Early Estrogen Replacement Therapy Attenuates Cardiac Dysfunction Caused by Aging and Ovariectomy in Female Wistar Rats.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of women's mortality, linked to aging and reduced estrogen during menopause. Estrogen replacement therapy (ERT) is suggested for CVDs prevention. Yet, its timing initiation remains contentious. Thus, we aimed to evaluate the effect of early and late estrogen therapy on cardiac function and lipid metabolism in ovariectomized old female Wistar rats. METHODS: Fifty randomized female Wistar rats were included in 5 groups (n = 10, 18 months old): (1) Sham, (2) 10 weeks post ovariectomy (Ovx-10 w), (3) 10 weeks post Ovx + early estrogen replacement therapy (Ovx 10 w-early ERT), (4) 20 weeks post Ovx (Ovx-20 w) and (5) Ovx 20 w-late ERT. Three days (early ERT) or 10 weeks (late ERT) after surgery 17-ß estradiol was given (5 µg/kg/day), and 10 weeks after the start of ERT, we assessed cardiac function by echocardiography, electrocardiography, and cardiac catheterization. Estradiol, cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were determined. Cardiac histology was performed with Masson's staining. RESULTS: Ovariectomy (Ovx) increases left ventricle internal systolic diameter (0.4 vs 0.3 cm, *p = 0.020) and decreases shortening fraction (40 vs 54 %, *p = 0.030) regardless of therapy. ERT prevents the increase in left ventricle mass after 10 weeks post-Ovx and the ejection fractionreduction after 20 weeks. Lower P wave amplitudes (18.8 vs 24.2 ms, *p = 0.013) were found in the Ovx-20 w group. A longer duration of the QRS complex after 20 weeks post-Ovx with and without ERT was found (32.5 and 32.1 vs 28.3 ms, *p = 0.003; *p = 0.007). Diastolic blood pressure was higher 20 weeks post-Ovx (86 vs 76 mmHg, *p = 0.047), regardless of ERT. The left ventricle (LV) -dP/dt was decreased in Ovx groups without ERT (-750 vs -1320 mmHg, *p = 0.034). An increase in LV collagen deposition was found in the Ovx 10 w group vs Sham (9.58 vs 4.54 %, *p = 0.028). Early ERT avoids the increase in body weight, cholesterol and LDL caused by Ovx. CONCLUSIONS: Ovariectomy causes time-dependent alterations in lipid metabolism, morphology, electrical activity, and heart contractile function. Early but not late ERT prevents some of these effects.

Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats.

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The "hunger hormone" ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs.

A mobile addiction service for community-based overdose prevention.

Mainstays of opioid overdose prevention include medications for opioid use disorder (e.g., methadone or buprenorphine) and naloxone distribution. Inadequate access to buprenorphine limits its uptake, especially in communities of color, and people with opioid use disorders encounter multiple barriers to obtaining necessary medications including insurance, transportation, and consistent availability of telephones. UMass Memorial Medical Center and our community partners sought to alleviate these barriers to treatment through the deployment of a mobile addiction service, called the Road to Care. Using this approach, multidisciplinary and interprofessional providers deliver holistic addiction care by centering our patients' needs with respect to scheduling, location, and convenience. This program also extends access to buprenorphine and naloxone among people experiencing homelessness. Additional systemic and individualized barriers encountered are identified, as well as potential solutions for future mobile addiction service utilization. Over a two-year period, we have cared for 1,121 individuals who have accessed our mobile addiction service in over 4,567 encounters. We prescribed buprenorphine/naloxone (Suboxone®) to 330 individuals (29.4% of all patients). We have distributed nearly 250 naloxone kits directly on-site or and more than 300 kits via prescriptions to local pharmacies. To date, 74 naloxone rescue attempts have been reported back to us. We have demonstrated that a community-based mobile addiction service, anchored within a major medical center, can provide high-volume and high-quality overdose prevention services that facilitate engagement with additional treatment. Our experience is described as a case study below.

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators.

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

Household Social Needs, Emotional Functioning, and Stress in Low-Income Latinx Children and their Mothers.

