Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies.

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD. OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose. METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose. RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg. CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state. CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies.

BACKGROUND: Obesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the 'inactive' unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake. AIMS: To report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity. METHODS: The SRD study investigated single doses of BI 1356225 (0.1-20.0 mg) in healthy male subjects with a BMI of 18.5-29.9 kg/m2 (SRD cohort) and assessed doses of 2.5 mg BI 1356225 under fed and fasted conditions (bioavailability [BA] cohort). The MRD study investigated multiple doses of BI 1356225 (0.2, 1.0, 2.5 or 10.0 mg) or 5.0 mg BI 1356225 with a single dose of midazolam and celecoxib (drug-drug interaction part) over 28 days in adults with a BMI of 27.0-39.9 kg/m2. RESULTS: Sixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration-time curve [AUC] and maximum plasma concentration [Cmax]) of BI 1356225 increased across dose groups, although this was less than dose-proportional across the entire dose range. In the BA cohort of the SRD study, AUC0-∞ was slightly increased and Cmax slightly decreased in fed versus fasted conditions, with fed/fasted ratios (90 % CI) of 101.10 % (92.42, 110.60) and 91.67 % (78.50, 107.05), respectively. In both studies, AG concentrations and the AG/UAG ratio were dose-dependently decreased after BI 1356225 treatment from baseline versus placebo. In the MRD study, UAG concentrations were increased from baseline, but not dose-dependently. No differences were observed in bodyweight, appetite, food cravings, ad libitum food uptake or obesity-related biomarkers after 28 days of treatment with BI 1356225. CONCLUSIONS: Treatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.

Limitation of life-sustaining treatment in NICU: Physicians' beliefs and attitudes in the Buenos Aires region.

OBJECTIVE: To explore the ethical beliefs and attitudes of Argentinean neonatologists regarding limitation of life-sustaining treatment (LST) for very sick infants. METHODS: We used an anonymous questionnaire including direct questions and hypothetical clinical cases (inevitable demise and anticipated survival with severe long-term disability). Multivariable analysis was carried out to assess the relation between type of clinical case and physicians' LST attitudes. RESULTS: Overall, 315 neonatologists in 34 units in the Buenos Aires region participated (response rate 54%). Most responders would agree with decisions to start or continue LST. In both clinical cases, continuing current treatment with no therapeutic escalation was the only form of LST limitation acceptable to a substantial proportion (about 60%) of neonatologists. Agreement with LST limitation was slightly but significantly more likely when death was inevitable. CONCLUSION: Argentinean neonatologists showed a conservative attitude regarding LST limitation. Patient prognosis and options of non-treatment decision significantly influenced their choices.

Low socio-economic conditions and prematurity-related morbidities explain healthcare use and costs for 2-year-old very preterm children.

AIM: To estimate healthcare use and related costs for 2-year-old very preterm (VP) children after discharge from the neonatal unit. METHODS: As part of a European project, we recruited an area-based cohort including all VP infants born in three Italian regions (Lazio, Emilia-Romagna and Marche) in 2011-2012. At 2 years corrected age, parents completed a questionnaire on their child health and healthcare use (N = 732, response rate 75.6%). Cost values were assigned based on national reimbursement tariffs. We used multivariable analyses to identify factors associated with any rehospitalisation and overall healthcare costs. RESULTS: The most frequently consulted physicians were the paediatrician (85% of children), the ophthalmologist (36%) and the neurologist/neuropsychiatrist (26%); 38% of children were hospitalised at least once after the initial discharge, for a total of 513 admissions and over one million euros cost, corresponding to 75% of total healthcare costs. Low maternal education and parental occupation index, congenital anomalies and postnatal prematurity-related morbidities significantly increased the risk of rehospitalisation and total healthcare costs. CONCLUSION: Rehospitalisation and outpatient care are frequent in VP children, confirming a substantial health and economic burden. These findings should inform the allocation of resources to preventive and rehabilitation services for these children.

