Sympathoinhibition during cardiopulmonary baroreceptor loading is attenuated in older females.

The purpose of the present study was to clarify the impact of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. Nine older females (mean±SD, 70±6 years) and eleven younger females (20±1 years) completed the study. A passive leg raising (PLR) test was performed wherein the participants were positioned supine (baseline, 0º), and their lower limbs were passively lifted at 10º, 20º, 30º, and 40º (3 min at each angle). Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. The central venous pressure was estimated based on peripheral venous pressure (eCVP), which was monitored using a cannula in the right large antecubital vein. Baseline MSNA was higher in older females compared to younger females. MSNA burst frequency (BF) decreased during the PLR test in both older and younger females, but the magnitude of the decrease in MSNA BF was smaller in older females than in younger females (older, -3.5±1.5 vs. younger, -6.3±1.5 bursts/min at 40º from baseline, P=0.014). The eCVP increased during the PLR in both groups, and there was no difference in the changes in eCVP between the two groups (older, +1.07±0.37 vs. younger, +1.12±0.33 mmHg at 40º from baseline, P=0.941). These results suggest that inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age in females.

The Impact of Nutrition on Pain: A Narrative Review of Recent Literature.

PURPOSE OF REVIEW: Pain is a complex phenomenon that affects millions of individuals worldwide and poses a significant burden on public health. While pain management typically focuses on pharmacological and physical interventions, emerging research suggests that nutrition plays a crucial role in pain modulation. This narrative review aims to explore the relationship between nutrition and pain, providing a comprehensive overview of recent literature. The review covers various dietary factors, including macronutrients, micronutrients, dietary patterns, and specific dietary interventions. Additionally, the potential mechanisms underlying the impact of nutrition on pain are discussed. The findings highlight the potential for dietary interventions to complement traditional pain management approaches and provide valuable insights for future research and clinical practice. RECENT FINDINGS: Literature suggested the impact of healthy nutrition on improvement in pain and that certain types of food may increase and worsen different pain conditions. Nutrition plays an important role in modulating pain. It is important to counsel patients in pain on best diet for their pain condition to alleviate pain. Our article summarizes very well the issue of nutrition and pain and provides a guide to all practitioners caring for patients with chronic pain.

Low COVID-19 vaccine uptake in people living with HIV and those with hypertension and diabetes without HIV at Mbarara and Masaka regional referral hospitals: A cross-sectional survey.

Chronic diseases such as HIV, hypertension, and diabetes increase the risk of severe coronavirus disease 2019 (COVID-19) and death. Thus, COVID-19 vaccine uptake data among these priority populations are needed to inform immunization programs. We assessed COVID-19 vaccine uptake among people living with HIV (PLWH) and those with hypertension/diabetes without HIV (PWoH) in Southwestern and Southcentral Uganda and determined factors influencing vaccination. We conducted a cross-sectional study from January to April 2023. We enrolled a random sample of participants aged 18 years and older seeking HIV, hypertension, or diabetes care at two regional referral hospitals (RRHs) in Mbarara and Masaka in Uganda. Using vaccination records abstraction and interviewer-administered questionnaires, we collected data on COVID-19 vaccine uptake, sociodemographic data, and reasons for non-uptake in unvaccinated persons. We compared COVID-19 vaccination uptake between PLWH and PWoH and applied modified Poisson regression to determine sociodemographic factors associated with vaccine uptake. The reasons for non-vaccine uptake were presented as percentages. Of the 1,376 enrolled participants, 65.6% were fully vaccinated against COVID-19. Vaccination coverage was 65% among PWLH versus 67% among PWoH. Higher education attainment and older age were associated with COVID vaccination. Participants with secondary education and those aged ≥50 years achieved >70% coverage. Fear of side effects was the most cited reason (67%) for non-vaccination among 330 unvaccinated participants, followed by vaccine mistrust (24.5%). People with chronic diseases in Southwestern Uganda had slightly lower than 70% COVID-19 vaccine coverage as recommended by WHO. Higher educational attainment and older age were linked to increased vaccine uptake. However, mistrust and fear of vaccine side effects were the main reasons for non-vaccination. To increase COVID-19 vaccine uptake, programs must reach those with lower educational attainment and younger age groups, and address the fear of vaccine side effects and mistrust among persons with underlying diseases in Uganda.