Latinx families may be particularly vulnerable to emotional dysfunction, due to higher rates of economic hardship and complex social influences in this population. Little is known about the impact of environmental stressors such as unmet social needs and maternal stress on the emotional health of Latinx children from low-income families. We conducted secondary analyses using survey and biomarker data from 432 Latinx children and mothers collected in a separate study. We used binomial and multinomial logistic regression to test if household social needs, or maternal perceived stress or hair cortisol concentration (HCC), predicted child measures of emotional functioning or child HCC, independent of relevant sociodemographic factors. Approximately 40% of children in the sample had symptoms consistent with emotional dysfunction, and over 37% of households reported five or more social needs. High perceived maternal stress predicted higher odds of child emotional dysfunction (OR = 2.15; 95% CI [1.14, 4.04]; p = 0.01), and high maternal HCC was positively associated with high child HCC (OR = 10.60; 95% CI [4.20, 26.74]; p < 0.01). Most individual household social needs, as well as the level of household social need, were not independently associated with child emotional dysfunction or child HCC. Our findings begin to define a framework for understanding emotional health, stress, and resilience when caring for Latinx children and mothers living with high levels of social need, and the need for integrated mental health and social needs screening and interventions in settings that serve this population.

COVID-19's Still-Urgent Lessons of Structural Inequality and Child Health in the United States.

COVID-19's lessons on structural inequality should have been painful and embarrassing to all of us. These daily experiences of an unacceptable status quo among US children are still with us in a post-COVID America. Addressing the multi-sectoral factors that undermine the nation...s health should remain urgent priorities for all health professionals.

Social Needs and Acculturation as Predictors of Emotional Problems and Perceived Stress Among Latinx Mothers with Low Income.

Associations between household social needs, acculturation, and emotional health remain understudied, particularly among Latinx mothers. We analyzed baseline survey data from 455 Latinx mothers in a previous study. Using multinomial regression, we examined whether emotional problems and perceived stress were associated with household social needs and acculturation. Almost half the sample reported four or more household social needs. Social needs cumulatively and independently predicted increased odds of frequent emotional problems or perceived stress. Lower acculturation predicted lower odds of frequent emotional problems. There is increased risk for emotional problems and stress in low-income Latinx mothers who experience high social need. Integrated social service and mental health care models may be one way to improve health outcomes. More research is needed to understand how clinical settings can leverage unique cultural protective factors to address the social and emotional health needs of Latinx mothers.

Automated Systems for Calculating Arteriovenous Ratio in Retinographies: A Scoping Review.

There is evidence of an association between hypertension and retinal arteriolar narrowing. Manual measurement of retinal vessels comes with additional variability, which can be eliminated using automated software. This scoping review aims to summarize research on automated retinal vessel analysis systems. Searches were performed on Medline, Scopus, and Cochrane to find studies examining automated systems for the diagnosis of retinal vascular alterations caused by hypertension using the following keywords: diagnosis; diagnostic screening programs; image processing, computer-assisted; artificial intelligence; electronic data processing; hypertensive retinopathy; hypertension; retinal vessels; arteriovenous ratio and retinal image analysis. The searches generated 433 articles. Of these, 25 articles published from 2010 to 2022 were included in the review. The retinographies analyzed were extracted from international databases and real scenarios. Automated systems to detect alterations in the retinal vasculature are being introduced into clinical practice for diagnosis in ophthalmology and other medical specialties due to the association of such changes with various diseases. These systems make the classification of hypertensive retinopathy and cardiovascular risk more reliable. They also make it possible for diagnosis to be performed in primary care, thus optimizing ophthalmological visits.

An Experimental Analysis of the High-Cycle Fatigue Fracture of H13 Hot Forging Tool Steels.

In this study, the axial fatigue behaviour of hot forging tool steels at room temperature was investigated. Fatigue tests were performed on two steels within the same H13 specification. The fatigue tests were carried out in the high-cycle fatigue domain under normal conditions. These tests were also performed on specimens in contact with a corrosive medium, applying stress values that led to the high-cycle fatigue domain under normal conditions for the sake of comparison. Both materials showed similar fatigue strengths when they were tested under normal conditions. In contrast, corrosion fatigue lives were much lower than in normal tests and differed significantly between the two steels. Crack initiation was triggered by microstructural and surface defects in the normal tests, whereas the formation of corrosion pits caused crack initiation in the corrosion fatigue tests. Moreover, a fracture surface analysis revealed dissimilar crack propagation areas between both steels, which suggested that both steels had different fracture toughness. These results were in line with the differences observed between the carbide and grain sizes of both of the material microstructures.