Risk of Developmental Coordination Disorder in Italian very preterm children at school age compared to general population controls.

BACKGROUND: Developmental Coordination Disorder (DCD) is a neurodevelopmental disorder that involves difficulties in goal-directed motor coordination, with ineffective control of fine and gross motor movements in the absence of sensory impairment or neurological condition. DCD is frequently reported in children born very preterm (VP) who survive without CP. AIMS: To measure the risk of DCD at school age in a large area-based cohort of VP children and general population controls, adjusting for gender, birth weight by gestational age and age at assessment. METHODS: VP children (N = 608) were part of a prospective cohort study in Italy. Controls (N = 370) were participants in the DCDQ-Italian validation study in the same age range. The Italian version of Developmental Coordination Disorder Questionnaire (DCDQ-Italian) was used to measure the performances in motor coordination during ordinary activities from the parental point of view. Multivariable regression analysis was used to obtain adjusted risk ratios of screening positive for DCD. RESULTS: VP children had scores significantly lower than peers, and about 30% of them appeared at risk of DCD using the 15th percentile cut-off of the Italian validation study. Birth-weight <10th percentile for gestational age and male gender were significant predictors. A slight trend effect was present, with extremely preterm children (<28 weeks gestation) showing the highest risk. CONCLUSIONS: Our study confirmed the higher DCD risk in VP children, particularly when males and SGA.

Breastfeeding outcomes in European NICUs: impact of parental visiting policies.

OBJECTIVE: The documented benefits of maternal milk for very preterm infants have raised interest in hospital policies that promote breastfeeding. We investigated the hypothesis that more liberal parental policies are associated with increased breastfeeding at discharge from the neonatal unit. DESIGN: Prospective area-based cohort study. SETTING: Neonatal intensive care units (NICUs) in 19 regions of 11 European countries. PATIENTS: All very preterm infants discharged alive in participating regions in 2011-2012 after spending >70% of their hospital stay in the same NICU (n=4407). MAIN OUTCOME MEASURES: We assessed four feeding outcomes at hospital discharge: any and exclusive maternal milk feeding, independent of feeding method; any and exclusive direct breastfeeding, defined as sucking at the breast. We computed a neonatal unit Parental Presence Score (PPS) based on policies regarding parental visiting in the intensive care area (range 1-10, with higher values indicating more liberal policies), and we used multivariable multilevel modified Poisson regression analysis to assess the relation between unit PPS and outcomes. RESULTS: Policies regarding visiting hours, duration of visits and possibility for parents to stay during medical rounds and spend the night in unit differed within and across countries. After adjustment for potential confounders, infants cared for in units with liberal parental policies (PPS≥7) were about twofold significantly more likely to be discharged with exclusive maternal milk feeding and exclusive direct breastfeeding. CONCLUSION: Unit policies promoting parental presence and involvement in care may increase the likelihood of successful breastfeeding at discharge for very preterm infants.

Maternal Education Is Associated with Disparities in Breastfeeding at Time of Discharge but Not at Initiation of Enteral Feeding in the Neonatal Intensive Care Unit.

OBJECTIVE: To investigate the relationship between maternal education and breastfeeding in very preterm infants admitted to neonatal intensive care units. STUDY DESIGN: This prospective, population-based cohort study analyzed the data of all very preterm infants admitted to neonatal care during 1 year in 3 regions in Italy (Lazio, Emilia-Romagna, and Marche). The use of mothers' own milk was recorded at initial enteral feedings and at hospital discharge. We used multilevel logistic analysis to model the association between maternal education and breastfeeding outcomes, adjusting for maternal age and country of birth. Region was included as random effect. RESULTS: There were 1047 very preterm infants who received enteral feeding, and 975 were discharged alive. At discharge, the use of mother's own milk, exclusively or not, and feeding directly at the breast were significantly more likely for mothers with an upper secondary education or higher. We found no relationship between maternal education and type of milk at initial enteral feedings. However, the exclusive early use of the mother's own milk at initial feedings was related significantly with receiving any maternal milk and feeding directly at the breast at discharge from hospital, and the association with feeding at the breast was stronger for the least educated mothers. CONCLUSION: In this population-based cohort of very preterm infants, we found a significant and positive association between maternal education and the likelihood of receiving their mother's own milk at the time of discharge. In light of the proven benefits of maternal milk, strategies to support breastfeeding should be targeted to mothers with less education.