Developing a production workflow for 3D-printed temporal bone surgical simulators.

INTRODUCTION: 3D-printed temporal bone models enable the training and rehearsal of complex otological procedures. To date, there has been no consolidation of the literature regarding the developmental process of 3D-printed temporal bone models. A brief review of the current literature shows that many of the key surgical landmarks of the temporal bone are poorly represented in models. This study aims to propose a novel design and production workflow to produce high-fidelity 3D-printed temporal bone models for surgical simulation. METHODS: Developmental phases for data extraction, 3D segmentation and Computer Aided Design (CAD), and fabrication are outlined. The design and fabrication considerations for key anatomical regions, such as the mastoid air cells and course of the facial nerve, are expounded on with the associated strategy and design methods employed. To validate the model, radiological measurements were compared and a senior otolaryngologist performed various surgical procedures on the model. RESULTS: Measurements between the original scans and scans of the model demonstrate sub-millimetre accuracy of the model. Assessment by the senior otologist found that the model was satisfactory in simulating multiple surgical procedures. CONCLUSION: This study offers a systematic method for creating accurate 3D-printed temporal bone models for surgical training. Results show high accuracy and effectiveness in simulating surgical procedures, promising improved training and patient outcomes.

Aging in females has minimal effect on changes in celiac artery blood flow during dynamic light-intensity exercise.

Blood flow to the active muscles and arterial blood pressure (ABP) increase during dynamic exercise, whereas blood flow to inactive organs (e.g., splanchnic organs and inactive limbs) declines. Aging leads to exaggerated ABP responses to exercise in females, but whether this is related to greater splanchnic vasoconstriction is unknown. This study sought to clarify the effect of aging in females on celiac artery blood flow during dynamic light-intensity exercise. Twelve healthy young females (YF: 20 ± 2 yr, mean ± SD) and 12 healthy older females (OF: 71 ± 4 yr) performed dynamic knee-extension and knee-flexion exercises at 30% of heart rate reserve for 4 min. The absolute changes from baseline (Δ) for mean arterial blood pressure (MAP), celiac artery mean blood flow (celMBF), and celiac vascular conductance (celVC) during exercise were calculated. ABP was measured using an automated sphygmomanometer, and celMBF was recorded by Doppler ultrasonography. The increase in MAP during exercise was greater in OF than in YF (YF: +14 ± 7 mmHg, OF: +24 ± 13 mmHg, P = 0.028). The celMBF decreased during exercise in both groups, but there was no significant difference in the response between YF and OF (YF: -93.0 ± 66.1 mL/min, OF: -89.6 ± 64.0 mL/min, P = 0.951). The celVC also decreased during exercise and remained lower than baseline during exercise. However, the response was not different between YF and OF (YF: -1.8 ± 1.0 mL/min/mmHg, OF: -1.5 ± 0.6 mL/min/mmHg, P = 0.517). These results demonstrate that aging in females has minimal influence on splanchnic artery hemodynamic responses during dynamic light-intensity exercise, suggesting that exaggerated ABP responses during exercise in OF are not due to greater splanchnic vasoconstriction.NEW & NOTEWORTHY During exercise, the splanchnic arteries vasoconstrict, contributing to blood flow redistribution and the blood pressure response. Blood pressure responses to exercise are exaggerated with aging in females; however, the physiological mechanism responsible has not been clarified. We show that celiac artery blood flow changes during light-intensity dynamic exercise do not differ with age in females. This indicates the exaggerated blood pressure to exercise with aging is likely not due to a difference in splanchnic vasoconstriction.

Monthly Sulfadoxine-Pyrimethamine During Pregnancy Prevents Febrile Respiratory Illnesses: A Secondary Analysis of a Malaria Chemoprevention Trial in Uganda.

Background: Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism. Methods: In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight. Results: Mean "birthweight for gestational age" Z scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" Z scores increased by 0.038 points (95% CI, .001-.074). Conclusions: Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.

Influence of sex on sympathetic vasomotor outflow responses to passive leg raising in young individuals.

