Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.

Examining the Light Heart Mobile Device App for Assessing Human Pulse Interval and Heart Rate Variability: Validation Study.

BACKGROUND: Pulse interval is a biomarker of psychological and physiological health. Pulse interval can now be assessed using mobile phone apps, which expands researchers' ability to assess pulse interval in the real world. Prior to implementation, measurement accuracy should be established. OBJECTIVE: This investigation evaluated the validity of the Light Heart mobile app to measure pulse interval and pulse rate variability in healthy young adults. METHODS: Validity was assessed by comparing the pulse interval and SD of normal pulse intervals obtained by Light Heart to the gold standard, electrocardiogram (ECG), in 14 young healthy individuals (mean age 24, SD 5 years; n=9, 64% female) in a seated posture. RESULTS: Mean pulse interval (Light Heart: 859, SD 113 ms; ECG: 857, SD 112 ms) demonstrated a strong positive linear correlation (r=0.99; P<.001) and strong agreement (intraclass correlation coefficient=1.00, 95% CI 0.99-1.00) between techniques. The Bland-Altman plot demonstrated good agreement for the mean pulse interval measured with Light Heart and ECG with evidence of fixed bias (-1.56, SD 1.86; 95% CI -5.2 to 2.1 ms), suggesting that Light Heart overestimates pulse interval by a small margin. When Bland-Altman plots were constructed for each participant's beat-by-beat pulse interval data, all participants demonstrated strong agreement between Light Heart and ECG with no evidence of fixed bias between measures. Heart rate variability, assessed by SD of normal pulse intervals, demonstrated strong agreement between techniques (Light Heart: mean 73, SD 23 ms; ECG: mean 73, SD 22 ms; r=0.99; P<.001; intraclass correlation coefficient=0.99, 95% CI 0.97-1.00). CONCLUSIONS: This study provides evidence to suggest that the Light Heart mobile app provides valid measures of pulse interval and heart rate variability in healthy young adults.

Evidence for the Efficacy of COVID-19 Convalescent Plasma.

During the global health emergency caused by the coronavirus disease 2019 (COVID-19), evidence relating to the efficacy of convalescent plasma therapy-evidence critically needed for both public policy and clinical practice-came from multiple levels of the epistemic hierarchy. The challenges of conducting clinical research during a pandemic, combined with the biological complexities of convalescent plasma treatment, required the use of observational data to fully assess the impact of convalescent plasma therapy on COVID symptomatology, hospitalization rates, and mortality rates. Observational studies showing the mortality benefits of convalescent plasma emerged early during the COVID-19 pandemic from multiple continents and were substantiated by real-time pragmatic meta-analyses. Although many randomized clinical trials (RCTs) were initiated at the onset of the pandemic and were designed to provide high-quality evidence, the relative inflexibility in the design of clinical trials meant that findings generally lagged behind other forms of emerging information and ultimately provided inconsistent results on the efficacy of COVID-19 convalescent plasma. In the pandemic framework, it is necessary to emphasize more flexible analytic strategies in clinical trials, including secondary, subgroup, and exploratory analyses. We conclude that in totality, observational studies and clinical trials taken together provide strong evidence of a mortality benefit conferred by COVID-19 convalescent plasma, while acknowledging that some randomized clinical trials examined suboptimal uses of convalescent plasma.

Central α2-adrenergic mechanisms regulate human sympathetic neuronal discharge strategies.

The present study investigated the impact of central α2-adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2-adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats-1, P = 0.003) most strongly for medium-sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats-1; P < 0.001). Dexmedetomidine progressively de-recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de-recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats-1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ -0.09 ± 0.07 to Δ -0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium-sized APs (normalized cluster 2: -6.0 ± 5 to -1.6 ± 2 % mmHg-1; P = 0.008). These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. KEY POINTS: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2-adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

No influence of steady-state postural changes on cerebrovascular compliance in humans.

