Pandemics of COVID-19 and racism: how HBCUs are coping.

Historically Black Colleges and Universities (HBCUs) are currently facing unique challenges to deal with parallel pandemics of COVID-19 and Racism, given the population they serve (mostly African American) are at high risk of these unprecedented crises. HBCU leaders are adopting various strategies to respond to both the pandemics in order to protect their stakeholders. This paper addresses various models that HBCUs have adopted or planned to adopt to cope with these pandemics, gleaning the data from various secondary sources and selected first-hand interviews with HBCU administrators.

Tobacco Use and Secondhand Smoke Exposure Among Older Adults in India.

Objectives: Current tobacco use (CTU) and secondhand smoke (SHS) exposure among older adults in India (≥60 years) are prevalent in India and indicate the importance of addressing associated factors. Methods: Pooled Global Adult Tobacco Survey India 2009-2010 and 2016-2017 data (n = 17,299) for older adults examined prevalence of CTU and SHS exposure at home and/or in public places and associated socioeconomic and demographic correlates. Results: CTU among older adults in India was 44.6%, and SHS exposure at home and public places were 20.0% and 30.0%, respectively. Men, younger age-group, rural, lower education, lower wealth index, and lower knowledge were independently associated with CTU. Men, rural, lower education, lower wealth index, CTU, and lower knowledge were independently associated with SHS exposure at home. Men, younger age, and rural residence were associated with SHS exposure in public places. Conclusion: CTU and SHS exposure among older adults in India suggest targeted interventions to address associated social and demographic factors.

Dysplasia severity is associated with poor quality of life in patients with Barrett's esophagus referred for endoscopic eradication therapy.

Limited data exist regarding patient-reported outcomes and quality of life (QOL) experienced by patients with Barrett's esophagus (BE) referred for endoscopic eradication therapy (EET). Specifically, the impact of grade of dysplasia has not been explored. The purpose of this study is to measure patient-reported symptoms and QOL and identify factors associated with poor QOL in BE patients referred for EET. This was a prospective multicenter study conducted from January 2015 to October 2017, which included patients with BE referred for EET. Participants completed a set of validated questionnaires to measure QOL, symptom severity, and psychosocial factors. The primary outcome was poor QOL defined by a PROMIS score >12. Multivariable logistic regression analysis was performed to identify factors associated with poor QOL. In total, 193 patients participated (mean age 64.6 years, BE length 5.5 cm, 82% males, 92% Caucasians) with poor QOL reported in 104 (53.9%) participants. On univariate analysis, patients with poor QOL had lower use of twice daily proton pump inhibitor use (61.5% vs. 86.5%, P = 0.03), shorter disease duration (4.9 vs. 5.9 years, P = 0.04) and progressive increase in grade of dysplasia (high-grade dysplasia: 68.8% vs. 31.3%, esophageal adenocarcinoma: 75.5% vs. 24.5%, P < 0.001). Multivariate analysis demonstrated that high-grade dysplasia was independently associated with poor QOL (OR: 5.57, 95% CI: 1.05, 29.5, P = 0.04). In summary, poor QOL is experienced by the majority of patients with BE referred for EET and the degree of dysplasia was independently associated with poor QOL, which emphasizes the need to incorporate patient-centered outcomes when studying treatment of BE-related dysplasia.

Contrasting Trends of Smoking Cessation Status: Insights From the Stages of Change Theory Using Repeat Data From the Global Adult Tobacco Survey, Thailand (2009 and 2011) and Turkey (2008 and 2012).