The purpose of this study was to clarify sex differences in the inhibition of sympathetic vasomotor outflow which is caused by the loading of cardiopulmonary baroreceptors. Ten young males and ten age-matched females participated. The participants underwent a passive leg raising (PLR) test wherein they were positioned supine (baseline, 0º), and their lower limbs were lifted passively at 10º, 20º, 30º, and 40º. Each angle lasted for 3 min. Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. Baseline MSNA was lower in females compared to males. MSNA burst frequency was decreased during the PLR in both males (- 6.2 ± 0.4 bursts/min at 40º) and females (- 6.5 ± 0.4 bursts/min at 40º), but no significant difference was detected between the two groups (P = 0.61). These results suggest that sex has minimal influence on the inhibition of sympathetic vasomotor outflow during the loading of cardiopulmonary baroreceptors in young individuals.

'No zone' approach in the management of penetrating neck injuries - an Australian Tertiary Trauma Centre experience.

PURPOSE: Penetrating neck injuries (PNIs), defined as deep to the platysma, can result in significant morbidity and mortality. Management has evolved from a zone-based approach to a 'no zone' algorithm, resulting in reduced non-therapeutic neck exploration rates. The aim of this study was to examine PNIs and its management trends in an Australian tertiary trauma centre, to determine if a 'no zone' approach could be safely implemented in this population, as has been demonstrated internationally. METHODOLOGY: This was a retrospective observational study at a level 1 adult Australian tertiary trauma centre using prospectively collated data from January 2008 to December 2018. Observed data included age, gender, mechanism of injury, computed tomography angiography (CT-A) use and operative intervention. Patients were examined based on zone of injury and presenting signs - 'hard', 'soft' or 'asymptomatic'. Major outcomes were CT-A usage, positive CT-A correlation with therapeutic neck explorations and negative neck exploration rates. RESULTS: This study identified 238 PNI patients, with 204 selected for review. Most injuries occurred in zone 2 (71.6%), with soft signs accounting for 53.4% of cases. Over 10 years, CT-A utilization increased from 55% to 94.1%, with positive CT-As being more likely to yield therapeutic neck explorations. There was a general decreased trend in operative intervention but without a clear reduction in non-therapeutic neck explorations. CONCLUSION: Our data suggests similarities with results from around the world, demonstrating that the 'no zone' approach should be considered when managing PNIs, but with clinician discretion in individual cases.

Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics.

Cardiovascular responses to combined mechanoreflex and metaboreflex activation in healthy adults: effects of sex and low- versus high-hormone phases in females.

Females generally have smaller blood pressure (BP) responses to isolated muscle mechanoreflex and metaboreflex activation compared with males, which may explain sex differences in BP responses to voluntary exercise. The mechanoreflex may be sensitized during exercise, but whether mechanoreflex-metaboreflex interactions differ by sex or variations in sex hormones remains unknown. Thirty-one young healthy subjects (females, n = 16) performed unilateral passive cycling (mechanoreflex), active cycling (40% peak Watts), postexercise circulatory occlusion (PECO; metaboreflex), and passive cycling combined with PECO (combined mechanoreflex and metaboreflex activation). Beat-to-beat BP, heart rate, inactive leg vascular conductance, and active leg muscle oxygenation were measured. Ten females underwent exploratory testing during low- and high-hormone phases of their self-reported menstrual cycle or oral contraceptive use. Systolic BP and heart rate responses did not differ between sexes during active cycling [Δ30 ± 9 vs. 29 ± 11 mmHg (males vs. females), P = 0.9; Δ33 ± 8 vs. 35 ± 6 beats/min, P = 0.4] or passive cycling with PECO (Δ26 ± 11 vs. 21 ± 10 mmHg, P = 0.3; Δ14 ± 7 vs. 18 ± 15 beats/min, P = 0.3). Passive cycling with PECO revealed additive, not synergistic, effects for systolic BP [males: Δ23 ± 14 vs. 26 ± 11 mmHg (sum of isolated passive cycling and PECO vs. combined activation); females: Δ26 ± 11 vs. 21 ± 12 mmHg, interaction P = 0.05]. Results were consistent in subset analyses with sex differences in active cycling BP (P > 0.1) and exploratory analyses of hormone phase (P > 0.4). Despite a lack of statistical equivalence, no differences in cardiovascular responses were found during combined mechanoreflex-metaboreflex activation between sexes or hormone levels. These results provide preliminary data regarding the involvement of muscle mechanoreflex-metaboreflex interactions in mediating sex differences in voluntary exercise BP responses.NEW & NOTEWORTHY The muscle mechanoreflex may be sensitized by metabolites during exercise. We show that cardiovascular responses to combined mechanoreflex (passive cycling) and metaboreflex (postexercise circulatory occlusion) activation are primarily additive and do not differ between males and females, or across variations in sex hormones in females. Our findings provide new insight into the contributions of muscle mechanoreflex-metaboreflex interactions as a cause for prior reports that females have smaller blood pressure responses to voluntary exercise.

