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The outcomes of cervical incomplete spinal cord injury (SCI) are heterogeneous. This study sought to dissociate subgroups of cervical incomplete SCI patients with distinct longitudinal temporal profiles of recovery in upper limb motor function. Patients with cervical incomplete SCI (American Spinal Injury Association Impairment Scale [AIS] B-D; C1-C8) were identified from four prospective, multi-center SCI datasets. A group-based trajectory model was fit to longitudinal upper extremity motor scores out to 1 year. Multi-variable multinomial logistic regression was performed to identify features that characterize each trajectory group. A classification system for predicting trajectory group at baseline was developed by recursive partitioning. In total, 801 patients were eligible. Four distinct trajectory groups were identified: 1) "Poor outcome": Severe injury, very minimal recovery; 2) "Moderate recovery": Moderate-to-severe injury, moderate recovery; most recovery occurs by 6 months, with mild, gradual recovery continuing thereafter; 3) "Good recovery": Moderate injury, good recovery; most recovery occurs by 3 months, with mild, gradual recovery continuing thereafter; and 4) "Excellent outcome": Mild injury, recovery to normal/near-normal by 3 months. On adjusted analyses, older age was associated with lower likelihood of "excellent outcome" (

Antipsychotics are used in the treatment of schizophrenia and other psychiatric disorders. Generally, they are divided into typical and atypical ones, according to the fact that atypical antipsychotics induce fewer side effects and are more effective in terms of social and cognitive improvements. Their pharmacological effects are mediated via broad range of receptors that consequently influence different cellular signalling pathways. Antipsychotics produce undesirable side effects that range from relatively minor to life threatening. In vitro and in vivo studies have pointed to neurotoxic effect exerted by some antipsychotics and have shown that apoptosis might play role in some side effects induced by antipsychotics, including tardive dyskinesia, weight gain, agranulocytosis, osteoporosis, myocarditis, etc. Although cumulative data have suggested safety of atypical antipsychotics use during pregnancy, some of them have been shown to induce apoptotic neurodegenerative and structural changes in fetal brains with long-lasting impact on cognitive impairment of offspring. Typical antipsychotics seem to be more cytotoxic than atypical ones. Recently, epidemiological studies have shown lower incidence of cancer in schizophrenic patients that suggest the ability of antipsychotics to suppress risk of cancer development. Some antipsychotics have been reported to inhibit cancer cell proliferation and induce their apoptosis. Therefore, antipsychotics apoptotic effect may be used as a tool in the treatment of some types of cancer, especially in combinatorial therapies. In this mini-review, we focused on pro- and antiapoptotic or 'Dr. Jekyll and Mr. Hyde' effects of antipsychotics, which can be involved in their side effects, as well as their promising therapeutic indications.

Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells’ proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL’s/OLA’s inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes’ expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes’ expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.

Objective. Olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) belong to antipsychotics, which administration represents still most reliable way for the treatment of schizophrenic and bipolar disorders. The intention of the present study was to explore whether the acute administration of a particular antipsychotic, indicated by the presence of c-Fos, will: a) stimulate neurons already activated by a long lasting homogeneous or heterogeneous stress preconditioning, indicated by the FosB/ΔFosB (ΔFosB) expression, or b) have a stimulatory effect only on a not activated, so called silent neurons. The pattern of ΔFosB and c-Fos spatial relationship was investigated in three forebrain structures, including the septal ventrolateral nucleus (seVL), the striatal dorsolateral area (stDL), and the shell of the nucleus accumbens (shell). Methods. The rats were divided into 10 groups and exposed to two types of stressors. Half of them was exposed to a sequence of homogeneous stressor – handling (HDL) and the other half to a heterogeneous stressor (CMS) daily for 20 days. CMS consisted of five types of stressors: crowding, air-puff, wet bedding, predator stress, and forced swimming applied in an unexpected order. On the 21st day of the experiment, the rats were free of the stress exposure and on the 22nd day, both groups of animals receive a single intraperitoneal injection of vehicle (4% DMSO in saline, 0.1 ml/100 g) or OLA (5 mg/kg), AMI (20 mg/kg), ARI (10 mg/kg), and QUE (15 mg/kg). 90 min after the drugs administration the animals were transcardially perfused, brains removed, cut into 30 µm thick coronal sections, and double stained: first with ΔFosB antibody linked with Alexa488 fluorescent dye and second with c-Fos antibody linked to Alexa596 one. Quantitative evaluation of ΔFosB and c-Fos colocalizations was performed on fluorescence photomicrographs transformed into a final picture containing only yellow, green, and red colored circles. Results. The data of this investigation demonstrate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell ones, in both HDL as well as CMS preconditioned rats. The levels of ΔFosB and c-Fos colocalizations varied in the individual forebrain areas studied. From the total 22 areas measured, level of c-Fos colocalization prevailed over ΔFosB in 18 ones. However, neither c-Fos nor ΔFosB reached 100% level of colocalization in any of the forebrain areas investigated. Conclusion. The present findings indicate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell, in both HDL and CMS preconditioned rats, whereas the parallel occurrence of free c-Fos as well as c-Fos colocalized with ΔFosB might speak out for a possible involvement of the c-Fos activated by antipsychotics applied in dual, i.e. short- and long-lasting, functions.

Pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or microvascular complications like albuminuria, retinopathy and pre-eclampsia. In this study we aimed to identify whether mechanistic pathways associated with microvascular complications are active in pregnant women with GDM or microvascular disease.Urinary albumin excretion and biomarkers of inflammation, lipoprotein metabolism and tubular injury were quantified in 355 pregnant women with and without GDM. Participants underwent fundus photography graded for retinopathy. Adjusted associations between individual biomarkers and each outcome variable, including GDM status, albuminuria and retinopathy of interest, were performed using logistic regression.After adjusting for age, systolic blood pressure, body mass index and ethnicity, significant associations between GDM status and apolipoprotein A1, interleukin (IL)-6, IL-8, soluble tumour necrosis factor receptor-I and -II (sTNFR-I and -II), vascular endothelial growth factor and von Willebrand factor were observed. Increased high-sensitivity C-reactive protein (hsCRP) and sTNFR-II were associated with higher levels of albuminuria. hsCRP and previous GDM were associated with retinopathy.Mechanistic pathways associated with microvascular complications appear to be active in pregnant women with GDM or microvascular disease.

Background Legionnaires’ disease is a notifiable condition in New South Wales (NSW), Australia; clinicians and laboratories are required to report the disease to NSW Health. We describe the investigation of a sporadic case associated with the use of a communal spa pool in the case’s apartment building complex and the use of whole genome sequencing to examine relatedness between clinical and environmental Legionella pneumophila serogroup 1 (Lp1) strains. Methods In February 2018, a confirmed case of Lp1 infection was notified in a man in his 60s hospitalised with pneumonia. We asked the clinical team to obtain sputum in the event we found a potential source. The case described the use of the communal spa pool in his apartment building on two occasions during the putative exposure period. Environmental Health Officers from the Public Health Unit inspected the spa pool and found that the free chlorine level was well below the recommended concentration; a water sample was submitted for microbial analysis. Results Lp1 was grown from the case’s sputum and microbial analysis of the spa water sample found Lp1 at a concentration of 20 CFU/mL. The human and environmental isolates were subjected to whole genome sequencing and found to be highly genomically related. There was no other plausible environmental source of legionella. Conclusions Whole genome sequencing of the clinical and environmental Lp1 isolates implicated a contaminated spa pool as the source of the case’s exposure. This strongly supports the application of whole genome sequencing to the investigation of single cases of legionellosis. Communal spa pools in apartment buildings are not regulated in most Australian jurisdictions but must be considered to pose a potential legionella risk if improperly maintained.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico, ex vivo, and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) receptors are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. Acute pre-treatment with L-17 robustly increased c-Fos immunoreactivity in the amygdala (central nucleus), suggesting increased neuronal excitability in this brain area after L-17 administration. Acute L-17 also dose-dependently inhibited of 5-HT neurons of the dorsal raphe nucleus (DRN). This inhibition was partially reversed by subsequent administration of WAY100135, suggesting the involvement of extracellular 5-HT. Based on in silico predictions, c-Fos immunohistochemistry, and in vivo electrophysiology, we suggest that L-17 is a potent 5-HT reuptake inhibitor and/or partial 5-HT1A receptor antagonist. Thus, L-17 might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardio-protective properties, it can be useful in post-stroke and post-myocardial infarction (MI) depression. In general, combined in silico predictions and ex vivo neurochemical and in vivo electrophysiological assessment might be a useful strategy for early preclinical assessment of the affectivity and neural mechanism in action of the novel CNS drugs.

BACKGROUND Living donor renal transplantation is widely performed in Switzerland with a superior long-term outcome and lower waiting time compared with deceased renal transplantation. However the chances of receiving a living donor kidney transplant are not the same for all transplant candidates. The current study aimed to identify psychosocial and demographic characteristics that predict lower access to living kidney donation in Switzerland. METHODS The study was a nationwide multicentre study nested within the Swiss Transplant Cohort Study. Pre-transplant demographic, psychosocial and health characteristics of 1126 deceased and 859 living renal transplant recipients were compared using logistic regression analysis. RESULTS Transplant candidates with higher age (odds ratio [OR] per 10 years 0.67, 95% confidence interval [CI] 0.60–0.74), lower education (OR 0.46, 95% CI 0.36–0.59), a work capacity of less than 50% (OR 0.48, 95% CI 0.35–0.66), single or formerly married (OR 0.38, 95% CI 0.26–0.53 / OR 0.37, 95% CI 0.26–0.53) or with a higher hospital depression score (OR per 5 points 0.61, 95% CI 0.50–0.74) were less likely to receive an allograft from a living donor. In some regions of Switzerland candidates were more likely to undergo living transplantation than in other regions. No association was found with gender or income. CONCLUSIONS Interventions to increase access to kidney transplantation from living donors should target transplant candidates of older age, lower education, lower working capacity and not living in a committed relationship. The observed regional differences suggest that additional determinants of living donation may play a role such as population and health professional attitudes toward living donation.

