Sex differences in hippocampal ß-adrenergic receptor subtypes drive retrieval, retention, and learning of cocaine-associated memories.

Background: Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. ß-adrenergic receptors (ß-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of ß-adrenergic receptors in drug memories remain unknown. Hypothesis: Prior reports indicate a selective role for ß2-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of ß-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of ß-ARs during different stages of memory encoding and retrieval. Methods: The role of ß-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague-Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (ß1 and ß2) or ICI-118,551 (ß1) and/or Betaxolol (ß2), immediately prior to testing (retrieval), or paired to each cocaine (10 mg/kp, IP) conditioning session (learning). Results: In males, administration of either ß1, ß2, or combined ß1 and ß2-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, ß2-ARs transiently decreased CPP memories, whereas ß1 had long lasting but not immediate effects to decrease CPP memories. Additionally, ß1 and combined ß1 and ß2-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos + neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos + neurons predicted cocaine CPP expression in females. Conclusion: There are significant sex differences in the role of dorsal hippocampus ß-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.

Serratus Anterior Plane Blocks for Early Rib Fracture Pain Management: The SABRE Randomized Clinical Trial.

Importance: Rib fractures secondary to blunt thoracic trauma typically result in severe pain that is notoriously difficult to manage. The serratus anterior plane block (SAPB) is a regional anesthesia technique that provides analgesia to most of the hemithorax; however, SAPB has limited evidence for analgesic benefits in rib fractures. Objective: To determine whether the addition of an SAPB to protocolized care bundles increases the likelihood of early favorable analgesic outcomes and reduces opioid requirements in patients with rib fractures. Design, Setting, and Participants: This multicenter, open-label, pragmatic randomized clinical trial was conducted at 8 emergency departments across metropolitan and regional New South Wales, Australia, between April 12, 2021, and January 22, 2022. Patients aged 16 years or older with clinically suspected or radiologically proven rib fractures were included in the study. Participants were excluded if they were intubated, transferred for urgent surgical intervention, or had a major concomitant nonthoracic injury. Data were analyzed from September 2022 to July 2023. Interventions: Patients were randomly assigned (1:1) to receive an SAPB in addition to usual rib fracture management or standard care alone. Main Outcomes and Measures: The primary outcome was a composite pain score measured 4 hours after enrollment. Patients met the primary outcome if they had a pain score reduction of 2 or more points and an absolute pain score of less than 4 out of 10 points. Results: A total of 588 patients were screened, of whom 210 patients (median [IQR] age, 71 [55-84] years; 131 [62%] male) were enrolled, with 105 patients randomized to receive an SAPB plus standard care and 105 patients randomized to standard care alone. In the complete-case intention-to-treat primary outcome analysis, the composite pain score outcome was reached in 38 of 92 patients (41%) in the SAPB group and 18 of 92 patients (19.6%) in the control group (relative risk [RR], 0.73; 95% CI, 0.60-0.89; P = .001). There was a clinically significant reduction in overall opioid consumption in the SAPB group compared with the control group (eg, median [IQR] total opioid requirement at 24 hours: 45 [19-118] vs 91 [34-155] milligram morphine equivalents). Rates of pneumonia (6 patients [10%] vs 7 patients [11%]), length of stay (eg, median [IQR] hospital stay, 4.2 [2.2-7.7] vs 5 [3-7.3] days), and 30-day mortality (1 patient [1%] vs 3 patients [4%]) were similar between the SAPB and control groups. Conclusions and Relevance: This randomized clinical trial found that the addition of an SAPB to standard rib fracture care significantly increased the proportion of patients who experienced a meaningful reduction in their pain score while also reducing in-hospital opioid requirements. Trial Registration: http://anzctr.org.au Identifier: ACTRN12621000040864.

Evaluation of an Outpatient Pharmacist Consult Service at a Large Academic Medical Center.

OBJECTIVE: To evaluate a novel outpatient pharmacist consult service in a large academic medical center. SETTING: Four outpatient pharmacies that are part of a large academic medical center. METHODS: An outpatient pharmacist consult order was created and embedded in the electronic medical record (EMR). Medical center providers utilized this consult order when identifying patients in need of specific services provided by outpatient pharmacists. Descriptive data about each individual consult was collected including number completed, type of service, and duration. Rate of accepted pharmacy recommendations and patient cost savings were also evaluated. A survey was administered at the completion of the study period to assess provider and pharmacist satisfaction with the service. Patient demographic information was collected for those who had a documented completed consult. RESULTS: A total of 193 consults were completed: 137 immunizations, 37 care affordability, 15 education, 3 polypharmacy and 1 OTC recommendation. 89% of completed consults took pharmacists 20 minutes or less to complete. Of completed care affordability consults (n=31), 55% of patients saved between $100 - $500 per medication fill. Of providers who completed a survey and utilized the service (n=12), 83.3% were extremely satisfied and 16.7% were satisfied with it. The provider acceptance rate of pharmacist's recommendations was 74%. CONCLUSION: Implementation of an outpatient pharmacist consult service provided an alternative method for the utilization of pharmacist provided MTM services in outpatient pharmacies at a large academic medical center. The service was well received by both providers and pharmacists.