Effects of sex and menstrual cycle phase on celiac artery blood flow during dynamic moderate-intensity leg exercise in young individuals.

The purpose of this study was to clarify the effect of sex and menstrual cycle phase on celiac artery blood flow during dynamic exercise in healthy young humans. Eleven healthy young females (21 ± 2 yr, means ± SD) and 10 males (23 ± 3 yr) performed dynamic knee-extension and -flexion exercises at 30% of heart rate reserve for 4 min. The percent changes from baseline (Δ) for mean arterial blood pressure (MAP), mean blood flow (celMBF) in the celiac artery, and celiac vascular conductance (celVC) during exercise were calculated. Arterial blood pressure was measured using an automated sphygmomanometer, and celiac artery blood flow was recorded by Doppler ultrasonography. Female subjects performed the exercise test in the early follicular phase (EF) and in the midluteal phase (ML) of their menstrual cycle. The increase in MAP during exercise was not significantly (P > 0.05) different between sexes or between menstrual cycle phases (ΔMAP, EF in females: +16.6 ± 6.4%, ML in females: +20.2 ± 11.7%, and males: +19.9 ± 12.2%). The celMBF decreased during exercise in each group, but the response was not significantly (P > 0.05) different between sexes or between menstrual cycle phases (ΔcelMBF, EF in females: -24.6 ± 15.5%, ML in females: -25.2 ± 18.7%, and males: -29.2 ± 4.0%). The celVC decreased during dynamic exercise in each group, with no significant (P > 0.05) difference in the responses between sexes or between menstrual cycle phases (ΔcelVC, EF in females: -38.3 ± 15.0%, ML in females: -41.5 ± 19.1%, and males: -43.4 ± 7.2%). These results suggest that sex and menstrual cycle phase have minimal influence on hemodynamic responses in the splanchnic artery during dynamic moderate-intensity exercise in young healthy individuals.NEW & NOTEWORTHY During dynamic exercise, splanchnic organ blood flow is reduced from resting values. Whether sex and menstrual cycle phase influence splanchnic blood flow responses during exercise remains unknown. We show that the decrease in celiac artery blood flow during dynamic leg exercise does not differ between young females and males or between menstrual cycle phases. In young individuals, sex and menstrual cycle have minimal influence on splanchnic artery hemodynamic responses during dynamic moderate-intensity leg exercise.

Understanding Internalizing and Externalizing Behaviors in Autistic Toddlers.

PURPOSE: The majority of autistic toddlers present with clinically significant levels of internalizing or externalizing behaviors. Despite the prevalence of internalizing and externalizing behaviors in caseloads, the overwhelming majority of speech-language pathologists (SLPs) have not received specialized instruction in how to support children with these behaviors. The purpose of this study was to identify which child and caregiver characteristics are most associated with internalizing and externalizing behaviors in autistic toddlers in order to consider how SLPs may tailor their treatment to better support the individual needs of autistic children. METHOD: Participants included 109 mothers and their autistic children between 18 and 48 months of age. This study was a secondary analysis of data from a randomized clinical trial. Participants' baseline data included a variety of child (i.e., expressive language, receptive language, restricted and repetitive behavior [RRB], and nonverbal cognition) and caregiver (i.e., self-efficacy and responsiveness) characteristics. Seemingly unrelated regressions were conducted to determine which characteristics were associated with internalizing and externalizing behaviors in autistic toddlers. RESULTS: Higher RRB scores were associated with both higher internalizing and externalizing behavior scores. A lower nonverbal cognition score was also associated with higher internalizing behavior scores but to a lesser extent than RRB. CONCLUSION: These findings suggest that SLPs may support internalizing and externalizing behaviors in autistic children by taking RRBs and nonverbal cognition into consideration.