The aim of this study was to determine the effect of posture changes on vascular compliance in intracranial (brain) versus extracranial vascular beds (forearm). Eighteen young adults (nine females) performed a supine-to-seated-to-standing protocol involving 5 min of rest in each position. Continuous blood pressure, middle cerebral artery (MCA) blood velocity, and brachial artery blood velocity were recorded at each posture. Three to five consecutive steady-state cardiac cycles at each posture were analyzed by a four-element lumped parameter modified Windkessel model to calculate vascular compliance. Mean arterial pressure (MAP) increased from supine to seated (76(9) vs. 81(12) mmHg; P = 0.006) and from supine to standing (76(9) vs. 82(13) mmHg; P = 0.034). Mean blood flow was greater in the MCA relative to the forearm (forearm: 40(5) mL·min-1, MCA: 224(17) mL·min-1; main effect P < 0.001). Conversely, vascular resistance (forearm: 3.25(0.50) mmHg-1·mL·min-1, brain: 0.36(0.04) mmHg-1·mL·min-1; main effect P < 0.001) and compliance (forearm: 0.010(0.001) mL·min-1·mmHg-1, brain: 0.005(0.001) mL·min-1·mmHg-1; main effect P = 0.001) were greater in the forearm compared to the brain. Significant main effects of posture were observed with decreasing values in upright positions for mean blood flow (P = 0.001) in both vascular beds, but not for resistance (P = 0.163) or compliance (P = 0.385). There were no significant interaction effects between vascular bed and posture for mean flow (P = 0.057), resistance (P = 0.258), or compliance (P = 0.329). This study provides evidence that under steady-state conditions, posture does not affect cerebrovascular compliance.

The relationship between hemoglobin and [Formula: see text]: A systematic review and meta-analysis.

OBJECTIVE: There is widespread agreement about the key role of hemoglobin for oxygen transport. Both observational and interventional studies have examined the relationship between hemoglobin levels and maximal oxygen uptake ([Formula: see text]) in humans. However, there exists considerable variability in the scientific literature regarding the potential relationship between hemoglobin and [Formula: see text]. Thus, we aimed to provide a comprehensive analysis of the diverse literature and examine the relationship between hemoglobin levels (hemoglobin concentration and mass) and [Formula: see text] (absolute and relative [Formula: see text]) among both observational and interventional studies. METHODS: A systematic search was performed on December 6th, 2021. The study procedures and reporting of findings followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Article selection and data abstraction were performed in duplicate by two independent reviewers. Primary outcomes were hemoglobin levels and [Formula: see text] values (absolute and relative). For observational studies, meta-regression models were performed to examine the relationship between hemoglobin levels and [Formula: see text] values. For interventional studies, meta-analysis models were performed to determine the change in [Formula: see text] values (standard paired difference) associated with interventions designed to modify hemoglobin levels or [Formula: see text]. Meta-regression models were then performed to determine the relationship between a change in hemoglobin levels and the change in [Formula: see text] values. RESULTS: Data from 384 studies (226 observational studies and 158 interventional studies) were examined. For observational data, there was a positive association between absolute [Formula: see text] and hemoglobin levels (hemoglobin concentration, hemoglobin mass, and hematocrit (P<0.001 for all)). Prespecified subgroup analyses demonstrated no apparent sex-related differences among these relationships. For interventional data, there was a positive association between the change of absolute [Formula: see text] (standard paired difference) and the change in hemoglobin levels (hemoglobin concentration (P<0.0001) and hemoglobin mass (P = 0.006)). CONCLUSION: These findings suggest that [Formula: see text] values are closely associated with hemoglobin levels among both observational and interventional studies. Although our findings suggest a lack of sex differences in these relationships, there were limited studies incorporating females or stratifying results by biological sex.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

Exercise and Experiments of Nature.

In this article, we highlight the contributions of passive experiments that address important exercise-related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical "knockout" animal models among human research participants. Natural experiments are gleaned from data sets that allow population-based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879-4907, 2023.

Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Baroreflex resetting of human sympathetic action potential subpopulations during exercise.