Promoting Healthy Child Development via a Two-Generation Translational Neuroscience Framework: The Filming Interactions to Nurture Development Video Coaching Program.

In this article, we focus on applying methods of translational neuroscience to two-generation, family-based interventions. In recent years, a small but growing body of evidence has documented the reversibility of some of the neurobiological effects of early adversity in the context of environmental early interventions. Some of these interventions are now being implemented at scale, which may help reduce disparities in the face of early life stress. Further progress may occur by extending these efforts to two-generation models that target caregivers' capabilities to improve children's outcomes. In this article, we describe the content and processes of the Filming Interactions to Nurture Development (FIND) video coaching intervention. We also discuss the two-generation, translational neuroscience framework on which FIND is based, and how similar approaches can be developed and scaled to mitigate the effects of adversity.

Non-pharmacological Intervention for Chronic Pain in Veterans: A Pilot Study of Heart Rate Variability Biofeedback.

OBJECTIVE: Chronic pain is an emotionally and physically debilitating form of pain that activates the body's stress response and over time can result in lowered heart rate variability (HRV) power, which is associated with reduced resiliency and lower self-regulatory capacity. This pilot project was intended to determine the effectiveness of HRV coherence biofeedback (HRVCB) as a pain and stress management intervention for veterans with chronic pain and to estimate the effect sizes. It was hypothesized that HRVCB will increase parasympathetic activity resulting in higher HRV coherence measured as power and decrease self-reported pain symptoms in chronic pain patients. STUDY DESIGN: Fourteen veterans receiving treatment for chronic pain were enrolled in the pre-post intervention study. They were randomly assigned, with 8 subjects enrolled in the treatment group and 6 in the control group. The treatment group received biofeedback intervention plus standard care, and the other group received standard care only. The treatment group received four HRVCB training sessions as the intervention. MEASURES: Pre-post measurements of HRV amplitude, HRV power spectrum variables, cardiac coherence, and self-ratings of perceived pain, stress, negative emotions, and physical activity limitation were made for both treatment and control groups. RESULTS: The mean pain severity for all subjects at baseline, using the self-scored Brief Pain Inventory (BPI), was 26.71 (SD=4.46; range=21-35) indicating a moderate to severe perceived pain level across the study subjects. There was no significant difference between the treatment and control groups at baseline on any of the measures. Post-HRVCB, the treatment group was significantly higher on coherence (P=.01) and lower (P=.02) on pain ratings than the control group. The treatment group showed marked and statistically significant (1-tailed) increases over the baseline in coherence ratio (191%, P=.04) and marked, significant (1-tailed) reduction in pain ratings (36%, P<.001), stress perception (16%, P=.02), negative emotions (49%, P<.001), and physical activity limitation (42%, P<.001). Significant between-group effects on all measures were found when pre-training values were used as covariates. CONCLUSIONS: HRVCB intervention was effective in increasing HRV coherence measured as power in the upper range of the LF band and reduced perceived pain, stress, negative emotions, and physical activity limitation in veterans suffering from chronic pain. HRVCB shows promise as an effective non-pharmacological intervention to support standard treatments for chronic pain.

Cardiac coherence and posttraumatic stress disorder in combat veterans.

BACKGROUND: The need for treatment of posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing concern. PTSD has been associated with reduced cardiac coherence (an indicator of heart rate variability [HRV]) and deficits in early stage information processing (attention and immediate memory) in different studies. However, the co-occurrence of reduced coherence and cognition in combat veterans with PTSD has not been studied before. PRIMARY STUDY OBJECTIVE: A pilot study was undertaken to assess the covariance of coherence and information processing in combat veterans. An additional study goal was assessment of effects of HRV biofeedback (HRVB) on coherence and information processing in these veterans. METHODS/DESIGN: A two-group (combat veterans with and without PTSD), pre-post study of coherence and information processing was employed with baseline psychometric covariates. SETTING: The study was conducted at a VA Medical Center outpatient mental health clinic. PARTICIPANTS: Five combat veterans from Iraq or Afghanistan with PTSD and five active-duty soldiers with comparable combat exposure who were without PTSD. INTERVENTION: Participants met with an HRVB professional once weekly for 4 weeks and received visual feedback in HRV patterns while receiving training in resonance frequency breathing and positive emotion induction. PRIMARY OUTCOME MEASURES: Cardiac coherence, word list learning, commissions (false alarms) in go-no go reaction time, digits backward. RESULTS: Cardiac coherence was achieved in all participants, and the increase in coherence ratio was significant post-HRVB training. Significant improvements in the information processing indicators were achieved. Degree of increase in coherence was the likely mediator of cognitive improvement. CONCLUSION: Cardiac coherence is an index of strength of control of parasympathetic cardiac deceleration in an individual that has cardinal importance for the individual's attention and affect regulation.