OBJECTIVE: The World Health Organization recommends that smokers be offered help to quit. A better understanding of smokers' interest in and commitment to quitting could guide tobacco control efforts. We assessed temporal differences in stages of change toward quitting among smokers in Thailand and Turkey. METHODS: Two waves (independent samples) of data from the Global Adult Tobacco Survey, a national household survey of adults aged 15 years or older, were assessed for Thailand (2009 and 2011) and Turkey (2008 and 2012). Current smokers were categorized into 3 stages of change based on their cessation status: precontemplation, contemplation, and preparation. Relative change in the proportion of smokers in each stage between waves 1 and 2 was computed for each country. RESULTS: Between waves, overall current tobacco smoking did not change in Thailand (23.7% to 24.0%) but declined in Turkey (31.2% to 27.1%; P < .001). Between 2009 and 2011, precontemplation increased among smokers in Thailand (76.1% to 85.4%; P < .001), whereas contemplation (17.6% to 12.0%; P < .001) and preparation (6.3% to 2.6%; P < .001) declined. Between 2008 and 2012, there were declines in precontemplation among smokers in Turkey (72.2% to 64.6%; P < .001), whereas there were increases in contemplation (21.2% to 26.9%; P = .008) and no significant change in preparation (6.5% to 8.5%; P = .097). CONCLUSION: Nearly two-thirds of smokers in Turkey and more than two-thirds in Thailand were in the precontemplation stage during the last survey wave assessed. The proportion of smokers in the preparation stage increased in Turkey but declined in Thailand. Identifying stages of cessation helps guide population-based targeted interventions to support smokers at varying stages of change toward quitting.

Direct one-pot synthesis of glutathione capped hydrophilic FePt-CdS nanoprobe for efficient bimodal imaging application.

One-pot synthesis methods for development of hydrophilic imaging nanoprobes have advantages over multi-pot methods due to their simple procedures, less probability for degradation of efficiency, superior control over growth and morphology, cost effectiveness, improved scope for scale-up synthesis etc. Here, we present a novel one-pot facile synthesis of hydrophilic colloidal bimodal nanoprobe (FePt-CdS) prepared through a seed-mediated nucleation and growth technique. In this facile synthesis of complex nanostructure, glutathione (GSH) was used as the capping agent to render biocompatibility and dispersibility. The microstructure, surface, optical, magnetic, biocompatibility, relaxivity and imaging property of the developed nanoprobe have been studied. The microstructural characterizations reveal average size of the particle as ~9-11nm with bleb shaped morphology. Spectroscopic characterization depicts the development of GSH capped CdS QDs on FePt, surface functionalities and their stability. The magnetic measurements confirm the superparamagnetic property in the developed bimodal nanoprobe. In addition, the GSH capping imparts excellent biocompatibility, water dispersibility, and fluorescence property to the probe. In RAW 264.7 macrophage cells, the bimodal nanoprobes exhibit intense green and red fluorescence. The magnetic resonance imaging (MRI) and fluorescence imaging (FI) study depict high transverse relaxivity and visible range fluorescent property in the synthesized FePt-CdS nanoprobe. Hence, the developed bimodal nanoprobe can be used as a potential candidate in simultaneous FI and MR imaging.

Effects of preceding endoscopic mucosal resection on the efficacy and safety of radiofrequency ablation for treatment of Barrett's esophagus: results from the United States Radiofrequency Ablation Registry.

The effects of preceding endoscopic mucosal resection (EMR) on the efficacy and safety of radiofrequency ablation (RFA) for treatment of nodular Barrett's esophagus (BE) is poorly understood. Prior studies have been limited to case series from individual tertiary care centers. We report the results of a large, multicenter registry. We assessed the effects of preceding EMR on the efficacy and safety of RFA for nodular BE with advanced neoplasia (high-grade dysplasia or intramucosal carcinoma) using the US RFA Registry, a nationwide study of BE patients treated with RFA at 148 institutions. Safety outcomes included stricture, gastrointestinal bleeding, and hospitalization. Efficacy outcomes included complete eradication of intestinal metaplasia (CEIM), complete eradication of dysplasia (CED), and number of RFA treatments needed to achieve CEIM. Analyses comparing patients with EMR before RFA to patients undergoing RFA alone were performed with Student's t-test, Chi-square test, logistic regression, and Kaplan-Meier analysis. Four hundred six patients were treated with EMR before RFA for nodular BE, and 857 patients were treated with RFA only for non-nodular BE. The total complication rates were 8.4% in the EMR-before-RFA group and 7.2% in the RFA-only group (P = 0.48). Rates of stricture, bleeding, and hospitalization were not significantly different between patients treated with EMR before RFA and patients treated with RFA alone. CEIM was achieved in 84% of patients treated with EMR before RFA, and 84% of patients treated with RFA only (P = 0.96). CED was achieved in 94% and 92% of patients in EMR-before-RFA and RFA-only group, respectively (P = 0.17). Durability of eradication did not differ between the groups. EMR-before-RFA for nodular BE with advanced neoplasia is effective and safe. The preceding EMR neither diminished the efficacy nor increased complication rate of RFA treatment compared to patients with advanced neoplasia who had RFA with no preceding EMR. Preceding EMR is not associated with poorer outcomes in RFA.

