Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Neonatal neural responses to novelty related to behavioral inhibition at 1 year.

Behavioral inhibition (BI), an early-life temperament characterized by vigilant responses to novelty, is a risk factor for anxiety disorders. In this study, we investigated whether differences in neonatal brain responses to infrequent auditory stimuli relate to children's BI at 1 year of age. Using functional magnetic resonance imaging (fMRI), we collected blood-oxygen-level-dependent (BOLD) data from N = 45 full-term, sleeping neonates during an adapted auditory oddball paradigm and measured BI from n = 27 of these children 1 year later using an observational assessment. Whole-brain analyses corrected for multiple comparisons identified 46 neonatal brain regions producing novelty-evoked BOLD responses associated with children's BI scores at 1 year of age. More than half of these regions (n = 24, 52%) were in prefrontal cortex, falling primarily within regions of the default mode or frontoparietal networks or in ventromedial/orbitofrontal regions without network assignments. Hierarchical clustering of the regions based on their patterns of association with BI resulted in two groups with distinct anatomical, network, and response-timing profiles. The first group, located primarily in subcortical and temporal regions, tended to produce larger early oddball responses among infants with lower subsequent BI. The second group, located primarily in prefrontal cortex, produced larger early oddball responses among infants with higher subsequent BI. These results provide preliminary insights into brain regions engaged by novelty in infants that may relate to later BI. The findings may inform understanding of anxiety disorders and guide future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Naturally menstruating women exhibit lower cardiovagal baroreflex sensitivity than oral contraceptive users during the lower hormone phase.

The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2  = 0.15, P = 0.024), but not progesterone (R2  = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2  = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2  = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS. NEW FINDINGS: What is the central question of this study? Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)? What is the main finding and its importance? The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.

A Novel Cognitive Training Program Targets Stimulus-Driven Attention to Alter Symptoms, Behavior, and Neural Circuitry in Pediatric Anxiety Disorders: Pilot Clinical Trial.

Objective: Pediatric anxiety disorders are associated with increased stimulus-driven attention (SDA), the involuntary capture of attention by salient stimuli. Increased SDA is linked to increased activity in the right ventrolateral prefrontal cortex (rVLPFC), especially in the portion corresponding to the ventral attention network (VAN). In this study, we present a small clinical trial using a novel attention training program designed to treat pediatric anxiety by decreasing SDA and activity in the rVLPFC. Methods: Children ages 8-12 with anxiety disorders (n = 18) participated in eight sessions of attention training over a 4-week period. At baseline and after completing training, participants completed clinical anxiety measures and a battery of cognitive tasks designed to measure three different aspects of attention: SDA, goal-oriented attention, and threat bias. A subset of participants (n = 12) underwent baseline and post-training neuroimaging while engaged in an SDA task. Brain analyses focused on activity within the rVLPFC. Results: Parent (p < 0.001)-, child (p < 0.002)-, and clinician-rated (p < 0.02) anxiety improved significantly over the course of training. Training significantly altered SDA [F(1,92) = 8.88, corrected p-value (pcor) < 0.012, uncorrected p-value (puncor) < 0.004]. Anxiety improvement correlated with improvements in goal-directed attention [r(10) = 0.60, pcor < 0.12 puncor < 0.04]. Within an area of the rVLPFC corresponding to the cingulo-opercular network (CON), there was a main effect of training [F(1,20) = 6.75, pcor < 0.16, puncor < 0.02], with decreasing signal across training. There was a significant interaction between training and anxiety on this region's activity [F(1,20) = 9.48, pcor < 0.048, puncor < 0.006]. Post hoc testing revealed that post-training activity within this CON area correlated with residual anxiety [r(10) = 0.68, p < 0.02]. Conclusions: SDA and rVLPFC neural activity may be novel therapeutic targets in pediatric anxiety. After undergoing a training paradigm aimed at modifying this aspect of attention and its underlying neural circuitry, patients showed lower anxiety, changes in SDA and goal-oriented attention, and decreased activity in the CON portion of the rVLPFC.

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Reproducibility and diurnal variation in middle cerebral artery blood velocity in healthy humans.