ST-Elevation Myocardial Infarction With Occluded Culprit Coronary Artery in a Young Patient Recovered From Mild COVID-19: A Case Report.

ST-elevation myocardial infarction (STEMI) is a cardiovascular emergency that requires an early reperfusion strategy to reduce mortality and hemodynamic, mechanical, and electrical complications. STEMI is more frequent in men older than 40 years with well-known cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, and smoking. The coronavirus disease 2019 (COVID-19) changed this reality worldwide due to the fact that STEMI cases associated with severe forms of COVID-19 began to be reported, which generally affected the older adult population; in contrast, there is still limited data on young healthy patients recovering from mild COVID-19. The exact mechanism behind the association remains unclear. We present a case of a healthy 29-year-old man with a history of mild COVID-19, diagnosed by reverse-transcription polymerase chain reaction 20 days before his admission with inferior STEMI. Coronary angiography revealed an occluded mid-right coronary artery, and he was successfully treated with a drug-eluting stent. The patient evolved favorably and was discharged on the fifth day of hospitalization.

Improving Children's Behavior in Seven Sessions: A Randomized Controlled Trial of Parent-Child Care (PC-CARE) for Children Aged 2-10 Years.

Parent-Child Care (PC-CARE) is a brief intervention for children with externalizing behaviors designed to address issues with their access to and retention in treatment. A growing evidence base of open trials and comparison studies support PC-CARE's benefits, but no randomized controlled trials (RCTs) of its effectiveness exist. The current study presents the first RCT of PC-CARE, a 7-session dyadic parenting intervention (trial number removed for blind review). Participants included a racially/ethnically diverse sample of 49 children (29% female) aged 2-10 years and their caregivers. Participants were randomly assigned to PC-CARE or waitlist control. Families participating in PC-CARE showed greater reductions in children's externalizing behaviors, improvements in children's adaptive skills, declines in parental stress, and increases in parents' positive communication skills, compared to families on the waitlist. The results of this first RCT of PC-CARE support the effectiveness of this brief intervention in improving children's behaviors.

Isolation housing elevates amphetamine seeking independent of nucleus accumbens glutamate receptor adaptations.

Overdose death rates caused by psychostimulants have increased by 22.3% annually from 2008 to 2017. Cue-evoked drug craving progressively increases and contributes to perpetual relapse. Preclinical models have determined that glutamate receptor plasticity within the nucleus accumbens (NAc) drives amplified cue-evoked drug seeking after prolonged abstinence (>40 days). Isolated condition (IC) rearing increases cocaine and amphetamine (AMP) self-administration and cue-induced reinstatement. We tested the hypothesis that housing in the IC will augment AMP seeking after short and prolonged abstinence from AMP self-administration when compared with rats reared in the enrichment condition (EC). EC and IC male rats acquired stable AMP or SAL self-administration and were tested in a cue-induced AMP-seeking test after 1 and 40 days of abstinence. After the seeking test, the whole NAc was extracted and prepared for western blot analysis. Results indicate that IC rats had more active lever presses during a brief extinction interval and during the cue-induced seeking test. After 40 days of abstinence, IC rats had more active lever presses than EC rats during the cue-induced seeking test. Western blots indicated that the expression ratio between GluA1:mGlur5 was reduced only in IC-AMP-trained rats and the ratio between GluA1:mGlur1 was positively correlated with AMP seeking after prolonged abstinence in IC-AMP rats. These results indicate that IC housing engenders a vulnerable phenotype prone to persistent AMP seeking. The behavioural momentum of this vulnerable phenotype is further revealed when AMP-associated cues are presented following prolonged abstinence.

Differential Use of Pediatric Video Visits by a Diverse Population During the COVID-19 Pandemic: A Mixed-Methods Study.