This study tested the hypothesis that during fatiguing volitional exercise in humans, descending cortical signals and ascending skeletal muscle metaboreflex signals exert divergent control over baroreflex resetting of sympathetic action potential (AP) discharge. We quantified the baroreflex gain for sympathetic AP clusters within the muscle sympathetic nerve activity neurogram (peroneal microneurography and continuous wavelet transform) during baseline (BSL), the first 2-min of a 5-min isometric handgrip (20% of maximal effort; IHG1), the last 2-min of IHG (IHG2), and during postexercise circulatory occlusion (PECO) in seven healthy participants. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability (%) versus diastolic blood pressure (DBP; mmHg) for 10 normalized AP clusters. Compared with BSL, during IHG1, AP baroreflex threshold functions were only reset to greater DBP and baroreflex gain was unaffected. Compared with BSL, during IHG2 and PECO, baroreflex functions were reset to greater DBP and to greater AP firing probabilities, with medium-sized APs demonstrating the largest upward resetting (e.g., cluster 3 BSL: 26 ± 7%, cluster 3 IHG2: 78 ± 22%, cluster 3 PECO: 88 ± 46%). Compared with BSL, AP baroreflex threshold gain was not different during IHG2 but was increased during PECO, with medium-sized APs demonstrating the largest increase in baroreflex gain (e.g., cluster 3 BSL: -6.31 ± 3.1%/mmHg, cluster 3 IHG2: -6.18 ± 5.4%/mmHg, cluster 3 PECO: -12.13 ± 6.5%/mmHg). These findings indicate that during IHG exercise, descending cortical signaling and ascending skeletal muscle metaboreceptor signals differentially affect baroreflex resetting of subpopulations of human muscle sympathetic postganglionic neurons.NEW & NOTEWORTHY This study provides new insight to baroreflex resetting of MSNA during exercise in humans. Both fatiguing IHG and PECO reset baroreflex control of sympathetic APs to higher blood pressures and greater MSNA. However, only PECO increased baroreflex threshold gain of medium-sized sympathetic APs, an effect that was concealed when focusing on the integrated MSNA neurogram to quantify baroreflex gain. These data suggest that descending central versus ascending muscle metaboreflex mechanisms differentially affect baroreflex resetting of sympathetic APs.

Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans: a pharmacological study.

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (Ci) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm.NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.

Limited Correlation between SARS-CoV-2 Serologic Assays for Identification of High-Titer COVID-19 Convalescent Plasma Using FDA Thresholds.

In August 2020, the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for COVID-19 convalescent plasma (CCP) specified 12 authorized serologic assays and associated assay-specific cutoff values for the selection of high-titer CCP for use in hospitalized patients. The criteria used for establishing these cutoff values remains unclear. Here, we compare the overall agreement and concordance of five serologic assays included in the August 2020 FDA EUA at both the manufacturer-recommended qualitative cutoff thresholds and at the FDA-indicated thresholds for high-titer CCP, using serum samples collected as part of the CCP Expanded Access Program (EAP). The qualitative positive percent agreement (PPA) across assays ranged from 92.3% to 98.8%. However, the high-titer categorization across assays varied significantly, with the PPA ranging from 26.5% to 82.7%. The Roche anti-NC ECLIA provided the lowest agreement compared to all other assays. Efforts to optimize high-titer cutoffs could reduce, although not eliminate, the discordance across assays. The consequences of using nonstandardized assays are apparent in our study, and the high-titer cutoffs chosen for each assay are not directly comparable to each other. The generalized findings in our study will be relevant to any future use of convalescent plasma for either COVID-19 or future pandemics of newly emerged pathogens. IMPORTANCE COVID-19 convalescent plasma (CCP) was one of the first therapeutic options available for the treatment of SARS-CoV-2 infections and continues to be used selectively for immunosuppressed patients. Given the emergence of novel SARS-CoV-2 variants which are resistant to treatment with available monoclonal antibody (MAb) therapy, CCP remains an important therapeutic consideration. The FDA has released several emergency use authorizations (EUA) that have specified which serological assays can be used for qualification of CCP, as well as assay-specific cutoffs that must be used to identify high-titer CCP. In this study, a cohort of donor CCP was assessed across multiple serological assays which received FDA EUA for qualification of CCP. This study indicates a high degree of discordance across the assays used to qualify CCP for clinical use, which may have precluded the optimal use of CCP, including during clinical trials. This study highlights the need for assay standardization early in the development of serological assays for emerging pathogens.

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia-induced sympathetic long-term facilitation.