Priority Setting and Influential Factors on Acceptance of Pharmaceutical Recommendations in Collaborative Medication Reviews in an Ambulatory Care Setting - Analysis of a Cluster Randomized Controlled Trial (WestGem-Study).

BACKGROUND: Medication reviews are recognized services to increase quality of therapy and reduce medication risks. The selection of eligible patients with potential to receive a major benefit is based on assumptions rather than on factual data. Acceptance of interprofessional collaboration is crucial to increase the quality of medication therapy. OBJECTIVE: The research question was to identify and prioritize eligible patients for a medication review and to provide evidence-based criteria for patient selection. Acceptance of the prescribing general practitioner to implement pharmaceutical recommendations was measured and factors influencing physicians' acceptance were explored to obtain an impression on the extent of collaboration in medication review in an ambulatory care setting. METHODS: Based on data of a cluster-randomized controlled study (WestGem-study), the correlation between patient parameters and the individual performance in a medication review was calculated in a multiple logistic regression model. Physician's acceptance of the suggested intervention was assessed using feedback forms. Influential factors were analyzed. RESULTS: The number of drugs in use (p = 0.001), discrepancies between prescribed and used medicines (p = 0.014), the baseline Medication Appropriateness Index score (p<0.001) and the duration of the intervention (p = 0.006) could be identified as influential factors for a major benefit from a medication review, whereas morbidity (p>0.05) and a low kidney function (p>0.05) do not predetermine the outcome. Longitudinal patient care with repeated reviews showed higher interprofessional acceptance and superior patient benefit. A total of 54.9% of the recommendations in a medication review on drug therapy were accepted for implementation. CONCLUSIONS: The number of drugs in use and medication reconciliation could be a first rational step in patient selection for a medication review. Most elderly, multimorbid patients with polymedication experience a similar chance of receiving a benefit from a medication review. Longitudinal patient care should be preferred over confined medication reviews. The acceptance of medication reviews by physicians supports further implementation into health care systems. TRIAL REGISTRATION: ISRCTN ISRCTN41595373.

Measurement of liver iron concentration by superconducting quantum interference device biomagnetic liver susceptometry validates serum ferritin as prognostic parameter for allogeneic stem cell transplantation.

