:Ten weeks of ACE at 70% VO2Peak in high motor complete SCI improves aerobic capacity, community mobility, and metabolic profiles independent of changes in body composition.

PURPOSE:The effect of acute nitrate supplementation on muscle fatigue is largely unknown. This study aimed to evaluate the effect of acute nitrate supplementation on muscle fatigue. METHODS:Thirty-five recreationally active subjects consumed 140 ml of beetroot (BR) juice (nitrate: 8 mmol·d-1) or placebo (PL) 12 and 2.5 hours before two exercise sessions. Peak torque was measured during 50 repetitions, at maximal effort, and during concentric knee extensions at 90°·s-1. Blood pressure (BP) was recorded pre- and post-exercise. RESULTS:Peak torque, maximum work, rate of fatigue, and rate of work fatigue were similar between the BR and PL conditions. Post-exercise diastolic BP (BR: 67.2 ± 9.8 vs. PL: 64.5 ± 7.9 mmHg, p < 0.05) and mean arterial pressure (BR: 91.6 ± 9.3 vs. PL: 88.8 ± 8.2 mmHg, p < 0.05) were higher with BR supplementation. CONCLUSION:These findings suggest that the acute intake of BR juice had no effect on knee extensor muscle strength or fatigue but increased BP in a healthy recreationally active population.

Abstract AZD1775 is a highly selective, small-molecule inhibitor of WEE1 being developed to treat patients with advanced solid tumors, as monotherapy and in combination with olaparib. Experimental Procedures Patient-derived explant (PDX) and xenografted models with a range of sensitivities to AZD1775 were tested for response to different doses and schedules of AZD1775. WEE1 inhibition was assessed by pCDK1 as a direct substrate of Wee1 and RRM2 as a surrogate of CDK2 activity. Concentration of AZD1775 in plasma was measured in the same animals. Mathematical models were developed to describe the relationship between drug exposure, biomarker modulation and resulting tumour growth inhibition. Results The PKPD relationship of both pCDK1 and RRM2 could be described by the mathematical model with significant delay between PK and RRM2 reduction due to this being a protein degradation event. Three factors influenced anti-tumour activity in the A427 xenograft and three TNBC PDX models, namely the AZD1775 dose, the number of consecutive days of dosing and the number of days between AZD1775 doses. The minimally effective preclinical dose with anti-tumour activity was 60 mg/kg od. TGI was seen to increase with increased days of consecutive AZD1775 dosing from 3 days on, such that a 5 days on/9 days off schedule was more efficacious than 3 days on/4 days off schedule for two weeks. A mathematical model successfully described this efficacy by using the predicted dose and schedule dependent reduction in pCDK1. Conclusions The insights from this predictive modelling informed the starting dose of 125mg BID AZD1775 on a 5 day on/9 day off schedule; with the clinical goal to optimize the days of consecutive AZD1775 dosing as well as the maximum tolerated dose. Citation Format: James W. Yates, Elaine Cadogan, Jennifer Hare, Adina Hughes, Urszula M. Polanska, Mark O'Connor, Susan E. Critchlow. Understanding the dose and schedule dependence of efficacy for the Wee1 inhibitor AZD1775 in xenograft and patient derived explant models by mathematical modelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2017-4541

Abstract Macht, JW, Abel, MG, Mullineaux, DR, and Yates, JW. Development of 1RM prediction equations for bench press in moderately trained men. J Strength Cond Res 30(10): 2901–2906, 2016—There are a variety of established 1 repetition maximum (1RM) prediction equations, however, very few prediction equations use anthropometric characteristics exclusively or in part, to estimate 1RM strength. Therefore, the purpose of this study was to develop an original 1RM prediction equation for bench press using anthropometric and performance characteristics in moderately trained male subjects. Sixty male subjects (21.2 ± 2.4 years) completed a 1RM bench press and were randomly assigned a load to complete as many repetitions as possible. In addition, body composition, upper-body anthropometric characteristics, and handgrip strength were assessed. Regression analysis was used to develop a performance-based 1RM prediction equation: 1RM = 1.20 repetition weight + 2.19 repetitions to fatigue − 0.56 biacromial width (cm) + 9.6 (R 2 = 0.99, standard error of estimate [SEE] = 3.5 kg). Regression analysis to develop a nonperformance-based 1RM prediction equation yielded: 1RM (kg) = 0.997 cross-sectional area (CSA) (cm2) + 0.401 chest circumference (cm) − 0.385%fat − 0.185 arm length (cm) + 36.7 (R 2 = 0.81, SEE = 13.0 kg). The performance prediction equations developed in this study had high validity coefficients, minimal mean bias, and small limits of agreement. The anthropometric equations had moderately high validity coefficient but larger limits of agreement. The practical applications of this study indicate that the inclusion of anthropometric characteristics and performance variables produce a valid prediction equation for 1RM strength. In addition, the CSA of the arm uses a simple nonperformance method of estimating the lifter's 1RM. This information may be used to predict the starting load for a lifter performing a 1RM prediction protocol or a 1RM testing protocol.