The Process of Cessation Among Current Tobacco Smokers: A Cross-Sectional Data Analysis From 21 Countries, Global Adult Tobacco Survey, 2009-2013.

We analyzed data from the Global Adult Tobacco Survey (GATS) from 21 countries to categorize smokers by stages of cessation and highlight interventions that could be tailored to each stage. GATS is a nationally representative household survey that measures tobacco use and other key indicators by using a standardized protocol. The distribution of smokers into precontemplation, contemplation, and preparation stages varied by country. Using the stages of change model, each country can design and implement effective interventions suitable to its cultural, social, and economic situations to help smokers advance successfully through the stages of cessation.

Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry.

BACKGROUND: Esophageal motor disorders are a heterogeneous group of conditions identified by esophageal manometry that lead to esophageal dysfunction. The aim of this study was to assess the clinical utility of endoscopic ultrasound (EUS) in the further evaluation of patients with esophageal motor disorders categorized using the updated Chicago Classification. METHODS: We performed a retrospective, single center study of 62 patients with esophageal motor disorders categorized according to the Chicago Classification. All patients underwent standard radial endosonography to assess for extra-esophageal findings or alternative explanations for esophageal outflow obstruction. Secondary outcomes included esophageal wall thickness among the different patient subsets within the Chicago Classification. KEY RESULTS: EUS identified 9/62 (15%) clinically relevant findings that altered patient management and explained the etiology of esophageal outflow obstruction. We further identified substantial variability in esophageal wall thickness in a proportion of patients including some with a significantly thickened non-muscular layer. CONCLUSIONS & INFERENCES: EUS findings are clinically relevant in a significant number of patients with motor disorders and can alter clinical management. Variability in esophageal wall thickness of the muscularis propria and non-muscular layers identified by EUS may also explain the observed variability in response to standard therapies for achalasia.

In vivo NMR studies of regional cerebral energetics in MPTP model of Parkinson's disease: recovery of cerebral metabolism with acute levodopa treatment.

In this study, we have evaluated cerebral atrophy, neurometabolite homeostasis, and neural energetics in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) model of Parkinson's disease. In addition, the efficacy of acute l-DOPA treatment for the reversal of altered metabolic functions was also evaluated. Cerebral atrophy and neurochemical profile were monitored in vivo using MRI and (1) H MR Spectroscopy. Cerebral energetics was studied by (1) H-[(13) C]-NMR spectroscopy in conjunction with infusion of (13) C labeled [1,6(-13) C2 ]glucose or [2-(13) C]acetate. MPTP treatment led to reduction in paw grip strength and increased level of GABA and myo-inositol in striatum and olfactory bulb. (13) C Labeling of glutamate-C4 (1.93 ± 0.24 vs. 1.48 ± 0.06 µmol/g), GABA-C2 (0.24 ± 0.04 vs. 0.18 ± 0.02 µmol/g) and glutamaine-C4 (0.26 ± 0.04 vs. 0.20 ± 0.04 µmol/g) from [1,6-(13) C2 ]glucose was found to be decreased with MPTP exposure in striatum as well as in other brain regions. However, glutamine-C4 labeling from [2-(13) C]acetate was found to be increased in the striatum of the MPTP-treated mice. Acute l-DOPA treatment failed to normalize the increased ventricular size and level of metabolites but recovered the paw grip strength and (13) C labeling of amino acids from [1,6-(13) C2 ]glucose and [2-(13) C]acetate in MPTP-treated mice. These data indicate that brain energy metabolism is impaired in Parkinson's disease and acute l-DOPA therapy could temporarily recover the cerebral metabolism. Cerebral atrophy, neurometabolite homeostasis, and neural energetics have been evaluated in an MPTP model of Parkinson's disease using MRI, in vivo (1) H MRS and (1) H-[(13) C]-NMR spectroscopy, respectively. MPTP treatment led to reduced paw grip strength and neuronal function. Acute Levodopa treatment was able to recover the diminished motor function and cerebral function. CMRGlc, Cerebral metabolic rate of glucose oxidation; MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin.

