Micro-consolidation occurs when learning an implicit motor sequence, but is not influenced by HIIT exercise.

We investigated if micro-consolidation, a phenomenon recently discovered during the brief rest periods between practice when learning an explicit motor sequence, generalises to learning an implicit motor sequence task. We demonstrate micro-consolidation occurs in the absence of explicit sequence awareness. We also investigated the effect of a preceding bout of high-intensity exercise, as exercise is known to augment the consolidation of new motor skills. Micro-consolidation was not modified by exercise.

Chronic kidney disease and risk of kidney or urothelial malignancy: systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent, affecting approximately 11% of U.S. adults. Multiple studies have evaluated a potential association between CKD and urinary tract malignancies. Summary estimates of urinary tract malignancy risk in CKD patients with and without common co-existing conditions may guide clinical practice recommendations. METHODS: Four electronic databases were searched for original cohort studies evaluating the association between CKD and urinary tract cancers (kidney cancer and urothelial carcinoma) through May 25, 2023, in persons with at least moderate CKD and no dialysis or kidney transplantation. Quality assessment was performed for studies meeting inclusion criteria using the Newcastle-Ottawa Scale. Meta-analysis with a random-effects model was performed for unadjusted incidence rate ratios (IRR) as well as adjusted hazard ratios (aHR) for confounding conditions (diabetes, hypertension, and/or tobacco use), shown to have association with kidney cancer and urothelial carcinoma. Sub-analysis was conducted for estimates associated with CKD stages separately. RESULTS: Six cohort studies with 8 617 563 persons were included. Overall, methodological quality of the studies was good. CKD was associated with both higher unadjusted incidence and adjusted hazard of kidney cancer (IRR, 3.36; 95% confidence interval [CI], 2.32-4.88; aHR, 2.04; 95% CI, 1.77-2.36) and urothelial cancer (IRR, 3.96; 95% CI, 2.44-6.40; aHR, 1.40; 95% CI, 1.22-1.68) compared with persons without CKD. Examining incident urinary tract cancers by CKD severity, risks were elevated in stage 3 CKD (kidney aHR, 1.89; 95% CI, 1.56-2.30; urothelial carcinoma aHR, 1.40; 95% CI, 1.18-1.65) as well as in stages 4/5 CKD (kidney cancer aHR, 2.30; 95% CI, 2.00-2.66, UC aHR, 1.24; 95% CI, 1.04-1.49). CONCLUSIONS: Even moderate CKD is associated with elevated risk of kidney cancer and UC. Providers should consider these elevated risks when managing individuals with CKD, particularly when considering evaluation for the presence and etiology of hematuria.

Does a Five-Day Drama Program Support Men in Prison to Develop Their Self-Confidence?

This paper evaluates an established five-day drama project, designed, and delivered by a professional company, aimed to support the development of self-confidence of seven men with a history of substance misuse in a category C prison. The project involved creation of a safe space, improvised role-play, development of communication skills, and exploration of substance misuse, culminating in a performance. Audience members included prison staff, governors, healthcare staff, and prisoners. A mixed method approach was used to evaluate the project. Participant's pre and post project self-confidence and feelings of positivity were collated by a questionnaire compromising of closed questions and measured using a Likert scale. On the last day of the project qualitative interviews were conducted using open ended questions. The findings conclude that the use of drama can support development of self-confidence in men in prison. The project encouraged skills such as, commitment, communication, collaboration, and motivation enhancing the likelihood of rehabilitation and promoting crime abstinence. Further research with a larger sample size will identify if the changes the men experienced were statistically significant and maintained.

Plant Promoters and Terminators for High-Precision Bioengineering.

High-precision bioengineering and synthetic biology require fine-tuning gene expression at both transcriptional and posttranscriptional levels. Gene transcription is tightly regulated by promoters and terminators. Promoters determine the timing, tissues and cells, and levels of the expression of genes. Terminators mediate transcription termination of genes and affect mRNA levels posttranscriptionally, e.g., the 3'-end processing, stability, translation efficiency, and nuclear to cytoplasmic export of mRNAs. The promoter and terminator combination affects gene expression. In the present article, we review the function and features of plant core promoters, proximal and distal promoters, and terminators, and their effects on and benchmarking strategies for regulating gene expression.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality

Objectives: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. Methods: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. Results: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. Conclusion: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality.

OBJECTIVES: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. METHODS: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. RESULTS: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. CONCLUSION: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Three-Dimensional-Printed Electrochemical Multiwell Plates for Monitoring Food Intolerance from Intestinal Organoids.

