Resting heart rate is a population-level biomarker of cardiorespiratory fitness: The Fenland Study.

INTRODUCTION: Few large studies have evaluated the relationship between resting heart rate (RHR) and cardiorespiratory fitness. Here we examine cross-sectional and longitudinal relationships between RHR and fitness, explore factors that influence these relationships, and demonstrate the utility of RHR for remote population monitoring. METHODS: In cross-sectional analyses (The UK Fenland Study: 5,722 women, 5,143 men, aged 29-65y), we measured RHR (beats per min, bpm) while seated, supine, and during sleep. Fitness was estimated as maximal oxygen consumption (ml⋅min-1⋅kg-1) from an exercise test. Associations between RHR and fitness were evaluated while adjusting for age, sex, adiposity, and physical activity. In longitudinal analyses (6,589 participant subsample), we re-assessed RHR and fitness after a median of 6 years and evaluated the association between within-person change in RHR and fitness. During the coronavirus disease-2019 pandemic, we used a smartphone application to remotely and serially measure RHR (1,914 participant subsample, August 2020 to April 2021) and examined differences in RHR dynamics by pre-pandemic fitness level. RESULTS: Mean RHR while seated, supine, and during sleep was 67, 64, and 57 bpm. Age-adjusted associations (beta coefficients) between RHR and fitness were -0.26, -0.29, and -0.21 ml⋅kg-1⋅beat-1 in women and -0.27, -0.31, and -0.19 ml⋅kg-1⋅beat-1 in men. Adjustment for adiposity and physical activity attenuated the RHR-to-fitness relationship by 10% and 50%, respectively. Longitudinally, a 1-bpm increase in supine RHR was associated with a 0.23 ml⋅min-1⋅kg-1 decrease in fitness. During the pandemic, RHR increased in those with low pre-pandemic fitness but was stable in others. CONCLUSIONS: RHR is a valid population-level biomarker of cardiorespiratory fitness. Physical activity and adiposity attenuate the relationship between RHR and fitness.

Burosumab in management of X-linked hypophosphataemia: a retrospective cohort study of growth and serum phosphate levels.

BACKGROUND: Burosumab, an antifibroblast growth factor 23 monoclonal antibody, improves rickets severity, symptoms and growth in children with X-linked hypophosphataemia (XLH) followed up to 64 weeks in clinical trials. International dosing guidance recommends targeting normal serum phosphate concentration; however, some children may not achieve this despite maximal dosing. This study compares clinical outcomes in children with XLH on long-term burosumab treatment who achieved normal phosphate versus those who did not. METHODS: Single-centre retrospective review of a large paediatric cohort with XLH treated with burosumab. We evaluated growth and biochemical markers of bone health in those who did compared with those who did not achieve normal plasma phosphate concentration. RESULTS: Fifty-five children with XLH with median age of 11.7 (IQR 6.8-15.5) years were included. 27 (49%) had low plasma phosphate concentration, and 27 (49%) had normal phosphate after a median burosumab treatment duration of 3.3 (IQR 2.6-3.7) years. 1 (2%) did not have a recent phosphate level recorded. No difference in growth was found between normal and abnormal phosphate groups (p=0.9). CONCLUSIONS: Young children with XLH experience sustained growth on long-term burosumab treatment, although without normal plasma phosphate concentration in many. Consideration should be made to changing burosumab dosing recommendations to target normalisation of alkaline phosphatase, as opposed to plasma phosphate concentration.

Management of Metastatic Colorectal Carcinoma in Older Adults: Balancing Risks and Benefits of Novel Therapies.

The prevalence of older patients with metastatic colorectal cancer (mCRC) will continue to increase with our aging population. Treatment of mCRC has changed significantly in the last few decades as we have learned how to personalize the treatment of mCRC to the biology of the tumor, utilizing new treatment approaches. With an ever-changing treatment paradigm, managing the population of older adults becomes paramount. This review highlights the pivotal clinical trials that defined the use of systemic therapy, immunotherapy and targeted therapies for mCRC, and how those are applied to the older patient population. In addition, we outline the tools for an in-depth assessment of an older adult in regards to treatment planning and management of therapy-related toxicities. A comprehensive geriatric assessment can assist in the selection of treatment for an older adult with mCRC. While frail older patients can frequently only tolerate single agents or modified regimens, fit older adults remain candidates for a wider range of treatment options. However, since all of these treatments are associated with possible toxicities, each patient's treatment must be personalized to the patient's goals and wishes through a shared decision-making process.

An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer.

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.

Severe Type B Lactic Acidosis in a Rare and Aggressive HIV-Related Lymphoma.