INTRODUCTION: There are conflicting data regarding the role of serum ferritin (SF) as surrogate parameter for iron overload as an independent prognostic factor for outcome after allogeneic stem cell transplantation (SCT). Superconducting quantum interference device (SQUID) biomagnetic liver susceptometry, a noninvasive measurement of iron overload, allows measurement of the interference of an exteriorly applied small but highly constant magnetic field by the paramagnetic liver storage iron. By measuring the true iron load of patients through SQUID, we wanted to assess the effect of iron overload on patients undergoing SCT. METHODS: We conducted a single-center retrospective analysis (1994-2010), comparing the effect of SF and liver iron content measured by SQUID shortly before transplantation on overall survival (OS), event-free survival (EFS), and transplant-related mortality (TRM) in 142 patients (median age 54.5 yr, range 5.6-75 yr) undergoing SCT (80% reduced intensity regimen). Patients were subdivided into five groups: myelodysplastic syndrome, de novo acute myeloid leukemia (AML), secondary AML, primary myelofibrosis, and others. RESULTS: Correlation between SF and SQUID was significant (r = 0.6; P < 0.001; log function). The chance of infection was increased 2.4-fold (95% CI 1.22-4.71) when SQUID values ranged ≥1000 µg Fe/g liver (P = 0.012). We found similar results for SF >1000 ng/mL (P = 0.003). A significant association between SQUID and fungal infection was also seen (P = 0.004). For patients with SQUID ≥1000, the risk of proven fungal infection was increased 3.08-fold (95% CI 1.43-6.63). A similar association between SF >1000 and fungal infection was shown (P = 0.01). In univariate analysis, age was a prognostic factor for TRM (P = 0.034, HR 1.04, CI 1.00-1.08). SF ≥1000 was associated with OS (P = 0.033, HR 2.09, CI 1.06-4.11) and EFS (P = 0.016, HR 2.15, 95% CI 1.15-4.10). In multivariate analysis on EFS, only age and SF >1000 remained as independent factors (HR 1.027, P = 0.040, 95% CI 1.001-1.054 and HR 2.058, P = 0.034, 95% CI 1.056-4.008, respectively). The multivariate analysis on TRM left age and SQUID values ≥1000 in the final model (HR 1.045, P = 0.041, 95% CI 1.002-1.090 and HR 2.110, P = 0.103, 95% CI 0.859-5.183, respectively). CONCLUSION: Our data confirmed that SF ≥1000 increases the risk of infection, moreover fungal infection in transplant recipients. As SQUID values correlate well with SF, we could show that SF is indeed a good surrogate parameter for iron overload when measured shortly before SCT. Prospective trials are needed to investigate the effect of iron chelation before or during SCT on transplant outcome.

[Patient Groups with Different Risk Profiles for Irregular Drop-Out from Forensic Psychiatry (§â€Š64 StGB)]. / Patientengruppen mit unterschiedlichem Risikoprofil für eine vorzeitige Erledigung des Maßregelvollzugs (§â€Š64 StGB).

OBJECTIVE: About 50 - 70 % of the patients with substance abuse disorders who are mandated to forensic treatment according to the section 64 of the German penal code are discharged from treatment irregularly. Previous research identified a number of potential risk factors for irregular treatment dropout. Systematic assessment of risks factors and their consideration for treatment planning may help to improve treatment retention. Therefore, the aim of this study was to identify groups of patients with a comparable risk profile for treatment dropout. METHODS: From 2007 - 2012, patients entering forensic treatment completed the MATE-Crimi and a sociodemographic questionnaire. RESULTS: From 431 patients entering forensic treatment, 357 patients agreed to participate. Of the 357 included patients 35.9 % had completed the forensic treatment irregular. Using cox regression, young age, low treatment motivation and a primary criminal behaviour with the substance use as a consequence of criminal behaviour were identified as risk factors for early drop-out. A subsequent analysis of latent classes using these variables resulted in three classes. CONCLUSIONS: Our study revealed a small number of risk factors being relevant for treatment drop-out. Furthermore, we identified three groups of patients with different risk profiles. Next steps include the development of treatment pathways for these patient groups.

Limitations in Ankle Dorsiflexion Range of Motion, Gait, and Walking Efficiency in Childhood Cancer Survivors.