Baroreflex resetting permits sympathetic long-term facilitation (sLTF) following hypoxia; however, baroreflex control of action potential (AP) clusters and AP recruitment patterns facilitating sLTF is unknown. We hypothesized that baroreflex resetting of arterial pressure operating points (OPs) of AP clusters and recruitment of large-amplitude APs would mediate sLTF following hypoxia. Eight men (age: 24 (3) years; body mass index: 24 (3) kg/m2 ) underwent 20 min isocapnic hypoxia ( PETO2${P_{{\rm{ET}}{{\rm{O}}_{\rm{2}}}}}$ : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and a continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 5 min), and late recovery (last 5 min). AP amplitude (normalized to largest baseline AP amplitude), percentage APs occurring outside a MSNA burst (percentage asynchronous APs), and proportion of APs firing in small (1-3), medium (4-6) and large (7-10) normalized cluster sizes was calculated. Normalized clusters were used to assess baroreflex OPs and sensitivity. Hypoxia increased total MSNA activity, which remained elevated during recovery (P < 0.0001). Baroreflex OPs were shifted rightward for all clusters in recovery, with no effect on slope. Compared to baseline, AP amplitude was elevated by 3 (2)% and 4 (2)% while asynchronous APs were reduced by 9 (5)% and 7 (6)% in early and late recovery, respectively. In early recovery, the proportion of APs firing in large clusters was increased compared to baseline. Hypoxia-induced sLTF is mediated by baroreflex resetting of AP clusters to higher OPs, reduced asynchronous AP firing, and increased contribution from large-amplitude APs. KEY POINTS: Acute isocapnic hypoxia resets the arterial baroreflex and permits long-lasting sympathoexcitation, termed sympathetic long-term facilitation. Our understanding of sympathetic long-term facilitation following hypoxia in humans is based on multiunit muscle sympathetic nerve activity and does not fully characterize the underlying baroreflex control of sympathetic neuronal subpopulations or their discharge/recruitment strategies. We show that sympathetic long-term facilitation is mediated by baroreflex resetting of sympathetic action potential clusters to higher arterial pressure operating points, a reduction in the percentage of action potentials firing asynchronously, and a shift toward larger amplitude action potential activity. The results advance our fundamental understanding of how the sympathetic nervous system mediates sympathetic long-term facilitation following exposure to acute isocapnic hypoxia in humans.

Aging is associated with enhanced central but impaired peripheral arms of the sympathetic baroreflex arc.

We tested the hypotheses that spontaneous baroreflex control of integrated muscle sympathetic nerve activity (MSNA) burst occurrence and action potential (AP) subpopulations would be blunted in older compared with young adults and that sympathetic transduction will be blunted in older adults relative to young adults. Integrated muscle sympathetic nerve activity (MSNA) and the underlying sympathetic APs were obtained using microneurography and a continuous wavelet analysis approach, respectively, during 5 min of supine rest in 13 older (45-75 yr, 6 females) and 14 young (21-30 yr, 7 females) adults. Baroreflex threshold relationships were quantified as the slope of the linear regression between MSNA burst occurrence (%) and diastolic blood pressure (mmHg), or AP cluster firing probability (%) and diastolic blood pressure (mmHg). Integrated MSNA baroreflex threshold gain was greater in older compared with young adults (older: -5.7 ± 2.6%/mmHg vs. young: -2.7 ± 1.4%/mmHg, P < 0.001). Similarly, the baroreflex threshold gain of AP clusters was modified by aging (group-by-cluster effect: P < 0.001) such that older adults demonstrated greater baroreflex threshold gains of medium-sized AP clusters (e.g., Cluster 4, older: -8.2 ± 3.2%/mmHg vs. young: -3.6 ± 1.9%/mmHg, P = 0.003) but not for the smallest-sized (Cluster 1, older: -1.6 ± 1.9%/mmHg vs. young: -1.0 ± 1.7%/mmHg, P > 0.999) and largest-sized (Cluster 10, older: -0.5 ± 0.5%/mmHg vs. young: -0.2 ± 0.1%/mmHg, P = 0.819) AP clusters compared with young adults. In contrast, the peak change in mean arterial pressure (MAP) following a spontaneous MSNA burst (i.e., sympathetic transduction) was impaired with aging (older: -0.7 ± 0.3 mmHg vs. young: 1.8 ± 1.2 mmHg, P < 0.001). We conclude that aging is associated with elevated baroreflex control over high-probability AP content of sympathetic bursts that may compensate for impaired sympathetic neurovascular transduction.NEW & NOTEWORTHY The present study demonstrates for the first time that the spontaneous baroreflex threshold gains of integrated muscle sympathetic nerve activity burst occurrence and medium-sized action potential clusters are greater in older compared with young adults. Since sympathetic transduction was blunted in older compared with young adults, we interpret the data to indicate that the central arc of the baroreflex is enhanced in older adults to compensate for impairments in the peripheral arc.