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepres-sants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobro-mide (L-17), a recently designed thiadiazine derivative with putative neuro-and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreac-tivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro-and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Funding: The work of the authors of this study was supported by the Slovak Research and Development Agency (contract APVV-19-0435), Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Academy of Sciences (grant VEGA 2/0046/18), and a Government Contract of the Russian Federation with the Institute of Immunology and Physiology (AAAA-A18-118020690020-1).

CRH system integrates responses to stress challenges, whereas antipsychotics may impinge on this process. Effect of haloperidol (HAL) and aripiprazole (ARI) on chronic mild stress (CMS) induced neurobehavioral and CRH/CRHR1 system changes was studied in functionally interconnected rat brain areas including prefrontal cortex (PFC), bed nucleus of the stria terminalis (BNST), hypothalamic paraventricular nucleus (PVN), hippocampus (HIP), and amygdala (AMY). Animals were exposed to CMS for 3-weeks and since the 7th day of CMS injected with vehicle (VEH), HAL (1 mg/kg) or ARI (10 mg/kg) for 4-weeks. Expression levels of CRH, CRHR1, and c-fos genes and anxiety-like and anhedonia behavioural patterns were evaluated. CMS in VEH animals suppressed CRH gene expression in the PFC and BNST, c-fos expression in all areas, except HIP, and increased CRHR1 gene expression in the HIP. Antipsychotics decreased CRH gene expression in all areas, except HIP and by CMS elevated CRHR1 expression in the HIP (ARI also in AMY). CMS and antipsychotics decreased the sucrose preference. Aripiprazole prevented CRH expression decrease in the BNST and sucrose preference induced by CMS. Haloperidol increased time spent in the EPM open arms. These data indicate that HAL and ARI selectively influenced behavioural parameters and CRH/CRHR1 gene expression levels in CMS animals.

Background Since there is sound evidence that communication skills training (CST) programs modify communication behavior of oncology clinicians, they have been widely implemented over the last decades. However, more recently, certain aspects of this training have been criticized. Methods Based on this background, a call to re-launch a discussion about the future of CST led to the third European consensus meeting on communication in cancer care, organized by the Swiss Cancer League. During this meeting, which brought together European experts in the field of clinical communication and training of communication in the oncology setting, oncology clinicians, representatives of the European Society of Medical Oncology and a member of the European Oncology Nursing Society, the recommendations of the second European consensus meeting were updated and expanded. Results The expanded recommendations recall the guiding principles of communication in cancer care, underline the important role of clinician’s self-awareness, and of relational and contextual factors in clinical communication, and provide direction for the further development of communication training. Conclusion This third European consensus meeting defines key elements for the development of a next generation of communication training for oncology clinicians.

ObjectiveTo determine the relationship between white matter hyperintensities (WMH) presumed to indicate disease of the cerebral small vessels, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease (AD) and other dementias.MethodsWe recruited groups of participants with and without AD, including strata with extensive WMH and minimal WMH, into a cross-sectional proof-of-principle study (n = 118). A consecutive case series from a memory clinic was used as an independent validation sample (n = 702; Sunnybrook Dementia Study; NCT01800214). We assessed WMH volume and left temporal lobe atrophy (measured as the brain parenchymal fraction) using structural MRI and verbal memory using the California Verbal Learning Test. Using path modeling with an inferential bootstrapping procedure, we tested an indirect effect of WMH on verbal recall that depends sequentially on temporal lobe atrophy and verbal learning.ResultsIn both samples, WMH predicted poorer verbal recall, specifically due to temporal lobe atrophy and poorer verbal learning (proof-of-principle −1.53, 95% bootstrap confidence interval [CI] −2.45 to −0.88; and confirmation −0.66, 95% CI [−0.95 to −0.41] words). This pathway was significant in subgroups with (−0.20, 95% CI [−0.38 to −0.07] words, n = 363) and without (−0.71, 95% CI [−1.12 to −0.37] words, n = 339) AD. Via the identical pathway, WMH contributed to deficits in recognition memory (−1.82%, 95% CI [−2.64% to −1.11%]), a sensitive and specific sign of AD.ConclusionsAcross dementia syndromes, WMH contribute indirectly to verbal memory deficits considered pathognomonic of Alzheimer disease, specifically by contributing to temporal lobe atrophy.