NEW FINDINGS: What is the central question of this study? We sought to establish between-day reproducibility in estimates of middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity (CVR) in young, healthy male and female adults in tightly controlled experimental conditions. What is the main finding and its importance? Measures of MCAv assessed during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in CVR, with values being highest during the evening compared with the morning. Greater diurnal variation in CVR is associated with more efficient sleep and greater nocturnal blood pressure dipping. These data enhance our understanding of modulators of MCAv and CVR. ABSTRACT: Transcranial Doppler (TCD) is used to assess cerebral blood velocity (CBV) and cerebrovascular reactivity (CVR). Assessments of TCD reproducibility are limited, and few include multiple within-day measurements. We sought to establish reproducibility of CBV and CVR in healthy adults during three time periods (morning, afternoon and evening). We hypothesized that CBV and CVR measured at the same time of day are reproducible between days. We also hypothesized that CBV and CVR exhibit diurnal variation, with measurements being higher in the evening compared with morning/afternoon hours. Twelve adults [six male and six female, 27 years (95% CI, 22-31 years)] completed three measurements (morning, afternoon and evening) on two separate days in controlled conditions (e.g., meals, activity and sleep). Middle cerebral artery blood velocity (MCAv, TCD) was measured continuously at rest and during two CVR tests (end-expiratory apnoea and carbogen inhalation). Intraclass correlation coefficients for resting MCAv showed moderate to good reproducibility, which did not differ between morning, afternoon and evening (0.87, 0.56 and 0.67, respectively; P > 0.05). Intraclass correlation coefficients for peak MCAv during apnoea (0.80, 0.46 and 0.65, respectively; P > 0.05) and minute 2 of carbogen inhalation (0.81, 0.74 and 0.73, respectively; P > 0.05) were also not different from morning compared with afternoon/evening. Time of day had no effect on resting MCAv (F = 0.69, P = 0.51, ƞp 2  = 0.06) or the peak response to apnoea (F = 1.00, P = 0.39, ƞp 2  = 0.08); however, peak MCAv during carbogen breathing exhibited diurnal variation, with highest values in the evening (F = 3.41, P = 0.05, ƞp 2  = 0.24). Measures of CBV and CVR assessed via TCD during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in the MCAv response to carbogen exposure, with CVR being highest during evening compared with morning hours.

Henipaviruses and lyssaviruses target nucleolar treacle protein and regulate ribosomal RNA synthesis.

The nucleolus is a common target of viruses and viral proteins, but for many viruses the functional outcomes and significance of this targeting remains unresolved. Recently, the first intranucleolar function of a protein of a cytoplasmically-replicating negative-sense RNA virus (NSV) was identified, with the finding that the matrix (M) protein of Hendra virus (HeV) (genus Henipavirus, family Paramyxoviridae) interacts with Treacle protein within nucleolar subcompartments and mimics a cellular mechanism of the nucleolar DNA-damage response (DDR) to suppress ribosomal RNA (rRNA) synthesis. Whether other viruses utilise this mechanism has not been examined. We report that sub-nucleolar Treacle targeting and modulation is conserved between M proteins of multiple Henipaviruses, including Nipah virus and other potentially zoonotic viruses. Furthermore, this function is also evident for P3 protein of rabies virus, the prototype virus of a different RNA virus family (Rhabdoviridae), with Treacle depletion in cells also found to impact virus production. These data indicate that unrelated proteins of viruses from different families have independently developed nucleolar/Treacle targeting function, but that modulation of Treacle has distinct effects on infection. Thus, subversion of Treacle may be an important process in infection by diverse NSVs, and so could provide novel targets for antiviral approaches with broad specificity.

Endothelin-1 receptor blockade does not alter the sympathetic and hemodynamic response to acute intermittent hypoxia in men.

Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans are unclear. We hypothesized that ET-receptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual's baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ET-receptors in healthy young men.NEW & NOTEWORTHY Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

Effectiveness of universal school-based mindfulness training compared with normal school provision on teacher mental health and school climate: results of the MYRIAD cluster randomised controlled trial.

