A trial of implementation facilitation to increase timely admission to methadone treatment.

BACKGROUND: During the ongoing opioid epidemic, some Opioid Treatment Programs (OTPs) are unable to admit program applicants in a timely fashion. Interim methadone (IM) treatment (without routine counseling) is an effective approach to overcome this challenge when counseling capacity is inadequate to permit admissions within 14 days of request. It requires both federal and state approval and has been rarely utilized since its incorporation into the federal OTP regulations in 1993. METHODS: We evaluated the impact of Implementation Facilitation (IF) on OTPs providing timely admission to methadone treatment (i.e., within 14 days of request), adopting IM, and changing admissions procedures. IF included data collection on admission processes and an external facilitator who engaged OTP leadership, Local Champions through site visits, remote academic detailing, and feedback. Local Champions and State Opioid Treatment Authorities (SOTAs) participated in learning collaboratives. Using a modified stepped wedge design, six OTPs in four US states on the east and west coasts were randomly assigned to one of two clusters that staggered the timing of IF receipt. Study Phases included: Pre-Implementation, IF, and Sustainability. OTPs submitted data on treatment requests and admissions for 28 months (N = 3108 requests for treatment). RESULTS: Although none of the OTPs adopted IM, all six developed policies and procedures to enable its use. Some OTPs streamlined admissions processes prior to study launch and during the IF intervention. OTPs reduced admission delays over time, although there was substantial site heterogeneity. The IF Phase for the early cluster coincided with the onset of COVID-19, complicating the study. Rates of timely admission within 14 days of request were 56.2 % (Pre-Implementation), 55.8 % (IF), and 78.8 % (Sustainability). Compared to the Pre-Implementation Phase, the odds of timely admission were not significantly different during the IF Phase but significantly higher during the Sustainability Phase (OR = 2.35 [95 % CI = 1.34, 4.12]; p = 0.003). CONCLUSIONS: Committing to study participation and IF activities may have prompted some OTPs to change practices that improved timely admission. Attributing changes to IF should be done with caution considering study limitations. Data collection for the study spanned the COVID-19 pandemic, which complicates interpretation. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT04188977.

HIV-Risk Behavior Among Adults with Opioid Use Disorder During 12 Months Following Pre-trial Detention: Results from a Randomized Trial of Methadone Treatment.

This was a three group randomized clinical trial of interim methadone and patient navigation involving 225 pre-trial detainees with opioid use disorder in Baltimore. The HIV Risk Assessment Battery (RAB) was administered at baseline (in jail), and at 6 and 12 months post-release. Generalized linear mixed model analyses indicated the condition × time interaction effect failed to reach significance (ps > .05) for both the drug risk and sex risk subscale scores. Therefore, findings suggest that there were no intervention effects on drug or sex risk behaviors. However, increased use of cocaine at baseline was associated with increases in drug- (b = .04, SE = .02) and sex-risk (b = .01, SE = .003) behaviors. These results suggest that interventions targeting cocaine use among pre-trial detainees may serve as a means of reducing HIV risk associated with drug- and sex-risk behaviors.Clinical Trials Registration: Clinicaltrials.gov NCT02334215.

Effects of age on the pharmacokinetics and selected pharmacodynamics of intravenously administered fentanyl in foals.

REASONS FOR PERFORMING STUDY: The use of fentanyl is limited in adult horses, in part due to potential for central nervous system excitation. The pharmacokinetics and the plasma concentration-related behavioural actions of fentanyl have not been described for young foals. OBJECTIVES: The goal of the present study was to describe the pharmacokinetics and behavioural effects of fentanyl following administration to the same group of foals at 3 different ages. STUDY DESIGN: Experimental study in healthy foals. METHODS: Fentanyl was administered i.v. (4 µg/kg bwt) to a group of 9 foals on 3 separate occasions at 6­8, 20­22 and 41­42 days of age. Blood samples were collected prior to administration and at multiple times until 24 h post administration. Blood samples were analysed for fentanyl concentrations and pharmacokinetics determined at each age. Behavioural and physiological effects were also assessed. RESULTS: The average volume of distribution was 3.55, 1.53 and 1.82 l/kg bwt and clearance 50.2, 40.7 and 35.7 ml/min/kg bwt when foals were 6­8, 20­22 and 41­42 days of age, respectively. The elimination half-life was slightly prolonged (49.3 min) at 6­8 days relative to 20­22 and 41­42 days of age (25.8 and 33.7 min, respectively). The primary metabolite detected in blood samples was the same as for adult horses. While the onset and duration varied widely between foals, sedation was observed at all ages studied. CONCLUSIONS: Fentanyl appears to be consistently well tolerated following i.v. administration of 4 µg/kg bwt to foals ranging in age from 1 to 6 weeks. The results of this study support further study of fentanyl for clinical use in foals.