Common symptoms of food intolerance are caused by chemical components within food that have a pharmacological activity to alter the motility of the gastrointestinal tract. Food intolerance is difficult to diagnose as it requires a long-term process of eliminating foods that are responsible for gastrointestinal symptoms. Enterochromaffin (EC) cells are key intestinal epithelium cells that respond to luminal chemical stimulants by releasing 5-HT. Changes in 5-HT levels have been shown to directly alter the motility of the intestinal tract. Therefore, a rapid approach for monitoring the impact of chemicals in food components on 5-HT levels can provide a personalized insight into food intolerance and help stratify diets. Within this study, we developed a three-dimensional (3D)-printed electrochemical multiwell plate to determine changes in 5-HT levels from intestinal organoids that were exposed to varying chemical components found in food. The carbon black/poly-lactic acid (CB/PLA) electrodes had a linear range in physiological concentrations of 5-HT (0.1-2 µM) with a limit of detection of 0.07 µM. The electrodes were stable for monitoring 5-HT overflow from intestinal organoids. Using the electrochemical multiwell plate containing intestinal organoids, increases in 5-HT were observed in the presence of 0.1 mM cinnamaldehyde and 10 mM quercetin but reduction in 5-HT levels was observed in 1 mM sorbitol when compared to control. These changes in the presence of chemicals commonly found in food were verified with ex vivo ileum tissue measurements using chromatography and amperometry with boron-doped diamond electrodes. Overall, our 3D electrochemical multiwell plate measurements with intestinal organoids highlight an approach that can be a high-throughput platform technology for rapid screening of food intolerance to provide personalized nutritional diet.

Disorders of Salt and Water Balance After Pituitary Surgery.

Transsphenoidal surgery is the first-line treatment for many clinically significant pituitary tumors and sellar lesions. Although complication rates are low when performed at high-volume centers, disorders of salt and water balance are relatively common postoperatively. Both, or either, central diabetes insipidus (recently renamed arginine vasopressin deficiency - AVP-D), caused by a deficiency in production and/or secretion of arginine vasopressin, and hyponatremia, most commonly secondary to the syndrome of inappropriate antidiuresis, may occur. These conditions can extend hospital stay and increase the risk of readmission. This article discusses common presentations of salt and water balance disorders following pituitary surgery, the pathophysiology of these conditions, and their diagnosis and management.

"It cannot be boring!": Developing a measure of function for young adults accessing integrated youth services.

BACKGROUND: In Canada, the prevalence of mental health challenges is highest in young people aged 12-24. Mental health challenges frequently cause marked functional impairment. Despite this, we are unaware of any existing conceptualization and/or measures of function that has been developed from the perspective of young people. The objective of this paper is to develop a conceptual and measurement model, including a preliminary set of items, for an outcome measure of function for young adults accessing mental health services. METHODS: We conducted this study in three phases. In phase 1, we conducted three focus groups to conceptualize function as a construct from the perspective of young adults. In phase 2, we co-designed a set of items with youth (n = 4) to capture the construct. In phase 3, we invited young people (n = 12) accessing mental health services to complete workbooks and participate in one of two focus groups to evaluate whether items were clear, captured function comprehensively, and were relevant. We transcribed and compiled all data to eliminate, refine and generate new items. RESULTS: In phase 1, a conceptual model of function was developed with three main themes: basic needs, roles and responsibilities, and social connections. In phase 2, 97 candidate items were developed, and in phase 3, a candidate pool of 50 items resulted for psychometric testing. CONCLUSION: This youth-centred conceptualization of function and preliminary item bank has the potential to advance person-centred care, outcomes, and experiences for youth seeking mental health services.

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

PURPOSE: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. EXPERIMENTAL DESIGN: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. CONCLUSIONS: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

'Make the Most of the Situation'. Older Adults' Experiences during COVID-19: A Longitudinal, Qualitative Study.

The COVID-19 pandemic restrictions have been associated with increased social isolation and reduced participation in older adults. This longitudinal qualitative study drew on life course theory to analyse data from a series of four sequential semi-structured interviews conducted between May 2020-February 2021 with adults aged 65+ (n = 12) to explore older adults' experiences adjusting to the COVID-19 pandemic. We identified three themes: (1) Struggling 'You realize how much you lost' describes how older adults lost freedoms, social connections and activities; (2) Adapting 'whatever happens, happens, I'll do my best', revealing how older adults tried to maintain well-being, participation and connection; and (3) Appreciating 'enjoy what you have', exploring how older adults found pleasure and contentment. Engagement in meaningful activities and high-quality social interactions supported well-being during the COVID-19 pandemic for older adults. This finding highlights the need for policies and services to promote engagement during longstanding global crises.