BACKGROUND: Education is broader than academic teaching. It includes teaching students social-emotional skills both directly and indirectly through a positive school climate. OBJECTIVE: To evaluate if a universal school-based mindfulness training (SBMT) enhances teacher mental health and school climate. METHODS: The My Resilience in Adolescence parallel group, cluster randomised controlled trial (registration: ISRCTN86619085; funding: Wellcome Trust (WT104908/Z/14/Z, WT107496/Z/15/Z)) recruited 85 schools (679 teachers) delivering social and emotional teaching across the UK. Schools (clusters) were randomised 1:1 to either continue this provision (teaching as usual (TAU)) or include universal SBMT. Data on teacher mental health and school climate were collected at prerandomisation, postpersonal mindfulness and SBMT teacher training, after delivering SBMT to students, and at 1-year follow-up. FINDING: Schools were recruited in academic years 2016/2017 and 2017/2018. Primary analysis (SBMT: 43 schools/362 teachers; TAU: 41 schools/310 teachers) showed that after delivering SBMT to students, SBMT versus TAU enhanced teachers' mental health (burnout) and school climate. Adjusted standardised mean differences (SBMT minus TAU) were: exhaustion (-0.22; 95% CI -0.38 to -0.05); personal accomplishment (-0.21; -0.41, -0.02); school leadership (0.24; 0.04, 0.44); and respectful climate (0.26; 0.06, 0.47). Effects on burnout were not significant at 1-year follow-up. Effects on school climate were maintained only for respectful climate. No SBMT-related serious adverse events were reported. CONCLUSIONS: SBMT supports short-term changes in teacher burnout and school climate. Further work is required to explore how best to sustain improvements. CLINICAL IMPLICATIONS: SBMT has limited effects on teachers' mental and school climate. Innovative approaches to support and preserve teachers' mental health and school climate are needed.

Effectiveness and cost-effectiveness of universal school-based mindfulness training compared with normal school provision in reducing risk of mental health problems and promoting well-being in adolescence: the MYRIAD cluster randomised controlled trial.

BACKGROUND: Systematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health. OBJECTIVE: The My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU). METHODS: MYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11-14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included. FINDINGS: Analysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI -0.05 to 0.06) for risk for depression; 0.02 (-0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (-0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed. CONCLUSIONS: Findings do not support the superiority of SBMT over TAU in promoting mental health in adolescence. CLINICAL IMPLICATIONS: There is need to ask what works, for whom and how, as well as considering key contextual and implementation factors. TRIAL REGISTRATION: Current controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

Effect of oral hormonal contraceptive pill use on the hemodynamic response to the cold pressor test.

Acute increases in sympathetic nervous system activity (SNA) often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in SNA. We hypothesized sympathoexcitation via cold pressor test (CPT) would elicit greater peripheral vasoconstriction and increases BP in females with natural menstrual cycles (NC) compared with females taking OC. We further hypothesized that SNA-mediated vasoconstriction would be attenuated during the high estradiol (HE) phase versus the low estradiol (LE) phase of the menstrual/pill cycle. Female NC (n = 11, 25 ± 1 yr) and OC (n = 10, 24 ± 1 yr) participants were studied during the LE (early follicular, placebo pill) and HE (late follicular, active pill) phase of the menstrual/pill cycle. BP (finger photoplethysmography), heart rate (HR, ECG), and forearm blood flow (FBF, venous occlusion plethysmography) were measured during a 5-min baseline and a 2-min CPT. CPT elicited an increase in BP in both groups (time, P < 0.01). During CPT, OC participants exhibited greater and sustained increases in HR compared with NC participants (group × time, P < 0.01). Higher HRs were met with increases in FBF in OC participants during the CPT, which was not observed in NC participants (group × time, P < 0.01). OC participants exhibit greater increases in HR, and paradoxical vasodilation during acute sympathetic activation compared with NC participants. Group differences are unaffected by menstrual/pill phase.NEW & NOTEWORTHY Acute increases in sympathetic nervous system activity often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in sympathetic nervous system activity via the cold pressor test. We show OC participants exhibit paradoxical vasodilation during acute sympathetic activation compared with participants with natural menstrual cycles; notably, group differences were unaffected by menstrual/pill phase.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Protocol for the Pilot Study of Group Video Yogic Breathing App in Breast Cancer Survivors.