Endoscopic management of Barrett's esophagus associated dysplasia and early esophageal cancer.

The last decade has seen a transformation in the endoscopic management of Barrett's esophagus associated dysplasia from simple surveillance to therapeutic tissue eradication. The combined approach using endoscopic mucosal resection and ablative techniques has proven to be safe and effective. This strategy provides a more cost-effective and safer alternative to esophagectomy for patient with high-grade dysplasia. Despite its safety and efficacy, many questions remain regarding durability, complications, and risk-stratification of patients for endoscopic therapy. However, endoscopic therapy provides a safe and effective weapon against the rising incidence of esophageal adenocarcinoma.

Radiofrequency ablation for dysplasia in Barrett's esophagus restores ß-catenin activation within esophageal progenitor cells.

BACKGROUND AND AIMS: Endoscopic therapies for Barrett's esophagus (BE) associated dysplasia, particularly radiofrequency ablation (RFA), are popular alternatives to surgery. The effect of such therapies on dysplastic stem/progenitor cells (SPC) is unknown. Recent studies suggest that AKT phosphorylation of ß-Catenin occurs in SPCs and may be a marker of activated SPCs. We evaluate the effect of RFA in restoring AKT-mediated ß-Catenin signaling in regenerative epithelium. METHODS: Biopsies were taken from squamous, non-dysplastic BE, dysplastic BE and esophageal adenocarcinoma (EAC). Also, post-RFA, biopsies of endoscopically normal appearing neosquamous epithelium were taken at 3, 6, and 12 months after successful RFA. Immunohistochemistry and Western blot analysis was performed for Pß-Catenin(552) (Akt-mediated phosphorylation of ß-Catenin), Ki-67 and p53. RESULTS: There was no difference in Pß-Catenin552 in squamous, GERD, small bowel and non-dysplastic BE. There was a fivefold increase in Pß-Catenin(552) in dysplasia and EAC compared to non-dysplastic BE (P < 0.05). Also, there was a persistent threefold increase in Pß-Catenin(552) in neosquamous epithelium 3 months after RFA compared to native squamous epithelium (P < 0.05) that correlated with increased Ki-67. Six months after RFA, Pß-Catenin(552) and Ki-67 are similar to native squamous epithelium. CONCLUSIONS: Enhanced AKT-mediated ß-Catenin activation is seen in BE-associated carcinogenesis. Three months after RFA, squamous epithelial growth from SPC populations exhibited increased levels of Pß-Catenin(552). This epithelial response becomes quiescent at 6 months after RFA. These data suggest that elevated Pß-Catenin(552) after RFA denotes a repair response in the neosquamous epithelium 3 months post-RFA.

Diagnostic yield of a novel jumbo biopsy "unroofing" technique for tissue acquisition of gastric submucosal masses.

BACKGROUND AND STUDY AIMS: Adequate tissue acquisition for the diagnosis of gastric submucosal masses (GSMs) has been challen ging for gastroenterologists. The use of standard biopsy forceps generally recovers non-diagnostic overlying mucosa. Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) provides a significant improvement, but is often still inadequate for diagnosis. The aim of the current study was to assess the efficacy of a novel jumbo biopsy unroofing technique (JUT) for tissue acquisition in GSM. PATIENTS AND METHODS: This prospective study recruited patients who were referred for EUS for the evaluation of GSM between 2006 and 2009. All patients underwent EUS with FNA when feasible followed by JUT. The primary outcome was diagnostic yield of JUT. RESULTS: A total of 93 patients were enrolled, 72 of whom were included in the investigation; 16 patients were excluded with no evidence of a submucosal mass or extrinsic compression, and five patients were further excluded by pathology confirming mucosal lesions. Of the 72 jumbo biopsies 66 (92%) provided diagnostic tissue without significant complications and 42 (58%) had lesions amenable to FNA. Although 34 of the 42 lesions were deemed adequate at the time of on-site cytological evaluation, only 28 (67%) provided sufficient tissue for final diagnosis. More importantly, only 37/72 (52%) of all patients had lesions that required any further intervention. CONCLUSIONS: Utilization of JUT is safe and effective for diagnosis of GSM. The data suggest that the jumbo biopsy unroofing technique should be considered as an initial diagnostic strategy for GSMs found during upper endoscopy.

