Cardiorespiratory Improvements Achieved by American College of Sports Medicine's Exercise Prescription Implemented on a Mobile App

Background: Strong evidence shows that an increase in cardiorespiratory fitness (CRF) and physical activity (PA) reduces cardiovascular disease risk. Objective: To test whether a scientifically endorsed program to increase CRF and PA, implemented on an easy-to-use, always-accessible mobile app would be effective in improving CRF. Methods: Of 63 healthy volunteers participating, 18 tested the user interface of the Cardio-Fitness App (CF-App); and 45 underwent a 2-week intervention period, of whom 33 eventually concluded it. These were assigned into three groups. The Step-based App (Step-App) group (n=8), followed 10,000 steps/day prescription, the CF-App group (n=13), and the Supervised Cardio-Fitness (Super-CF) group (n=12), both followed a heart rate (HR)-based program according to American College of Sports Medicine (ACSM) guidelines, but either implemented on the app, or at the gym, respectively. Participants were tested for CRF, PA, resting systolic and diastolic blood pressures (SBP, DBP), resting, exercise, and recovery HR. Results: CRF increased in all groups (+4.9%; P<.001). SBP decreased in all groups (-2.6 mm Hg; P=.03). DBP decrease was higher in the Super-CF group (-3.5 mm Hg) than in the Step-App group (-2.1 mm Hg; P<.001). Posttest exercise HR decreased in all groups (-3.4 bpm; P=.02). Posttest recovery HR was lower in the Super-CF group (-10.1 bpm) than in the other two groups (CF-App: -4.9 bpm, Step-App: -3.3 bpm; P<.001). The CF-App group, however, achieved these improvements with more training heart beats (P<.01). Conclusions: A 10,000 steps/day target-based app improved CRF similar to an ACSM guideline-based program whether it was implemented on a mobile app or in supervised gym sessions. (JMIR Mhealth Uhealth 2016;4(2):e77) doi:10.2196/mhealth.551

Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies

Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT-APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n\u2009=\u2009160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29

DeCoClu: Density consensus clustering approach for public transport data

Automatic Vehicle Monitoring (AVM) systems are exploited by public transport companies to manage and control their fleet of vehicles. However, these systems are usually based on the background knowledge of the transport network which can change during the time and in some cases can be missing or erroneous. GPS data and other information captured by the vehicles during their work can be exploited to update the network knowledge. This paper presents a novel approach, namely DeCoClu (Density Consensus Clustering), that aims at mining the topology of a public transport network by means of a consensus clustering density-based approach. In particular, the method exploits static information from time series of positioning signals (i.e., GPS data) to infer geographical locations of stops by means of a consensus clustering strategy based on a new distance function. Moreover, the logical pathway of a route (i.e., stops sequence) is defined by an Hamiltonian cycle. Experiments performed on real-data collections provided by a public transport company demonstrate the effectiveness of the proposed approach. (C) 2015 Elsevier Inc. All rights reserved

Autonomic nervous system changes during 21 half-marathon in 21 days: a case report