Identification of a ß-arrestin-biased negative allosteric modulator for the ß2-adrenergic receptor.

Catecholamine-stimulated ß2-adrenergic receptor (ß2AR) signaling via the canonical Gs-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous ß-agonists in the treatment of airway disease. ß2AR signaling is tightly regulated by GRKs and ß-arrestins, which together promote ß2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias ß2AR signaling toward the Gs pathway while avoiding ß-arrestin-mediated effects may provide a strategy to improve the functional consequences of ß2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the ß2AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit ß-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of ß-arrestin recruitment to the ß2AR while having no effect on ß2AR coupling to Gs. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the ß2AR and protects against the functional desensitization of ß-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the ß2AR with minimal effects on the ß1AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the ß2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the ß2AR.

Renal vascular conductance is unrelated to leg vascular conductance or muscle sympathetic nerve activity at rest and during stress in humans.

The sympathetic nervous system is important for cardiovascular regulation, particularly during acute stress. Efferent sympathetic outflow can be regulated in an organ-dependent manner, but whether renal and leg vasoconstriction are associated at rest or during sympathetic stressors is unknown. Therefore, we sought to determine the relationships between muscle sympathetic nerve activity (MSNA), leg vascular conductance (LVC), and renal vascular conductance (RVC) at rest and during common laboratory-based sympathoexcitatory stimuli in a cohort of young healthy adults. Beat-to-beat arterial pressure (photoplethysmography), MSNA (microneurography), superficial femoral artery blood flow, and renal artery blood velocity (Doppler ultrasound) were measured at rest and during static handgrip exercise (30% maximal voluntary contraction), postexercise circulatory occlusion (PECO), and cold stress (hand in 3.8 ± 1.3°C water) in 37 young healthy adults (16 females, 21 males). At rest, RVC was unrelated to LVC (r = -0.11, P = 0.55) or MSNA burst frequency (ρ = -0.22, P = 0.26). Static handgrip, PECO, and cold stress each induced an increase in mean arterial pressure and MSNA and a reduction in RVC (all P < 0.001). LVC was unaltered during stress (all P ≥ 0.16), with the exception of a reduction during the second minute of cold stress (P = 0.03). During stress, changes in RVC were not associated with changes in LVC (handgrip: r = -0.24, P = 0.21; PECO: ρ = -0.04, P = 0.82; cold stress: r = -0.17, P = 0.38) or MSNA (handgrip: ρ = -0.14, P = 0.48; PECO: r = 0.27, P = 0.15; cold stress: r = -0.27, P = 0.16). Furthermore, MSNA was not associated with LVC at rest or during stress (all P ≥ 0.12). The present findings highlight the differential control of regional sympathetic vasoconstriction at rest and during stress in young healthy humans.NEW & NOTEWORTHY The sympathetic nervous system plays a critical role in cardiovascular regulation at rest and during stress. We demonstrate that renal artery vascular conductance is unrelated to superficial femoral artery vascular conductance or muscle sympathetic nerve activity at rest or during laboratory-based sympathetic stressors in young healthy adults. These findings support the concept of differential control of peripheral sympathetic outflow at rest and during stress in humans.

A Comparison of Maternal and Clinician Perception of Communication in Autistic Toddlers.

PURPOSE: Parent instruction in communication facilitation strategies for autistic toddlers relies on assumptions that parents interpret child behaviors in alignment with clinician definitions of communication. The purpose of this study was to identify features of child behaviors that are predictive of alignment in identification of child communication between clinical researchers and mothers of young autistic children. METHOD: Participants were 33 mothers and their autistic children between 18 and 48 months of age. Mothers' and clinical researchers' perceptions of child communication were assessed using a procedure in which mothers and clinical researchers each independently identified child communication in the same ten 1-min video clips of each mother's child. Endorsed communicative acts were coded for the presence of conventional forms (e.g., vocalization) and potentially communicative forms (e.g., body movement). Multilevel binomial regressions, fit with Bayesian inference, were conducted to predict classification of maternal endorsements of child communication based on the presence of conventional and potentially communicative forms as either an aligned act (i.e., act endorsed by mother and clinical researcher as communicative) or a unique maternal endorsement (i.e., act endorsed by mother but not clinical researcher). RESULTS: The presence of vocalization, verbalization, and gesture each significantly predicted increased likelihood of alignment; the presence of eye contact did not. Although repetitive and sensory behaviors significantly increased the likelihood of unique maternal endorsement, affect shifts and body movements each significantly reduced the likelihood of unique maternal endorsement, and hand activity was not significantly predictive of unique maternal endorsement. CONCLUSIONS: Misalignment in mothers' and clinical researchers' identification of communication may be in part due to mothers' endorsement of behavioral forms that are not traditionally classified as part of a child's communication repertoire. Findings emphasize the need to work toward designing communication interventions that consider the ways in which clinicians and parents of autistic children each bring their own interpretive frameworks to the early intervention experience.

