Effect of Glycocalyx-targeted Therapy on Vascular Function in Older Adults: A Randomized Controlled Trial.

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro{trade mark, serif}, could improve both glycocalyx thickness and endothelial function in older adults, however, this has yet to be tested. We hypothesized that Endocalyx Pro{trade mark, serif} supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66±7 years (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-week Endocalyx Pro{trade mark, serif} supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro{trade mark, serif} did not increase glycocalyx thickness in microvessels 4-25µm (P=0.33), 4-7µm (P=0.07), or 10-25µm (P=0.47) in diameter when compared with placebo. Additionally, Endocalyx Pro did not significantly improve FMD [mean ratio (95% CI) for between-group comparisons, 1.16 (0.77-1.74); P=0.48]. However, Endocalyx Pro{trade mark, serif} improved FMD normalized to shear rate area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P=0.001]. Moreover, Endocalyx Pro{trade mark, serif} increased capillary glycocalyx thickness more than placebo in individuals not taking anti-hypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15,-0.01); P=0.02]. Our pilot study suggests that Endocalyx Pro{trade mark, serif} supplementation is feasible in older adults but had no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro{trade mark, serif} may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted.

Availability and use of institutional support programs for emergency department healthcare personnel during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic placed health care personnel (HCP) at risk for stress, anxiety, burnout, and post-traumatic stress disorder (PTSD). To address this, hospitals developed programs to mitigate risk. The objectives of the current study were to measure the availability and use of these programs in a cohort of academic emergency departments (EDs) in the United States early in the pandemic and identify factors associated with program use. METHODS: Cross-sectional survey of ED HCP in 21 academic EDs in 15 states between June and September 2020. Site investigators provided data on the availability of 28 programs grouped into 9 categories. Individual support programs included: financial, workload mitigation, individual COVID-19 testing, emotional (e.g., mental health hotline), and instrumental (e.g., childcare) Clinical work support programs included: COVID-19 team communication (e.g., debriefing critical incident), patient-family communication facilitation, patient services (e.g., social work, ethics consultation), and system-level exposure reduction. Participants provided corresponding data on whether they used the programs. We used generalized linear mixed models clustered on site to measure the association between demographic and facility characteristics and program use. RESULTS: We received 1,541 survey responses (96% response rate) from emergency physicians or advanced practice providers, nurses, and nonclinical staff. Program availability in each of the 9 categories was high (>95% of hospitals). Program use was variable, with clinical work support programs used more frequently (28-50% of eligible HCP across categories) than individual employee support programs (6-13% of eligible HCP across categories). Fifty-seven percent of respondents reported that the COVID-19 pandemic had affected their stress and anxiety, and 12% were at elevated risk for PTSD. Program use did not significantly differ for HCP who reported symptoms of anxiety and/or stress compared to those who did not. CONCLUSIONS: Early in the pandemic, support programs were widely available to ED HCP, but program use was low. Future work will focus on identifying barriers and facilitators to use and specific programs most likely to be effective during periods of highest occupational stress.

Enhanced Spine Stability and Survival Lead to Increases in Dendritic Spine Density as an Early Response to Local Alpha-Synuclein Overexpression in Mouse Prefrontal Cortex.

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. However, the impact of local pathology in the cortex is unknown. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1 to 2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow-up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

Increased Maternal BMI at Time of Delivery Associated with Poor Maternal and Neonatal Outcomes.

OBJECTIVE: Current literature on the risks and outcomes of obesity in pregnancy almost exclusively utilizes prepregnancy body mass index (BMI). Given the rising obesity rate across the United States along with a paucity of available information on the relationship between delivery BMI and maternal and neonatal outcomes, our study aimed to determine the association of maternal BMI at delivery with antepartum, intrapartum, and neonatal complications at an academic referral hospital. STUDY DESIGN: This study is a secondary analysis of data collected for a prospective cohort study of Coronavirus Disease-2019 (COVID-19) in pregnancy. This analysis included all patients who delivered term singleton infants between May 1, 2020, and April 30, 2021, at the University of Iowa Hospitals and Clinics. Demographic and clinical data were obtained from the electronic medical record. The relationship between maternal BMI and maternal and neonatal characteristics of interest was assessed using logistic regression models. A statistical significance threshold of 0.05 was used for all comparisons. RESULTS: There were 1,996 women who delivered term singleton infants during the study period. The median BMI at delivery was 31.7 kg/m2 (interquartile range 27.9, 37.2), with 61.1% of women having a BMI ≥ 30.0 kg/m2. Increasing BMI was significantly associated with nonreassuring fetal status, unscheduled cesarean birth, overall cesarean birth rate, postpartum hemorrhage, prolonged postpartum stay, hypertensive diseases of pregnancy, neonatal hypoglycemia, neonatal intensive care unit admission, decreased APGAR score at 1 minute, and increasing neonatal birth weight. Even when controlling for preexisting hypertension in a multivariate model, increasing BMI was associated with gestational hypertension and preeclampsia. CONCLUSION: Increased maternal BMI at delivery was associated with adverse perinatal outcomes. These findings have implications for clinical counseling regarding risks of pregnancy and delivery for overweight and obese patients and may help inform future studies to improve safety, especially by examining reasons for high cesarean rates. KEY POINTS: · Sixty-one percent of delivering patients had a BMI330 kg/m2 at delivery.. · There was a higher cesarean rate with increasing delivery BMI.. · For every 5-unit increase in maternal BMI, neonatal weight increased by 0.47 g..

