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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

OBJECTIVE Migraine affects about 15% of the world's population and disproportionately affects adults who are working age. It is associated with higher healthcare costs, absenteeism, and lost productivity. A metropolitan school district in the southern U.S. offered a virtual migraine education program to their teaching employees. METHODS Seventy-nine employees completed a migraine questionnaire at both baseline and 3-month follow-up. The program included webinars, educational videos, and other intranet-based resources. RESULTS Results found that program participants reported a significant improvement in the frequency and severity of migraine as well as a reduction in lost on-the-job productivity. A majority of participants reported making positive changes to reduce triggers and better manage stress. CONCLUSIONS An employer-offered migraine education program distributed virtually to remote workers has the potential to improve migraine symptoms and treatment as well as productivity.

A significant amount of illness has origins in oral microorganisms. The current SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has reduced the general population’s access to and use of routine and nonemergency dental care. This creates a dangerous situation in which oral bacteria, fungi, and viruses may remain unchecked and allowed to flourish, which in turn increases risks for several systemic diseases as well as negative outcomes for pregnancies and surgical patients. This situation presents opportunities for health maintenance and disease prevention by individuals as well as for dental health professionals to use anti-infective treatments and procedures. Lifestyle medicine professionals have a chance to encourage behaviors that individuals can undertake to promote good oral health outside of the dentist’s office as well as shaping public perceptions about and reinforcing the importance of resuming dental visits as governmental restrictions allow.

Although interorganizational relationships (IORs) are essential to the effective delivery of human services, very little research has examined relationships between juvenile justice agencies and behavioral health providers, and few studies have identified the most critical organizational and individual-level characteristics influencing IORs. Across 36 sites, juvenile probation officials (n = 458) and community behavioral health providers (n = 91) were surveyed about characteristics of their agencies, themselves, and IORs with each other. Generalized Linear Mixed Models were used to analyze the data. The strongest predictors included Perceived Organizational Support and individual Adaptability. Implications for research, theory and practice are discussed.

Developmental and epileptic encephalopathy (DEE) associated with de novo variants in the gene encoding dynamin-1 (DNM1) is a severe debilitating disease with no pharmacological remedy. Like most genetic DEEs, the majority of DNM1 patients suffer from therapy-resistant seizures and comorbidities such as intellectual disability, developmental delay, and hypotonia. We tested RNAi gene therapy in the Dnm1 fitful mouse model of DEE using a Dnm1-targeted therapeutic microRNA delivered by a self-complementary adeno-associated virus vector. Untreated or control-injected fitful mice have growth delay, severe ataxia, and lethal tonic-clonic seizures by 3 weeks of age. These major impairments are mitigated following a single treatment in newborn mice, along with key underlying cellular features including gliosis, cell death, and aberrant neuronal metabolic activity typically associated with recurrent seizures. Our results underscore the potential for RNAi gene therapy to treat DNM1 disease and other genetic DEEs where treatment would require inhibition of the pathogenic gene product., Graphical Abstract, Toxic mutations in DNM1, a gene involved in the proper functioning of brain cells, cause developmental and epileptic encephalopathy—a severe class of epilepsy with no cure. Aimiuwu and colleagues show that a single gene therapy treatment via RNA interference eliminated the toxic allele sufficiently to curb severe lethal seizures, eliminate motor and developmental deficits, and extend survival of treated mice.

This study contributes to the substance abuse treatment literature by examining recidivism across treatment groups, the level of aggregation between the individual and the program. The sample consisted of 618 drug-involved offenders who participated in 12 different treatment groups within a single prison. Reincarceration significantly varied across groups, controlling for time at risk and treatment modality. This between-unit variation was explained by individual level treatment response measures and control variables. Results demonstrated that treatment effectiveness is impacted by the group in which the individual participates. These findings have substantial implications for correctional treatment theory, research, and policy.

