We tested the hypothesis that differences in sympathetic reflex responses to head-up tilt (HUT) between males (n = 9) and females (n = 8) were associated with decrements in postural vasomotor responses in women. Muscle sympathetic nerve activity (MSNA; microneurography), heart rate, stroke volume (SV; Doppler), and blood pressure (Finapres) were measured during a progressive HUT protocol (5 min at each of supine, 20 degrees, 40 degrees, and 60 degrees ). MSNA and hemodynamic responses were also measured during the cold pressor test (CPT) to examine nonbaroreflex neurovascular control. SV was normalized to body surface area (SV(i)) to calculate the index of cardiac output (Q(i)), and total peripheral resistance (TPR). During HUT, heart rate increased more in females versus males (P < 0.001) and SV(i) and Q(i) decreased similarly in both groups. Mean arterial pressure (MAP) increased to a lesser extent in females versus males in the HUT (P < 0.01) but increases in TPR during HUT were similar. MSNA burst frequency was lower in females versus males in supine (P < 0.03) but increased similarly during HUT. Average amplitude/burst increased in 60 degrees HUT for males but not females. Both males and females demonstrated an increase in MAP as well as MSNA burst frequency, mean burst amplitude, and total MSNA during the CPT. However, compared with females, males demonstrated a greater neural response (DeltaTotal MSNA) due to a larger increase in mean burst amplitude (P < 0.05). Therefore, these data point to gender-specific autonomic responses to cardiovascular stress. The different MSNA response to postural stress between genders may contribute importantly to decrements in blood pressure control during HUT in females.

Obstructive sleep apnea (OSA) is associated with oscillations of arterial blood pressure (BP) that occur in phase with irregularities of respiration. To explore the role of the sympathetic nervous system in these responses, we studied muscle sympathetic nerve activity (MSNA; peroneal microneurography), an index of vasoconstrictor nerve traffic, and BP during awake regular breathing and during spontaneous apneas in patients with OSA. To determine the role of the arterial chemoreflex, we also examined the effects of 100% O2 (hyperoxia) on MSNA and BP. In awake regularly breathing patients with OSA (n = 12), resting MSNA was markedly higher than in an age-matched control population (n = 15) [41 +/- 23 (SD) vs. 24 +/- 17 bursts/min; P < 0.05] and was unchanged during hyperoxia (n = 9). Apneas during sleep (n = 8) were associated with surges in MSNA followed by transient rises in BP when breathing resumed. In contrast to room air apneas, hyperoxic apneas of similar duration were associated with attenuated MSNA responses (+82 +/- 84% vs. +5 +/- 25% compared with awake baseline; P < 0.05; n = 6), even though O2 did not affect sleep stage and the occurrence of arousal. Thus the BP oscillations that occur with apnea during sleep may in part be mediated by intermittent surges of sympathetic activity resulting in vasoconstriction. Because the MSNA responses to obstructive apnea are blunted during O2 administration, they appear to be linked to intermittent arterial hypoxemia and stimulation of arterial chemoreceptors.

We compared reflex responses to static handgrip at 30% maximal voluntary contraction (MVC) in 26 untrained men (mean age 35 +/- 3 yr) and 23 untrained women (mean age 39 +/- 4 yr). Women demonstrated attenuated increases in blood pressure and muscle sympathetic nerve activity (MSNA; by microneurography) compared with men. This difference was also observed during a period of posthandgrip circulatory arrest. 31P-nuclear magnetic resonance (NMR) spectroscopy studies demonstrated attenuations in the production of diprotonated phosphate and the development of cellular acidosis in women compared with men. Subjects also performed ischemic handgrip to fatigue. During this paradigm, MSNA responses were similar in the two groups, suggesting that freely perfused conditions are necessary for the full expression of the gender effect. Finally, we examined MSNA responses to adductor pollicus exercise in 7 men (26 +/- 1 yr) and 6 women (25 +/- 2 yr). MVC values and times to fatigue were similar in the two groups (MVC: men, 4.3 +/- 0.4 kg; women, 4.0 +/- 0.3 kg; not significant. Time to fatigue: men, 209 +/- 16 s; women, 287 +/- 50 s; not significant). At periods of end exercise and postexercise circulatory arrest, MSNA responses were attenuated in the women compared with the men. We conclude that, during nonischemic static exercise, sympathetic neural outflow is less in women compared with men. This response is due to an attenuated metaboreflex in women. Finally, on the basis of the adductor pollicus experiments, this effect appears independent of muscle mass, workload, and the level of training.

Skeletal muscle metaboreceptor responses are impaired in heart failure. Because MSNA responses during static exercise are similar in the two groups, mechanisms aside from metaboreceptor stimulation must be important in increasing sympathetic nervous system activity.