Use of a continuing medical education course to improve fellows' knowledge and skills in esophageal disorders.

Advanced esophageal endoscopic procedures such as stricture dilation, hemostasis tools, and stent placement as well as high-resolution manometry (HRM) interpretation are necessary skills for gastroenterology fellows to obtain during their training. Becoming proficient in these skills may be challenging in light of higher complication rates compared with diagnostic procedures and infrequent opportunities to practice these skills. Our aim was to determine if intensive training during a continuing medical education (CME) course boosts the knowledge and skills of gastroenterology fellows in esophageal diagnostic test interpretation and performance of therapeutic procedures. This was a pretest-posttest design without a control group of a simulation-based, educational intervention in esophageal stricture balloon dilation and HRM interpretation. The participants were 24 gastroenterology fellows from 21 accredited US training programs. This was an intensive CME course held in Las Vegas, Nevada from August 7 to August 9, 2009. The research procedure had two phases. First, the subjects were measured at baseline (pretest) for their knowledge and procedural skill. Second, the fellows received 6 hours of education sessions featuring didactic content, instruction in HRM indications and interpretation, and deliberate practice using an esophageal stricture dilation model. After the intervention, all of the fellows were retested (posttest). A 17-item checklist was developed for the esophageal balloon dilation procedure using relevant sources, expert opinion, and rigorous step-by-step procedures. Nineteen representative HRM swallow studies were obtained from Northwestern's motility lab and formed the pretest and posttest in HRM interpretation. Mean scores on the dilation checklist improved 81% from 39.4% (standard deviation [SD]= 33.4%) at pretest to 71.3% (SD = 29.5%) after simulation training (P < 0.001). HRM mean examination scores increased from 27.2% (SD = 16.4%) to 46.5% (SD = 15.8%), representing a 71% improvement (P < 0.001). Pearson's correlations indicated there was no correlation between pretest performance, medical knowledge measured by United States Medical Licensing Examination examinations, prior clinical experience, or procedural self-confidence and posttest performance of esophageal dilation or HRM interpretation. The education program was rated highly. This study demonstrated that a CME course significantly enhanced the technical skills and knowledge of gastroenterology fellows in esophageal balloon dilation and HRM interpretation. CME courses such as this may be a valuable adjunct to standard fellowship training in gastroenterology.

Increases in free radicals and cytoskeletal protein oxidation and nitration in the colon of patients with inflammatory bowel disease.

BACKGROUND: Overproduction of colonic oxidants contributes to mucosal injury in inflammatory bowel disease (IBD) but the mechanisms are unclear. Our recent findings using monolayers of intestinal cells suggest that the mechanism could be oxidant induced damage to cytoskeletal proteins. However, oxidants and oxidative damage have not been well characterised in IBD mucosa. AIMS: To determine whether there are increases in oxidants and in tissue and cytoskeletal protein oxidation in IBD mucosa. METHODS: We measured nitric oxide (NO) and markers of oxidative injury (carbonylation and nitrotyrosination) to tissue and cytoskeletal proteins in colonic mucosa from IBD patients (ulcerative colitis, Crohn's disease, specific colitis) and controls. Outcomes were correlated with IBD severity score. RESULTS: Inflamed mucosa showed the greatest increases in oxidants and oxidative damage. Smaller but still significant increases were seen in normal appearing mucosa of patients with active and inactive IBD. Tissue NO levels correlated with oxidative damage. Actin was markedly (>50%) carbonylated and nitrated in inflamed tissues of active IBD, less so in normal appearing tissues. Tubulin carbonylation occurred in parallel; tubulin nitration was not observed. NO and all measures of oxidative damage in tissue and cytoskeletal proteins in the mucosa correlated with IBD severity. Disruption of the actin cytoarchitecture was primarily within the epithelial cells and paracellular area. CONCLUSIONS: Oxidant levels increase in IBD along with oxidation of tissue and cytoskeletal proteins. Oxidative injury correlated with disease severity but is also present in substantial amounts in normal appearing mucosa of IBD patients, suggesting that oxidative injury does not necessarily lead to tissue injury and is not entirely a consequence of tissue injury. Marked actin oxidation (>50%)-which appears to result from cumulative oxidative damage-was only seen in inflamed mucosa, suggesting that oxidant induced cytoskeletal disruption is required for tissue injury, mucosal disruption, and IBD flare up.