OBJECTIVE This study examined demographics, health risks and conditions, preventive services, and health care experiences of lesbian, gay, bisexual, transgender, or questioning (LGBTQ) adults who are employed in the United States. METHODS Male and female gay, lesbian, or bisexual employees (N = 1191) from seven companies participated in an online survey. RESULTS Differences were observed in the characteristics of gays, lesbians, and bisexuals on a number of demographic, health, and preventive services measures. Differences were also seen compared to previous studies about LGBTQ adults in the general population. CONCLUSIONS Employers have a vested interest in making sure their employees have access to quality health care that addresses their unique needs. There is much room for improvement in this area, since a large percentage of respondents reported negative health care experiences, avoiding or postponing care, and difficulty finding an LGBTQ-experienced healthcare provider.

The issue of employee productivity has become a major concern for companies. Inefficiency can occur at every stage of production either as poor design, worker limitation, or other factors. It is generally assumed that a healthy worker is more productive than an unhealthy worker. As early as 1776 Adam Smith observed and published in The Wealth of Nations that poor worker health was a detriment to industrial productivity. The objective of this article is to review the literature documenting the gain or loss of productivity related to the health of workers, as well as any lifestyle management strategies that can be used to improve employee health and productivity. The impact of employee obesity, smoking, physical activity, sleep, and behavioral health on productivity will be explored. By identifying and addressing health risks that impair worker performance, lifestyle medicine professionals can demonstrate a significant return on investment by creating a healthier and more productive work force.

Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell-specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.

Objective Higher probability of developing severe COVID-19 has been associated with health risk factors and medical conditions which are common among workers globally. For at risk workers, return to work may require additional protective policies and procedures. Methods A review of the medical literature was conducted on health risk factors and medical conditions associated with increased COVID-19 morbidity and mortality, standardized measures for community COVID transmission, and occupation-specific risk. Results The relative risk of acquiring and the severity of COVID-19 for workers is associated with three pillars: individual risk, workplace risk, and community risk. Matrices were developed to determine a worker's individual risk based on these three pillars. Conclusions A practical decision tool is proposed for physicians evaluating and managing individual worker COVID-19 risk in the context of returning to work.

NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

Developmental epileptic encephalopathies (DEEs) are severe seizure disorders that occur in infants and young children, characterized by developmental delay, cognitive decline, and early mortality. Recent efforts have identified a wide variety of genetic variants that cause DEEs. Among these, variants in the DNM1 gene have emerged as definitive causes of DEEs, including infantile spasms and Lennox-Gastaut syndrome. A mouse model of Dnm1-associated DEE, known as “Fitful” (Dnm1Ftfl), recapitulates key features of the disease, including spontaneous seizures, early lethality, and neuronal degeneration. Previous work showed that DNM1 is a key regulator of synaptic vesicle (SV) endocytosis and synaptic transmission, and suggested that inhibitory neurotransmission may be more reliant on DNM1 function than excitatory transmission. The Dnm1Ftfl variant is thought to encode a dominant negative DNM1 protein, however, the effects of the Dnm1Ftfl variant on synaptic transmission are largely unknown. To understand these synaptic effects, we recorded from pairs of cultured mouse cortical neurons and characterized all four major connection types (E-E, E-I, I-E, I-I). Miniature and spontaneous EPSCs and IPSCs were larger, but less frequent, at all Dnm1Ftfl synaptic types, and Dnm1Ftfl neurons had reduced expression of excitatory and inhibitory SV markers. Baseline evoked transmission, however, was reduced only at inhibitory synapses onto excitatory neurons, due to a smaller pool of releasable SVs. In addition to these synaptic alterations, Dnm1Ftfl neurons degenerated later in development, even though their activity levels were reduced, suggesting that Dnm1Ftfl may impair synaptic transmission and neuronal health through distinct mechanisms. Significance Statement Recent work has identified genetic variants in DNM1 as among the more common causes of developmental epileptic encephalopathies (DEEs), but the physiological consequences of its mutation are unclear. Here, we make use of an in vitro model of Dnm1-associated DEE to determine the effects of a Dnm1 variant on the four main cortical synapse types. The variant caused both synapse-specific and synapse-wide alterations, and decreased neuronal activity. Despite this, neurons still degenerated after two weeks in vitro, suggesting that neuronal degeneration in these mice may be independent of seizures, and that stopping seizures may do little to mitigate key features of DEEs.