Research examining the association between physical activity (PA) and prostate cancer (PCa) has accumulated; however, few studies have examined this association in the context of active surveillance. The current study examines this among men initially diagnosed with favorable-risk PCa and managed by active surveillance at Sunnybrook Health Sciences Centre in Canada and the Royal Marsden Hospital in the United Kingdom. Participants completed a questionnaire on daily participation in non-leisure, transport, and recreational PA. A logistic regression was employed using PA as the independent variable and whether the patient reclassified to higher-risk PCa while on active surveillance as the dependent variable. Demographic and lifestyle covariates were incorporated in the analysis to assess potential confounding and effect modification. Men from both hospitals presented with similar clinical and demographic characteristics. Total PA was inversely associated with odds of reclassification while on active surveillance (p-trend = 0.027). A weaker inverse association was observed with recreational PA (p-trend = 0.30). Men who participated in weekly vigorous PA were less likely to reclassify than those who did not (odds ratio (95% confidence interval): 0.42 (0.20–0.85)). Total and vigorous PA were inversely associated with odds of reclassification in two active surveillance cohorts. Given the limitations of this study, more robust prospective observational studies involving objective PA measures are warranted to confirm findings.

Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 μm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3′-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact.

Background Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. Objective The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. Methods We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Results Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p Conclusions Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

The impacts of three pyridoindole derivatives (PDs), designated as PD144, PD143, and PD104, which have previously been shown to have antidepressant (PD144) and anxiolytic (PD143, PD104) properties, were investigated on the Fos expressions in 11 different rat brain areas, including the medial prefrontal cortex, striatum, septum, accumbens nucleus (shell, core), bed nucleus of the stria terminalis, hypothalamic paraventricular nucleus, central amygdala, locus coeruleus, dorsal raphe nucleus, and the solitary tract nucleus. Control rats received vehicle, while the other three groups the PDs in a dose of 25 mg/kg/b.w. The animals were transcardially perfused with a fixative 90 min after the treatments. Coronal sections of 40-µm thickness were processed for Fos-immunostaining by avidin-biotin-peroxidase complex and visualized by nickel-intensified diaminobenzidine complex. Fos-labeled sections were counterstained with neuropeptides including corticoliberine (CRH), oxytocin (OXY), vasopressin (AVP), and vasoactive intestinal polypeptide (VIP) and processed for immunofluorescence staining using Alexa Fluor 555 dye. In all the three groups of animals, the upregulation of PDs-induced Fos expression only in 2 of 11 brain areas was investigated, namely, in the hypothalamic paraventricular nucleus (PVN) and the central amygdaloid nucleus (CeA). The other brain structures studied were devoid of Fos expression. Counterstaining of the Fos-labeled CeA-containing sections with VIP antibody revealed that the Fos expression stimulated by the PDs was upregulated in all the CeA subdivisions (lateral, ventral, capsular), except the medial one. Dual immunoprocessings showed Fos/CRH-labeling in both the PVN and the amygdala and Fos/OXY in the PVN. No Fos/AVP colocalizations were seen in the PVN. The obtained data provide the first view on the intracerebral effects of three new PDs derivatives, which effects were restricted only to the PVN and CeA areas. The present data may help to improve our understanding of the impact of the selected PDs on the brain and to anticipate possible behavioral and neuroendocrine consequences.

Women with a BRCA1 or BRCA2 mutation are at high risk for breast cancer and must make important decisions about breast cancer prevention and screening. In the current study, we report a multisite, randomized, controlled trial evaluating the effectiveness of a decision aid for breast cancer prevention in women with a BRCA mutation with no previous diagnosis of cancer. Within 1 month of receiving a positive BRCA result, women were randomized to receive either usual care (control group) or decision aid (intervention group). Participants were followed at 3, 6, and 12 months; were asked about preventive measures; and completed standardized questionnaires assessing decision making and psychosocial functioning. One hundred fifty women were randomized. Mean cancer-related distress scores were significantly lower in the intervention group compared with the control group at 6 months (P = 0.01) and at 12 months postrandomization (P = 0.05). Decisional conflict scores declined over time for both groups and at no time were there statistical differences between the two groups. The decision aid for breast cancer prevention in women with a BRCA1 or BRCA2 mutation is effective in significantly decreasing cancer-related distress within the year following receipt of positive genetic test results. Genet Med 19 3, 330–336.

Numerous studies have shown significant neighbourhood level variation in out-of-hospital cardiac arrest (OHCA) incidence rates, however, few have provided an explanation for these disparities beyond traditional socioeconomic measures.This was a retrospective study using data from a large population-based OHCA database (Rescu Epistry). We included adults ≥20 years who experienced a non-traumatic OHCA and were treated by emergency medical services within Toronto, Canada between 2006-2012. The residential address of each OHCA patient was spatially mapped to 1 of 517 Toronto census tracts (CTs). Patient and CT level characteristics were included in multivariate regression models to assess their association with OHCA incidence per 100,000 persons.Of the 7775 OHCAs occurring in the study area, 7692 (98.9%) were eligible for inclusion. OHCA incidence rates varied widely across CT quintiles, with rates differing almost 4-fold (109.1 per 100,000 yearly Q5 most deprived vs. 30.0 per 100,000 yearly Q1 least deprived p 0.0001). Numerous areas of high incidence adjacent to areas of low incidence were observed. After adjustment, all variables except the Activity Friendly Index showed highly significant linear trends, with increasing age, sex ratio, diabetes prevalence, material deprivation and ethnic concentration being independently associated with increasing OHCA incidence. In contrast, we did not observe a linear relationship between high OHCA incidence and median household income.This study showed almost 4-fold OHCA incidence variability across a large metropolitan area. This variability was partially correlated with population and health data, but not typical socioeconomic predictors, such as median household income.

