A Randomized Clinical Trial Testing Hydroxychloroquine for Reduction of SARS-CoV-2 Viral Shedding and Hospitalization in Early Outpatient COVID-19 Infection.

Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. At the University of Utah, Salt Lake City, Utah, we conducted a phase 2 prospective parallel group randomized placebo-controlled trial (NCT04342169) to determine whether hydroxychloroquine given early in disease reduces the duration of SARS-CoV-2 shedding. We enrolled nonhospitalized adults (≥18 years of age) with a recent positive diagnostic test for SARS-CoV-2 (within 72 h of enrollment) and adult household contacts. Participants received either 400 mg hydroxychloroquine by mouth twice daily on day 1 followed by 200 mg by mouth twice daily on days 2 to 5 or oral placebo with the same schedule. We performed SARS-CoV-2 nucleic acid amplification testing (NAAT) on oropharyngeal swabs on days 1 to 14 and 28 and monitored clinical symptomatology, rates of hospitalization, and viral acquisition by adult household contacts. We identified no overall differences in the duration of oropharyngeal carriage of SARS-CoV-2 (hazard ratio of viral shedding time comparing hydroxychloroquine to placebo, 1.21; 95% confidence interval [CI], 0.91, 1.62). Overall, 28-day hospitalization incidence was similar between treatments (4.6% hydroxychloroquine versus 2.7% placebo). No differences were seen in symptom duration, severity, or viral acquisition in household contacts between treatment groups. The study did not reach the prespecified enrollment target, which was likely influenced by a steep decline in COVID-19 incidence corresponding to the initial vaccine rollout in the spring of 2021. Oropharyngeal swabs were self-collected, which may introduce variability in these results. Placebo treatments were not identical to hydroxychloroquine treatments (capsules versus tablets) which may have led to inadvertent participant unblinding. In this group of community adults early in the COVID-19 pandemic, hydroxychloroquine did not significantly alter the natural history of early COVID-19 disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT04342169). IMPORTANCE Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. Hydroxychloroquine received attention as a possible early treatment; however, quality prospective studies were lacking. We conducted a clinical trial to test the ability of hydroxychloroquine to prevent clinical worsening of COVID-19.

Evaluation of Posttraumatic Headache Phenotype and Recovery Time After Youth Concussion.

Importance: The Four Corners Youth Consortium was created to fill the gap in our understanding of youth concussion. This study is the first analysis of posttraumatic headache (PTH) phenotype and prognosis in this cohort of concussed youth. Objective: To describe the characteristics of youth with PTH and determine whether the PTH phenotype is associated with outcome. Design, Setting, and Participants: This cohort study examined outcomes from patients in a multi-institutional registry of traumatic brain injury (TBI) clinics from December 2017 to June 2019. Inclusion criteria included being between ages 5 and 18 years at enrollment and presentation within 8 weeks of a mild TBI. Data were analyzed between February 2019 and January 2021. Exposure: Mild TBI with standard care. Main Outcomes and Measures: Time to recovery and headache 3 months after injury; measurement device is the Postconcussion Symptom Inventory (PCSI). PTH with migraine phenotype was defined as moderate-severe headache that is new or significantly worse compared with baseline and associated with nausea and/or photophobia and phonophobia. Results: A total of 612 patients with 625 concussions were enrolled, of whom 387 patients with 395 concussions consented to participate in this study. One hundred nine concussions were excluded (concussions, rather than patients, were the unit of analysis), leaving 281 participants with 286 concussions (168 [58.7%] girls; 195 [75.6%] White; 238 [83.2%] aged 13-18 years). At the initial visit, 133 concussions (46.5%) were from patients experiencing PTH with a migraine phenotype, 57 (20%) were from patients experiencing PTH with a nonmigraine phenotype, and 96 (34%) were from patients with no PTH. Patients with any PTH after concussion were more likely to have prolonged recovery than those without PTH (median [interquartile range], 89 [48-165] days vs 44 [26-96] days; log-rank P < .001). Patients with PTH and a migraine phenotype took significantly longer to recover than those with nonmigraine phenotype (median [interquartile range], 95 [54-195] days vs 70 [46-119] days; log-rank P = .01). Within each phenotype, there was no significant difference between sexes in recovery or PTH at 3 months. Conclusions and Relevance: PTH with a migraine phenotype is associated with persistent symptoms following concussion compared with nonmigraine PTH or no PTH. Given that female sex is associated with higher rates of migraine and migraine PTH, our finding may be one explanation for findings in prior studies that girls are at higher risk for persistent postconcussion symptoms than boys.

Mechanisms of sinus node cycle length changes during ventricular fibrillation.