Pharmacokinetics and selected pharmacodynamics of cobalt following a single intravenous administration to horses.

Cobalt has been used by human athletes due to its purported performance-enhancing effects. It has been suggested that cobalt administration results in enhanced erythropoiesis, secondary to increased circulating erythropoietin (EPO) concentrations leading to improvements in athletic performance. Anecdotal reports of illicit administration of cobalt to horses for its suspected performance enhancing effects have led us to investigate the pharmacokinetics and pharmacodynamic effects of this compound when administered in horses, so as to better regulate its use. In the current study, 18 horses were administered a single intravenous dose of cobalt chloride or cobalt gluconate and serum and urine samples collected for up to 10 days post administration. Cobalt concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and pharmacokinetic parameters determined. Additional blood samples were collected for measurement of equine EPO concentrations as well as to assess any effects on red blood cell parameters. Horses were observed for adverse effects and heart rate monitored for the first 4 h post administration. Cobalt was characterized by a large volume of distribution (0.939 L/kg) and a prolonged gamma half-life (156.4 h). Cobalt serum concentrations were still above baseline values at 10 days post administration. A single administration of cobalt had no effect on EPO concentrations, red blood cell parameters or heart rate in any of the horses studied and no adverse effects were noted. Based on the prolonged gamma half-life and prolonged residence time, regulators should be able to detect administration of a single dose of cobalt to horses.

Disposition, behavioural and physiological effects of escalating doses of intravenously administered fentanyl to young foals.

REASONS FOR PERFORMING STUDY: Foal responses to a broader range of plasma fentanyl concentrations than currently reported are desirable to support (or not) clinical use. OBJECTIVES: To describe fentanyl plasma concentrations following an escalating i.v. fentanyl dosing schedule in foals aged 5-13 days and describe selected, associated dose- and time-related behavioural and physiological responses to plasma fentanyl concentration. STUDY DESIGN: Experimental. METHODS: Fentanyl was administered i.v. in an escalating fashion (2, 4, 8, 16 and 32 µg/kg bwt) at 10-min intervals. Blood samples were collected before and at selected times until 24 h post administration. Blood samples were analysed for fentanyl and metabolite concentrations and correlated with behavioural and physiological observations and selected blood analytes. RESULTS: Foals mostly appeared to be unaffected following 2 µg/kg bwt (1.09 ± 0.41 µg/l; average maximal plasma concentration) of fentanyl, but 6 of the 8 foals appeared to be sedated following 4 µg/kg bwt (3.07 ± 1.11 µg/l). Ataxia with increased locomotor activity, muscle rigidity and head pressing posture was observed in many foals at 8 (7.24 ± 3.22 µg/l) and 16 µg/kg bwt (17.4 ± 5.67 µg/l). All foals were heavily sedated after 32 µg/kg bwt (34.5 ± 10.3 µg/l); 3 of the 8 foals became recumbent. The average (± s.d.) terminal half-life following administration of the final dose was 44.2 ± 9.85 min. CONCLUSIONS: Behavioural and physiological responses to i.v. fentanyl in young foals are dose related. As with mature horses, the window of fentanyl plasma concentrations related to possible clinically desirable actions appears relatively narrow.

Detection and pharmacokinetics of three formulations of firocoxib following multiple administrations to horses.