BACKGROUND: Improvements in survival rates in pediatric oncology have resulted in a growing need to identify adverse effects and improve rehabilitation in this population. OBJECTIVE: This cross-sectional study aimed to investigate active ankle dorsiflexion (DF) range of motion (ROM), gait, walking efficiency, and motor performance in a mixed childhood cancer survivor population in comparison to healthy peers. METHODS: Active ankle DF-ROM (goniometer), gait (Microgate Optogait 2D Gait Analysis), walking efficiency (6-minute walk test), and motor performance (German Motor Test 6-18) were assessed in a mixed childhood cancer survivor population after cessation of medical treatment (n = 13) in comparison to healthy children matched for age and gender (n = 13). RESULTS: Active ankle DF-ROM, gait (stance, swing, and preswing phase), and walking efficiency were significantly impaired in survivors compared with control subjects. No significant difference between groups was found in motor performance. CONCLUSION: Despite sufficient total motor performance levels, specific limitations in physical functioning were identified in a mixed childhood cancer survivor sample. This highlights the importance of the present findings. IMPLICATION FOR PRACTICE: The results from this study highlight the potential significance of limited ankle DF function, inhibited gait, and reduced walking efficiency as adverse effects of various types of childhood cancer. It is hoped this enhanced recognition by pediatric cancer patients, parents, and exercise professionals will initiate specific supportive strategies and potentially prevent further limitations.

Implantation of venous access devices under local anesthesia: patients' satisfaction with oral lorazepam.

OBJECTIVE: The aim of the study reported here was to evaluate patients' satisfaction with implantation of venous access devices under local anesthesia (LA) with and without additional oral sedation. MATERIALS AND METHODS: A total of 77 patients were enrolled in the prospective descriptive study over a period of 6 months. Subcutaneous implantable venous access devices through the subclavian vein were routinely implanted under LA. Patients were offered an additional oral sedative (lorazepam) before each procedure. The level of anxiety/tension, the intensity of pain, and patients' satisfaction were evaluated before and immediately after the procedure using a visual analog scale (ranging from 0 to 10) with a standardized questionnaire. RESULTS: Patients' satisfaction with the procedure was high (mean: 1.3±2.0) with no significant difference between the group with premedication and the group with LA alone (P=0.54). However, seven out of 30 patients (23.3%) in the group that received premedication would not undergo the same procedure without general anesthesia. There was no significant influence of lorazepam on the intensity of pain (P=0.88). In 12 out of 30 patients (40%) in the premedication group, the level of tension was higher than 5 on the visual analog scale during the procedure. In 21 out of 77 patients (27.3%), the estimate of the level of tension differed between the interventionist and the patient by 3 or more points in 21 out of 77 patients (27.3%). CONCLUSION: Overall patient satisfaction is high for implantation of venous access devices under LA. A combination of LA with lorazepam administered orally might not be adequate for patients with a high level of anxiety and tension. The level of tension is often underestimated by the interventionist. Pre-procedural standardized questionnaires could be used to identify patients for whom a gradual approach of individualized sedation may be more effective.

Effect evaluation of an interprofessional medication therapy management approach for multimorbid patients in primary care: a cluster-randomized controlled trial in community care (WestGem study protocol).

BACKGROUND: Pharmaceutical practice worldwide is developing towards patient care. Medication Review (MR) and Medication Therapy Management (MTM) are evolving as the most prominent services in pharmaceutical care and have a strong potential to provide a large benefit for patients and society. MTMs can only be performed in an interprofessional, collaborative setting. Several international studies have explored the effects of a MTM on the quality of therapy and costs. For Germany the data is still deficient. This study aims to provide data on the effects of an interprofessional MTM regarding quality of therapy, quality of life, costs and cost-effectiveness. METHOD/DESIGN: The study is designed as a cluster-randomized controlled trial in primary care, involving 12 outpatient clinics (clusters) and 165 patients. Primary care units are allocated to interventions using a Stepped Wedge Design. All units are initially assigned to the control group. After a 6 month observation period, general practitioners (GP) are randomly allocated to one of three groups and the interprofessional medication therapy management approach is implemented sequentially per each group with a lag of 3 months between. The primary outcome is the change in the quality of therapy measured by the MAI (Medication Appropriateness Index). Secondary outcomes include changes in the number of drug related problems, medication complexity, changes in drug-adherence, changes in health-status and function, quality of life, direct costs and the incremental cost-effectiveness ratio. The acceptance of the interprofessional Medication Therapy Management approach is assessed by qualitative methods. DISCUSSION: The patient interview and brown bag review are activities, typically provided by the pharmacist. In this trial the patient is blinded to the pharmacist. The strength of having the patient blinded to the pharmacists is to exclude skepticism of the patient toward unknown pharmacies, which might be a major confounder in a regional and community setting. A weakness is that some patient related data might reach the pharmacists in a way, which might differ from self-acquired data. TRIAL REGISTRATION: Current controlled trials ISRCTN41595373 .