Objective: To describe and explore pediatric ambulatory video visit use by patient characteristics during the coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted an explanatory sequential mixed methods study with integration at the design and methods level. Phase 1 was a cross-sectional analysis of general and specialty pediatric ambulatory encounters to profile the use of video visits by patient characteristics. We performed descriptive analyses for each variable of interest and estimated a multivariable logistic regression model to analyze factors associated with the odds of having a video visit. Phase 2 was a qualitative exploration using semi-structured interviews with healthcare team members to understand the contextual factors influencing video visit usage. We used an interview guide to solicit information related to general perceptions about ambulatory video visits, reactions to the quantitative phase data, and strategies for optimizing equitable reach of video visits. Data were analyzed using a combination of deductive and inductive analysis. Results: Among the 5,464 pediatric ambulatory encounters completed between March 11 and June 30, 2020, 2,127 were video visits. Patient factors associated with lower odds of having a video visit rather than an in-person visit included being Spanish-speaking (aOR 0.27, 95% CI 0.20-0.37) and other non-English-speaking (aOR 0.50, 95% CI 0.34-0.75) in comparison to English-speaking. Patients with public insurance also had a lower odds of having a video visit in comparison to privately insured patients (aOR 0.77, 95% CI 0.67-0.88). Qualitative interviews identified five solution-based themes: (1) Promoting video visits in a way that reaches all patient families; (2) Offering video visits to all patient families; (3) Mitigating digital literacy barriers; (4) Expanding health system resources to support families' specific needs; and (5) Engaging and empowering health system personnel to expand video visit access. Conclusion: We identified differences in pediatric ambulatory video visit use by patient characteristics, with lower odds of video visit use among non-English-speaking and publicly insured patients. The mixed-methods approach allowed for the perspectives of our interview participants to contextualize the finding and lead to suggestions for improvement. Both our findings and the approach can be used by other health systems to ensure that all patients and families receive equal video visit access.

Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties.

Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.

Environmental enrichment and a selective metabotropic glutamate receptor2/3 (mGluR2/3) agonist suppress amphetamine self-administration: Characterizing baseline differences.

A challenge for developing effective treatments for substance use disorders (SUDs) is understanding how environmental variables alter the efficacy of therapeutics. Environmental enrichment (EC) enhances brain development and protects against behaviors associated with drug abuse vulnerability when compared to rats reared in isolation (IC) or standard conditions (SC). EC rearing enhances the expression and function of metabotropic glutamate receptor2/3 (mGlurR2/3) and activating mGluR2/3 reduces psychostimulant self-administration (SA). However, the ability for mGluR2/3 activation to suppress amphetamine (AMP) SA in differentially reared rats is not determined. Therefore, we tested the hypothesis EC reduces AMP (SA) by augmenting mGluR2/3 function. At postnatal day 21, male Sprague-Dawley rats were assigned to EC, IC, or SC environments for 30 days. Then, they acquired AMP SA and were moved to a progressive ratio (PR) schedule of reinforcement. EC, IC, and SC rats were pretreated with LY379268 (vehicle, 0.3 and 1 mg/kg), a selective mGluR2/3 agonist, before PR behavioral sessions. Linear mixed effects analysis determined EC rats had reduced motivation for AMP SA when compared to IC or SC rats and that LY379268 dose-dependently suppressed AMP SA, but there was no evidence of an interaction. Cumming/Gardner-Altman estimation plots illustrate that the 0.3 mg/kg dose suppressed infusions in EC rats while the 1 mg/kg dose suppressed infusions in SC rats. LY379268 was incapable of suppressing the motivation for AMP SA in IC rats. Controlling for baseline differences in differentially reared rats remains a challenge. Normalizing to a baseline introduced error which is illustrated in the precision of the estimated effect size differences. The data indicate that environmental enrichment enhances the ability of a selective mGluR2/3 agonist to suppress AMP SA and indicates the functional status of the mGluR2/3 is formed during development. Therefore, environmental history must be considered when evaluating pharmacological therapeutics particularly those aimed at the mGluR2/3.

Gastrointestinal symptoms are predictive of trajectories of cognitive functioning in de novo Parkinson's disease.