Treatment strategies for clozapine-induced hypotension: a systematic review.

Background: Clozapine is the most effective medication for treatment-refractory schizophrenia but is associated with significant adverse drug effects, including hypotension and dizziness, which have a negative impact on quality of life and treatment compliance. Available evidence for the management of clozapine-induced hypotension is scant. Objectives: Due to limited guidance on the safety and efficacy of pharmacological treatments for clozapine-induced hypotension, we set out to systematically review and assess the evidence for the management of clozapine-induced hypotension and provide guidance to clinicians, patients, and carers. Design: We undertook a systematic review of the safety and efficacy of interventions for clozapine-induced hypotension given the limited available evidence. Data Sources and Methods: PubMed, Embase, PsycINFO, CINAHL, and the Cochrane trial Registry were searched from inception to November 2021 for literature on the treatment strategies for clozapine-induced hypotension and dizziness using a PROSPERO pre-registered search strategy. For orthostatic hypotension, we developed a management framework to assist in the choice of intervention. Results: We identified nine case studies and four case series describing interventions in 15 patients. Hypotension interventions included temporary clozapine dose reduction, non-pharmacological treatments, and pharmacological treatments. Midodrine, fludrocortisone, moclobemide and Bovril® combination, and etilefrine were associated with improvement in symptoms or reduction in orthostatic hypotension. Angiotensin II, arginine vasopressin, and noradrenaline successfully restored and maintained mean arterial pressure in critical care situations. A paradoxical reaction of severe hypotension was reported with adrenaline use. Conclusion: Orthostatic hypotension is a common side effect during clozapine titration. Following an assessment of the titration schedule, salt and fluid intake, and review of hypertensive and nonselective α1-adrenergic agents, first-line treatment should be a temporary reduction in clozapine dose or non-pharmacological interventions. If orthostatic hypotension persists, fludrocortisone should be trialled with monitoring of potassium levels and sodium and fluid intake. Midodrine may be considered second-line or where fludrocortisone is contraindicated or poorly tolerated. For patients on clozapine with hypotension in critical care settings, the use of adrenaline to maintain mean arterial pressure should be avoided. Registration: PROSPERO (Registration No. CRD42020191530).

Treatment strategies for clozapine-induced nocturnal enuresis and urinary incontinence: a systematic review.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia but is associated with significant adverse drug reactions, including nocturnal enuresis and urinary incontinence. This side effect can be burdensome and lead to medication nonadherence and psychotic relapse. Evidence to guide treatment of clozapine-induced nocturnal enuresis and urinary incontinence is sparse. We therefore aimed to synthesize the evidence base to guide management for clinicians, patients, and their carers. METHODS: We systematically searched PubMed, Embase, PsycInfo, CINAHL, and the Cochrane Trial Registry databases from inception to May 2021 for publications on management of clozapine-induced nocturnal enuresis and urinary incontinence using a PROSPERO preregistered search strategy. RESULTS: We identified 22 case reports and case series describing 74 patients. Interventions included clozapine dose reduction, nonpharmacological treatment, and pharmacological treatments. Among pharmacological treatments, desmopressin, oxybutynin, trihexyphenidyl, tolterodine, imipramine, amitriptyline, ephedrine, pseudoephedrine, aripiprazole, and verapamil were associated with complete resolution of nocturnal enuresis and urinary incontinence. Balancing evidence for effectiveness against risk of adverse effects, we developed a management framework for clozapine-induced nocturnal enuresis and urinary incontinence. CONCLUSIONS: Following assessment of urological, psychiatric, pharmacological, and common comorbid medical issues, first-line treatments should be nonpharmacological, including bathroom alarms, voiding before bedtime, and nocturnal fluid restriction. If these interventions do not provide adequate relief, aripiprazole should be trialed. Desmopressin may be considered for severe refractory cases, but monitoring for hyponatremia is essential.