Effects of a 15-Month Supervised Exercise Program on Physical and Psychological Outcomes in Prostate Cancer Patients Following Prostatectomy: The ProRehab Study.

PURPOSE: Despite advanced medical treatment options, many prostate cancer patients are still confronted with unfavorable physical and psychological burdens. Physical exercise has proven to be beneficial for prostate cancer patients, yet specific exercise offers are rare. The ProRehab Study aimed to evaluate the exercise program offered in rehabilitative prostate cancer sports groups in Germany and determine whether it is beneficial for patients following prostatectomy. METHODS: Eighty-five prostate cancer patients were recruited for a multicenter, 2-armed, nonrandomized controlled trial 6 to 12 weeks after prostatectomy. The intervention group (n = 56) took part in a 15-month supervised multimodal exercise program. Exercise sessions took place once a week for 60 minutes at a moderate intensity (3.84-4.84 MET-hour). The control group (n = 29) received no intervention. Outcomes included aerobic fitness, activity levels, quality of life, disease- and treatment-related adverse effects, such as urinary incontinence and erectile dysfunction, and relapse-relevant blood values. Intention-to-treat analysis was performed. RESULTS: A significant between-group difference was observed in the urinary symptom score (P = .027). Physical fitness, urinary incontinence, physical, role, emotional, and social functioning, as well as further disease- and treatment-related side effects (dyspnea, urinary, and bowel symptoms) significantly improved within the intervention group. Erectile dysfunction and physical activity levels improved similarly in both groups. CONCLUSIONS: The presented data hint at the potential of rehabilitative sports groups for prostate cancer patients. However, according to the current state of the art, exercise intensity and volume may need to be increased to enhance the effects. A number of shorter studies (8-24 weeks) have proven significant between-group differences in quality of life, incontinence, and fitness outcomes when patients exercised 2 to 3 times per week. This is the first exercise intervention study with prostate cancer patients that was conducted over 15 months. Further studies are necessary to investigate whether prostate cancer patients recover sooner when receiving a supervised exercise program.

Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory.

Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs.

Characteristics of episodic breathlessness as reported by patients with advanced chronic obstructive pulmonary disease and lung cancer: Results of a descriptive cohort study.

BACKGROUND: Episodic breathlessness is one form of refractory breathlessness. Better understanding of the symptom is necessary for effective management. AIM: The aim was to describe the characteristics of episodic breathlessness in patients with advanced chronic obstructive pulmonary disease or lung cancer. DESIGN: This is a longitudinal cohort study. Outcomes were assessed monthly by up to 13 telephone interviews: peak severity (modified Borg scale: 0-10), duration, frequency, and timing of breathlessness episodes. Data from each episode were pooled and analyzed using descriptive statistics. Associations between outcomes were explored by correlation coefficients. SETTING/PARTICIPANTS: Patients with chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease classification stage III or IV) or primary lung cancer (any stage) were recruited in two inpatient units (internal medicine) and two outpatient clinics in Oldenburg, Germany. RESULTS: A total of 82 patients (50 chronic obstructive pulmonary disease, 32 lung cancer), mean age (standard deviation) 67 years (8 years) and 36% female, were included reporting on 592 breathlessness episodes (chronic obstructive pulmonary disease: 403, lung cancer: 189). Peak severity was perceived significantly higher in chronic obstructive pulmonary disease patients than in lung cancer patients (mean (standard deviation) Borg scale: 6.2 (2.1) vs 4.2 (1.9); p < 0.001). Episodes described by chronic obstructive pulmonary disease patients were longer than those described by lung cancer patients (median (range): 7 min (0-600) vs 5 min (0.3-120), p = 0.002)). Frequency was similar and most often daily in both groups. Severity and frequency of episodes were correlated in lung cancer patients (r = 0.324, p = 0.009). CONCLUSION: Most breathlessness episodes are short (minutes) and severe with significant differences between chronic obstructive pulmonary disease and lung cancer patients. Effective management strategies are warranted to improve symptom relief and coping.

