Case studies in physiology: Impact of a long-distance hike on the Pacific Crest Trail on arterial function and body composition in a highly fit young male

The Pacific Crest Trail (PCT) is a 4265-km hiking trail that extends from the US-Mexican border to the US-Canadian border through the mountain ranges of western North America. Individuals who hike the entire length of the trail in one season (4-6 months) perform long daily exercise durations while exposed to extreme environmental temperatures, high altitudes, intense solar radiation, and the consumption of calorie-rich, nutrient-poor diets. This case study reports changes in arterial function and body composition in a subject before and after a 112-day long-distance hike of the PCT. Brachial artery flow-mediated dilation, a measure of vascular endothelial function, decreased from: 6.97% to 5.00%. Carotid-femoral pulse wave velocity, a measure of aortic stiffness, increased from 5.39 to 5.76 m/s. Dual-energy x-ray absorptiometry scans detected no major changes in total-body bone mineral density, fat mass, or lean mass, although there were minor, unfavorable changes in some subregions of the body. It is important for individuals completing a long-distance hike to be aware of the potential deleterious changes associated with large volumes of exercise and consuming a high-calorie, low-quality diet. &nbsp;</p

Vascular Endothelial Function in Midlife/Older Adults Classified According to 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines

Background Impaired endothelial function is thought to contribute to the increased cardiovascular risk associated with above‐normal blood pressure (BP). However, the association between endothelial function and BP classified by 2017 American College of Cardiology/American Heart Association guidelines is unknown. Our objective was to determine if endothelial function decreases in midlife/older adults across the 2017 American College of Cardiology/American Heart Association guidelines BP classifications and identify associated mechanisms of action. Methods and Results A retrospective analysis of endothelial function (brachial artery flow‐mediated dilation) from 988 midlife/older adults (aged 50+&nbsp;years) stratified by BP status (normal BP; elevated BP; stage 1 hypertension; stage 2 hypertension) was performed. Endothelium‐independent dilation (sublingual nitroglycerin), reactive oxygen species&ndash;mediated suppression of endothelial function (∆brachial artery flow‐mediated dilation with vitamin C infusion), and endothelial cell and plasma markers of oxidative stress and inflammation were assessed in subgroups. Compared with normal BP (n=411), brachial artery flow‐mediated dilation was 12% (P=0.04), 15% (P&lt;0.01) and 20% (P&lt;0.01) lower with elevated BP (n=173), stage 1 hypertension (n=248) and stage 2 hypertension (n=156), respectively, whereas endothelium‐independent dilation did not differ (P=0.14). Vitamin C infusion increased brachial artery flow‐mediated dilation in those with above‐normal BP (P&le;0.02) but not normal BP (P=0.11). Endothelial cell p47phox (P&lt;0.01), a marker of superoxide/reactive oxygen species&ndash;generating nicotinamide adenine dinucleotide phosphate oxidase, and circulating interleukin‐6 concentrations (P=0.01) were higher in individuals with above‐normal BP. Conclusions Vascular endothelial function is progressively impaired with increasing BP in otherwise healthy adults classified by 2017 American College of Cardiology/American Heart Association guidelines. Impaired endothelial function with above‐normal BP is mediated by excessive reactive oxygen species signaling associated with increased endothelial expression of nicotinamide adenine dinucleotide phosphate oxidase and circulating interleukin‐6.</p

Time-Efficient Inspiratory Muscle Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO Bioavailability, and Oxidative Stress in Midlife/Older Adults With Above-Normal Blood Pressure