INTRODUCTION: Non-motor symptoms such as cognitive and gastrointestinal (GI) symptoms are common in Parkinson's disease (PD). In PD, GI-symptoms often present prior to motor symptoms. It is hypothesized that GI-symptoms reflect disruptions of the microbiome-gut-brain axis, which leads to altered immune functioning, chronic neuroinflammation, and subsequent neurodegeneration. Initial evidence links gut-dysbiosis to PD pathology and motor symptom severity. The present study examines the longitudinal relationship between severity of GI-symptoms and cognitive impairment in newly diagnosed PD patients. METHODS: A secondary data analysis of the Parkinson's Progression Markers Initiative (PPMI) included 423 newly diagnosed PD patients who were followed for up to 5 years. Participants underwent neuropsychological tests of processing speed, attention, visuospatial functioning, verbal learning and verbal delayed recall. Participant were classified as cognitive intact, mild cognitive impairment or Parkinson's disease dementia. Frequency of GI-symptoms were assessed with the Scales for Outcomes in Parkinson's Disease Autonomic (SCOPA-AUT). Multi-level models (MLM) examined the longitudinal relationship between GI symptoms and cognitive impairment. RESULTS: All cognitive outcomes were predicted by the main effect of GI symptoms, or the GI-symptom X Occasion interaction term. Specifically, more severe GI-symptoms were predictive of a less favorable trajectory of performance on tests of letter fluency, visuospatial, learning and memory. Cognitive performance was uniquely associated with GI-symptoms and unrelated to non-GI autonomic symptoms. CONCLUSIONS: The presence of GI symptoms may serve as an early marker of cognitive impairment in PD. Future studies should examine specific mechanisms underlying the relationship between gut-dysbiosis and cognitive impairment.

Disparities in Donor Human Milk Supplementation Among Well Newborns.

BACKGROUND: Donor human milk supplementation for healthy newborns has increased. Racial-ethnic disparities in supplementation have been described in the neonatal intensive care unit but not in the well newborn setting. RESEARCH AIM: The aim of this study was to identify maternal characteristics associated with donor human milk versus formula supplementation in the well newborn unit. METHODS: This retrospective cohort study includes dyads of well newborns and their mothers (N = 678) who breastfed and supplemented with formula (n = 372) or donor human milk (n = 306) during the birth hospitalization at a single hospital in the midwestern United States. Maternal characteristics and infant feeding type were extracted from medical records. Chi-square and logistic regression were used to examine associations between maternal characteristics and feeding type. RESULTS: Nonwhite women were less likely to use donor human milk. Compared to non-Hispanic white women, the largest disparity was with Hispanic (adjusted odds ratio [OR] = 0.28, 95% CI [0.12, 0.65]), then non-Hispanic black (adjusted OR = 0.32, 95% CI [0.13, 0.76]) and Asian women (adjusted OR = 0.34, 95% CI [0.16, 0.74]). Lower donor human milk use was associated with primary language other than English and public versus private insurance. CONCLUSION: The goal of improving public health through breastfeeding promotion may be inhibited without targeting donor human milk programs to these groups. Identifying the drivers of these disparities is necessary to inform person-centered interventions that address the needs of women with diverse backgrounds.

Histone deacetylase inhibition differentially attenuates cue-induced reinstatement: An interaction of environment and acH3K9 expression in the dorsal striatum.

Substance use disorder is driven by complex gene-environment interactions. Epigenetic histone regulation is a significant contributor to several behavioral phenotypes of drug abuse. The primary epigenetic mechanisms that drive drug taking and drug seeking are still being investigated, and it is unclear how environmental conditions alter epigenetic histone acetylation to change behaviors geared toward drug reward. This study examined the effects of environmental condition on amphetamine self-administration, and whether drug-taking and drug-seeking behaviors could be influenced through inhibition of an epigenetic regulator, histone deacetylase (HDAC). Male rats reared for 30 days in enriched (EC), isolated (IC), or standard conditions (SC) prior to amphetamine (0.03, 0.05, 0.1 mg/kg/infusion, IV) self-administration, extinction, and reinstatement sessions. The HDAC inhibitor, Trichostatin A (TsA; 0.3 mg/kg, IV), was injected 30 min prior to operant sessions. After amphetamine-induced reinstatement (0.25 mg/kg, subcutaneous [s.c.]), tissue was extracted for Western blot analyses of acetylated histone H3 lysine 9 (acH3K9) in the nucleus accumbens (NAc) and dorsal striatum (DSt). While TsA did not significantly affect amphetamine self-administration or extinction, TsA decreased cue-, but not drug-induced reinstatement in IC rats only. In the DSt, but not in the NAc, IC rats exhibited significantly less acH3K9 expression than EC and SC rats, irrespective of TsA treatment. HDAC inhibition decreases cue-induced reinstatement of amphetamine seeking in IC rats. While IC rats exhibit less acH3K9 expression in the DSt, future studies are needed to elucidate the critical epigenetic factors that drive substance abuse, particularly in vulnerable populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).