Objective. Prolonged treatment with neuroleptics has been shown to induce FosB/ΔFosB expression in several brain regions including the medial prefrontal cortex, dorsomedial and dorsolateral striatum, ventrolateral and dorsolateral septum, nucleus accumbens shell and core, and the hypothalamic paraventricular nucleus (PVN). Some of these regions are known to be also stress responsive. This study was designed to determine whether repeated clozapine (CLZ) administration for 7 consecutive days to Wistar rats may modify FosB/ΔFosB expression in the above-mentioned brain areas induced by acute stress or novel stressor that followed 13-day chronic mild stress preconditioning. Methods. Following experimental groups were used: unstressed animals treated with vehicle/ CLZ for 7 days; 7-day vehicle/CLZ-treated animals on the last day exposed to acute stress – forced swimming (FSW); and animals preconditioned with stress for 13 days treated from the 8th day with vehicle/CLZ and on the 14th day exposed to novel stress – FSW. Results. In the unstressed animals CLZ markedly increased FosB/ΔFosB immunoreactivity in the ventrolateral septum and PVN. FSW elevated FosB/ΔFosB expression in the medial prefrontal cortex, striatum, and septum. CLZ markedly potentiated the effect of the FSW on FosB/ΔFosB expression in the PVN, but suppressed it in the dorsomedial striatum. Novel stress with stress preconditioning increased FosB/ΔFosB immunoreactivity in the prefrontal cortex, striatum, ventrolateral septum, and the PVN. In the nucleus accumbens the effect of the novel stressor was potentiated by CLZ. Conclusion. Our data indicate that CLZ may modulate the acute as well as novel stress effects on FosB/ΔFosB expression but its effect differs within the individual brain regions.

Objective. The aim of the present study was to demonstrate the spatial relationship between the c-Fos immunoreactive cells elicited by an acute treatment with neuroleptics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI) and enkephalinergic (ENK), substance P (SP), and tyrosine hydroxylase (TH) innervation fields in the rat septum. Methods. Male Sprague Dawley rats received a single injection of OLA (5 mg), ARI (10 mg), AMI (20 mg), QUE (15 mg/kg/b.w.). Ninety min after antipsychotics administration, the animals were transcardially perfused with a fixative and the brains cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black endproduct. Afterwards, the sections were exposed to ENK, SP, and TH antibodies and the reaction product visualized by biotin-labeled fluorescent AlexaFluor 564 dye. The data were evaluated from the sections either simultaneously illuminated with fluorescent and transmission microscope beams or after merging the separately illuminated sections in the Adobe Photoshop 7.0 software. Results. ENK, SP, and TH displayed characteristic spatial images formed by a dense accumulation of immunoreactive fibers and terminals on the both sides of the septum. A dense plexus of axons formed by ENK and SP immunopositive terminals were situated predominantly in the lateral, while TH ones more medial portion of the septum. QUE and AMI activated distinct amount of c-Fos expression in cells located within the SP-immunoreactive principal innervation field. The OLA effect on the c-Fos expression was very pronounced in the ventral TH-labeled principal innervation field including the space between the ENK field ventral portion and the dorsal margin of the accumbens nucleus shell. Generally, the occurrence of c-Fos cells in the ENK-immunoreactive principal innervation field, in comparison with the surrounding septal area, was less abundant after all of the four antipsychotics treatments. Conclusion. The data of the present study indicate that ENK, SP, and TH innervation fields may influence separate populations of septal cells activated by AMI, OLA, QUE, and ARI and that each of these region-differently innervated cells may be associated with the functional heterogeneity of the individual lateral septal nuclei.

Agitation is a prevalent and difficult-to-treat symptom in patients with moderate-to-severe Alzheimer's disease (AD). Though there are nonpharmacological and pharmacological interventions recommended for the treatment of agitation, the efficacy of these are modest and not always consistent. Furthermore, the safety profiles of currently prescribed medications are questionable. Nabilone, a synthetic cannabinoid, has a distinct pharmacological profile that may provide a safer and more effective treatment for agitation, while potentially having benefits for weight and pain. Additionally, emerging evidence suggests nabilone may have neuroprotective effects. We describe a clinical trial investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe AD. This will be a double-blind, randomized cross-over study comparing 6 weeks of nabilone (0.5–2 mg) and placebo, with a 1-week washout preceding each phase. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be agitation as assessed by the Cohen-Mansfield Agitation Inventory. The secondary outcomes include safety, behaviour (Neuropsychiatric Inventory), cognition (standardized Mini Mental Status Exam and either Severe Impairment Battery or Alzheimer's disease Assessment Scale-Cognitive subscale) and global impression (Clinician's Global Impression of Change). Exploratory outcomes include pain (Pain Assessment in Advanced AD), nutritional status (Mini-Nutritional Assessment-Short Form), caregiver distress (NPI caregiver distress), and blood-based biomarkers. A safe and efficacious pharmacological intervention for agitation, with effects on pain and weight loss in patients with moderate-to-severe AD could increase quality-of-life, reduce caregiver stress and avoid unnecessary institutionalization and related increases in health care costs. Clinical trials number: NCT02351882 Keywords: Agitation, Cannabinoid, Alzheimer's disease, Neuropsychiatric symptoms, Clinical trial