Effect of solid meal on gastric emptying of, and glycemic and cardiovascular responses to, liquid glucose in older subjects.

Gastric emptying is a determinant of the postprandial glycemic and cardiovascular responses to oral carbohydrate. We evaluated the effects of a solid meal on gastric emptying and the glycemic and cardiovascular responses to oral glucose in healthy older subjects. Ten subjects aged 72.1 +/- 1.9 yr were studied. Each subject had measurements of gastric emptying, blood glucose, serum insulin, blood pressure, and heart rate after ingestion of a 50-g glucose drink (300 ml) with (mixed meal) or without (liquid only) a solid meal (300 g ground beef). Gastric emptying of liquid was initially slightly more rapid (P < 0.05) after the mixed meal compared with liquid only at 5 min (92.0 +/- 1.5 vs. 96.0 +/- 1.3%) and much slower (P < 0.05) after 120 min. The time to peak blood glucose was less (39.0 +/- 4.0 vs. 67.5 +/- 10.3 min; P < 0.01) and blood glucose subsequently lower (P < 0.01) after the mixed meal. The increase in serum insulin was greater (P < 0.001) after the mixed meal. Blood pressure fell (P < 0.05) in the first 30 min, with no difference between the two meals. Increase in heart rate after both meals (P < 0.005), was greater (P < 0.05) after the mixed meal. The presence of a noncarbohydrate solid meal had discrepant effects on early and subsequent emptying of a nutrient liquid, which affects postprandial glycemia and increased heart rate.

A longitudinal study of gastric emptying and upper gastrointestinal symptoms in patients with diabetes mellitus.

PURPOSE: To evaluate the natural history of gastric emptying and upper gastrointestinal symptoms in patients with diabetes mellitus. SUBJECTS AND METHODS: We enrolled 20 patients (6 men, 14 women) with diabetes mellitus (16 with type 1 diabetes, 4 with type 2 diabetes). Each had measurements of gastric emptying of a solid (100 g of ground beef) and liquid (150 mL of 10% dextrose) meal using scintigraphy, glycemic control (glycosylated hemoglobin [HbA(1c)] and mean blood glucose levels), upper gastrointestinal symptoms, and autonomic nerve function at baseline and after a mean (+/- SD) of 12.3 +/- 3.1 years of follow-up. RESULTS: There were no differences in mean gastric emptying of the solid component (retention at 100 minutes at baseline: 56% +/- 19% vs. follow-up: 51% +/- 21%, P = 0.23) or the liquid component (time for 50% to empty at baseline: 33 +/- 11 minutes vs. follow-up: 31 +/- 12 minutes, P = 0.71) during follow-up. Mean blood glucose (17.0 +/- 5.6 mmol/L vs. 13.8 +/- 4.9 mmol/L, P = 0.007) and HbA(1c) (8.4% +/- 2.3% vs. 7.6% +/- 1.3%, P = 0.03) levels were lower at follow-up. There was no difference in symptom score (baseline: 3.9 +/- 2.7 vs. follow-up: 4.2 +/- 4.0, P = 0.78). There was evidence of autonomic neuropathy in 7 patients (35%) at baseline and 16 (80%) at follow-up. CONCLUSION: In patients with diabetes mellitus, we did not observe any marked changes in either gastric emptying or upper gastrointestinal symptoms during a 12-year period.

Helicobacter pylori infection is not associated with delayed gastric emptying or upper gastrointestinal symptoms in diabetes mellitus.

This study evaluated the relationship between gastric emptying and upper gastrointestinal symptoms with H. pylori status in patients with diabetes mellitus. Sixty-three outpatients (44 type 1, 19 type 2, age 45 +/- 1.5 years) underwent measurements of gastric emptying of a mixed solid and liquid meal, gastrointestinal symptoms (gastric and esophageal), glycemic control (HbA1c), and autonomic nerve function. Anti-H. pylori IgG antibodies were quantified using a validated kit. Gastric emptying of solid and/or liquid was delayed in 47 (75%) patients, and 31 (49%) had autonomic neuropathy. Fifteen (24%) of the patients were H. pylori positive. There were no differences in gastric emptying (solid retention at 100 min: 67.5 +/- 5.7% vs 63.2 +/- 3.6%; P = 0.63, liquid T50: 35.5 +/- 2.9 min vs 42.5 +/- 3.4 min; P = 0.42), upper gastrointestinal symptoms (gastric 3.9 +/- 0.7 vs 4.0 +/- 0.4; P = 0.94 or esophageal 1.7 +/- 0.5 vs 1.3 +/- 0.2; P = 0.42) or HbA1c (8.8 +/- 0.4% vs 8.6 +/- 0.2%; P = 0.89) between H. pylori-positive and -negative patients. We conclude that H. pylori infection is not associated with delayed gastric emptying or upper gastrointestinal symptoms in diabetes.