Objective: The purpose of this study was to investigate the effect of manual manipulations targeting the lumbar spine and/or sacroiliac joint on concentric knee extension and flexion forces. Torque production was measured during isometric and isokinetic contractions.Methods: This was a randomized, controlled, single-blind crossover design with 21 asymptomatic, college-aged subjects who had never received spinal manipulation. During 2 separate sessions, subjects' peak torques were recorded while performing maximal voluntary contractions on an isokinetic dynamometer. Isometric knee extension and flexion were recorded at 60 degrees of knee flexion, in addition to isokinetic measurements obtained at 60 degrees/s and 180 degrees/s. Baseline measurements were acquired before either treatment form of lumbosacral manipulation or sham manipulation, followed by identical peak torque measurements within 5 and 20 minutes posttreatment. Data were analyzed with a repeated measures analysis of variance.Results: A statistically significant difference did not occur between the effects of lumbosacral manipulation or the sham manipulation in the percentage changes of knee extension and flexion peak torques at 5 and 20 minutes posttreatment. Similar, nonsignificant results were observed in the overall percentage changes of isometric contractions (spinal manipulation 4.0 +/- 9.5 vs sham 1.2 +/- 6.3, P = .067), isokinetic contractions at 60 degrees/s (spinal manipulation -4.0 +/- 14.2 vs sham -0.3 +/- 8.2, P = .34), and isokinetic contractions at 180 degrees/s (spinal manipulation - 1.4 +/- 13.9 vs sham - 5.5 +/- 20.0, P = .18).Conclusion: The results of the current study suggest that spinal manipulation does not yield an immediate strength-enhancing effect about the knee in healthy, college-aged subjects when measured with isokinetic dynamometry. (C) 2015 National University of Health Sciences.

Abstract Beck, AQ, Clasey, JL, Yates, JW, Koebke, NC, Palmer, TG, and Abel, MG. Relationship of physical fitness measures vs. occupational physical ability in campus law enforcement officers. J Strength Cond Res 29(8): 2340–2350, 2015—Law enforcement officers (LEOs) on university campuses are required to perform a variety of physical occupational tasks. Identifying which physical fitness characteristics are associated with these occupational tasks will assist in the development of appropriate exercise programs and physical fitness assessments. Therefore, the purpose of this study was to identify physical fitness and demographic characteristics that were correlated with occupational tasks commonly performed by campus LEOs. The occupational assessment was conducted using an Officer Physical Ability Test (OPAT), which simulated a foot chase of a suspect. Sixteen male LEOs (age: 33.1 ± 8.7 years; body mass: 87.2 ± 11.2 kg; height: 179.0 ± 7.9 cm) performed the OPAT. A battery of physical fitness tests were used to assess aerobic capacity, muscular endurance, strength, power, flexibility, agility, and body composition. Bivariate correlations were performed to identify significant (p ⩽ 0.05) correlations between physical fitness characteristics and OPAT time. The officers' age was significantly correlated to the majority of OPAT tasks, physical fitness, and anthropometric assessments. Therefore, partial correlations were used to control for the confounding effects of age. After controlling for the officers' age, the overall OPAT time was significantly correlated with agility (r = 0.57) and aerobic endurance (r = −0.65). Furthermore, push-up, curl-up, body mass, waist circumference, and abdominal circumference were significantly correlated to individual OPAT tasks. In conclusion, exercise programs and fitness assessments should be used for campus LEOs that address a variety of physical fitness characteristics associated with occupational performance. In addition, exercise programs should focus on body composition management and fitness for older LEOs.

One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach.