An audit of the utility of in-patient fecal occult blood testing.

OBJECTIVES: Recent surveys of physician practice have suggested the existence of excessive, inappropriate use of the fecal occult blood test (FOBT). We studied the implementation of this test in hospitalized patients. METHODS: We performed a retrospective chart review of 1000 randomly selected patients who had been discharged from the Medicine service at four teaching hospitals. Patient demographics, clinical presentation, presence or absence of overt GI bleeding, and use of medications that might affect the FOBT were recorded. Reviewers assessed whether patients who had FOBT would have been candidates for colon resection if asymptomatic colon cancer had been found. RESULTS: Digital rectal examination was documented in 44.8% of patients; the findings were recorded in only 9%. A total of 421 patients had FOBT on admission, usually on stool obtained at digital rectal examination. Of the patients with a positive FOBT, 17% had active GI bleeding. Only 41.1% of patients with a positive FOBT were referred to the gastroenterology service. In 70.5% of patients, FOBT could be considered inappropriate because of factors such as age, active GI bleeding, or use of aspirin or other nonsteroidal anti-inflammatory drugs. CONCLUSIONS: The FOBT, which is validated only for colorectal cancer screening, is often performed inappropriately in patients admitted to the hospital. This test should be restricted in hospital practice. It would be preferable to identify patients who are appropriate candidates for colorectal cancer screening at the time of hospital discharge and to advise them about the appropriate performance of the FOBT at home.

Management of paroxysmal atrioventricular nodal reentrant tachycardia in the critically ill surgical patient.

OBJECTIVES: Paroxysmal atrioventricular nodal reentrant tachycardia is an infrequently encountered supraventricular arrhythmia that continues to present difficult management problems in the critically ill surgical patient. The purpose of this study was to evaluate the efficacy of a new treatment algorithm involving the sequential administration of different classes of antiarrhythmic agents until conversion to sinus rhythm was achieved. DESIGN: Nonrandomized, consecutive, protocol-driven descriptive cohort. SETTING: University hospital surgical and trauma intensive care unit (ICU). PATIENTS: During an 11-month period, we prospectively evaluated all hemodynamically stable patients who sustained new-onset atrioventricular nodal reentrant tachycardia. INTERVENTIONS: Vagal maneuver, followed by the rapid, sequential infusion of antiarrhythmic agents (i.e., adenosine, verapamil, and esmolol, respectively) until the arrhythmia was terminated. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients (4% of all admissions) were evaluated, including 16 trauma patients (injury Severity Score of 20 +/- 8) and 11 general surgical patients (Acute Physiology and Chronic Health Evaluation II score of 17 +/- 7). Time from ICU admission to onset of atrioventricular nodal reentrant tachycardia was 4.5 +/- 5 days (median 2.5). Arrhythmia termination was achieved in all patients within minutes (mean 13 +/- 10 [SD]). Incremental sequential adenosine administration alone, however, was successful in affecting conversion to sinus rhythm in only 44% of initial episodes of atrioventricular nodal reentrant tachycardia (95% confidence interval 21% to 67%). A total of 14 (52%) patients developed 38 relapses of paroxysmal supraventricular tachycardia in the ICU after initial conversion to sinus rhythm. These relapses required additional antiarrhythmic therapy. Adenosine was only effective in 34% of the relapses (95% confidence interval 17% to 53%). Seven (50%) of these 14 patients developed multiple relapses. However, only two patients were receiving suppressive calcium-channel or beta-adrenergic receptor blockade at the time of relapse. CONCLUSIONS: The use of a multiagent algorithm was effective for the initial conversion of new-onset atrioventricular nodal reentrant tachycardia to sinus rhythm in critically ill surgical and trauma patients. This preliminary report suggests that adenosine has marginal efficacy in the critically ill surgical or trauma patient. Given the high frequency of relapses, regardless of the agents used to achieve initial control, suppression therapy for the arrhythmia during the period of maximal cardiovascular stress is essential.