OBJECTIVE: We have previously shown that up to one-third of patients develop no change or an increase in sinus node cycle length (SNCL) during ventricular fibrillation (VF). The purpose of the present study was to investigate the mechanism of SNCL changes during VF in a swine model. We hypothesized that changes in SNCL during VF are vagally-mediated. METHODS: In 33 anesthetized pigs DC current was used to induce VF for 10 s followed by defibrillation. SNCL changes were assessed during VF and compared to baseline. Animals that had ventriculo-atrial conduction during VF were excluded. Post-defibrillation, the pigs were randomized to receive atropine, propranolol, atropine + propranolol or placebo followed by repeat VF induction and measurement of SNCL changes. RESULTS: Ventriculo-atrial conduction was present in 14 pigs prohibiting SNCL measurements. In the remaining 19 animals, 10 demonstrated SNCL shortening (S-Group) and 9 demonstrated non-shortening (NS-Group). Atropine decreased the absolute change in SNCL from 51.2 to 26.6 ms (n = 6; p = 0.03). It attenuated the SNCL shortening previously observed in the S-Group (-99.2 ms versus -47.9 ms, p = 0.04) and reversed the SNCL prolongation initially observed in the NS-Group (27.1 ms versus -6.5 ms, p = 0.13). Similarly, atropine + propranolol decreased the absolute change in SNCL from 33.3 to 12.2 ms (n = 4; p = 0.05). No significant changes were noted with propranolol or placebo. INTERPRETATION: The SNCL changes during VF appear to be vagally-mediated. The clinical implications vis-à-vis defibrillation threshold and future device programming await future studies.

Alterations in atrial perfusion during atrial fibrillation.

Left atrial (LA) perfusion during disease states has been a topic of much interest, because the clinical implications and detrimental effects of lack of blood flow to the atria are numerous. In the chronic setting, changes in perfusion may lead to LA ischaemia and structural remodelling, a factor implicated in the self-perpetuation of chronic atrial fibrillation (AF). The association between AF and altered LA perfusion has been studied, but a direct causal association between perfusion changes and AF has not been established. A comprehensive literature search of Medline, Embase and Google Scholar databases was conducted from 1960 to February 2014. We systematically analysed reference lists of physiological articles and reviews for other possibly relevant studies. The aim of this review is to provide a comprehensive discussion of the AF-mediated changes in LA perfusion and the potential mechanisms underlying the alterations in coronary flow to the LA in this setting. In addition, we discuss the clinical contexts in which changes in LA perfusion may be relevant. Finally, this article highlights the need for longitudinal studies of AF that would elucidate the changes in LA perfusion resulting from chronic AF and lead to advancements in effective treatments to prevent progression of this disease.

Acute improvement in hemodynamic control after osteopathic manipulative treatment in the third trimester of pregnancy.

OBJECTIVES: The physiological changes that occur during pregnancy, including increased blood volume and cardiac output, can affect hemodynamic control, most profoundly with positional changes that affect venous return to the heart. By using Osteopathic Manipulative Treatment (OMT), a body-based modality theorized to affect somatic structures related to nervous and circulatory systems, we hypothesized that OMT acutely improves both autonomic and hemodynamic control during head-up tilt and heel raise in women at 30 weeks gestation. DESIGN: One hundred subjects were recruited at 30 weeks gestation. SETTING: The obstetric clinics of UNTHealth in Fort Worth, TX. INTERVENTION: Subjects were randomized into one of three treatment groups: OMT, placebo ultrasound, or time control. Ninety subjects had complete data (N=25, 31 and 34 in each group respectively). MAIN OUTCOME MEASURES: Blood pressure and heart rate were recorded during 5 min of head-up tilt followed by 4 min of intermittent heel raising. RESULTS: No significant differences in blood pressure, heart rate or heart rate variability were observed between groups with tilt before or after treatment (p>0.36), and heart rate variability was not different between treatment groups (p>0.55). However, blood pressure increased significantly (p=0.02) and heart rate decreased (p<0.01) during heel raise after OMT compared to placebo or time control. CONCLUSIONS: These data suggest that OMT can acutely improve hemodynamic control during engagement of the skeletal muscle pump and this was most likely due to improvement of structural restrictions to venous return.

Suboccipital decompression enhances heart rate variability indices of cardiac control in healthy subjects.