The cost of medical care in the United States is increasing at an unsustainable rate. The lifestyle medicine (LM) approach is essential to influence the root causes of the growing chronic disease burden. LM addresses health risk factors in primary, secondary, and tertiary prevention of developing disease rather than limiting resources and medical expenditures on acute care and reacting to illness, injury, and disease. Employers have much to gain financially from such an approach due to their status as the payer of health care costs for their employees, and as the recipient of productivity gains among their employees. This article discusses LM programs delivered at the worksite, including important findings from the University of Michigan Health Management Research Center. Examples of evidenced-based population LM interventions are summarized for physical activity, weight management, and nutrition programs that address chronic diseases such as cardiovascular disease, cancer, and diabetes mellitus. These approaches have the potential to reduce health care cost trends, increase employee performance/productivity, and improve patient health outcomes.

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated neuroanatomical abnormalities, global developmental delay, impaired ultrasonic vocalizations and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the subiculum—a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPU-mediated disease mechanisms, and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduced a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, found motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increased KNa currents in cortical excitatory and inhibitory neurons, there was a selective increase in the KNa current across subthreshold voltages in inhibitory neurons, particularly in those with non-fast spiking properties, resulting in impaired excitability and AP generation. We further observed evidence of synaptic rewiring associated with hyperexcitable networks, including increases in homotypic synaptic connectivity and the ratio of excitatory-to-inhibitory synaptic input. These findings support inhibitory neuron-specific mechanisms in mediating the epileptogenic effects of K+ channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.

Sleep disturbance is negatively associated with workplace productivity. This study sought to identify whether or not changes in sleep from 2012 to 2013 were associated with changes in health risks, medical conditions, or workplace economic outcomes. Employees of a Fortune 100 financial services corporation were categorized based on changes in self-reported hours of sleep from 2012 to 2013 and compared based on their health risk factors, medical conditions, health care costs, and productivity measures. Consistently poor sleepers had more health risks and medical conditions compared to consistently optimal sleepers. Sleep improvers had a significant reduction in lost on-the-job productivity while consistently poor sleepers and downgraders had significantly more lost productivity compared to optimal sleepers. Employers may wish to incorporate sleep education initiatives as part of their overall health and wellness strategy.

Objective:To conduct a comprehensive literature review to develop recommendations for managing obesity among workers to improve health outcomes and to explore the impact of obesity on health costs to determine whether a case can be made for surgical interventions and insurance coverage.Methods:We se

Research has examined responses to substance abuse treatment among criminal justice populations primarily through client self-assessments, and comparatively fewer studies have focused on clinician ratings of client progress. Recently, Blasko and Hiller examined counselor ratings and their association with reincarceration but found no relationship between the two. The current study partially replicated their analyses and explored its own factor structure to compare the findings from a different sample using the same instrument, the Criminal Justice Counselor Rating of Client (CJ CRC). Analyses revealed that although none of the replicated counselor measures predicted reincarceration, higher levels of one measure produced from the factor analysis, Psychological Barriers to Recovery, indicated a significantly higher probability for reincarceration. In light of these conflicting findings, practical implications of this research suggested that clinical assessments of clients may be useful for criminal justice decision making.

Poor sleep can impact occupational functioning. The current study examines health risks, medical conditions, and workplace economic outcomes associated with self-reported hours of sleep among employees.Employees of a global financial services corporation were categorized on the basis of their self-reported average hours of sleep. Differences in health care costs, productivity measures, health risks, and medical conditions were analyzed by hours of sleep while controlling for confounding variables.A strong U-shaped relationship between health care costs, short-term disability, absenteeism, and presenteeism (on-the-job work loss) and the hours of sleep was found among employees. The nadir of the "U" occurs for 7 or 8 hours of sleep per night.Worksite wellness programs often address health risks and medical conditions and may benefit from incorporating sleep education.

NMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants ofGRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). Ade novomissense variant, p.Ser644Gly (c.1930A>G), was identified in a child with DEE, andGrin2aknockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.

SUMMARYDe novo mutations in GNB1, encoding the Gβ1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy. Mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and frequent spike-wave discharges (SWD). Cultured mutant cortical neurons display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses SWD in vivo. In contrast, while valproic acid suppresses SWD, it does not restore normal network behavior, suggesting that ETX has mechanistic specificity for the effects of aberrant Gβ1 signaling. Consistent with this, we show that K78R is a gain-of-function of G protein-coupled potassium channel (GIRK) activation that is potently inhibited by ETX. This work suggests that altered Gβ1 signaling causes disease in part through effects on GIRK channels, illustrates the utility of cultured neuronal networks in pharmacological screening, and establishes effective pre-clinical models for GNB1 Encephalopathy.