Introduction. Heart Rate Variability (HRV) has recently been proposed to detect the Autonomic Nervous System (ANS) adaptations to endurance training and performance. However, the effect of training on HRV indexes remains inconclusive. To assess whether the morning short-term HR recording in clinostatic position may be useful in evaluating the training-induced autonomic changes, detecting fatigue and predict the possible overtraining. Methods. A 42 yrs old woman (height 162 cm; body mass 52 kg; fat mass 16,6%; VO2max 45,9 ml\uf0d7kg-1\uf0d7min-1), voluntarily perform 21 half-marathons in 21 days, one half-marathon each day. Every day before the half marathon, the subject performed RR series were recorded after awakening supine (10 min) positions. The HRV parameters considered were LogRMSSD, LogpNN50, LogHF, [0.15-0.40 Hz]. Frequencies: absolute powers, LF/HF ratio, and the non-linear index Sample Entropy (SampEn) and Detrended Fluctuations (\uf0611). In addition the velocity (km\uf0d7h-1) of each half-marathon was reported. Results. ANS changed in relation to half-marathon performances. The mean velocity of all half-marathons was 11.0\uf0b10.5 km\uf0d7h-1. A positively correlation between RMSSD (r=0.63), pNN50 (r=0.53), HF (r=0.57), SampEn (r=0.42) index and the number of half-marathon (p<0.05), while negative correlation in LF/HF ratio (r=-0.57) and DFA\uf0611 (r=-0.57) (p=ns), was found. In particular, HRV indexes of cardiac vagal tone comparing the 21th half-marathon with the 1st tended to increase (LogRMSSD: 2.18 vs 1.95, +11.8%; LogpNN50: 1.72 vs 1.65, + 4.2%; LogHF: 3.65 vs 3.20, +14.1%; SampEn: 1.60 vs 1.42, +12.7%). The cardiac sympathovagal balance tended to decrease (LF/HF ratio: 1.19 vs 5.74, -79.3%; \uf0611: 0.92 vs 1.30, -29.3%). A positively correlation between RMSSD (r=0.45, p<0.05), pNN50 (r=0.58, p<0.05), HF (r=0.52, p<0.05), SampEn (r=0.45, p=0.057) index and the velocity during half-marathon, while negative correlations in LF/HF ratio (-0.57, p<0.05) and \uf0611 (-0.57, p<0.05) was found. Especially, the min \u2013 max velocity during all half-marathons was respectively 10.1 \u2013 11.6 km\uf0d7h-1, and in this range of velocities there is a changing in HRV indexes: RMSSD (+41.9%), pNN50 (+52.1%), HF (+78.0%), SampEN (+100.0%), LF/HF (+707.6%), \uf0611 (+70.7%). Conclusions. A large amount of exercise is related to parasympatic modulation. In fact, during the 21 half-marathons cardiac autonomic balance shift to sympathetic over parasympathetic drive. HRV may be useful in detecting the autonomic changes induced by endurance performance. This type of changes could be determined by fatigue or a result of possible overtraining

Effects of 21 half-marathon in 21 days on autonomic nervous system and psychological parameters : a case report

Aim. Heart Rate Variability (HRV) measurement is a non-invasive method used to investigate the Autonomic Nervous System (ANS) responsiveness in healthy as well as patients. Even if consequences of a short term training period on ANS is well ancknoledged, the long-term (>15 days) effect of repeated submaximal exercise remains elusive. We investigated the cardiac ANS adaptation to 21 consecutive half-marathons and its possible relationships with psychological fatigue. Methods. A 42 yrs old woman (BMI: 19.8; VO2max: 45,9 ml/kg/min), voluntarily performed 21 half-marathons in 21 consecutive days. Every morning, after awakening, heart rate (HR) for 10 min on a beat-to-beat basis (RR series) in supine position. RR series spectral powers, indexes of vagal (HFnu; 0.15-0.40 Hz), mixed para- and sympathetic tone (LFnu; 0.04-0.15 Hz) and sympatho-vagal balance (LF/HF ratio), were derived. A 32-item profile of mood states (POMS) questionnaire and Session RPE (mins x RPE 10 points scale) were daily collected. Results. Running time did not change significantly (1h54\u201955\u2019\u2019\ub1 4\u201955\u2019\u2019; p=0.44, r=-0.18). Number of consecutive running days (NcRD) negatively linearly correlated with HR rest (p<0.001, r=-0.7) and LogLF/HF (p<0.01, r=0.64), and positively with LogHF Power (n.u.) (p<0.01, r=0.62). NcRD did not linearly correlated with LogLF Power (n.u.) (p<0.01, r2=0.55). NcRD negatively linearly correlated with the Energy Index (EI) (p<0.0001, r=-0.87). NcRD positively correlated with session-RPE (p<0.01, r=0.62), whose scores ranged between 0.3 and 5. A positive correlation between LogLF/HF ratio and EI (p<0.01, r=0.61) and a negative correlation between LogHF Power (n.u.) (p<0.01, r=-0.61) were found. There were no correlations between EI (vigor-fatigue) and LogLF Power (n.u.). Conclusions. Twenty-one consecutive half-marathons at sub-maximal intensity led to a continuous improvement of cardio-vagal control and sympatho-vagal balance, without a clear plateau. This suggests a training effect, that could be extended further. The EI increase seemed to reveal an accumulation of psychological fatigue, probably due to lack of recovery days and monotony of training. Therefore, long-term daily repetitions of sub-maximal exercise seems to improve cardio-vagal tone, but to induce also a psychological fatigue accumulation, which could demotivate the atlete in continuing the training. References 1. Aubert AE et al.(2003) Heart Rate Varibility in Athletes. Sports Med.;33(12):889-919