Utility of Two iPhone Device Apps in Assessing Heart Rate at Rest and During Activity

Heart rate (HR) is a critical physiological variable used for prescribing exercise, assessing fitness level and tracking fitness improvements. Electrocardiography (ECG) stands as the criterion measure of HR. While recent development of HR-detecting mobile device applications (apps) has made evaluating HR more convenient; their degree of accuracy is unknown. Therefore, the purpose of this current study was to examine the accuracy and reliability of two-iPhone applications to detect HR at rest and during low-intensity exercise conditions. Eighteen female and 22 male subjects (26 + 9.5 yrs) were prepped for simultaneous detection of HR via three methods: ECG and two HR-detecting apps. App 1, a camera-based app called Azumio Instant Heart Rate (CAM), was used by placement of a finger over the camera lens of the mobile device. App 2, a microphone-based app called Heart Monitor by Bluespark, was employed via placement of an external microphone over the radial pulse. The participants underwent a series of 5-minute stages: seated rest followed by cycle then treadmill walking at low intensities. HR was recorded concurrently, at several time intervals from the three methods once a steady-state HR was reached. The means of the three devices were compared via ANOVA with the significance level set, a priori, at 0.05. Correlation analysis was employed to investigate relationships between the apps and ECG. No statistical difference was found between the CAM and ECG HR (p \u3e 0.05) during the resting and cycle stages. However, during the treadmill phase, there was a significant difference (p = 0.018) between CAM and ECG. Nevertheless, there was a significant (p \u3c 0.05), positive correlation between CAM and ECG under the resting, cycle and treadmill conditions (r = .966, r = .984, r = .877, respectively). Significant differences (p \u3c 0.05) were found for each condition when comparing ECG and MIC HR. Data also revealed poor correlations (p \u3e 0.05; r between -.004 and -.136) between MIC and ECG. The utility of CAM and MIC-based apps to detect HR remains in question as evidence appears to indicate exercise mode and app specificity. Caution should be shown when using these devices. The CAM-based app may accurately detect HR during resting and seated cycling but not during treadmill activity. The MIC-based app is not recommended for use in any condition. Of note, statistical significance may not mitigate usefulness when considering the accuracy of palpation. Additional research is necessary

Benign Conduction Abnormalities in Response to Acute, Moderately-High, Simulated Altitude Exposure

Acclimatization to altitude can improve endurance performance above levels achieved solely by training at sea level. There is natural limitation in the applicability of employing terrestrial altitude training – namely proximity. A simple, non-cumbersome method of simulating altitude is desirable to many types of endurance athletes. The Alto2Lab (Pharma Pacific Inc.), consisting of primarily a breathing tube and silo stack, has shown some potential in this role. There is a lack of evidence regarding whether simulated altitude exposure triggers abnormal cardiovascular responses. The aim of this study was to provide initial evidence of cardiac changes associated with usage patterns that follow distributor guidelines. Twenty-five participants (mean age 29 ± 10.7; 16 males; 9 females) volunteered for the study. Subjects underwent a baseline ECG recording followed by ECG recording during sham (4-5 mins), hypoxia (~6 mins), and recovery (3-4 mins) phases. The sham phase consisted of subjects breathing normoxive air through a foam-filled silo system. The sham stack mimicked the look and feel of the silo system used to produce hypoxia with the difference being a single, soda lime-filled silo. A recovery phase followed hypoxia. Pulse oximetry (SpO2) was used to assess oxygen saturation. Cochran’s Q was employed to test the frequencies of responses across the phases. An independent, blinded, experienced clinician (DK) analyzed the recordings. Two subjects were removed from the final analysis (inability to finish the protocol, baseline right bundle branch block). All subjects demonstrated an increase in heart rate (mean = +16.8 ± 8.0) during the hypoxia (mean oxygen saturation = 82 ± 4.1%) phase. No ECG ischemic changes were seen across any of the phases. Benign conduction abnormalities (sinus arrhythmia = 9; junctional rhythms = 4) occurred with some regularity during hypoxia. These abnormalities occurred with less frequency during the sham and recovery phases. It is possible that an altered breathing pattern or an inadequate washout period between phases might account for these findings. Overall, there was no significant relationship between the heart response and phase (p = .375). While the Alto2Lab did not produce any ECG changes indicative of an ischemic response, the present study used a small sample of healthy, recreationally-active participants. A larger study employing patients among higher risk categories would provide data that is not currently present in the literature and to which this trial cannot speak