This study describes the effects of common health conditions associated with absenteeism and presenteeism in a population-based sample of workers in Brazil.Data were analyzed from the cross-sectional São Paulo Megacity Mental Health Survey on 1737 employed residents aged more than 18 years old conducted from 2005 to 2007.Physical diseases and mental disorders are highly prevalent among Brazilian workers. The prevalence of absenteeism was 12.8%, and the prevalence of presenteeism was 14.3%. The condition most commonly associated with work impairment was mood disorder.Improving access to care and increasing detection and management of mental disorders should be a priority in Brazil. Occupational health programs and services can play a key role in increasing the productivity of the Brazilian workforce.

Many people spend years dreaming about their retirement. Unfortunately, today’s workers will likely work longer, suffer greater economic uncertainty, and might have poorer health status compared with retirees in previous generations. Preserving good health during the working years is associated with a more consistent employment record, greater financial resources, and reduced risk of disease. Making smart financial decisions as a younger adult also translates to improved finances in retirement. While many people are aware of these relationships, many continue to make poor health choices. Employers and lifestyle medicine professionals can both work to improve financial well-being in retirement. Employers can offer effective worksite financial wellness programs and promote participation in retirement savings programs. Physicians and other health providers can foster healthy behaviors, encourage preventive services compliance, and help adults foster overall financial and health well-being. Adopting a healthy lifestyle as early as possible would increase the likelihood that today’s workers will enjoy financial security in retirement.

Dynamin 1 is a large neuron-specific GTPase involved in the endocytosis and recycling of pre-synaptic membranes and synaptic vesicles. Mutations in the gene encoding dynamin 1 (DNM1) underlie two epileptic encephalopathy syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Mice homozygous for the Dnm1 "fitful" mutation, a non-synonymous coding variant in an alternatively spliced exon of Dnm1 (exon 10a; isoform designation: Dnm1a(Ftfl)) have an epileptic encephalopathy-like disorder including lethal early onset seizures, locomotor and neurosensory deficits. Although fitful heterozygotes have milder recurrent seizures later in life, suggesting an additive or semi-dominant mechanism, the molecular etiology must also consider the fact that Dnm1a(Ftfl) exerts a dominant negative effect on endocytosis in vitro. Another complication is that the fitful mutation induces alterations in the relative abundance of Dnm1 splice variants; mutants have a downregulation of Dnm1a and an upregulation of Dnm1b, changes which may contribute to the epileptic pathology. To examine whether Dnm1a loss of function, Dnm1a(Ftfl) dominance or compensation by Dnm1b is the most critical for severe seizures, we studied alternate isoform-specific mutant mice. Mice lacking Dnm1 exon 10a or Dnm1 exon 10b have neither spontaneous seizures nor other overt abnormalities, suggesting that in normal conditions the major role of each isoform is redundant. However, in the presence of Dnm1a(Ftfl) only exon 10a deleted mice experience severe seizures. These results reveal functional differences between Dnm1a and Dnm1b isoforms in the presence of a challenge, i.e. toxic Dnm1(Ftfl), while reinforcing its effect explicitly in this model of severe pediatric epilepsy.

OBJECTIVE Migraine affects approximately 10% of working-age adults and is associated with increased health care costs, absenteeism, and presenteeism in the workplace. A migraine education program was offered to United States employees of a global financial services organization. METHODS Two hundred forty three employees (46% response rate) completed both a baseline and 6-month follow-up migraine questionnaire. The program included webinars, E-mailed educational tips, and intranet-based resources. RESULTS No change was found in the frequency of migraines but improvements were observed in the severity, workdays missed, effectiveness at work during migraine, and work/activity limitations. Participants reported taking action to identify and reduce migraine triggers. CONCLUSIONS A worksite disease education program for migraine headache has the potential to significantly impact lost productivity and absenteeism for migraineurs.