INTRODUCTION: Breast cancer remains a leading cause of cancer deaths; however, recent improvements in treatment have improved survivorship. As a result of this improvement, more individuals are living with the long-term side effects of cancer treatment. Therefore, methods that incorporate lifestyle and mind-body approaches are becoming increasingly used in the patient treatment pathway. METHODS: In this study, PranaScience Institute will develop and test a group video mobile application for Yogic Breathing (YB). YB is shown to reduce symptomatic conditions associated with several conditions including breast cancer. For this initial feasibility study, PranaScience will collaborate with the Medical University of South Carolina to implement the study app-based program in breast cancer survivors. This research is aimed to understand if the YB could be delivered via an app, if participants are able to practice it satisfactorily, and if there is any symptom relief by the YB practice. In the control group, participants will be directed to the Attention Control (AC) feature of the app, which guides users to focus on a mindfulness activity not involving YB. Participants will be randomly assigned to the YB or AC study plan (N = 20 per group). Breast cancer survivors who have completed radiation therapy within last 2 months will be recruited for this study and provided access to the app for a 12-weeks program. The study app will record total practice times. Virtual visits by a study yoga instructor during group video sessions will measure participant compliance with proper technique. Feasibility will be examined by evaluating intervention delivery factors and resource needs. Acceptability of using the mobile study app to support symptom management will be evaluated using a satisfaction and system usability scale. Behavioral survey measures will help guide effect sizes and power calculations for the next larger-scale study. Biomarkers in the saliva (tumor suppressors, cytokines), and fingernails (cortisol, differential proteomics) will be measured at baseline and end of study at 12 weeks. DISCUSSION: All findings from this pilot study will be synthesized to refine the mobile study app in preparation for large-scale evaluation in Phase II involving all-study site participants with cancer. ClinicalTrials.gov Identifier NCT05161260.

Sex differences in the effect of acute intermittent hypoxia on respiratory modulation of sympathetic activity.

Sex-related differences in respiratory modulation of sympathetic activity have been observed in rodent models of sleep apnea [intermittent hypoxia (IH)]. In light of sex disparities in the respiratory response to acute IH in humans as well as changes in respiratory modulation of muscle sympathetic nerve activity (MSNA) in clinical sleep apnea, we examined sex-related differences in respiratory modulation of MSNA following acute IH. We hypothesized that respiratory modulation of MSNA would be altered in both male and female participants after IH; however, the respiratory patterning of MSNA following IH would be sex specific. Heart rate, MSNA, and respiration were evaluated in healthy male (n = 21, 30 ± 5 yr) and female (n = 10, 28 ± 5 yr) participants during normoxic rest before and after 30 min of IH. Respiratory modulation of MSNA was assessed by fitting polynomials to cross-correlation histograms constructed between sympathetic spikes and respiration. MSNA was elevated after IH in male (20 ± 6 to 24 ± 8 bursts/min) and female (19 ± 8 to 22 ± 10 bursts/min) participants (P < 0.01). Both male and female participants exhibited respiratory modulation of MSNA (P < 0.01); however, the pattern differed by sex. After IH, modulation of MSNA within the breath was reduced in male participants (P = 0.03) but increased in female participants (P = 0.02). Both male and female adults exhibit changes in respiratory patterning of MSNA after acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory modulation of MSNA and may have implications for conditions such as sleep apnea.

Sex differences in the vascular response to sympathetic activation during acute hypoxaemia.

NEW FINDINGS: What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control comes from predominantly male cohorts. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not? What is the main finding and its importance? Sympathetically mediated vasoconstriction is preserved or even enhanced during steady-state hypoxia in young men, and the peripheral vascular response to sympathetic activation during hypoxaemia is attenuated in young women. These data advance our understanding of sex-related differences in hypoxic vascular control. ABSTRACT: Activation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. Sympathetically mediated vasoconstriction may be attenuated during systemic hypoxia to maintain oxygen delivery; however, in predominantly male participants sympathetically mediated vasoconstriction is preserved or even enhanced during hypoxaemia. Given the potential for sex-specific differences in hypoxic vascular control, prior results are limited in application. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not. Healthy young men (n = 13, 25 ± 4 years) and women (n = 11, 24 ± 4 years) completed two trials consisting of a 2-min cold pressor test (CPT, a well-established sympathoexcitatory stimulus) during baseline normoxia and steady-state hypoxaemia. Beat-to-beat blood pressure (finger photoplethysmography) and forearm blood flow (venous occlusion plethysmography) were measured continuously. Total and forearm vascular conductance (TVC and FVC, respectfully) were calculated. A change (Δ) in TVC and FVC from steady-state during the last 1 min of CPT was calculated and differences between normoxia and systemic hypoxia were assessed. In men, the reduction in TVC during CPT was greater during hypoxia compared to normoxia (ΔTVC, P = 0.02), whereas ΔTVC did not differ between conditions in women (P = 0.49). In men, ΔFVC did not differ between normoxia and hypoxia (P = 0.92). In women, the reduction in FVC during CPT was attenuated during hypoxia (ΔFVC, P < 0.01). We confirm sympathetically mediated vasoconstriction is preserved or enhanced during hypoxaemia in young men, whereas peripheral vascular responsiveness to sympathetic activation during hypoxaemia is attenuated in young women. The results advance our understanding of sex-related differences in hypoxic vascular control.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of ß-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Brown meets green: light and nutrients alter detritivore assimilation of microbial nutrients from leaf litter.