Exercise Knowledge, Exercise Beliefs, Physical Activity Engagement and Physical Function in Older Adults

Historically, recall surveys have been used to gather information about exercise knowledge and beliefs (EKB) and physical activity (PA). There seems to be a disconnect between what people know and believe about exercise and the choices they make about engaging in exercise. Advancements in the capacity to capture verifiable PA data have greatly improved with application of accelerometers. The ability to objectively verify PA makes reexamining the relationship between EKB and both PA and physical function (PF) worthwhile. The aim of this investigation was to revisit the relationship between EKB and PA and PF in older adults using recall surveys and accelerometry. Fourteen older adults (8 females; 6 males; M age 69.5 ± 9.4) underwent a single, 75-minute session consisting of questionnaires to gather information about EKB and PA (CHAMPS) and PF tasks (examples: chair sit and reach and 400m aerobic walk) to assess function. The EKB questionnaires were comprised of subsets, such as knowledge about aerobic exercise, beliefs about flexibility exercise, and beliefs about resistance training. Subset scores were compared to PF outcomes in that specific area. A total knowledge score was summed from the subset scores. Based upon age and sex specific norms, PF tasks were scored as below average, average, or above average. A 7-day period of objectively-determined PA was recorded by the ActivPal accelerometer. Partial correlations controlling for age were run on the variables described below. Neither CHAMPS PA nor total steps (accelerometry) correlated with the total EKB score (p \u3e 0.05). The flexibility subset score rating correlated negatively with the chair sit and reach rating (r = -.554, p = 0.049). The aerobic knowledge and beliefs subset score trended towards significance when correlated with the 400 meter walk task (r = -.518, p = 0.070). The resistance training subset score did not correlate with either the arm curl or the chair stand task (p \u3e 0.05). Previous research employing recall surveys has shown that EKB do not predict activity engagement. The present research (with accelerometry) supports this assertion which suggests the lack of relationship is not connected to survey collection recall bias. Subset EKB in flexibility and aerobic exercise correlated or trended towards (respectively) functional outcomes in those areas. It is interesting to speculate that the convenience of engaging in flexibility and aerobic exercise makes acting upon knowledge and beliefs easier when compared with resistance training

Rules for Growth: Promoting Innovation and Growth Through Legal Reform

The United States economy is struggling to recover from its worst economic downturn since the Great Depression. After several huge doses of conventional macroeconomic stimulus - deficit-spending and monetary stimulus - policymakers are understandably eager to find innovative no-cost ways of sustaining growth both in the short and long runs. In response to this challenge, the Kauffman Foundation convened a number of America’s leading legal scholars and social scientists during the summer of 2010 to present and discuss their ideas for changing legal rules and policies to promote innovation and accelerate U.S. economic growth. This meeting led to the publication of Rules for Growth: Promoting Innovation and Growth Through Legal Reform, a comprehensive and groundbreaking volume of essays prescribing a new set of growth-promoting policies for policymakers, legal scholars, economists, and business men and women. Some of the top Rules include: • Reforming U.S. immigration laws so that more high-skilled immigrants can launch businesses in the United States. • Improving university technology licensing practices so university-generated innovation is more quickly and efficiently commercialized. • Moving away from taxes on income that penalize risk-taking, innovation, and employment while shifting toward a more consumption-based tax system that encourages saving that funds investment. In addition, the research tax credit should be redesigned and made permanent. • Overhauling local zoning rules to facilitate the formation of innovative companies. • Urging judges to take a more expansive view of flexible business contracts that are increasingly used by innovative firms. • Urging antitrust enforcers and courts to define markets more in global terms to reflect contemporary realities, resist antitrust enforcement from countries with less sound antitrust regimes, and prohibit industry trade protection and subsidies. • Reforming the intellectual property system to allow for a post-grant opposition process and address the large patent application backlog by allowing applicants to pay for more rapid patent reviews. • Authorizing corporate entities to form digitally and use software as a means for setting out agreements and bylaws governing corporate activities. The collective essays in the book propose a new way of thinking about the legal system that should be of interest to policymakers and academic scholars alike. Moreover, the ideas presented here, if embodied in law, would augment a sustained increase in U.S. economic growth, improving living standards for U.S. residents and for many in the rest of the world

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

International audienceThe RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domai