Effects of rurality and distance to care on perinatal outcomes over a 1-year period during the COVID-19 pandemic.

PURPOSE: Our aim was to investigate the roles of rurality and distance to care on adverse perinatal outcomes and COVID-19 seroprevalence at the time of delivery over a 1-year period. METHODS: Data were collected from the electronic medical record on all pregnant patients who delivered at a single, large, Midwest academic medical center over 1 year. Rurality was classified using standard Rural-Urban Commuting Area codes. Geographic Information System tools were used to map outcomes. Data were analyzed with univariate and multivariate models, controlling for Body Mass Index (BMI), insurance status, and parity. FINDINGS: A total of 2,497 patients delivered during the study period; 20% of patients were rural (n = 499), 18.6% were micropolitan (n = 466), and 61.4% were metropolitan (n = 1,532). 10.4% of patients (n = 259) were COVID-19 seropositive. Rural patients did not experience higher rates of any measured adverse outcomes than metropolitan patients; micropolitan patients had increased odds of preterm labor (OR = 1.41, P = .022) and pre-eclampsia (OR = 1.78, P<.001). Patients living 30+ miles away from the medical center had increased odds of preterm labor (OR = 1.94, P<.001), pre-eclampsia (OR = 1.73, P = .002), and infant admission to the neonatal intensive care unit (OR = 2.12, P<.001), as well as lower gestational age at delivery (ß = -9.2 days, P<.001) and birth weight (ß = -206 grams, P<.001). CONCLUSION: Distance to care, rather than rurality, was the key predictor of multiple adverse perinatal outcomes in this cohort of deliveries over a 1-year period. Our study suggests that rurality should not be used as a standalone indicator of access to care without further knowledge of the specific barriers affecting a given population.

Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex.

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial.

BACKGROUND: Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes. METHODS: Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation. RESULTS: The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors. CONCLUSIONS: Resveratrol supplementation improved endothelial function in patients with CKD and diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Resveratrol and Vascular Function in CKD, NCT03597568 .

Disruption of the circadian rhythm of melatonin: A biomarker of critical illness severity.

Circadian dysrhythmias occur commonly in critically ill patients reflecting variable effects of underlying illness, ICU environment, and treatments. We retrospectively analyzed the relationship between clinical outcomes and 24-h urinary 6-sulfatoxymelatonin (aMT6s) excretion profiles in 37 critically ill patients with shock and/or respiratory failure. Nonlinear regression was used to fit a 24-h cosine curve to each patient's aMT6s profile, with rhythmicity determined by the zero-amplitude test. From these curves we determined acrophase, amplitude, phase, and night/day ratio. After assessing unadjusted relationships, we identified the optimal multivariate models for hospital survival and for discharge to home (vs. death or transfer to another facility). Normalized aMT6s rhythm amplitude was greater (p = 0.005) in patients discharged home than in those who were not, while both groups exhibited a phase delay. Patients with rhythmic aMT6s excretion were more likely to survive (OR 5.25) and be discharged home (OR 8.89; p < 0.05 for both) than patients with arrhythmic profiles, associations that persisted in multivariate modelling. In critically ill patients with shock and/or respiratory failure, arrhythmic and/or low amplitude 24-h aMT6s rhythms were associated with worse clinical outcomes, suggesting a role for the melatonin-based rhythm as a novel biomarker of critical illness severity.

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.

OBJECTIVE: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). METHODS: We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. RESULTS: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. SIGNIFICANCE: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.

The Association of Anesthesia Type and Neonatal Outcomes Following Category-1 Cesarean Delivery: A Retrospective Cohort Study.