REASON FOR PERFORMING STUDY: The use of firocoxib in horses and its ability to affect performance and potential to allow a horse to compete when it otherwise should not, necessitates establishing appropriate withdrawal time guidelines prior to performance. OBJECTIVES: To describe plasma concentrations and characterise the pharmacokinetics of 3 firocoxib formulations following multiple administrations of the label dose, with respect to recommended plasma thresholds for performance horses. STUDY DESIGN: Balanced 3-way crossover prospective study. METHODS: Nine healthy mature horses were administered firocoxib injectable solution (0.09 mg/kg bwt i.v. s.i.d. for 5 days), firocoxib paste (0.1 mg/kg bwt per os s.i.d. for 14 days) and firocoxib tablets (57 mg s.i.d. for 14 days). Blood samples were collected at Time 0 and at various times post drug administration until plasma concentrations were below the limit of detection of the assay. Plasma samples were analysed using liquid chromatography-mass spectrometry and data analysed using noncompartmental analysis. RESULTS: The mean plasma half-life was 1.64 ± 0.737, 1.70 ± 0.800 and 1.73 ± 0.767 days for injectable, paste and tablet formulations, respectively. Plasma concentrations fell below the Racing Medication and Testing Consortium's recommended threshold for racehorses (20 ng/ml) by 7 days post administration of the final dose for all formulations. Plasma concentrations never exceeded the threshold concentration (240 ng/ml) for horse competing in US Equestrian Federation events for any of the formulations. CONCLUSIONS: This study extends current knowledge regarding the pharmacokinetics of firocoxib and provides information that can be used to establish appropriate withdrawal time guidelines following multiple administrations, with respect to already established plasma regulatory threshold concentrations.

Detection, pharmacokinetics and cardiac effects following administration of clenbuterol to exercised horses.

REASONS FOR PERFORMING STUDY: The use of clenbuterol in performance horses necessitates the establishment of appropriate withdrawal times. OBJECTIVES: To describe plasma and urine concentrations of clenbuterol following administration of 2 commonly used dosing regimens to racing fit Thoroughbreds. STUDY DESIGN: Experimental. METHODS: Twenty-two horses received an oral dose of 0.8 µg/kg bwt of clenbuterol twice daily for 30 days. A second group of 6 horses received clenbuterol according to the escalating dose protocol on the manufacturer's label. Blood and urine samples were collected prior to, throughout and at various times up to 35 days post administration of the final dose. Drug concentrations were measured using liquid chromatography-mass spectrometry, and plasma data were analysed using noncompartmental analysis. Behavioural and physiological effects were monitored and heart rate was recorded throughout the course of the study. RESULTS: Clenbuterol plasma concentrations were below the limit of quantification (10 pg/ml) of the assay by Day 4 in all horses receiving the chronic low-dose regimen and by Day 7 in 5 of 6 horses receiving the escalating dosing protocol. Urine clenbuterol concentrations fell below the limit of quantification of the assay between Days 21 and 28 in all 22 horses in the low-dose group and in 5 of 6 of the horses in the escalating dose group. Muscle fasciculations, sweating and transient increases in heart rate were noted in a small number of horses following clenbuterol administration, but tolerance to these effects occurred rapidly. CONCLUSIONS AND POTENTIAL RELEVANCE: Establishment of appropriate withdrawal times for specific racing jurisdictions depends upon the threshold adopted by that specific jurisdiction. This study extends previous studies describing the pharmacokinetics of clenbuterol and describes plasma and urine concentrations following administration of 2 commonly used dosing regimens to racing fit Thoroughbreds, which will allow jurisdictions to establish withdrawal times in order to prevent inadvertent positive regulatory findings.

X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma.

Scleroderma (SSc) is a rare connective tissue disease characterized by fibrosis, microvasculopathy and autoimmune features. The role of genetics is limited in SSc, as suggested by similar concordance rates in monozygotic and dizygotic twin pairs, while environmental factors may act through epigenetic changes, as demonstrated for specific genes. Further, sex chromosome changes have been reported in SSc and may explain the female preponderance. In the present study we compared the methylation profile of all X chromosome genes in peripheral blood mononuclear cells from monozygotic twins discordant (n=7) and concordant (n=1) for SSc. Methylated DNA immunoprecipitations from each discordant twin pair were hybridized to a custom-designed array included 998 sites encompassing promoters of all X chromosome genes and randomly chosen autosomal genes. Biostatistical tools identified sites with an elevated probability to be consistently hypermethylated (n=18) or hypomethylated (n=25) in affected twins. Identified genes include transcription factors (ARX, HSFX1, ZBED1, ZNF41) and surface antigens (IL1RAPL2, PGRMC1), and pathway analysis suggests their involvement in cell proliferation (PGK1, SMS, UTP14A, SSR4), apoptosis (MTM1), inflammation (ARAF) and oxidative stress (ENOX2). In conclusion, we propose that X chromosome genes with different methylation profiles in monozygotic twin pairs may constitute candidates for SSc susceptibility.