With notable exceptions, few studies have looked critically at the role and effects of factors other than individual or programmatic differences that contribute to the climate within substance abuse treatment programs. De Leon's work on the therapeutic community, however, indicates that factors beyond the individual and program can contribute to the overall functioning of similarly situated communities.In this study, we introduce and examine the concept of the "treatment group," the level of aggregation between the individual who participates in treatment and the organization that provides it. The treatment group refers to the social context and dynamics that operate among treatment participants, and we sought to study differences in treatment climate across 12 prison-based treatment groups within a single prison.Using data from 604 participants who were assigned at random to one of the 12 groups, we analyzed differences on seven treatment climate indicators from one month and six months into the program across the treatment groups.No differences were found among the treatment groups at after one month; however, after 6 months, significant differences emerged across the groups on three treatment climate variables: program structure, counselor rapport, and counselor competence.This study is among the first of its kind to conceptualize and examine treatment climate across otherwise similar groups and find that differences emerge on several indicators of climate. As such, we argue that the treatment group may be important to consider in both the delivery and evaluation of substance abuse treatment.

Objective To describe fentanyl pharmacokinetics during isoflurane anesthesia and on recovery from anesthesia with concurrent administration of acepromazine, dexmedetomidine or saline in dogs. Study design Experimental blinded, randomized, crossover study. Animals Seven adult hound dogs. Methods Dogs were administered intravenous (IV) fentanyl as a bolus (5 μg kg −1 ) followed by an infusion (5 μg kg −1 hour −1 ) for 120 minutes during isoflurane anesthesia and emergence from anesthesia, and for 60 minutes after extubation during recovery from anesthesia. At the time of extubation, dexmedetomidine (2.5 μg kg −1 ), acepromazine (0.05 mg kg −1 ) or saline were administered IV. Venous blood was sampled during the maintenance and recovery periods. Fentanyl plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry and population pharmacokinetic analyses were performed. Results Mean fentanyl plasma concentrations were 1.6-4.5 ng mL −1 during isoflurane anesthesia and 1.6-2.0 ng mL −1 during recovery from anesthesia. Recovery from isoflurane anesthesia without sedation was associated with an increase in the volume of the central compartment from 0.80 to 1.02 L kg −1 . After administration of acepromazine, systemic clearance of fentanyl increased from 31.5 to 40.3 mL minute −1 kg −1 and the volume of the central compartment increased from 0.70 to 0.94 L kg −1 . Administration of dexmedetomidine did not significantly change fentanyl pharmacokinetics. Inter-individual variability for fentanyl parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4%. Conclusions and clinical relevance The dose rates of fentanyl used in this study achieved previously established analgesic plasma concentrations for the duration of the infusion. Despite alterations in fentanyl pharmacokinetics, differences in fentanyl plasma concentrations among treatments during recovery from anesthesia were small and were unlikely to be of clinical significance.

Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in-vitro and in-vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug-screening platforms, and the establishment of collaborative research groups. Moving forward, it is crucial that these collaborations are strengthened, particularly through integrated research platforms, to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.

Medication-assisted treatment (MAT) is effective for alcohol and opioid use disorders but it is stigmatized and underutilized in criminal justice settings.This study cluster-randomized 20 community corrections sites to determine whether an experimental implementation strategy of training and an organizational linkage intervention improved staff perceptions of MAT and referral intentions more than training alone. The 3-hour training was designed to address deficits in knowledge, perceptions and referral information, and the organizational linkage intervention brought together community corrections and addiction treatment agencies in an interagency strategic planning and implementation process over 12 months.Although training alone was associated with increases in familiarity with pharmacotherapy and knowledge of where to refer clients, the experimental intervention produced significantly greater improvements in functional attitudes (e.g. that MAT is helpful to clients) and referral intentions. Corrections staff demonstrated greater improvements in functional perceptions and intent to refer opioid dependent clients for MAT than did treatment staff.Knowledge, perceptions and information training plus interorganizational strategic planning intervention is an effective means to change attitudes and intent to refer clients for medication assisted treatment in community corrections settings, especially among corrections staff.