Determination of liver-specific r2 * of a highly monodisperse USPIO by (59) Fe iron core-labeling in mice at 3 T MRI.

Accurate determination of tissue concentration of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) using T2 * MR relaxometry is still challenging. We present a reliable quantification method for local USPIO amount with the estimation of the liver specific relaxivity r2 * using monodisperse (59) Fe-core-labeled USPIO ((59) FeUSPIO). Dynamic and relaxometric in vivo characteristics of unlabeled monodisperse USPIO were determined in MRI at 3 T. The in vivo MR studies were performed for liver tissue with (59) FeUSPIO using iron dosages of 9 (n = 3), 18 (n = 2) and 27 (n = 3) µmol Fe kg(-1) body weight. The R2 * of the liver before and after USPIO injection (∆R2 *) was measured and correlated with (59) Fe activity measurements of excised organs by a whole body radioactivity counter (HAMCO) to define the dependency of ∆R2 * and (59) FeUSPIO liver concentration and calculate the r2 * of (59) FeUSPIO for the liver. Ultrastructural analysis of liver uptake was performed by histology and transmission electron microscopy. ∆R2 * of the liver revealed a dosage-dependent accumulation of (59) FeUSPIO with a percentage uptake of 70-88% of the injection dose. Hepatic ∆R2 * showed a dose-dependent linear correlation to (59) FeUSPIO activity measurements (r = 0.92) and an r2 * in the liver of 481 ± 74.9 mm(-1) s(-1) in comparison to an in vitro r2 * of 60.5 ± 3.3 mm(-1) s(-1) . Our results indicate that core-labeled (59) FeUSPIO can be used to quantify the local amount of USPIO and to estimate the liver-specific relaxivity r2 *.

Impact of clinical and sociodemographic patient characteristics on the outcome of cardiac rehabilitation in older patients.

BACKGROUND: Cardiac rehabilitation (CR) seeks to simultaneously improve several outcome parameters related to patient risk factors, exercise capacity and subjective health. A single score, the multiple outcome criterion (MOC), comprised of alterations in 13 outcome variables was used to measure the overall success of CR in an older population. As this success depends on the older patient's characteristics at the time of admission to CR, we attempted to determine the most important influences. METHODS: The impact of baseline characteristics on the success of CR, measured by MOC, was analysed using a mixed model for 1,220 older patients (70.9 ± 7.0 years, 78.3 % men) who enrolled in 12 CR clinics. A multitude of potentially influential baseline patient characteristics was considered including sociodemographic variables, comorbidity, duration of hospital stay, exercise capacity, cardiovascular risk factors, emotional status, and laboratory and echocardiographic data. RESULTS: Overall, CR was successful, as indicated by the mean value of the MOC (0.6 ± 0.45; min -1.0, max 2.0; positive values denoting improvement, negative ones deterioration). Examples of association with negative MOC values included smoking (MOC -0.15, p < 0.001), female gender (MOC -0.07, p = 0.049), and a longer hospital stay (MOC -0.03, p = 0.03). An example of association with positive MOC value was depression score (MOC 0.06, p = 0.003). Further associations included maximal exercise capacity, blood pressure, heart rate and the rehabilitation centre attended. CONCLUSION: Our results emphasize the necessity to take into consideration baseline characteristics when evaluating the success of CR and setting treatment targets for older patients.