Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner.

Serotonin 2A receptors (5-HT 2A Rs) mediate the effects of psychedelic drugs. 5-HT 2A R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT 2A R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT 2A Rs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT 2A R expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a -Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT 2A R-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT 2A R expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a -Cre compared with control mice, indicating that optogenetic activation of 5-HT 2A R+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT 2A R expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT 2A R expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT 2A Rs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT 2A R agonist but is necessary for induction of HTRs by a 5-HT 2A R agonist in a sex-dependent manner.

Understanding transitions in care for persons with limb loss: a qualitative study exploring health care providers' perspectives.

PURPOSE: To explore health care providers' (HCP) experiences related to transitions in care from inpatient rehabilitation to the community for patients with limb loss. MATERIALS AND METHODS: A qualitative study was conducted using semi-structured interviews. Participants were eligible if they were HCPs currently working in amputation rehabilitation at a rehabilitation hospital in Ontario, Canada, with at least 1-year experience in this setting, and could speak and understand English. Data were analyzed thematically using the six-step process of the DEPICT model dynamic reading, engaged codebook development, participatory coding, inclusive reviewing and summarizing of categories, collaborative analyzing and translating. RESULTS: Fourteen HCPs from a variety of health care professions participated in this study. Five key themes describe participants' perspectives on the factors impacting patients' transition in care following limb loss. Specifically, participants emphasized patient preparedness, HCP follow-up, finances and funding, patient self-management skills, and psychosocial support as factors that could influence the transition in care. CONCLUSION: This study identified challenges to transitions in care for people with limb loss. Future research is needed to evaluate solutions to address these challenges in transitions in care.

Suboptimal transitions in care can result in readmission to the hospital, emergency department visits, and increased health care costs.Patient preparedness, follow-up, finances and funding, patient self-management skills, and psychosocial support are perceived to influence transitions in care from inpatient rehabilitation to the community.Improved access to follow-up and supports in the community and improved communication across the continuum of care could improve transitions for people with limb loss.

Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia.

Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer's disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice. To identify Egr3-dependent genes that may regulate these processes, we conducted an expression microarray on hippocampi from wildtype (WT) and Egr3-/- mice following electroconvulsive seizure (ECS), a stimulus that induces maximal expression of immediate early genes including Egr3. We identified 69 genes that were differentially expressed between WT and Egr3-/- mice one hour following ECS. Bioinformatic analyses showed that many of these are altered in, or associated with, schizophrenia, including Mef2c and Calb2. Enrichr pathway analysis revealed the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g) as a leading group of differentially expressed genes. Together with differentially expressed genes in the AP-1 transcription factor family genes (Fos, Fosb), and the centromere organization protein Cenpa, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the DNA damage response. Our findings show that EGR3 is critical for the expression of genes that are mis-expressed in schizophrenia and reveal a novel requirement for EGR3 in the expression of genes involved in activity-induced DNA damage response.

Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3.

Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6-8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (-/-) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.

Developing a research agenda on exercise and physical activity for people with limb loss in Canada.

PURPOSE: There is a lack of high-quality evidence about the effects of exercise or physical activity interventions for adults with lower limb amputations (LLAs). A planning meeting involving stakeholders (i.e., people with LLA, community advocates, health care providers, researchers) was organized to identify key research priorities related to exercise and physical activity for people with LLAs. METHODS: We used a collaborative prioritized planning process with a pre-meeting survey and 2-day virtual meeting that included: identification and prioritization of challenges or gaps; identification and consolidation of solutions; and action planning. This process integrated a modified Delphi approach, including anonymous feedback in two surveys. RESULTS: Thirty-five stakeholders participated. Six challenges related to exercise and physical activity for people with LLA were prioritized. One solution was prioritized for each challenge. After consolidation of solutions, participants developed five research action plans for research including: developing an on-line interface; developing and evaluating peer-support programs to support physical activity; examining integration of people with LLA into cardiac rehabilitation; development and evaluation of health provider education; and determining priority outcomes related to physical activity and exercise. CONCLUSIONS: This collaborative process resulted in an action plan for amputation research and fostered collaborations to move identified priorities into action.IMPLICATIONS FOR REHABILITATIONLower limb amputations impact mobility leading to lower levels of physical activity.There are research gaps in our understanding of the effects of exercise or physical activity interventions for adults with lower limb amputations.Through a collaborative planning process, participants prioritized research directions on physical activity and exercise for people with LLA to advance research in the field.Action plans for research focused on developing online resources, peer support, cardiac rehabilitation for people with LLA, health provider education and determining priority outcomes related to physical activity and exercise.

Establishing competency-based measures for Department of Veterans Affairs post-graduate nurse practitioner residencies.