Background High‐resistance inspiratory muscle strength training (IMST) is a novel, time‐efficient physical training modality. &nbsp; Methods and Results We performed a double‐blind, randomized, sham‐controlled trial to investigate whether 6&nbsp;weeks of IMST (30&nbsp;breaths/day, 6&nbsp;days/week) improves blood pressure, endothelial function, and arterial stiffness in midlife/older adults (aged 50&ndash;79&nbsp;years) with systolic blood pressure &ge;120&nbsp;mm&nbsp;Hg, while also investigating potential mechanisms and long‐lasting effects. Thirty‐six participants completed high‐resistance IMST (75% maximal inspiratory pressure, n=18) or low‐resistance sham training (15% maximal inspiratory pressure, n=18). IMST was safe, well tolerated, and had excellent adherence (&asymp;95% of training sessions completed). Casual systolic blood pressure decreased from 135&plusmn;2&nbsp;mm&nbsp;Hg to 126&plusmn;3&nbsp;mm&nbsp;Hg (P&lt;0.01) with IMST, which was &asymp;75% sustained 6&nbsp;weeks after IMST (P&lt;0.01), whereas IMST modestly decreased casual diastolic blood pressure (79&plusmn;2&nbsp;mm&nbsp;Hg to 77&plusmn;2&nbsp;mm&nbsp;Hg, P=0.03); blood pressure was unaffected by sham training (all P&gt;0.05). Twenty‐four hour systolic blood pressure was lower after IMST versus sham training (P=0.01). Brachial artery flow‐mediated dilation improved &asymp;45% with IMST (P&lt;0.01) but was unchanged with sham training (P=0.73). Human umbilical vein endothelial cells cultured with subject serum sampled after versus before IMST exhibited increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity (P&lt;0.05). IMST decreased C‐reactive protein (P=0.05) and altered select circulating metabolites (targeted plasma metabolomics) associated with cardiovascular function. Neither IMST nor sham training influenced arterial stiffness (P&gt;0.05). &nbsp; Conclusions High‐resistance IMST is a safe, highly adherable lifestyle intervention for improving blood pressure and endothelial function in midlife/older adults with above‐normal initial systolic blood pressure. &nbsp; Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03266510. &nbsp;</p

Commentaries on viewpoint : physiology and fast marathons

Q2Q1N/

Tumor Cell Marker PVRL4 (Nectin 4) Is an Epithelial Cell Receptor for Measles Virus

Vaccine and laboratory adapted strains of measles virus can use CD46 as a receptor to infect many human cell lines. However, wild type isolates of measles virus cannot use CD46, and they infect activated lymphocytes, dendritic cells, and macrophages via the receptor CD150/SLAM. Wild type virus can also infect epithelial cells of the respiratory tract through an unidentified receptor. We demonstrate that wild type measles virus infects primary airway epithelial cells grown in fetal calf serum and many adenocarcinoma cell lines of the lung, breast, and colon. Transfection of non-infectable adenocarcinoma cell lines with an expression vector encoding CD150/SLAM rendered them susceptible to measles virus, indicating that they were virus replication competent, but lacked a receptor for virus attachment and entry. Microarray analysis of susceptible versus non-susceptible cell lines was performed, and comparison of membrane protein gene transcripts produced a list of 11 candidate receptors. Of these, only the human tumor cell marker PVRL4 (Nectin 4) rendered cells amenable to measles virus infections. Flow cytometry confirmed that PVRL4 is highly expressed on the surfaces of susceptible lung, breast, and colon adenocarcinoma cell lines. Measles virus preferentially infected adenocarcinoma cell lines from the apical surface, although basolateral infection was observed with reduced kinetics. Confocal immune fluorescence microscopy and surface biotinylation experiments revealed that PVRL4 was expressed on both the apical and basolateral surfaces of these cell lines. Antibodies and siRNA directed against PVRL4 were able to block measles virus infections in MCF7 and NCI-H358 cancer cells. A virus binding assay indicated that PVRL4 was a bona fide receptor that supported virus attachment to the host cell. Several strains of measles virus were also shown to use PVRL4 as a receptor. Measles virus infection reduced PVRL4 surface expression in MCF7 cells, a property that is characteristic of receptor-associated viral infections

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation &lt;92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p&lt;0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p&lt;0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

A novel running mechanic\u27s class changes kinematics but not running economy

Craighead, DH, Lehecka, N, and King, DL. A novel running mechanic\u27s class changes kinematics but not running economy. J Strength Cond Res 28(11): 3137-3145, 2014-A novel method of running technique instruction, Midstance to Midstance Running (MMR), was studied to determine how MMR affected kinematics and running economy (RE) of recreational runners. An experimental pre-post randomized groups design was used. Participants (n = 18) were recreational runners who ran at least 3 days a week and 5 km per run. All testing was performed on a treadmill at 2.8 m·s21. The intervention group (n = 9) completed 8 weeks of instruction in MMR; the control group (n = 9) continued running without instruction. The MMR group showed significant decreases in stride length (SL) (p = 0.02) and maximum knee flexion velocity in stance (p = 0.01), and a significant increase in stride rate (SR) (p = 0.02) after 8 weeks. No significant changes were found in heart rate, rating of perceived exertion, or RE. Midstance to Midstance Running was effective in changing SR and SL, but was not effective in changing other kinematic variables such as foot contact position and maximum knee flexion during swing. Midstance to Midstance Running did not affect RE. Evidence suggests that MMR may be an appropriate instructional method for recreational runners trying to decrease SL and increase SR