Abstract AZD6738 is a potent and selective inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase with the potential to be used in the clinic. We report the discovery of a morpholino-pyrimidine series and its subsequent optimisation to the pre-clinical candidate AZD6738 which has a good overall balance of potency, selectivity, pharmacokinetic and biopharmaceutical properties suitable for oral dosing. ATR is a serine/threonine protein kinase involved in DNA damage response signalling caused by DNA replication associated stress. Activation of ATR at stalled replication forks leads to suppression of replication fork origin firing, promotes repair and S/G2-cell cycle checkpoints to prevent premature mitosis and maintain genomic integrity. Failure to resolve damage leads to genomic instability and if sufficiently high, cell death. Stalled replication forks may collapse leading to formation of DNA double stranded breaks and activation of the ataxia telangiectasia mutated (ATM) kinase. ATM works in conjunction with ATR to efficiently resolve replication associated DNA damage creating a co-dependency with loss of one leading to a greater reliance on the other to maintain genomic stability. ATM is frequently inactivated across B-cell malignancies, head and neck, breast and lung cancers through chromosomal deletion, promoter hypermethylation or mutation. ATM-deficient tumours are hypothesised to be more reliant on ATR for survival and specific inhibition of ATR may lead enhanced anti-tumour activity while minimizing normal tissue toxicity. AZD6378 has the potential to test the clinical efficacy of ATR inhibition in cancer patients as monotherapy against ATM-deficient tumours or in combination with chemo or radiotherapy. Citation Format: Clifford D. Jones, Kevin Blades, Kevin M. Foote, Sylvie M. Guichard, Philip J. Jewsbury, Thomas McGuire, Johannes W. Nissink, Rajesh Odedra, Kin Tam, Pia Thommes, Paul Turner, Gary Wilkinson, Christine Wood, James W. Yates. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2348. doi:10.1158/1538-7445.AM2013-2348

Drug-induced liver injury (DILI) is a clinically important adverse drug reaction, which prevents the development of many otherwise safe and effective new drugs. Currently, there is a lack of sensitive and specific biomarkers that can be used to predict, assess and manage this toxicity. The aim of this work was to evaluate gadoxetate-enhanced MRI as a potential novel biomarker of hepatobiliary transporter inhibition in the rat. Initially, the volume fraction of extracellular space in the liver was determined using gadopentetate to enable an estimation of the gadoxetate concentration in hepatocytes. Using this information, a compartmental model was developed to characterise the pharmacokinetics of hepatic uptake and biliary excretion of gadoxetate. Subsequently, we explored the impact of an investigational hepatobiliary transporter inhibitor on the parameters of the model in vivo in rats. The investigational hepatobiliary transporter inhibitor reduced both the rate of uptake of gadoxetate into the hepatocyte, k1 , and the Michaelis-Menten constant, Vmax , characterising its excretion into bile, whereas KM values for biliary efflux were increased. These effects were dose dependent and correlated with effects on plasma chemistry markers of liver dysfunction, in particular bilirubin and bile acids. These results indicate that gadoxetate-enhanced MRI provides a novel functional biomarker of inhibition of transporter-mediated hepatic uptake and clearance in the rat. Since gadoxetate is used clinically, the technology has the potential to provide a translatable biomarker of drug-induced perturbation of hepatic transporters that may also be useful in humans to explore deleterious functional alterations caused by transporter inhibition.

Firefighting is a strenuous occupation that requires optimal levels of physical fitness. The National Fire Protection Association suggests that firefighters should be allowed to exercise on duty to maintain adequate fitness levels. However, no research has addressed the effect of exercise-induced fatigue on subsequent fire ground performance. Therefore, the primary purpose of this study was to determine the effect that a single exercise session had on the performance of a simulated fire ground test (SFGT). Secondarily, this study sought to compare the effect of physical training status (i.e., trained vs. untrained firefighters) on the performance of an SFGT. Twelve trained (age: 31.8 ± 6.9 years; body mass index [BMI]: 27.7 ± 3.3 kg·m(-2); VO2peak: 45.6 ± 3.3 ml·kg(-1)·min(-1)) and 37 untrained (age: 31.0 ± 9.0 years; BMI: 31.3 ± 5.2 kg·m(-2); VO2peak: 40.2 ± 5.2 ml·kg(-1)·min(-1)) male career firefighters performed a baseline SFGT. The trained firefighters performed a second SFGT after an exercise session. Time to complete the SFGT, heart rate, and blood lactate were compared between baseline and exercise SFGT (EX-SFGT) conditions. In the trained firefighters, time to complete the SFGT (9.6% increase; p = 0.002) and heart rate (4.1% increase; p = 0.032) were greater during the EX-SFGT compared with baseline, with no difference in post-SFGT blood lactate (p = 0.841). The EX-SFGT time of the trained firefighters was faster than approximately 70% of the untrained firefighters' baseline SFGT time. In addition, the baseline SFGT time of the trained firefighters was faster than 81% of the untrained firefighters. This study demonstrated that on-duty exercise training reduced the work efficiency in firefighters. However, adaptations obtained through regular on-duty exercise training may limit decrements in work efficiency because of acute exercise fatigue and allow for superior work efficiency compared with not participating in a training program.