BACKGROUND: In the past decade, numerous nurse residency models have been created and implemented nationwide; however, validated specialty-specific competency standards have not been established to evaluate Nurse Practitioner (NP) resident core competencies. PURPOSE: To report the specialty-specific competency assessment tool devised to assess Department of Veterans Affairs (VA) NP residents' competencies and discuss the VA NP residency program's effectiveness in expanding new graduate NP knowledge and skills in the veteran-centric care setting. METHODS: The VA Nursing Academic Partnership NP residency faculty established and piloted a web-based Nurse Practitioner Resident Competency Assessment (NPRCA) instrument for the comprehensive, specialty-specific assessment of individual NP resident's skill competencies across 24 areas. RESULTS: The VA specialty-specific competency assessment instrument demonstrates strong internal consistency. The robust VA NP residency program enhances new graduate NP competencies. CONCLUSIONS: The VA NP residency model can further the goal of standardizing clinical competencies in NP residency programs.

A qualitative study examining prosthesis use in everyday life in individuals with lower limb amputations.

BACKGROUND: Lower limb amputation (LLA) is a life-changing event that affects functional mobility and participation in everyday life. Prostheses provide individuals with LLA the opportunity to improve mobility and quality of life; however, existing literature suggests that there is underuse of prostheses. OBJECTIVES: The purpose of this study is to describe how individuals with major LLA use their prosthesis in everyday life and describe barriers and facilitators that influence prosthesis use. STUDY DESIGN: A qualitative descriptive methodology was used. METHODS: Ten community dwelling adults (>18 years) with unilateral major LLAs (transtibial, transfemoral, and knee disarticulation) attending outpatient follow-up at a specialized rehabilitation center were recruited. Participants were purposively sampled for variation in prosthesis use and level of amputation. One-on-one semistructured in-depth interviews were conducted in person or by telephone. The interviews were audio recorded, transcribed verbatim, and analyzed inductively using thematic analysis. RESULTS: The experiences of individuals with major LLA were organized into three overarching themes: everyday experiences using a prosthesis, extrinsic factors influencing prosthesis use, and intrinsic factors influencing prosthesis use. These themes, and their associated subthemes, highlight how individuals use their prosthesis and the various factors perceived to act as barriers and facilitators to prosthesis use in everyday life. CONCLUSIONS: These findings provide valuable insight into the everyday experiences of individuals with LLA and can be used to implement strategies to optimize prosthesis use.

The aging veteran population: Promoting awareness to influence best practices.

The older adult population is the most rapidly growing population in the United States. It is projected that by 2035, the population of adults older than 65 years is expected to be greater than the population of children. The projected number of Veterans age 60 and older is about 11 million. Along with common age-related complex and high-risk chronic medical conditions, care of older adult Veteran requires a holistic approach that focuses on the culture, and subcultures, and unique health care needs resultant of military service. Veterans' health care is often multifocal and complex, requiring an integrated, collaborative, and comprehensive model of care that better facilitates meeting health goals to the degree most realistic and attainable for each older adult Veteran. This highlights the need to promote awareness and provide educational opportunities for engaging in best practices that meet the unique needs of the aging Veteran population.

Oral health and behaviours of people living with Multiple Sclerosis in Australia.

OBJECTIVES: The literature describing the oral health of people with Multiple Sclerosis (MS) is scant and the findings equivocal. The aim of this study was to describe the oral health and oral self-care behaviours of people living with MS and compare it to the Australian population. METHODS: Participants enrolled with the Australian MS Longitudinal Study (AMSLS) were invited to participate in the survey using an online or paper-based questionnaire. Data were collected on level of disability, oral health, oral self-care and factors influencing attendance for oral health care. RESULTS: Completed questionnaires were received for 1523 respondents. Over one-fifth (n = 320; 22%) rated their oral health as fair or poor, and more than half (n = 840; 57%) reported toothache in the last 12 months. These proportions were higher than those for the general Australian adult population (oral health prevalence ratio (PR) = 1.25 [1.12, 1.40]; toothache PR = 3.63 [3.39, 3.88]), and this is despite comparable or better self-maintenance habits and dental attendance reported by respondents. People with MS reported high rates of mouth dryness (68.4%), teeth sensitivity (64.7%), change of taste (40.5%) and orofacial pain (39.0%); fewer than 10% experienced none of these. There was a lower prevalence of self-reported need for treatment (extraction or filling) than in the Australian adult population (15.8% vs 32.9%). CONCLUSIONS: People with MS have a greater oral health burden, demonstrated by their poorer self-reported oral health than the Australian adult population. Furthermore, they experience high rates of toothache, mouth dryness, teeth sensitivity, change of taste and orofacial pain. These findings are contrary to their self-reported good oral self-care and dental attendance habits and suggest some of the oral health impacts are due to MS rather than dental behaviours.

Implementing an Integrated Team-Based Model of Care.