Objectives Neuraxial anesthesia is the preferred anesthesia technique for cesarean delivery due to a decreased risk of adverse events. However, general anesthesia is often employed during emergent cesarean deliveries to achieve a shorter decision-to-delivery interval. The objective of this study was to determine if the conversion of epidural labor analgesia to surgical anesthesia for a category-1 cesarean delivery is associated with significant neonatal morbidity. Study design This was a retrospective cohort study of all intrapartum category-1 cesarean deliveries performed at an academic tertiary care institution between August 2016 and July 2021. The primary outcome was neonatal morbidity, defined as a composite of neonatal umbilical artery pH < 7.10 and/or 5-min Apgar score < 7, and/or neonatal intensive care unit admission. A multivariate regression analysis was performed to control for the presence of covariates and examine the degree to which they influenced the outcome. Results A total of 185 mother-neonate pairs qualified for inclusion, of which 23 had cesarean delivery under general anesthesia and 162 under epidural anesthesia. There was no significant difference in adverse neonatal outcomes between category-1 cesarean deliveries done under general anesthesia compared to epidural anesthesia (47% vs 35%, p = 0.3). The incidence of umbilical arterial pH < 7.10 was higher in the general anesthesia group compared to the epidural anesthesia group (35% vs 12%, p = 0.018). The multivariate regression model showed that gestational age (OR = 0.63; 95% CI = 0.51-0.75, p = <0.001) and non-reassuring fetal heart trace (OR = 0.18; 95% CI = 0.05-0.58, p = 0.005) were significant predictors of adverse neonatal outcome. Conclusion Our results suggest that the conversion of epidural analgesia to surgical anesthesia for category-1 cesarean delivery in women with a functional labor epidural catheter is not associated with poorer neonatal outcomes.

Surgeon-Specific Treatment Selection Bias and Heterogeneous Perioperative Practices in an Observational Spine Surgery Study. A Statistical Tutorial with Implications for Analysis of Observational Studies of Perioperative Interventions.

BACKGROUND: It is essential that treatment effects reported from retrospective observational studies are as reliable as possible. In a retrospective analysis of spine surgery patients, we obtained a spurious result: tranexamic acid (TXA) had no effect on intraoperative blood loss. This statistical tutorial explains how this result occurred and why statistical analyses of observational studies must consider the effects of individual surgeons. METHODS: We used an observational database of 580 elective adult spine surgery patients, supplemented with a review of perioperative medication records. We tested whether common statistical methods (multivariable regression or propensity score-based methods) could adjust for surgeons' selection bias in TXA administration. RESULTS: Because TXA administration (frequency, timing, and dose) and surgeon were linked (collinear), estimating and testing the independent effect of TXA on outcome using multivariable regression without including surgeon as a variable would provide biased (spurious) results. Likewise, because of surgeon/TXA linkage, assumptions of propensity score-based analysis were violated, statistical methods to improve comparability between groups failed, and spurious blood loss results were worsened. Others numerous differences among surgeons existed in intraoperative and postoperative practices and outcomes. CONCLUSIONS: In observational studies in which individual surgeons determine whether their patients receive the treatment of interest, consideration must be given to inclusion of surgeon as an independent variable in all analyses. Failure to include the surgeon in an analysis of observational data carries a substantial risk of obtaining spurious results, either creating a spurious treatment effect or failing to detect a true treatment effect.

Selective Serotonin Reuptake Inhibitors and 5-HT2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice.

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.

Thromboprophylaxis for children hospitalized with COVID-19 and MIS-C.

Background: Limited data exist about effective regimens for pharmacological thromboprophylaxis in children with acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C). Objectives: Study the outcomes of institutional thromboprophylaxis protocol for primary venous thromboembolism (VTE) prevention in children hospitalized with acute COVID-19/MIS-C. Methods: This single-center retrospective cohort study included consecutive children (aged less than 21 years) with COVID-19/MIS-C who received tailored intensity thromboprophylaxis, primarily with low-molecular-weight heparin, from April 2020 through October 2021. Thromboprophylaxis was given to those with moderate to severe disease based on the World Health Organization scale and exposure to two or more VTE risk factors. Therapeutic intensity was considered for severe illness. Clinical recovery along with D-dimer improvement determined thromboprophylaxis duration. Outcomes were incident VTEs, bleeding, and mortality. Results: Among 211 hospitalizations, 45 (21.3%) received thromboprophylaxis (COVID-19, 16; MIS-C, 29). Median age was 14.8 years (interquartile range [IQR], 8.9-16.1). Among 35 (77.8%) with severe illness, 27 (60.0%) required respiratory support, and 19 (42.2%) required an intensive care unit stay. Median hospitalization was 6 days (IQR, 5.0-10.5). Median thromboprophylaxis duration was 19 days (IQR, 6.0-31.0) with therapeutic intensity in 24 (53.3%) and prophylactic in 21 (46.7%). Outcomes were as follows: VTE, 1 (2.2%); death, 1 (2.2%, unrelated to bleeding/thrombosis); major/clinically relevant nonmajor bleeding, 0; and minor bleeding, 7 (15.5%). D-dimer was elevated in a majority at diagnosis (median, 2.3; IQR, 1.2-3.3 mg/ml fibrinogen-equivalent units) and was noninformative in assessing disease severity. D-dimer normalized at thromboprophylaxis discontinuation. Conclusions: Our experience of using clinically directed thromboprophylaxis with tailored intensity approach for children hospitalized with COVID-19 and MIS-C favors its inclusion in current standard of care. The role of D-dimer in directing thromboprophylaxis management deserves further evaluation.