The Impact of COVID-19-Related Restrictions on Social and Daily Activities of Parents, People With Disabilities, and Older Adults: Protocol for a Longitudinal, Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has led to wide-scale changes in societal organization. This has dramatically altered people's daily activities, especially among families with young children, those living with disabilities such as spinal cord injury (SCI), those who have experienced a stroke, and older adults. OBJECTIVE: We aim to (1) investigate how COVID-19 restrictions influence daily activities, (2) track the psychosocial effects of these restrictions over time, and (3) identify strategies to mitigate the potential negative effects of these restrictions. METHODS: This is a longitudinal, concurrent, mixed methods study being conducted in British Columbia (BC), Canada. Data collection occurred at four time points, between April 2020 and February 2021. The first three data collection time points occurred within phases 1 to 3 of the Province of BC's Restart Plan. The final data collection coincided with the initial distribution of the COVID-19 vaccines. At each time point, data regarding participants' sociodemographics, depressive and anxiety symptoms, resilience, boredom, social support, instrumental activities of daily living, and social media and technology use were collected in an online survey. These data supplemented qualitative videoconference interviews exploring participants' COVID-19-related experiences. Participants were also asked to upload photos representing their experience during the restriction period, which facilitated discussion during the final interview. Five groups of participants were recruited: (1) families with children under the age of 18 years, (2) adults with an SCI, (3) adults who experienced a stroke, (4) adults with other types of disabilities, and (5) older adults (>64 years of age) with no self-reported disability. The number of participants we could recruit from each group was limited, which may impact the validity of some subgroup analyses. RESULTS: This study was approved by the University of British Columbia Behavioural Research Ethics Board (Approval No. H20-01109) on April 17, 2020. A total of 81 participants were enrolled in this study and data are being analyzed. Data analyses are expected to be completed in fall 2021; submission of multiple papers for publication is expected by winter 2021. CONCLUSIONS: Findings from our study will inform the development and recommendations of a new resource guide for the post-COVID-19 period and for future public health emergencies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/28337.

Copeptin is increased by nausea and vomiting during hypertonic saline infusion in healthy individuals.

OBJECTIVE: Measurement of hypertonic saline-stimulated copeptin has recently been described for the differentiation of polyuria-polydipsia syndrome. This study aims to determine the copeptin response to intravenous 3% hypertonic saline, including evaluation of adverse effects, in a local cohort of healthy adults >18 years in Australia. DESIGN: Prospective clinical study. METHODS: Twenty healthy volunteers (10 males and 10 females) were recruited. Participants underwent infusion of 3% hypertonic saline via a previously described standardized protocol, until the plasma sodium was ≥150 mmol/L, with measurement of plasma copeptin. RESULTS: Mean peak sodium was 152 mmol/L ± SD 1.4 with osmolality 315 mmol/kg ± SD 3.9. Median volume of hypertonic saline infused to reach target sodium ≥ 150 mmol/L was 1536 mL (IQR 1362, 1992). Mean rate of plasma sodium rise was 5.9 mmol/L/hour ± SD 1.5. Hypertonic saline-stimulated copeptin had non-parametrical distribution with median of 33.8 pmol/L (IQR 27.6, 63.6). Overall median symptom burden was 6/10 (range 3/10-9/10). Copeptin was significantly higher for those who experienced nausea and/or vomiting (n = 13) (median 39.0 pmol/L; IQR 32.5, 90), compared to those participants who did not experience either (median 20.0 pmol/L; IQR 13.0, 31.0) (P = 0.003). There were no serious adverse events. CONCLUSION: Hypertonic saline-stimulated copeptin measurements were similar in our population compared with previously reported reference intervals in healthy volunteers. There is a wide range of stimulated copeptin measurements in the healthy population. Nausea and vomiting are common adverse effects which enhance the copeptin response.

Exclusion of Suicidal Participants From Randomized Controlled Trials for Posttraumatic Stress Disorder: A Meta-Analysis.

There has been a lack of consensus regarding whether to include or exclude participants with suicidal ideation (SI) from posttraumatic stress disorder (PTSD) psychotherapy clinical trials and, until recently, how best to report adverse events related to suicide risk. Without consistent reporting or evaluation of SI as an outcome, clinical practice guidelines are limited in their ability to recommend interventions for this common co-occurrence. In the present meta-analysis, we compared randomized controlled trials (RCTs) of PTSD psychotherapies, based on their suicide exclusion criteria. The databases PILOTS, PsycINFO, and PubMed were searched for RCTs of psychotherapy that lasted more than 4 weeks and included adults who met the diagnostic criteria for PTSD. Included studies (N = 48) were coded by two independent reviewers. A random-effects model was used to calculate the pooled effect sizes for trials that excluded (n = 31) and did not exclude SI (n = 17). A test statistic for the significance of effect revealed that the difference between these two groups' effect sizes was not significant, z = 0.96, p = .341. This suggests that the effects observed in clinical trials are not significantly impacted by SI-related exclusion criteria.