Interactive effects of apneic and baroreflex stress on neuronal coding strategies in human muscle sympathetic nerve activity.

The sympathetic nervous system exhibits patterns of action potential (AP) discharge in human muscle sympathetic nerve activity that suggest coding strategies express reflex specificity. This study explored the interactive effects of baroreceptor unloading using lower body negative pressure (LBNP) and volitional end-expiratory apnea (APN) on sympathetic postganglionic neuronal discharge patterns inferred from the firing patterns of differently sized sympathetic AP clusters. Seven individuals were studied using multiunit microneurography (fibular) and a continuous wavelet approach to quantify AP discharge probability, recruitment, and latency during APN performed under ambient conditions, -10, and -40 mmHg LBNP. Compared with the ambient condition, LBNP increased AP discharge rate at -10 and -40 mmHg and recruited larger previously silent sympathetic neurons at -40 mmHg. Compared with spontaneous breathing, APN increased AP discharge when performed during the ambient condition (Δ351 ± 132 AP/min), -10 mmHg (Δ423 ± 184 AP/min), and -40 mmHg (Δ355 ± 278 AP/min; main effect APN: P < 0.01; LBNP-by-APN interaction: P = 0.55). APN recruited larger previously silent AP clusters during the ambient condition (Δ4 ± 3; P < 0.02) and -10 mmHg (Δ4 ± 3; P < 0.01), but not -40 mmHg (Δ0 ± 2; P = 0.53; LBNP-by-APN: P < 0.01). LBNP did not affect AP latency. However, APN reduced AP latency similarly during all conditions (ambient pressure: Δ-0.04 ± 0.04s, -10 mmHg: Δ-0.03 ± 0.03s, -40 mmHg: Δ-0.03 ± 0.04s; main effect APN: P < 0.01; LBNP-by-APN: P = 0.48). These data indicate that apneic and baroreflex mechanisms appear to additively modify the axonal discharge rate of previously active sympathetic postganglionic neurons and interact to affect recruitment of previously silent sympathetic neurons. Reductions in AP latency due to apneic stress were not impacted by baroreflex unloading.NEW & NOTEWORTHY Discrete physiological stressors differentially affect sympathetic postganglionic neuronal rate-, population-, and temporal-coding strategies. When performing end-expiratory apnea (APN) during graded baroreflex unloading via lower body negative pressure (LBNP), we found: 1) augmented sympathetic axonal firing probability, 2) recruitment of larger and previously silent sympathetic postganglionic neurons at ambient and -10 mmHg, but not -40 mmHg LBNP, and 3) APN reduced axonal discharge latency similarly across all conditions, independent of the level of baroreflex unloading.

Coagulation profile of human COVID-19 convalescent plasma.

Convalescent plasma is used to treat COVID-19. There are theoretical concerns about the impact of pro-coagulant factors in convalescent plasma on the coagulation cascade particularly among patients with severe COVID-19. The aim of this study was to evaluate the coagulation profile of COVID-19 convalescent plasma. Clotting times and coagulation factor assays were compared between fresh frozen plasma, COVID-19 convalescent plasma, and pathogen-reduced COVID-19 convalescent plasma. Measurements included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, von Willebrand factor activity, von Willebrand factor antigen, coagulation factors II, V, VII-XII, protein S activity, protein C antigen, and alpha-2 plasmin inhibitor. Clotting times and coagulation factor assays were not different between COVID-19 convalescent plasma and fresh frozen plasma, except for protein C antigen. When compared to fresh frozen plasma and regular convalescent plasma, pathogen reduction treatment increased activated partial thromboplastin time and thrombin time, while reducing fibrinogen, coagulation factor II, V, VIII, IX, X, XI, XII, protein S activity, and alpha-2 plasmin inhibitor. The coagulation profiles of human COVID-19 convalescent plasma and standard fresh frozen plasma are not different. Pathogen reduced COVID-19 convalescent plasma is associated with reduction of coagulation factors and a slight prolongation of coagulation times, as anticipated. A key limitation of the study is that the COVID-19 disease course of the convalesced donors was not characterized.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.