Team-based methods of delivering primary care were launched nationally within the US Department of Veterans Affairs (VA) through the Patient Aligned Care Teams (PACT) initiative in 2010. The most essential component of PACT is the establishment of partnerships between veterans and their health care teams. The purpose of PACT is to improve and transform the way in which veterans receive health care. This partnership is aimed at promoting efficiency and improving the quality of care and clinical outcomes by providing holistic care that embodies the whole person.

Aggressive behavior, brain size and domestication in clonal rainbow trout lines.

Domestication causes behavior and brain size changes in many species. We addressed three questions using clonal rainbow trout lines: What are the mirror-elicited aggressive tendencies in lines with varying degrees of domestication? How does brain size relate to genotype and domestication level? Finally, is there a relationship between aggressive behavior and brain size? Clonal lines, although sampling a limited subset of the species variation, provide us with a reproducible experimental system with which we can develop hypotheses for further research. We performed principal component analyses on 12 continuous behavior and brain/body size variables and one discrete behavioral variable ("yawn") and detected several aggression syndromes. Two behaviors, "freeze" and "escape", associated with high domestication; "display" and "yawn" behavior associated with wild lines and "swim against the mirror" behavior associated with semi-wild and domestic lines. Two brain size traits, total brain and olfactory volume, were significantly related to domestication level when taking total body size into account, with domesticated lines having larger total brain volume and olfactory regions. The aggression syndromes identified indicate that future QTL mapping studies on domestication-related traits would likely be fruitful.

Evaluating a fast-track discharge service for patients wishing to die at home.

BACKGROUND: The UK Department of Health's End of Life Care Strategy highlighted the low percentage of patients who achieve their wish to die at home (~20%). Figures in south west London were below the London regional average. This paper reports an attempt to improve the proportion of patients from one hospital in the area achieving their preferred place of death. METHODOLOGY: A funded initiative by two local primary care trusts allowed the development of a 7-day-per-week fast-track discharge service provided by the hospital palliative care team. The hospital team acted as coordinators, ensured that the correct medication and equipment would be available at the home, and personally transferred the patients to community services. RESULTS: Data is presented from the first representative period of fast-track discharging (June 2009-July 2010). A total of 110 discharges were facilitated over this time, with the rate increasing as the service developed. The vast majority of discharges occurred within 72 hours, and a significant number (~20%) occurred within 24 hours. CONCLUSIONS: The data indicate that the new service is effective. There are logistical problems in providing such a service and these are discussed. Further work is required to determine the feasibility of extending this service model to other acute hospitals and to evaluate its health-economic impact.

Achieving the preferred place of care for hospitalized patients at the end of life.

BACKGROUND: The Department of Health end-of-life strategy contains a number of quality markers which include taking into account patients' wishes for their final place of care. There is a wide variation in how this information is recorded. METHODS: An audit was conducted on discussion of preferred place of care (PPC) for all patients referred to the hospital palliative care team who died during the audit period. Barriers to achieving PPC and the efficacy of a fast track discharge service were also monitored. The audit was first done in 2007 and was repeated in 2009. RESULTS: There was an increase in recording PPC. Overall PPC wishes were ascertained for 87% of the patients seen by the team. The PPC was achieved in 76% of cases. The number of patients wishing to die in hospital significantly increased over the audit cycle (from 10% to 30%). Approximately one-third of patients changed their minds regarding PPC. CONCLUSIONS: The data highlights the need to distinguish between preferred place of care and preferred place of death. Patients' wishes regarding PPC change as death approaches. A greater number of patients wished to die in hospital than was expected.

Patient preference and gait efficiency in a geriatric population with transfemoral amputation using a free-swinging versus a locked prosthetic knee joint.

OBJECTIVE: To investigate patient preference, walking speed, and prosthetic use in a geriatric population with transfemoral amputation using a free-swinging prosthetic knee or a locked knee joint. DESIGN: Before-after trial. SETTING: Ambulatory patients at an amputee rehabilitation facility. PARTICIPANTS: A convenience sample of 14 geriatric individuals with a unilateral dysvascular transfemoral amputation (age range, 61-80y), who were using a prosthesis with a free-swinging knee in the community, 3 months after discharge from an amputee rehabilitation program. INTERVENTION: Change from a free-swinging knee to a locked knee. MAIN OUTCOME MEASURES: Patient preference, distance walked in 2 minutes, and prosthetic use as measured by the Houghton Scale. RESULTS: Eleven of 14 participants preferred the locked knee. Irrespective of preference, the mean 2-minute walk distance was 44.9 +/- 28.9m with the free-swinging knee and 54.4 +/- 35m with the locked knee (P = .001). Prosthetic use was greater with the locked knee (7.8 +/- 2.2) than with the free-swinging knee (6.6 +/- 2.5) (P = .01). CONCLUSIONS: Most geriatric participants with transfemoral amputation preferred locked knees and walked faster and used their prostheses more when using a locked knee prosthesis.