Weak coordination between community correctional agencies and community-based treatment providers is a major barrier to diffusion of medication-assisted treatment (MAT)--the inclusion of medications (e.g., methadone and buprenorphine) in combination with traditional counseling and behavioral therapies to treat substance use disorders. In a multisite cluster randomized trial, experimental sites (j = 10) received a 3-h MAT training plus a 12-month linkage intervention; control sites (j = 10) received the 3-h training alone. Hierarchical linear models showed that the intervention resulted in significant improvements in perceptions of interagency coordination among treatment providers, but not probation/parole agents. Implications for policy and practice are discussed.

Geriatric trauma patients are at increased risk of infections due to preexisting comorbidities as well as immunosenescence. Atypical presentations of infection should be anticipated. Care must be used in medication dosing due to decreased renal and hepatic clearance, hypoalbuminemia, and interactions with chronic medications. Hospital-acquired infections lead to substantial increases in cost, length of stay, and mortality, but can be reduced by the dedicated use of bundles.

We measured the antibody response in 10 victims of acute blunt trauma and penetrating trauma who were immunized against Klebsiella pneumoniae and Pseudomonas species within 72 hours of injury. The two vaccines, which were previously shown to be safe and immunogenic in uninjured humans, were a 24-valent K. pneumoniae capsular polysaccharide vaccine and an eight-valent Pseudomonas O-polysaccharide-toxin A conjugate vaccine. The patients were between 18 and 44 years of age, had Injury Severity Scores that ranged between 9 and 34, and did not have chronic infections or malignancies. On days 14 and 28 after immunization, all patients had a response of greater than fourfold to at least six of the nine Pseudomonas vaccine antigens. Half of the patients responded to eight of the nine antigens. Nine patients responded to at least 18 of 24 Klebsiella antigens, and seven patients responded to 22 of the 24 antigens. No important side effects were attributed to the vaccines. The results of this preliminary study indicate that active immunization against potential pathogens is possible in victims of acute trauma.

We have previously demonstrated excellent agreement in the dog between thermodilution (TD) and lithium chloride dilution (LCD) as measures of CO, with an intraclass correlation of 0.989. LCD results in an accumulation of lithium (Li) in the body, which results in background interference for subsequent determinations. The manufacturer of the LCD sensor has calculated a theoretical upper serum Li value of 0.2 mmol L−1, above which interference may become significant. The purpose of this study was: (1) to determine the relationship between the dose of lithium chloride (LiCl) administered and the background serum Li level; and (2) to examine the relationship between background serum Li levels and the degree of agreement for CO measured by LCD and TD. Ten healthy mixed breed mature dogs were studied, seven female and three male, with a mean body weight of 36.2 kg (range 30.5–45.4 kg). Each dog was premedicated with butorphanol (0.4 mg kg−1 IM), induced with thiopental (15–20 mg kg−1 IV), and maintained with 1.5% inspired halothane (except when depth was increased as outlined below) using a circle system and a fresh gas flow rate of 50 mL kg−1 minute−1. The dogs were instrumented with a central venous catheter, a Swan-Ganz pulmonary arterial catheter, a femoral venous balloon catheter, and a peripheral arterial catheter. Four levels of CO were induced in each dog. Ranging from the highest to lowest level of CO, these were induced by: dobutamine infusion, routine anesthesia, a deep plane of anesthesia, and preload reduction with balloon inflation in the caudal vena cava, respectively. A data collection set, measured at each level of CO, consisted of three determinations of CO by TD interspersed with two pairs of LCD. Anesthetic stability for each CO level was assessed before and after each CO determination. Cumulative dosages of 0.08 ± 0.03 and 0.17 ± 0.03 mmol kg−1 lithium chloride produced serum Li concentrations of 0.2 and 0.4 mmol L−1, respectively. There was a tendency for the difference between CO measured by LCD and TD to gradually increase as background serum Li concentration increased. At a background Li concentration of 0.2 mmol L−1 and 0.4 mmol L−1, mean difference between CO measured by LCD and TD was 0.25 L minute−1 and 0.55 L minute−1, respectively. It was concluded that it is possible to predict the background serum Li concentration knowing the animal's weight and the total cumulative administered LiCl dose. A higher level of agreement between CO measured by LCD and TD occurred at lower background serum Li levels.