IMPORTANCEThe National COVID Cohort Collaborative (N3C) is a centralized, harmonized, highgranularity electronic health record repository that is the largest, most representative COVID-19 cohort to date. This multicenter data set can support robust evidence-based development of predictive and diagnostic tools and inform clinical care and policy.OBJECTIVES To evaluate COVID-19 severity and risk factors over time and assess the use of machine learning to predict clinical severity. DESIGN, SETTING, AND PARTICIPANTSIn a retrospective cohort study of 1 926 526 US adults with SARS-CoV-2 infection (polymerase chain reaction >99% or antigen <1%) and adult patients without SARS-CoV-2 infection who served as controls from 34 medical centers nationwide between January 1, 2020, and December 7, 2020, patients were stratified using a World Health Organization COVID-19 severity scale and demographic characteristics. Differences between groups over time were evaluated using multivariable logistic regression. Random forest and XGBoost models were used to predict severe clinical course (death, discharge to hospice, invasive ventilatory support, or extracorporeal membrane oxygenation). MAIN OUTCOMES AND MEASURESPatient demographic characteristics and COVID-19 severity using the World Health Organization COVID-19 severity scale and differences between groups over time using multivariable logistic regression. RESULTSThe cohort included 174 568 adults who tested positive for SARS-CoV-2 (mean [SD] age, 44.4 [18.6] years; 53.2% female) and 1 133 848 adult controls who tested negative for SARS-CoV-2 (mean [SD] age, 49.5 [19.2] years; 57.1% female). Of the 174 568 adults with SARS-CoV-2, 32 472(18.6%) were hospitalized, and 6565 (20.2%) of those had a severe clinical course (invasive ventilatory support, extracorporeal membrane oxygenation, death, or discharge to hospice). Of the hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March to April 2020 to 8.6% in September to October 2020 (P = .002 for monthly trend). Using 64 inputs available on the first hospital day, this study predicted a severe clinical course using random forest and XGBoost models (area under the receiver operating curve = 0.87 for both) that were stable over time. The factor most strongly associated with clinical severity was pH; this result was consistent across machine learning methods. In a separate multivariable logistic regression model built for inference, (continued) Key Points Question In a US data resource large enough to adjust for multiple confounders, what risk factors are associated with COVID-19 severity and severity trajectory over time, and can machine learning models predict clinical severity? Findings In this cohort study of 174 568 adults with SARS-CoV-2, 32 472 (18.6%) were hospitalized and 6565 (20.2%) were severely ill, and first-day machine learning models accurately predicted clinical severity. Mortality was 11.6%

Background-During exercise, the sympathetic nervous system is activated and blood pressure and heart rate increase. In heart failure (HF), the muscle metaboreceptor contribution to sympathetic outflow is attenuated and the mechanoreceptor contribution is accentuated. Previous studies suggest that (1) capsaicin stimulates muscle metabosensitive vanilloid receptor subtype 1 (VR1), inducing a neurally mediated pressor response, and (2) activation of ATP-sensitive P2X receptors enhances the pressor response seen when muscle mechanoreceptors are engaged by muscle stretch. Thus, we hypothesized that the pressor response to VR1 stimulation would be smaller and the sensitizing effects of P2X stimulation greater in rats with HF due to chronic myocardial infarction (MI) than in controls. Methods and Results-Eight to 14 weeks after coronary ligation, rats with infarcts Ͼ35% had an increased left ventricular end-diastolic pressure and a marked increase in heart weight. Capsaicin injected into the arterial supply of the hindlimb increased blood pressure by 39% (baseline, 93.9Ϯ9.5 mm Hg) in control animals but only by 8% (baseline, 94.8Ϯ10.1 mm Hg) in rats with large MIs (PϽ0.05). P2X receptor stimulation by ␣,␤-methylene ATP enhanced the pressor response to muscle stretch by 42% in control animals and by 72% in rats with large MIs (PϽ0.05). Conclusions-Compared

1. In barbiturate-anesthetized cats we examined the interaction of lactic acid and static contraction on the discharge of group III muscle afferents. Only afferents whose receptive fields were located in the triceps surae muscles were studied. 2. Twelve of 20 afferents were stimulated by a 60-s static contraction. The majority of firing occurred within the first few seconds of contraction. Thirteen of 20 afferents were stimulated by femoral arterial injections of 24 mM lactic acid (1-4 ml) with the muscle at rest. Repeated injections of lactic acid with the muscle at rest led to tachyphylaxis. Lactic acid was then injected (24 mM; 4 ml) during the last 15 s of static contraction. In eight of nine afferents that were tachyphylactic to lactic acid with the muscle at rest, we noted a restored sensitivity to lactic acid during contraction. 3. In separate experiments we examined the effects of dichloroacetate (DCA) on the responses of group III muscle afferents to static contraction. DCA reduces the production of lactic acid by increasing levels of the active form of the enzyme pyruvate dehydrogenase. 4. DCA lowered arterial and venous lactate concentrations at rest and during contraction. DCA significantly decreased (31%; P < 0.05) the responses of the afferents to contraction. This effect was most prominent within the first 10 s of contraction and was not due to a reduced level of mechanical stimulation after DCA, because peak tension levels were the same during the two bouts of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

In heart failure, oxygen has a detrimental effect on cardiac output, stroke volume, pulmonary capillary wedge pressure and systemic vascular resistance. These changes are independent of sympathetic activity and ventilation.