OBJECTIVES: Osteopathic manipulative treatment (OMT) focused on the upper cervical spine is theorized to affect the function of the vagus nerve and thereby influence the parasympathetic branch of the autonomic nervous system. This study was designed to determine the acute effect of upper cervical spine manipulation on cardiac autonomic control as measured by heart rate variability. DESIGN: Nineteen healthy, young adult subjects underwent three different experimental interventions administered in random order: cervical OMT, sham manipulation, and time control. Six minutes of electrocardiographic data were collected before and after each intervention, and heart rate variability was assessed by both time-domain and frequency-domain measures. RESULTS: No differences in resting heart rate or any measure of heart rate variability were observed between the baseline periods prior to each intervention. The OMT protocol resulted in an increase in the standard deviation of the normal-to-normal intervals (0.12±0.082 seconds, p<0.01), an increase in the high frequency spectral power (p=0.03), and a decrease in the low/high frequency spectral ratio (p=0.01) relative to the sham and time control conditions. No significant differences between sham and time control were observed (p>0.11 for all variables). CONCLUSIONS: These data support the hypothesis that upper cervical spine manipulation can acutely affect measures of heart rate variability in healthy individuals.

Atrial bigeminy results in decreased left ventricular function: an insight into the mechanism of PVC-induced cardiomyopathy.

BACKGROUND: Premature ventricular complexes have been recently recognized as a reversible cause of cardiomyopathy. The purpose of this study was to determine if premature complexes independent of "dyssynchrony" resulted in increased left ventricular (LV) dimensions and decreased LV function. METHODS: Ten mongrel dogs underwent the implantation of a pacemaker and were randomized to a control group (n = 5) or a paced group (n = 5). In the paced group, the pacemaker was connected to two endocardial atrial leads, one inserted into the atrial port and the other one into the ventricular port with an atrioventricular delay adjusted to ensure the presence of coupled pacing simulating atrial bigeminy with conducted beats in the absence of aberrancy. Echocardiographic parameters of LV size (LV end-diastolic diameter [LV-EDD], LV end-systolic diameter [LV-ESD]), and LV ejection fraction (LVEF) were measured at baseline and after 4 weeks of monitoring (control group) or pacing (paced group). RESULTS: In the control group, LV size decreased with no significant changes in LVEF: 55% at baseline versus 70% at 4 weeks (P = 0.23). In the paced group, LV-EDD decreased with no significant change in LV-ESD. Unlike the control group, LVEF decreased significantly from 69 ± 9% at baseline to 32 ± 22% after 4 weeks of pacing (P = 0.05). CONCLUSION: We have shown that 4 weeks of coupled pacing simulating atrial bigeminy significantly reduced LV function. Our findings suggest that premature complexes independent of ventricular dyssynchrony might lead to the development of cardiomyopathy.

The effects of radio-frequency ablation on blood pressure control in patients with atrial fibrillation and hypertension.

PURPOSE: The effects of radio-frequency ablation (RFA) on blood pressure (BP) regulation in patients with atrial fibrillation (AF) and hypertension remain unknown. We hypothesized that patients with successful ablation had a lower BP and/or lesser utilization of antihypertensive drug therapy during follow-up when compared to patients with failed ablation. METHODS AND RESULTS: This was a retrospective evaluation of patients with AF and hypertension treated with ablation at the University of Utah between July 2006 and June 2010. BP and use of antihypertensive medications were assessed at baseline and 1 year follow-up. A total of 167 patients were identified. Eight patients were excluded due to the need for AAD therapy beyond the blanking period thus leaving 80 patients in the success group and 79 patients in the failure group. The mean BP and HR at baseline were not significant between the groups. In the success group, the mean systolic BP decreased from a baseline value of 129 ± 17 to 125 ± 14 mmHg at 1 year (p = 0.075). In contrast, in the failure group, the mean systolic BP increased from a baseline value of 124 ± 16 to 127 ± 14 mmHg at 1 year (p = 0.176). Between-group comparison revealed a p value of 0.026. Minimal changes in diastolic BP were noted in both groups. No significant changes in antihypertensive therapy were noted. CONCLUSION: We have shown that successful catheter ablation in patients with AF and hypertension is associated with a decrease in systolic BP when compared to an increase in patients with failed ablation. Our findings suggest that restoring sinus rhythm could have an antihypertensive effect in patients with AF and hypertension.

Pressor response to 30-s breathhold: a predictor of masked hypertension.

One in six adults has normal arterial blood pressure (BP) during a routine examination, but is hypertensive in other environments. This masked hypertension (MHT) may delay treatment until target organ damage has occurred. A sensitive, specific and economical test is needed to detect or exclude MHT in apparently normal subjects. The BP response to a 30-s breathhold (BH test) was observed in 269 young subjects with no evidence of cardiovascular disease. Of 226 normotensives (office BP ≤ 120/80), 25 (11%) had a positive BH test (test BP > 140/90 mmHg), and 12 (44%) of these subjects had MHT (positive 24-h ambulatory BP monitoring (BPM)). Of 201 subjects with negative BH test, none had MHT (negative BPM). Of 43 subjects with high normal BP (office BP > 120/80 < 140/90), 28 (65%) had a positive BH test and 22 of these subjects had MHT (positive BPM). Of the 15 subjects with high normal BP and with a negative BH test, none had MHT (negative BPM). Overall, the BH pressor test and BPM agreed in 93% of cases, and the BH test produced no false negative findings. The BH pressor test effectively ruled out MHT in normal subjects and accurately identified a population that should be further evaluated for MHT.