We describe the prognostic implication and aggressive clinical course of lymphoma-related lactic acidosis in a rare HIV-related lymphoma. Patient was diagnosed with plasmablastic lymphoma and developed severe lactic acidosis, and was treated on the medical floor and in the medical intensive care unit. Her lactic acidosis was considered to be type B, secondary to her underlying lymphoma since she never had an infectious source, hypovolemic state, or low/high cardiac-output state. The mechanism of the lymphoma-related lactic acidosis is from altered cellular metabolism, thought to aid in lymphoma proliferation, rather than tissue hypoperfusion. It is a rare complication of aggressive lymphomas and signifies a poor prognosis. Patients having this complication should be considered for close monitoring and management in an intensive care unit until definitive treatment (i.e., chemotherapy) can be implemented.

Role of Molecular Profiling in Soft Tissue Sarcoma.

Diagnosis and treatment of soft tissue sarcoma (STS) is a particularly daunting task, largely due to the profound heterogeneity that characterizes these malignancies. Molecular profiling has emerged as a useful tool to confirm histologic diagnoses and more accurately classify these malignancies. Recent large-scale, multiplatform analyses have begun the work of establishing a more complete understanding of molecular profiling in STS subtypes and to identify new molecular alterations that may guide the development of novel targeted therapies. This review provides a brief and general overview of the role that molecular profiling has in STS, highlighting select sarcoma subtypes that are notable for recent developments. The role of molecular profiling as it relates to diagnostic strategies is discussed, along with ways that molecular profiling may provide guidance for potential therapeutic interventions.

Osteoblast differentiation of equine induced pluripotent stem cells.

Bone fractures occur in horses following traumatic and non-traumatic (bone overloading) events. They can be difficult to treat due to the need for the horse to bear weight on all legs during the healing period. Regenerative medicine to improve fracture union and recovery could significantly improve horse welfare. Equine induced pluripotent stem cells (iPSCs) have previously been derived. Here we show that equine iPSCs cultured for 21 days in osteogenic induction media on an OsteoAssay surface upregulate the expression of osteoblast associated genes and proteins, including COL1A1, SPARC, SPP1, IBSP, RUNX2 and BGALP We also demonstrate that iPSC-osteoblasts are able to produce a mineralised matrix with both calcium and hydroxyapatite deposition. Alkaline phosphatase activity is also significantly increased during osteoblast differentiation. Although the genetic background of the iPSC donor animal affects the level of differentiation observed after 21 days of differentiation, less variation between lines of iPSCs derived from the same horse was observed. The successful, direct, differentiation of equine iPSCs into osteoblasts may provide a source of cells for future regenerative medicine strategies to improve fracture repair in horses undergoing surgery. iPSC-derived osteoblasts will also provide a potential tool to study equine bone development and disease.

A wireless accelerometer node for reliable and valid measurement of lumbar accelerations during treadmill running.

This study investigated the reliability of a wireless accelerometer and its agreement with optical motion capture for the measurement of root mean square (RMS) acceleration during running. RMS acceleration provides a whole-body metric of movement mechanics and economy. Fifteen healthy college-age participants performed treadmill running for two 60-s trials at 2.22, 2.78, and 3.33 m/s and one trial of 150 s (five 30-s epochs) at 2.78 m/s. We assessed between-trial and within-trial reliability, and agreement in each axis between a trunk-mounted wireless accelerometer and a reflective marker on the accelerometer measured by optical motion capture. Intraclass correlations assessing between-trial repeatability were 0.89-0.97, depending on the axis, and intraclass correlations assessing within-trial repeatability were 0.99-1.00. Bland-Altman analyses assessing agreement indicated mean difference values between -0.03 and 0.03 g, depending on the axis. Anterio-posterior acceleration had the greatest limits of agreement (LOA) (±0.12 g) and vertical acceleration had the smallest LOA (±0.03 g). For measuring RMS acceleration of the trunk, this wireless accelerometer node provides repeatable and valid measurement compared with the standard laboratory method of optical motion capture.

Contributions of lower extremity kinematics to trunk accelerations during moderate treadmill running.