Androgens coordinate neurotransmitter-related gene expression in male whiptail lizards.

Sex steroid hormones coordinate neurotransmitter systems in the male brain to facilitate sexual behavior. Although neurotransmitter release in the male brain has been well documented, little is known about how androgens orchestrate changes in gene expression of neurotransmitter receptors. We used male whiptail lizards (Cnemidophorus inornatus) to investigate how androgens alter neurotransmitter-related gene expression in brain regions involved in social decision making. We focused on three neurotransmitter systems involved in male-typical sexual behavior, including the N-methyl-d-aspartate (NMDA) glutamate receptor, nitric oxide and dopamine receptors. Here, we show that in androgen-treated males, there are coordinated changes in neurotransmitter-related gene expression. In androgen-implanted castrates compared with blank-implanted castrates (control group), we found associated increases in neuronal nitric oxide synthase gene expression in the nucleus accumbens (NAcc), preoptic area and ventromedial hypothalamus, a decrease of NR1 gene expression (obligate subunit of NMDA receptors) in the medial amygdaloid area and NAcc and a decrease in D1 and D2 dopamine receptor gene expression in the NAcc. Our results support and expand the current model of androgen-mediated gene expression changes of neurotransmitter-related systems that facilitate sexual behavior in males. This also suggests that the proposed evolutionarily ancient reward system that reinforces sexual behavior in amniote vertebrates extends to reptiles.

Quantitative immunoblotting with fusion proteins.

The development of vaccines against HIV-1 is currently hindered by incomplete understanding of correlates of protective immunity (1-3). Experiments are necessary to measure immune responses in sufficiently fine detail that specific protective responses can be discerned from those that are irrelevant or harmful. When vaccines are tested as potential therapeutics, it is further necessary to differentiate induced responses from those associated with the infection itself. Measurement of humoral responses to well-defined antigens particularly lends itself to detailed mapping (4). Small synthetic antigens may be used in ELISA or BIAcore assays (5-7). Larger antigens, such as fusion proteins, may require assays with more specificity, because of the possibility of immune-reactive contaminants. A particularly useful technique in this context is immunoblotting, because contaminating antigens are separated away during the electrophoresis step (8,9). In the authors' laboratory, immunoblots employing fusion proteins of HIV-1 envelope sequences have been successfully used to quantitate new responses post immunization with a vaccine candidate in spite of a substantial baseline response to the whole antigen (10,11). The same technique was used to measure responses against vaccine candidates in small animal models (12,13).

Student coping strategies and perceptions of fieldwork.

A questionnaire, the revised Ways of Coping Checklist, was sent to all professional (entry-level) graduate students in the United States in one academic year during their second fieldwork level II experience to determine what coping strategies they used during their fieldwork experience. Information was also gathered regarding their perceptions of this clinical experience. Responses from 101 students showed that they used Problem-Focused and Seeks Social Support strategies more than Wishful Thinking, Blamed Self, or Avoidance strategies. More than half of the students found the experience to be stressful, and almost all agreed that it was important. Most agreed that they had control over their present circumstances in the fieldwork experience.

Coping strategies used by occupational therapy students during fieldwork: an exploratory study.

This exploratory study examined the coping strategies and perceptions of 24 graduate students in occupational therapy who were participating in their second Level II fieldwork experience. The instruments used were the revised Ways of Coping Checklist (WCCL) (Vitaliano, Russo, Carr, Maiuro, & Becker, 1985) and a questionnaire developed by the authors. The results showed that of the five coping scales of the WCCL, the students used the Problem-Focused and Seeks Social Support strategies more than the Blamed Self, Wishful Thinking, and Avoidance strategies. Most of the students perceived the fieldwork experience as important, controllable, and stressful, but not disruptive to their lives.