Evaluation of Bayesian Forecasting Methods for Prediction of Tacrolimus Exposure Using Samples Taken on Two Occasions in Adult Kidney Transplant Recipients.

BACKGROUND: Bayesian forecasting-based limited sampling strategies (LSSs) for tacrolimus have not been evaluated for the prediction of subsequent tacrolimus exposure. This study examined the predictive performance of Bayesian forecasting programs/services for the estimation of future tacrolimus area under the curve (AUC) from 0 to 12 hours (AUC0-12) in kidney transplant recipients. METHODS: Tacrolimus concentrations were measured in 20 adult kidney transplant recipients, 1 month post-transplant, on 2 occasions one week apart. Twelve samples were taken predose and 13 samples were taken postdose at the specified times on the first and second sampling occasions, respectively. The predicted AUC0-12 (AUCpredicted) was estimated using Bayesian forecasting programs/services and data from both sampling occasions for each patient and compared with the fully measured AUC0-12 (AUCmeasured) calculated using the linear trapezoidal rule on the second sampling occasion. The bias (median percentage prediction error [MPPE]) and imprecision (median absolute prediction error [MAPE]) were determined. RESULTS: Three programs/services were evaluated using different LSSs (C0; C0, C1, C3; C0, C1, C2, C4; and all available concentrations). MPPE and MAPE for the prediction of fully measured AUC0-12 were <15% for each program/service (with the exclusion of when only C0 was used), when using estimated AUC from data on the same (second) occasion. The MPPE and MAPE for the prediction of a future fully measured AUC0-12 were <15% for 2 programs/services (and for the third when participants who had a tacrolimus dose change between sampling days were excluded), when the occasion 1-AUCpredicted, using C0, C1, and C3, was compared with the occasion 2-AUCmeasured. CONCLUSIONS: All 3 Bayesian forecasting programs/services evaluated had acceptable bias and imprecision for predicting a future AUC0-12, using tacrolimus concentrations at C0, C1, and C3, and could be used for the accurate prediction of tacrolimus exposure in adult kidney transplant recipients.

Effects of age and social isolation on murine hippocampal biochemistry and behavior.

Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone (CORT) and interleukin-6 (IL-6) were determined and serum collected for basal CORT analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum CORT determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum CORT post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum CORT post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA:5-HT). In conclusion, the lack of response to SI in the aged mice may affect health by preventing them adapting to new stressors, while the synergistic effects of SI with age would increase allostatic load and enhance the deleterious effects of the ageing process.

Involvement of muscarinic receptor mechanisms in antidepressant drug action.

Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Furey and Drevets in 2006 showed antidepressant response in patients after only a few doses with the antimuscarinic drug scopolamine. Several clinical reports have generally confirmed scopolamine as a rapid-acting antidepressant. The data with scopolamine are consistent with the adrenergic/cholinergic hypothesis of mania/depression derived from clinical reports originating in the 1970s from Janowsky and colleagues. Additional support for a role for muscarinic receptors in mood disorders comes from the greater efficacy of conventional antidepressants that have relatively high levels of muscarinic receptor blocking actions (e.g., the tricyclic antidepressant amitriptyline vs the selective serotonin reuptake inhibitor fluoxetine). There appears to be appreciable overlap in the mechanisms of action of scopolamine and other rapid-acting antidepressants (ketamine) or putative rapid-acting agents (mGlu2/3 receptor antagonists) although gaps exist in the experimental literature. Current hypotheses regarding the mechanisms underlying the rapid antidepressant response to scopolamine posit an M1 receptor subtype-initiated cascade of biological events that involve the amplification of AMPA receptors. Consequent impact on brain-derived neurotrophic factor and mTor signaling pathways result in the induction of dendritic spines that enable augmented functional connectivity in brain areas regulating mood. Two major goals for research in this area focus on finding ways in which scopolamine might best be utilized for depressed patients and the discovery of alternative compounds that improve upon the efficacy and safety of scopolamine.

From shadow to change agent: Revitalization of the clinical nurse specialist role.

In 2017, A Magnet designated 528-bed tertiary care community hospital underwent significant leadership change. With that, came the opportunity to redefine the Clinical Nurse Specialist (CNS) role within the largest of five hospitals in a two-billion-dollar health care system. Through evidence-based practice, effective leadership, and the vision of a change agent, this is the story of the revitalization of the CNS role.