BACKGROUND: Trunk accelerations during running provide useful information about movement economy and injury risk. However, there is a lack of data regarding the key biomechanical contributors to these accelerations. The purpose was to establish the biomechanical variables associated with root mean square (RMS) accelerations of the trunk. METHODS: Eighteen healthy males (24.0 ± 4.2 yr; 1.78 ± 0.07 m; 79.7 ± 14.8 kg) performed treadmill running with high resolution accelerometer measurement at the lumbar spine and full-body optical motion capture. We collected 60 sec of data at three speeds (2.22, 2.78, 3.33 m ∙ s(-1)). RMS was calculated for medio-lateral (ML), anterio-posterior (AP), vertical (VT), and the resultant Euclidean scalar (RES) acceleration. From motion capture, we calculated 14 kinematic variables, including mean sagittal plane joint angles at foot contact, mid-stance, and toe-off. Principal components analysis (PCA) was used to form independent components comprised of combinations of the original variables. Stepwise regressions were performed on the original variables and the components to determine contributions to RMS acceleration in each axis. RESULTS: Significant speed effects were found for RMS-accelerations in all axes (p < 0.05). Regressions of the original variables indicated from 4 to 5 variables associated with accelerations in each axis (R2 = 0.71 to 0.82, p < 0.001). The most prominent contributing variables were associated with the late flight and early stance phase. PCA reduced the data into four components. Component 1 included all hip angles before mid-stance and component 2 was primarily associated with propulsion. Regressions indicated key contributions from components 1 and 2 to ML, VT, and RES acceleration (p < 0.05). CONCLUSIONS: The variables with highest contribution were prior to mid-stance and mechanically relate to shock absorption and attenuation of peak forces. Trunk acceleration magnitude is associated with global running variables, ranging from energy expenditure to forces lending to the mechanics of injury. These data begin to delineate running gait events and offer relationships of running mechanics to those structures more proximal in the kinetic chain. These relationships may provide insight for technique modification to maximize running economy or prevent injury.

Effect of treadmill versus overground running on the structure of variability of stride timing.

Gait timing dynamics of treadmill and overground running were compared. Nine trained runners ran treadmill and track trials at 80, 100, and 120% of preferred pace for 8 min. each. Stride time series were generated for each trial. To each series, detrended fluctuation analysis (DFA), power spectral density (PSD), and multiscale entropy (MSE) analysis were applied to infer the regime of control along the randomness-regularity axis. Compared to overground running, treadmill running exhibited a higher DFA and PSD scaling exponent, as well as lower entropy at non-preferred speeds. This indicates a more ordered control for treadmill running, especially at non-preferred speeds. The results suggest that the treadmill itself brings about greater constraints and requires increased voluntary control. Thus, the quantification of treadmill running gait dynamics does not necessarily reflect movement in overground settings.

Perceptual cues in the regulation of exercise performance - physical sensations of exercise and awareness of effort interact as separate cues.

It has been argued that the physical sensations induced by exercise, measured as the ratings of perceived exertion (RPE), are distinct from the sense of effort. This study aimed to determine whether a new measure of task effort - the Task Effort and Awareness (TEA) score - is able to measure sensations distinct from those included in the conventional RPE scale. Seven well-trained cyclists completed a maximal effort 100 km time trial (TT) and a submaximal trial at 70% of the power sustained during the TT (70% TT). Five maximal 1 km sprints were included in both trials. Both the RPE related solely to physical sensation (P-RPE) and the TEA score increased during the TT and were linearly related. During the 70% TT, both P-RPE and TEA scores increased, but TEA increased significantly less than P-RPE (p<0.001). TEA scores reached maximal values in all 1 km sprints in both the maximal TT and 70% TT, whereas the RPE increased progressively, reaching a maximal value only in the final 1 km sprints in both the TT and the 70% TT. These results indicate that the physical sensations of effort measured as the P-RPE act as the template regulating performance during exercise and that deviation from that template produces an increase in the sense of effort measured by the TEA score. Together, these controls ensure that the chosen exercise intensity does not threaten bodily homeostasis. Our findings also explain why submaximal exercise conducted within the constraints of the template P-RPE does not produce any conscious awareness of effort.

Impact of body weight on performance of a weight-supported motor fitness test in men.

The impact of body weight on test scores is a common issue in applied measurement. Dimensional analysis suggests that heavier participants are disadvantaged in weight-supported tasks. The purpose of this study was to evaluate the impact of body weight on performance scores for a military obstacle course. Three cohorts of male participants completed the Indoor Obstacle Course Test (IOCT). In cohort 1 (N = 2,191), height and weight were measured. In cohort 2 (N = 134), skinfold measurements were also performed. In cohort 3 (N = 44), all aforementioned measurements were performed, as well as upper- and lower-body tests for aerobic power, anaerobic power, muscular strength, and muscular endurance. The R2 between IOCT scores and body weight was 0.06 and that between IOCT scores and percentage of body fat was 0.08. All cohort analyses suggested that, for male subjects, body weight had only a small impact on the performance score distribution and the IOCT is fit for purpose as a fair repeatable system for assessment of physical performance.