Citations

ABSTRACT Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% ( P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization. IMPORTANCE As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Plasma collected from people recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy employed to fight the pandemic. CCP was, however, often employed in combination with other drugs, such as the antiviral remdesivir and glucocorticoids. The possible effect of such interaction has never been investigated systematically. To assess the safety and efficacy of CCP combined with other agents for treatment of patients hospitalized for COVID-19, a systematic literature search using appropriate Medical Subject Heading (MeSH) terms was performed through PubMed, EMBASE, Cochrane central, medRxiv and bioRxiv. The main outcomes considered were mortality and safety of CCP combined with other treatments versus CCP alone. This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Measure of treatment effect was the risk ratio (RR) together with 95% confidence intervals (CIs). A total of 11 studies (8 randomized controlled trials [RCTs] and 3 observational) were included in the systematic review, 4 studies with CCP combined with remdesivir and 6 studies with CCP combined with corticosteroids, all involving hospitalized patients. One RCT reported information on both remdesivir and steroids use with CCP. The use of CCP combined with remdesivir was associated with a significantly reduced risk of death (RR 0.74; 95% CI 0.56–0.97; p = 0.03; moderate certainty of evidence), while the use of steroids with CCP did not modify the mortality risk (RR 0.72; 95% CI 0.34–1.51; p = 0.38; very low certainty of evidence). Not enough safety data were retrieved form the systematic literature analysis. The current evidence from the literature suggests a potential beneficial effect on mortality of combined CCP plus remdesivir compared to CCP alone in hospitalized COVID-19 patients. No significant clinical interaction was found between CCP and steroids.

This case report indicates that a recreationally trained 58-year-old man can reach similar or even higher values of energy expenditure (∼4 times their basal metabolic rate) than professional cyclists, who are likely near the ceiling of sustained energy expenditure for humans. This was possible owing to a total longer exercise time coupled with a lower absolute and relative intensity in the recreational athlete.

Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.

Objective Insulin has known sympathoexcitatory effects that have been historically attributed to primarily central mechanisms. Although controversy exists, recent evidence from rodents suggests the carotid chemoreceptors may play a role in the sympathoexcitatory response to hyperinsulinemia. Therefore, we sought to examine the contribution of the carotid chemoreceptors to insulin‐mediated increases in sympathetic nervous system activity in humans. We hypothesized reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia in humans – thus supporting a role for the carotid chemoreceptors in insulin‐mediated sympathoexcitation. Methods Young, healthy adults (n=15, 8M/7F, 27±1 yrs, 24±1 kg/m 2 ) completed a 30‐min euglycemic baseline followed by a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (90–100 mg/dL) clamp. Heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were continuously measured. The role of the carotid chemoreceptors was assessed using the following protocols: 1) acute (1‐min) hyperoxia (n=13), 2) low‐dose dopamine (1–4 μg/kg/min; n=7), 3) acute hyperoxia + low‐dose dopamine (n=8). The nadir 15‐s value for MSNA within each hyperoxic condition was determined and the nadir at baseline was compared to the nadir during hyperinsulinemia. Results MSNA increased from baseline during the hyperinsulinemic, euglycemic clamp [12±2 to 18±2 bursts/min (p<0.01)]. In protocol 1, MSNA was reduced during acute hyperoxia at baseline (12±1 to 6±1 bursts/min, p<0.01) and during the hyperinsulinemic clamp (17±2 to 12±2 bursts/min, p=0.02); however, the fall in MSNA during hyperoxia did not differ between baseline and hyperinsulinemia (p=0.82). In protocol 2, when low‐dose dopamine was given prior to the hyperinsulinemic clamp, MSNA did not increase from baseline (19±2 to 22±5 bursts/min, p=0.51); this is in contrast to increases observed under saline conditions (14±3 to 22±4 bursts/min, p=0.03). In protocol 3, in the presence of low‐dose dopamine, MSNA was reduced during acute hyperoxia at baseline (16±3 to 9±2 bursts/min, p=0.048) and during the hyperinsulinemic clamp (16±4 to 9±3 bursts/min, p=0.02); however, the fall in MSNA with hyperoxia did not differ between baseline and hyperinsulinemia (p=0.97). Conclusions Low‐dose dopamine given prior to the onset of a hyperinsulinemic, euglycemic clamp attenuates the sympathoexcitatory response to hyperinsulinemia. In contrast, acute carotid chemoreceptor desensitization (1‐min hyperoxia) during steady‐state hyperinsulinemia does not augment the fall in MSNA observed at baseline. Our data suggest the carotid chemoreceptors do not contribute acutely to insulin‐mediated increases in sympathetic nervous system activity in healthy humans; however, they may play a role during longer‐term exposure. Support or Funding Information Support: DK090541 (MJJ); HL83947 (MJJ); HL130339 (JKL); AHA15SDG25080095 (JKL)