Blood Pressure Responses to Postexercise Circulatory Occlusion Are Attenuated After Exercise-Induced Muscle Weakness.

PURPOSE: Exercise blood pressure (BP) responses are thought to be determined by relative exercise intensity (percent maximal voluntary contraction (MVC) strength). However, cross-sectional studies report that during a static contraction, higher absolute force is associated with greater BP responses to relative intensity exercise and subsequent muscle metaboreflex activation with postexercise circulatory occlusion (PECO). We hypothesized that a bout of unaccustomed eccentric exercise would reduce knee extensor MVC and subsequently attenuate BP responses to PECO. METHODS: Continuous BP, heart rate, muscle oxygenation, and knee extensor electromyography were recorded in 21 young healthy individuals (female, n = 10) during 2 min of 20% MVC static knee extension exercise and 2 min of PECO, performed before and 24 h after 300 maximal knee extensor eccentric contractions to cause exercise-induced muscle weakness. As a control, 14 participants repeated the eccentric exercise 4 wks later to test whether BP responses were altered when exercise-induced muscle weakness was attenuated via the protective effects of the repeated bout effect. RESULTS: Eccentric exercise reduced MVC in all participants (144 ± 43 vs 110 ± 34 N·m, P < 0.0001). BP responses to matched relative intensity static exercise (lower absolute force) were unchanged after eccentric exercise ( P > 0.99) but were attenuated during PECO (systolic BP: 18 ± 10 vs 12 ± 9 mm Hg, P = 0.02). Exercise-induced muscle weakness modulated the deoxygenated hemoglobin response to static exercise (64% ± 22% vs 46% ± 22%, P = 0.04). When repeated after 4 wks, exercise-induced weakness after eccentric exercise was attenuated (-21.6% ± 14.3% vs -9.3 ± 9.7, P = 0.0002) and BP responses to PECO were not different from control values (all, P > 0.96). CONCLUSIONS: BP responses to muscle metaboreflex activation, but not exercise, are attenuated by exercise-induced muscle weakness, indicating a contribution of absolute exercise intensity on muscle metaboreflex activation.

Mitochondrial DNA in cell death and inflammation.

Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.

Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.

Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.

The Role of Naturalistic Developmental Behavioral Interventions in Early Intervention for Autistic Toddlers: An Observational Study.

PURPOSE: Naturalistic developmental behavioral interventions (NDBIs) have demonstrated initial promise in facilitating social communication development for autistic toddlers, but their highly structured protocols may be a barrier toward their use by early intervention (EI) providers who must individualize intervention according to family-centered principles. This study aimed to characterize the extent to which EI speech-language pathologists (SLPs) use NDBI strategies, and the range of skills and behaviors addressed during their EI sessions, to contextualize the role of NDBIs within the scope of needs of families with autistic children in EI. METHOD: This observational study included 25 families with an autistic toddler and their EI SLP. One home-based session was recorded for each family, and an observational measure was used to describe SLPs' NDBI strategy use. Qualitative content analyses were also used to characterize the strategies SLPs recommended to families, and the child skills and behaviors they discussed. RESULTS: SLPs did not implement NDBI strategies with high quality, but they implemented developmental NDBI strategies with significantly higher quality than behavioral NDBI strategies. SLPs discussed many strategies and skills across disciplines within the session. CONCLUSIONS: SLPs may require further training to implement NDBI strategies, but given the breadth and depth of skills addressed during sessions, researchers should investigate and report on the impact of NDBIs on a wider range of communication skills and developmental domains. This will facilitate clinical decision making and make these interventions better aligned with family-centered EI principles. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21834480.