Do changes in pulmonary capillary wedge pressure adequately reflect myocardial ischemia during anesthesia? A correlative preoperative hemodynamic, electrocardiographic, and transesophageal echocardiographic study.

Pulmonary capillary wedge pressure (PCWP) is monitored during anesthesia in an attempt to detect changes in myocardial function in patients at risk of preoperative cardiac complications. Because the sensitivity with which preoperative PCWP monitoring indicates myocardial ischemia is uncertain, we monitored PCWP, 12-lead electrocardiogram, and left ventricular wall motion abnormalities as defined by transesophageal echocardiography (TEE) in 98 anesthetized patients before coronary artery bypass grafting. Measurements were made five times in each patient, before and after induction of anesthesia. Myocardial ischemia was identified by TEE in 14 patients; in 10 of these, it was associated with concomitant ST segment depression of at least 1 mm. The onset of ischemia, as defined by TEE, was accompanied by a mean increase in PCWP of 3.5 +/- 4.8 mm Hg, as compared with a mean change of 0 +/- 2.2 mm Hg between observations not associated with the onset of ischemia (p less than 0.01). An increase in PCWP of at least 3 mm Hg, tested as an indicator of ischemia, had a sensitivity of 25% and a positive predictive value of 15%; after correction for background changes associated with anesthetic induction, the sensitivity of this indicator was 33%, and its positive predictive value was 16%. These figures were not improved by selecting cutoff points higher or lower than 3 mm Hg. In this study, the onset of myocardial ischemia was associated with a small yet significant increase in mean PCWP at group level.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of arterial pressure after cardiopulmonary bypass with long radial artery catheters.

Radial arterial pressure can significantly underestimate central aortic pressure in the postcardiopulmonary bypass (post-CPB) period. At the study institution, routine monitoring of perioperative arterial pressure in adult patients undergoing cardiac surgery is performed with a long radial artery catheter with the distal end positioned in the subclavian artery. In 68 patients presenting for elective cardiac surgery, both a conventional short radial artery catheter and a contralateral long radial artery catheter were placed. Analysis of radial and subclavian arterial pressures post-CPB in the first 47 patients showed average maximum differences of 7 mm Hg systolic and 4 mm Hg mean. In 15% of patients, the differences were clinically significant (greater than 20 mm Hg systolic and/or greater than 14 mm Hg mean). In 28 patients, central aortic pressure was measured post-CPB, and subclavian artery pressure was found to be an excellent estimator of central aortic pressure. There were no significant complications related to using long radial artery catheters in the 68 patients who were followed prospectively. Monitoring subclavian arterial pressure by percutaneous insertion of a long radial artery catheter provides a reliable estimation of central aortic pressure, even in patients with significant radial artery-to-central aortic pressure gradients post-CPB.

Nitrous oxide does not induce myocardial ischemia in patients with ischemic heart disease and poor ventricular function.

Despite evidence from animal experiments to the contrary, nitrous oxide (N2O) reportedly does not induce myocardial ischemia when used as an adjunct to fentanyl anesthesia in patients with coronary artery disease who have well-preserved left ventricular (LV) function. However, the incidence of ischemia with N2O administration in similar patients with poor LV function may be different. The effects of N2O on segmental LV function, as determined by two-dimensional transesophageal echocardiography, changes in the ST-segment of the electrocardiogram were compared with the effects of an equal concentration of nitrogen (N2) (crossover design) in 70 patients who required elective coronary artery bypass grafting. Of these patients, 24% had left ventricular ejection fraction (LVEF) less than or equal to 40%. Myocardial ischemia was diagnosed in 14 patients during the study: four while awake, seven during induction of anesthesia and tracheal intubation, and four during the remainder of the study (one during N2O and three during 100% oxygen; one patient had two distinct periods of ischemia). No value for LVEF could be found that would distinguish between patients who did or did not have ischemia during the study. Patients treated with beta-adrenergic blocking drugs preoperatively were less likely to develop ischemia (P less than 0.05). Preoperative calcium channel blockers made no such differences. Onset of ischemia was not closely associated with hemodynamic changes. Thus, N2O does not induce clinically detectable myocardial ischemia in patients who have coronary artery disease, and poor LV function in situations in which the effects of deepening anesthetic depth and mild depression of global myocardial function are deemed desirable or harmless.