In aquatic detrital-based food webs, research suggests that autotroph-heterotroph microbial interactions exert bottom-up controls on energy and nutrient transfer. To address this emerging topic, we investigated microbial responses to nutrient and light treatments during Liriodendron tulipifera litter decomposition and fed litter to the caddisfly larvae Pycnopsyche sp. We measured litter-associated algal, fungal, and bacterial biomass and production. Microbes were also labeled with 14 C and 33 P to trace distinct microbial carbon (C) and phosphorus (P) supporting Pycnopsyche assimilation and incorporation (growth). Litter-associated algal and fungal production rates additively increased with higher nutrient and light availability. Incorporation of microbial P did not differ across diets, except for higher incorporation efficiency of slower-turnover P on low-nutrient, shaded litter. On average, Pycnopsyche assimilated fungal C more efficiently than bacterial or algal C, and Pycnopsyche incorporated bacterial C more efficiently than algal or fungal C. Due to high litter fungal biomass, fungi supported 89.6-93.1% of Pycnopsyche C growth, compared to 0.2% to 3.6% supported by bacteria or algae. Overall, Pycnopsyche incorporated the most C in high nutrient and shaded litter. Our findings affirm others' regarding autotroph-heterotroph microbial interactions and extend into the trophic transfer of microbial energy and nutrients through detrital food webs.

Development and Evaluation of a Navigation-Based, Multilevel Intervention to Improve the Delivery of Timely, Guideline-Adherent Adjuvant Therapy for Patients With Head and Neck Cancer.

PURPOSE: More than half of patients with head and neck squamous cell carcinoma (HNSCC) experience a delay initiating guideline-adherent postoperative radiation therapy (PORT), contributing to excess mortality and racial disparities in survival. However, interventions to improve the delivery of timely, equitable PORT among patients with HNSCC are lacking. This study (1) describes the development of NDURE (Navigation for Disparities and Untimely Radiation thErapy), a navigation-based multilevel intervention (MLI) to improve guideline-adherent PORT and (2) evaluates its feasibility, acceptability, and preliminary efficacy. METHODS: NDURE was developed using the six steps of intervention mapping (IM). Subsequently, NDURE was evaluated by enrolling consecutive patients with locally advanced HNSCC undergoing surgery and PORT (n = 15) into a single-arm clinical trial with a mixed-methods approach to process evaluation. RESULTS: NDURE is a navigation-based MLI targeting barriers to timely, guideline-adherent PORT at the patient, healthcare team, and organizational levels. NDURE is delivered via three in-person navigation sessions anchored to case identification and surgical care transitions. Intervention components include the following: (1) patient education, (2) travel support, (3) a standardized process for initiating the discussion of expectations for PORT, (4) PORT care plans, (5) referral tracking and follow-up, and (6) organizational restructuring. NDURE was feasible, as judged by accrual (88% of eligible patients [100% Blacks] enrolled) and dropout (n = 0). One hundred percent of patients reported moderate or strong agreement that NDURE helped solve challenges starting PORT; 86% were highly likely to recommend NDURE. The rate of timely, guideline-adherent PORT was 86% overall and 100% for Black patients. CONCLUSION: NDURE is a navigation-based MLI that is feasible, is acceptable, and has the potential to improve the timely, equitable, guideline-adherent PORT.