The purpose of this study was to evaluate the cardiopulmonary effects of anesthetic induction with diazepam/ketamine or xylazine/ketamine with subsequent maintenance of anesthesia using isoflurane in foals undergoing abdominal surgery. Seventeen foals underwent laparotomy at 7–10 days of age and a laparoscopy 7–10 days later. Foals were randomly assigned to receive xylazine (0.8 mg kg−1)/ketamine (2 mg kg−1) (X/K)(n = 9) or diazepam (0.2 mg kg−1)/ketamine (2 mg kg−1) (D/K)(n = 8) for induction of anesthesia for both procedures. In all foals, anesthesia was maintained with isoflurane in oxygen with the inspired concentration adjusted to achieve adequate depth of anesthesia as assessed by an individual blinded to the treatments. IPPV was employed throughout using a tidal volume of 10 mL kg−1 adjusting the frequency to maintain eucapnia (PaCO2 35–45 mm Hg, 4.7–6.0 kPa). Cardiopulmonary variables were measured after induction of anesthesia prior to, during, and following surgery. To compare the measured cardiopulmonary variables between the two anesthetic regimes for both surgical procedures, results were analyzed using a three-way factorial anova for repeated measures (p

Treatment of bradycardia in horses has been historically ignored because of the motility depressant effects of nonselective antimuscarinics. This study evaluated the cardiopulmonary effects of a cardioselective (M2) muscarinic antagonist, methoctramine (MET), in anesthetized horses. In a previous in vitro study, we determined that supraphysiological doses of MET were necessary to inhibit acetylcholine-induced longitudinal jejunal smooth muscle contractions in this species. Six adult horses were allocated to two treatments in a randomized complete block design. Anesthesia was induced with xylazine/ketamine, and maintained with halothane (1% end-tidal) and a constant infusion of xylazine (1 mg kg−1 hour−1) under mechanical ventilation. Invasive hemodynamic variables were monitored at baseline (approximately 45 minutes after induction) and for 120 minutes after MET or saline (control) had been injected. MET was titrated at 10-minute intervals (10 µg kg−1 IV) until the heart rate (HR) increased at least 30% above the baseline, or a maximum cumulative dose of 30 µg kg−1 had been injected. A person blinded to the treatment evaluated recovery scores and monitored intestinal auscultation until 24 hours after the end of anesthesia using previously published methods. Cardiovascular parameters were analyzed by anova followed by a Dunnet's test, and nonparametrical data were analyzed by a Mann–Whitney U-test (p

The purpose of this study was to investigate the cardiopulmonary response, with quantitative M-mode echocardiography, of glycopyrrolate (G, 10 µg kg−1 IM) as a pretreatment (p) or administered concurrently (c) with romifidine (RO) SQ in dogs. Healthy adult dogs (3M, 3F) 18.5–25 kg (mean ± SD, 23 ± 2.4) were utilized in a randomized cross over design. All dogs were conditioned to lie in lateral recumbency with manual restraint. Doppler measurement of systolic blood pressure (SBP), with inflatable cuffs 40% of leg circumference, was performed simultaneously with echocardiographic measurements. Baseline measurements were recorded and one of the treatments was administered: T1, 0.5 mL saline (S)(p) + RO (40 µg kg−1); T2, G(p) + RO (40 µg kg−1); T3, S(p) + RO (120 µg kg−1); T4, G(p) + RO (120 µg kg−1); T5, S(p) + G(c) + RO (120 µg kg−1). Measurements were repeated 15 minutes after G(p) or S(p); RO or G(c) were administered 20 minutes after G(p) or S(p), and further measurements were taken at 10, 20, 30, 60, and 90 minutes after RO. Dimensions of the left ventricle (LVID), interventricular septum (IVS), and left ventricular free wall (LVFW) were obtained in systole (S) and diastole (D). Heart rate (HR) and amplitude of motion (Amp) of the IVS and LVFW were also measured. From these, measures of wall stress (SBPxLVID-S)/([4LVFW-S](1 + [LVFW-S/LVID-S])) and fractional shortening (FS) of the left ventricle (LVID-D – LVID-S)/(LVID-D) were obtained. Data were analyzed by a two-way anova, with an LSD posthoc test and 95% confidence level. Echocardiographic indices of cardiac performance (LVID-D, LVID-S, FS, AMP-LVFW) and HR were decreased in all RO sedated dogs (p