A history of hypertensive disorders of pregnancy, including preeclampsia, place women at an elevated risk of developing hypertension and cognitive impairments as they age. The purpose of this study was to determine if aortic hemodynamics were related to cognition in postmenopausal women with a history of hypertensive disorders of pregnancy. We evaluated 33 postmenopausal women with a history of preeclampsia (PE: age = 59 ± 5 y; BMI = 29 ± 5 kg/m 2 ; years since last pregnancy = 35 ± 3 y) and 29 postmenopausal women with a history of normotensive pregnancy (NTP: age = 59 ± 5 y; BMI = 26 ± 5 kg/m 2 ; years since last pregnancy = 35 ± 3 y). Participants underwent a cognitive testing battery including letter‐number sequencing, trail making test B, letter fluency, and category fluency tests to evaluate executive functioning and working memory. Mean arterial pressure (MAP) was measured with a brachial blood pressure cuff. Applanation tonometry (SphygmoCor) was used to derive the aortic pressure waveform and calculate aortic systolic blood pressure (ASBP), aortic diastolic blood pressure (ADBP), augmentation index (AI), and augmented pressure (AP). There were no differences in cognitive scores between groups (p > 0.05). Brachial blood pressure (MAP: 103 ± 2 vs. 103 ± 3 mmHg) and aortic hemodynamic measures (ASBP: 123 ± 3 vs. 121 ± 3 mmHg; ADBP: 78 ± 2 vs. 77 ± 2 mmHg; AI: 31 ± 2 vs. 28 ± 1 %; AP: 17 ± 1 vs. 15 ± 1 mmHg) were also similar between PE women and NTP women, respectively (p > 0.05 for all). There were no associations between measures of aortic hemodynamics and cognitive scores in women independent of their pregnancy history (p > 0.05). When evaluating these relationships within each group, ADBP was significantly associated with worse scores for letter‐number sequencing and letter fluency in PE women (r = −0.433 and r = −0.441, respectively, p < 0.05). Taken together, our results indicate aortic hemodynamic measures are not associated with cognition in middle‐aged postmenopausal women with different pregnancy histories; however, future studies should address the influence of elevated aortic hemodynamic variables and the longitudinal change in cognitive function in postmenopausal women with different pregnancy histories. Support or Funding Information NIH AG44170, NIH 118154

Post‐mortem analyses have identified carotid body hypertrophy in conditions of chronic hypoxemia, including sleep apnea; however, post‐mortem assessment limits the clinical relevance of such findings. We tested the hypotheses that: 1) carotid body size can be detected in living individuals by computed tomographic angiography (CTA), and 2) patients with sleep disordered breathing [Apnea Hypopnea Index (AHI) ≥ 30 events/hour] exhibit larger carotid bodies than those without sleep disordered breathing (AHI < 5 events/hour). A chart review was conducted from patients seen at the Mayo Clinic between January 2000 and February 2015 who had undergone neck CTA and polysomnography. From an initial pool of 583, 109 patients met our strict inclusion criteria. Widest axial measurements of the right and left carotid bodies were performed independently by two radiologists blinded to condition and average carotid body size was calculated for each patient of interest. Carotid body identification was possible in 81% of patients. Intra‐class correlation coefficients ranged from 0.93 to 0.95 (right carotid body: 0.93; left: 0.94; average: 0.95). From subjects with identifiable carotid bodies, widest axial measurements were greater in patients with high AHI (n=32; right: 2.9±0.2mm, left: 3.1±0.2mm, average: 3.0±0.1mm) compared to patients with low AHI (n=46; right: 2.5±0.1mm, left: 2.7±0.1mm, average: 2.6±0.1mm; p=0.04, p=0.04, p=0.02, respectively). Because participants in the high AHI group were significantly older than those in the low AHI group (65±2 years vs. 50±2 years; p<0.01), an analysis of covariance was performed to control for the influence of age on carotid body size. After adjusting for age, no differences in carotid body size were observed between the patient groups (p=0.45, p=0.59, p=0.54 for right, left, and average carotid body, respectively). Main findings are two‐fold: 1) carotid body size can be identified by CTA in approximately 80% of patients with good inter‐observer agreement, and 2) adults that exhibit sleep disordered breathing do not have larger carotid bodies when compared to controls, after adjusting for age. Support or Funding Information This work was supported by the National Institutes of Health [grant numbers T32 GM008685 (ARE), R01 DK090541 (MJJ)].