Purpose: We aimed to pilot and evaluate communication skills training (CST) for health care professionals (HCPs) interacting with adolescent patients with cancer and their parents based on particip...

This trial investigated the efficacy of omega-3 polyunsaturated fatty acid (n-3 PUFA) treatment for improving depressive symptoms and cognitive performance in patients with coronary artery disease (CAD) participating in cardiac rehabilitation. Patients with CAD aged 45 to 80 years were randomized to receive either 1.9-g/d n-3 PUFA treatment or placebo for 12 weeks. Depressive symptoms were measured using the Hamilton Depression Rating Scale (HAM-D, primary outcome) and the Beck Depression Inventory II (BDI-II). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were used to identify a depressive episode at baseline. Cognitive performance was measured using a standardized battery for vascular cognitive impairment. In 92 patients (age, 61.7 ± 8.7 y; 76% male, 40% depressed; HAM-D, 6.9 ± 5.9; BDI-II, 12.3 ± 10.9; n = 45 n-3 PUFA, n = 47 placebo), depression decreased (HAM-D, F3,91 = 2.71 and P = 0.049; BDI-II, F3,91 = 6.24 and P < 0.01), and cognitive performance improved (attention/processing speed, F1,91 = 5.57, P = 0.02; executive function, F1,91 = 14.64, P < 0.01; visuospatial memory, F1,91 = 4.01, P = 0.04) over cardiac rehabilitation. Omega-3 PUFA treatment increased plasma eicosapentaenoic acid (F1,29 = 33.29, P < 0.01) and docosahexaenoic acid (F1,29 = 15.29, P < 0.01) concentrations but did not reduce HAM-D (F3,91 = 1.59, P = 0.20) or BDI-II (F3,91 = 0.46, P = 0.50) scores compared with placebo. Treatment did not improve cognitive performance; however, n-3 PUFAs significantly increased verbal memory compared with placebo in a subgroup of nondepressed patients (F1,54 = 4.16, P = 0.04). This trial suggests that n-3 PUFAs do not improve depressive and associated cognitive symptoms in those with CAD. The possible benefits of n-3 PUFAs for verbal memory may warrant investigation in well-powered studies.

BACKGROUND The single-payer universal health care system in Ontario, Canada creates a setting with reduced socioeconomic barriers to treatment. Herein, the authors sought to elucidate the influence of sociodemographic marginalization on receipt of pancreatectomy, overall survival (OS), and receipt of adjuvant treatment among patients diagnosed with pancreatic cancer at the population level using an observational cohort study design. METHODS Patients diagnosed with pancreatic cancer in Ontario between January 2005 and January 2010 were identified using the provincial cancer registry and linked to administrative databases. Census data obtained from each patient's postal code were used as a proxy for that patient's median income, residential instability, material deprivation, ethnic concentration, and dependency (percentage aged 65 years, and unemployed). Surgical specimen pathology reports were abstracted for histopathology and margin status. Independent predictors of undergoing pancreatectomy, OS after surgical resection, and receipt of adjuvant treatment were identified by logistic regression and Cox proportional hazards analysis. RESULTS Of the 6296 patients diagnosed with pancreatic cancer, 820 (13%) underwent resection of their tumor. Increasing levels of residential instability (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.80-0.94) and material deprivation (OR, 0.86; 95% CI, 0.79-0.94) predicted a decreased likelihood of undergoing surgical resection. Patients living in rural areas (OR, 0.68; 95% CI, 0.51-0.91) and those living in urban areas with lower incomes (OR range, 0.49-0.77) were found to have a lower likelihood of undergoing surgical resection compared with patients in the urban areas with the highest income. After surgical resection, an association between sociodemographic marginalization with OS or receipt of adjuvant treatment was not identified. CONCLUSIONS Sociodemographic marginalization exerts its influence early in the pancreatic cancer care continuum, and appears to be associated more with which patients undergo surgical resection than the receipt of adjuvant treatment. Cancer 2016;122:3175–82. © 2016 American Cancer Society.