Oscillatory vagal maneuvers produce ventricular entrainment in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained dysrhythmia and appears to be an independent predictor of sudden cardiac death. The irregular ventricular rhythm contains both linear and non-linear patterns; however, it remains unclear whether vagally mediated effects are present within these patterns. OBJECTIVE: We sought to determine if (1) power spectral analysis of heart rate can detect changes in vagal activity in patients with AF and (2) if the vagus modulates ventricular response during AF. METHODS: Time and frequency domain parameters of heart rate variability (HRV) were calculated during forced vagal oscillations at 0.125 and 0.25 Hz imposed by neck suction and deep breathing in five AF patients. RESULTS: There was a significant increase in SDRRI during deep breathing/neck suction combined compared to baseline (p=0.01) and deep breathing (p=0.03). Neck suction significantly increased SDRRI compared to baseline (p=0.03). Deep breathing/neck suction significantly increased spectral power compared to baseline (p=0.02) and deep breathing (p=0.03). Neck suction significantly increased spectral power compared to baseline (p=0.03). Deep breathing did not significantly increase HRV compared to baseline (p>0.20). In addition, SDRRI and spectral power were significantly correlated during deep breathing (r=0.91, p=0.03) and deep breathing/neck suction combined (r=0.92, p=0.02). INTERPRETATION: These data suggest that (1) power spectral analysis can detect vagal influences on heart rate in AF patients, and (2) oscillatory vagal maneuvers produce ventricular entrainment during AF.

Sleep apnoea and hypertension: role of chemoreflexes in humans.

The link between sleep apnoea and systemic hypertension in humans is well documented. However, a direct causal association between the two diseases independent of comorbidities has been difficult to establish. Comorbidities clearly play an important role in this strong relationship; however, new findings also suggest that sleep apnoea is an independent risk factor for hypertension. This relationship appears to be at least in part a result of chronically elevated sympathetic activity, and therefore manifests as a neurally mediated hypertension. Although the mechanism(s) for this causal relationship of sleep apnoea to hypertension remains ill defined, a growing body of literature suggests that autonomic dysfunction, mediated by abnormal chemoreflex control of sympathetic activity, is a potential mechanism. Abnormal chemoreflex responses to both acute and chronic apnoea or hypoxia have been demonstrated. Hypothesized mechanisms by which chemoreflex dysfunction may contribute to chronically elevated sympathetic tone and ultimately hypertension are explored in this review. Thus, this review focuses on the current evidence linking chemoreflex function to obstructive sleep apnoea and systemic hypertension in humans and provides an analysis of these data and their implications.

Effect of treadmill and overground walking on function and attitudes in older adults.

PURPOSE: The purpose of this study was to determine whether treadmill walking, as a mode of physical activity for older adults, was comparable with overground walking when considering 1) spatiotemporal gait characteristics (walking velocity, stride length, and stride rate) at a preferred velocity and a prescribed intensity typical of many exercise prescriptions (i.e., RPE of 13); and 2) the effects on physical function (short physical performance battery (SPPB), lateral mobility, 400-m walk) and participants' attitude towards training and level of enjoyment. METHODS: Gait characteristics were measured at each participant's preferred and RPE 13 velocity during treadmill and overground walking (N=23, 74+/-4 yr). Participants were then randomized to either a treadmill or overground progressive intensity and duration walking program of 18 sessions. RESULTS: Both the preferred and RPE 13 walking velocities were significantly slower on the treadmill compared with overground (t(22)=-10.87, P<0.001 and t(22)=-8.54, P<0.001, respectively), as a result of significantly shorter stride lengths and slower stride rates. After training, there were no differences between the groups for RPE 13 velocity, SPPB or lateral mobility. However, following the intervention, the overground group completed the 400-m walk faster (F(1,15)=6.06, P<0.05), had a more favorable attitude towards training, and expressed a more favorable level of enjoyment about the training program than the treadmill group (F(1,16)=7.5; P<0.05). CONCLUSION: An overground walking program appears to offer some advantages over a treadmill walking program in older adults. Using RPE alone to regulate intensity may reduce the benefits of a treadmill walking program in older adults.