In this issue of Medicine & Science in Sports & Exercise®, Hopker et al. (4) report on the reliability of gross efficiency as measured using the Douglas bag technique (3) (often miscited), finding a total within-subject variation of 1.5%. This excellent reliability is considerably better than previously reported results in which breath-by-breath systems were used (e.g., Moseley and Jeukendrup [6] and Noordhof et al. [7]). The article of Hopker et al. (4) focuses largely on a meticulous investigation of the Douglas bag technique itself, particularly sampling reliability, residual volume of the Douglas bag, gas exchange between the Douglas bag and ambient air, and measurement of the gas volume. To be sure, they could have been even more complete by detailing exact methods of gas analyzer calibration via zero and span gases plus a midrange gas standard. Nevertheless, to their credit, they have previously reported on the equally important issue of accuracy and reliability of power measurement during cycling (5). In their current article (4), the overall attention to detail is impressive, and the methods and data are of the highest quality. However, one could argue that the results are neither original nor likely to be of high impact. In fact, as one reviewer noted, "These techniques have been 'common practice' in our lab for the past 40 years." So why publish this paper in MSSE® when acceptance rates are less than 25%? Before the invention of metabolic carts and breath-by-breath systems, scientists regularly collected gas samples during periods of 1 min or longer in large "Douglas" bags followed by later gas analysis and volume determination. As noted by Hopker et al. (4), accurate and reliable measurement of oxygen consumption (V˙O2) in this manner is based largely on first principles and requires a comprehensive understanding of the details of the setup and calculations. Careful researchers go through procedures similar to those described by Hopker et al. (4), checking accuracy and reliability at every link in the chain of V˙O2 and carbon dioxide production (V˙CO2) measurement (8). Final results are sometimes not available for a considerable period after the test is over. Recently, the ease of use and rapid feedback provided by computerized metabolic systems have tempted scientists and practitioners alike to use them "as is" with little concern for validation or accuracy. Megabytes of data showing results that "look like they should" can be collected shortly after the system arrives in the laboratory. However, although metabolic carts, including breath-by-breath systems, have become more sophisticated and reliable over time, attention to validation remains a necessity. Examples are available showing how to use the Douglas bag technique to validate such systems, whether ventilation is measured on the inspired or expired side of the system (1). Further, metabolic systems that have been previously validated can produce erroneous results when the user fails to pay attention to details such as adjusting sampling pump flow rates and using water vapor drying systems properly. Nevertheless, for scientists who are interested in gas exchange on-kinetics (e.g., Berger et al. [2]), breath-by-breath systems are not only state-of-the-art but also essential for the description of the time course of gas exchange. However, what seems to be often forgotten is that, for measurement of small differences in V˙O2 and V˙CO2 under steady-state conditions, Douglas's 100-year-old method (3) remains the state-of-the-art gold standard. Therefore, we consider the article of Hopker et al. (4) to be a cogent reminder of the constant need to establish accuracy and reliability, even in one of the most basic techniques in the history of exercise physiology. Accordingly, conscientious researchers are urged to pick up a bag and step away from the automated systems for accurately assessing potentially small, but important changes in efficiency and even V˙O2max. The Douglas bag approach should also be used for validation of automated systems on a routine basis. Students are urged to learn the details of the Douglas bag technique to have a better understanding of the underlying basis of the V˙O2 and V˙CO2 measurements. L. Bruce Gladden, PhD Department of Kinesiology Auburn University Auburn, AL James W. Yates, PhD Department of Kinesiology and Health Promotion University of Kentucky Lexington, KY Edward T. Howley, PhD Department of Kinesiology Recreation, and Sport Studies University of Tennessee Knoxville, TN