Background To date, 72% of variability in survival following out-of-hospital cardiac arrest (OHCA) is explained by the Utstein variables. Whether neighborhood factors further influence a return of spontaneous circulation or survival after OHCA is poorly understood. Methods We completed a retrospective cohort study of all paramedic-treated OHCA within the City of Toronto's 531 census tracts between 2006 and 2014. Neighborhood variables included the Ontario Marginalization Index – a measure of poverty, ethnicity and instability – crime rate and the density of family physicians. Hierarchical logistic regression analysis explored the association between a patient's census tract (neighborhood) characteristics and survival to hospital discharge and a prehospital return of spontaneous circulation (ROSC). Receiver operator characteristics curves measured how the Utstein variables and neighborhood factors discriminate OHCA outcomes. Results There were 23,067 OHCA during the study period, with 10,097 cases excluded due to obvious death, 896 from an obvious etiology and 2589 cases for other reasons, leaving 9485 patients for analysis. Of the neighborhood variables, only census tracts with a moderate ethnic concentration had an increased likelihood of survival-to-hospital discharge. The Utstein variables accounted for 89.2% of survival and 39.8% of prehospital ROSC. Adding all neighborhood factors to the Utstein model increased discrimination for survival to discharge to 89.8% ( p =0.005) and of a prehospital ROSC to 40.8% ( p =0.006). Conclusions Residential neighborhood factors marginally improve discrimination for outcomes after an OHCA, beyond the Utstein variables. Further research should explore the influence of other currently unmeasured neighborhood factors on OHCA outcomes.

BACKGROUND Professionals treating adolescents with cancer must communicate well with them and their parents. Evidence suggests that the communication needs of this population are rarely met. Skills training can improve professional communication, but has been criticized for not being based on the experience of the participants in the clinical encounter. We took a multiperspective approach, drawing on perspectives of former adolescents with cancer, patients' parents, physicians, and nurses with the aim to provide suggestions for improvement in communication in adolescent cancer care. METHODS Adolescent cancer survivors (n = 16), parents (n = 8), pediatric oncologists (n = 12), and pediatric oncology nurses (n = 18) participated in 11 focus groups. They discussed their experiences communicating with each other. Transcripts were analyzed by thematic analysis. RESULTS We identified themes within the following sections: (1) The framework in which professionals communicate with adolescents with cancer (regression in a time of detachment, adolescents' perception and knowledge of illness, cognitive versus legal maturity, "lost in transition" between pediatric and adult oncology); (2) communication difficulties between professionals and patients and parents (professionals and patients/parents identified the other party as the source of difficulties), and (3) effective professional communication (there was some overlap on how doctors and nurses should communicate, along with substantially different expectations for the two professions). CONCLUSIONS The framework within which professionals communicate, the different perspectives on the factors that make communication difficult, and the different expectations regarding good communication by doctors and nurses should be considered when communication skills training courses are developed for professionals who work in adolescent oncology.

Asenapine (ASE), an atypical antipsychotic drug used in the treatment of schizophrenia, induces Fos expression in forebrain. Effect of ASE on activity of basal nucleus of Meynert (NBM) cells, a part of the striatal-cortical circuits, was studied. We were also interested to reveal whether a chronic unpredictable variable mild stress (CMS) preconditioning might affect the ASE impact.Rats were divided into as follows: controls-vehicle, controls-ASE, stressed-vehicle and stressed-ASE groups. CMS included restrain, social isolation, crowding, swimming and cold applied for 21 days. On the 22nd day, rats were subcutaneously injected with ASE (0.3 mg/kg) or vehicle (saline 300 μl/rat), 90 min prior euthanizing. After transcardial fixation, brains were cut into 30 μm thick coronal sections. Fos protein presence, as indicator of cell activity, was detected by ABC immunohistochemistry. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH) containing cells were visualized with fluorescent dyes.ASE induced significant increase in Fos expression in NBM in both controls and CMS preconditioned rats in comparison with the related vehicle-treated controls. CMS preconditioning, however, significantly lowered the Fos response to ASE in NBM. From Hrct and MCH cells, only Hcrt ones displayed Fos presence in response to ASE.This study demonstrates for the first time that ASE may target a special group of cells occupying NBM, which effect can be modulated by CMS preconditioning. This finding extends a view that ASE impact may extend beyond the classical forebrain target areas common for the action of all antipsychotics and might be helpful in the identification of sites and side effects of its therapeutic actions.

Objective Highly distressed cancer patients often do not use psycho-oncological services (POS). Research on predictors of POS uptake has mainly focused on patient-related variables and less on communication variables, so we examined the link between patient-oncologist communication (ie, talking about psychosocial distress, providing detailed information, and recommending POS) and POS uptake. Methods We conducted a prospective, observational study in an Oncology Outpatient Clinic in Switzerland. Predictors (ie, patient-related variables and patient's reports of the patient-oncologist communication) were assessed via semistructured interviews, and information on outpatient POS uptake was assessed after 4 months. For statistical analysis, a multivariate logistic regression was performed. Results Of 333 participants (mean age 61 years; 55% male; 54% distress thermometer ≥5), 77 (23%) had used POS during a 4-month period. Patients who reported an oncologist-recommended POS (odds ratio [OR] = 6.27, 95% confidence interval [CI] = 3.14-12.85) and those who were not sure if they had received a recommendation (OR = 4.64, 95% CI = 1.83-11.97) were more likely to attend POS than those who reported receiving no recommendation. Talking about psychosocial distress (OR = 0.74, 95% CI = 0.38-1.46) and providing detailed information about POS did not predict POS uptake (OR = 1.06, 95% CI = 0.46-2.38). Conclusions Oncologists' expert recommendations to attend POS were strongly associated with patients' uptake of POS. The central role played by oncologists should be accounted for in stepped psycho-oncological care when POS referral pathways are defined.

Nasopharyngeal swabs from 148 adult patients with influenza were analyzed by polymerase chain reaction for Staphylococcus aureus and or Streptococcus pneumoniae. We found that patients colonized with S. pneumoniae were younger, had lower oxygen saturations, and were more likely to require admission to critical care.

Energy homeostasis is the result of a balance between energy intake and expenditure, and the hypothalamus plays a key role in the regulation of these processes. The hypothalamic prolactin-releasing peptide (PrRP) is involved in food intake regulation and energy homeostasis, although only its lipidized analogs exert central anorexigenic effects after peripheral administration. The aim of the present study was to delineate the extent of the Fos expression as a marker of neuronal activation within the hypothalamic structures involved in food intake regulation after peripherally administered palmitoylated PrRP31 (palm-PrRP31) and to determine whether the anorexigenic effect of peripherally administered palm-PrRP31 influence the activity of hypocretin (HCRT) and oxytocin (OXY) neurons, i.e., the neuropeptides crucially involved in the regulation of energy homeostasis. The data confirmed an anorexigenic effect of palm-PrRP31 treatment (5mg/kg, s.c.) in mice. In the palm-PrRP31-treated animals, a significant increase in Fos expression was observed in the hypothalamic paraventricular (PVN), dorsomedial (DMN), and arcuate (Arc) nuclei and in the neurons of the nucleus of the solitary tract (NTS). Moreover, significant Fos expression was observed in the lateral hypothalamic area (LHA) HCRT neurons and PVN OXY neurons after palm-PrRP31 administration. The present findings may indicate that palm-PrRP31 may be involved in energy homeostasis via the activation of several hypothalamic structures. Fos activation of the hypothalamic OXY and HCRT neurons in the PVN and LHA emphasizes the importance of the areas mentioned in the central action of palm-PrRP31.

We studied delayed effects of neonatal exposure to polymeric nanoparticle poly(ethylene glycol)-block-polylactide methyl ether (PEG-b-PLA) on the endpoints related to pubertal development and reproductive function in female Wistar rats from postnatal day 4 (PND4) to PND 176. Female pups were injected intraperitoneally, daily, from PND4 to PND7 with PEG-b-PLA (20 or 40mg/kg b.w.). Both doses of PEG-b-PLA accelerated the onset of vaginal opening compared with the control group. In the low-dose PEG-b-PLA-treated group, a significantly reduced number of regular estrous cycles, increased pituitary weight due to hyperemia, vascular dilatation and congestion, altered course of hypothalamic gonadotropin-releasing hormone-stimulated luteinizing hormone secretion, and increased progesterone serum levels were observed. The obtained data indicate that neonatal exposure to PEG-b-PLA might affect the development and function of hypothalamic-pituitary-ovarian axis (HPO), and thereby alter functions of the reproductive system in adult female rats. Our study indicates a possible neuroendocrine disrupting effect of PEG-b-PLA nanoparticles.

BackgroundTraditional variables used to explain survival following out-of-hospital cardiac arrest (OHCA) account for only 72% of survival, suggesting that other unknown factors may influence outcomes. Research on other diseases suggests that neighbourhood factors may partly determine health outcomes. Yet, this approach has rarely been used for OHCA. This work outlines a methodology to investigate multiple neighbourhood factors as determinants of OHCA outcomes.MethodsA retrospective, observational cohort study design will be used. All adult non-emergency medical service witnessed OHCAs of cardiac etiology within the city of Toronto between 2006 and 2010 will be included. Event details will be extracted from the Toronto site of the Resuscitation Outcomes Consortium Epistry—Cardiac Arrest, an existing population-based dataset of consecutive OHCA patients. Geographic information systems technology will be used to assign patients to census tracts. Neighbourhood variables to be explored include the Ontario Marginalization Index (deprivation, dependency, ethnicity, and instability), crime rate, and density of family physicians. Hierarchical logistic regression analysis will be used to explore the association between neighbourhood characteristics and 1) survival-to-hospital discharge, 2) return-of-spontaneous circulation at hospital arrival, and 3) provision of bystander cardiopulmonary resuscitation (CPR). Receiver operating characteristics curves will evaluate each model’s ability to discriminate between those with and without each outcome.DiscussionThis study will determine the role of neighbourhood characteristics in OHCA and their association with clinical outcomes. The results can be used as the basis to focus on specific neighbourhoods for facilitating educational interventions, CPR awareness programs, and higher utilization of automatic defibrillation devices.