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.

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.

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.

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.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

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.

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.

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 .

Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling and arrhythmias in the heart evoked by ß-adrenergic stimulation.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca(2+) release in cardiac myocytes evoked by ß-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca(2+) signals sensitive to inhibitors of both acidic Ca(2+) stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca(2+) transients caused by high concentrations of the ß-adrenergic agonist isoproterenol. Ca(2+) transients were recorded both as increases of the free cytosolic Ca(2+) concentration and as decreases of the sarcoplasmic luminal Ca(2+) concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca(2+) transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy.

Cartilage destruction in granulomatosis with polyangiitis (Wegener's granulomatosis) is mediated by human fibroblasts after transplantation into immunodeficient mice.

A key feature of granulomatosis with polyangiitis (GPA; or Wegener's granulomatosis) is the granulomatous inflammation of the upper respiratory tract, which leads to the subsequent destruction of adjacent tissues. The aim of our work was to study the histopathological and cellular components of tissue destruction of human GPA tissue transplanted into immunodeficient mice. Biopsy specimens from patients with active GPA (n = 10) or sinusitis (controls, n = 6) were s.c. co-implanted with healthy allogeneic human nasal cartilage into immunodeficient pfp/rag2(-/-) mice. Transplants were examined for their destructive capability of the allografted human cartilage. In addition, nasal fibroblasts from patients with GPA (n = 8) and control healthy nasal fibroblasts (n = 5) were cultured, and cell proliferation and apoptosis were quantified. mRNA and protein levels of matrix metalloproteinases and cytokines were evaluated at baseline and after proinflammatory stimulation. GPA implants showed massive destruction of the co-implanted human cartilage, whereas cartilage destruction was only marginal in control samples. Destruction was mediated by human fibroblasts and could be inhibited by corticoid treatment. The up-regulated production of matrix metalloproteinases 1, 3, and 13 and cytokines IL-6 and IL-8 was found in vivo and in vitro. Although proliferation of isolated fibroblasts was comparable between GPA and controls, GPA samples showed a significant delay of apoptosis. The destruction of nasal cartilage in GPA is mainly mediated by fibroblasts that can be blocked by corticosteroids, and this tissue destruction is not dependent on the influx of leukocytes.

Biogenetic explanations and public acceptance of people with eating disorders.

PURPOSE: It has been assumed that biogenetic causal models may improve public attitudes toward people with mental illnesses. The present study examines whether biogenetic attributions are positively associated with acceptance of people suffering from these disorders. METHODS: Population surveys were conducted in two large German cities. Respondents were presented with a vignette depicting a young female suffering from either anorexia nervosa (N = 680) or bulimia nervosa (N = 667), followed by a fully structured interview including questions on causal attributions, emotional reactions and desire for social distance. RESULTS: Attribution to hereditary factors showed hardly any relationship with attitudes toward people with symptoms of eating disorders. Respondents who endorsed brain disease as a cause tended more to hold those afflicted responsible for their condition, they also expressed more negative emotions and a stronger preference for social distance. CONCLUSIONS: Our results do not support the notion that promulgating biogenetic causal models of eating disorders helps decrease the stigma surrounding these illnesses; it may even entail the risk of increasing it.

Cardiac index assessment using bioreactance in patients undergoing cytoreductive surgery in ovarian carcinoma.

This clinical study compared the cardiac index (CI) assessed by the totally non-invasive method of bioreactance (CIBR) (NICOM™, Cheetah Medical, Vancouver, USA) to transpulmonary thermodilution (CITD) during cytoreductive surgery in ovarian carcinoma. The hypothesis was that CI could be assessed by bioreactance in an accurate and precise manner including accurate trending ability when compared to transpulmonary thermodilution. In 15 patients CIBR and CITD were assessed after induction of anesthesia, after opening of the peritoneum, hourly during the operative procedure, and 30 min after extubation. Trending ability was assessed between the described timepoints. In total 84 points of measurement were analyzed. Concordance correlation coefficient for repeated measures correlating the CIBR and CITD was 0.32. Bias was 0.26 l/min/m(2) (limits of agreement -1.39 and 1.92 l/min/m(2)). The percentage error was 50.7 %. Trending ability quantified by the mean of angles θ which are made by the ΔCI vector and the line of identity (y = x) showed a value for CIBR of θ = 23.4°. CI assessment by bioreactance showed acceptable accuracy and trending ability. However, its precision was poor. Therefore, CI measurement can not be solely based on bioreactance in patients undergoing cytoreductive surgery in ovarian carcinoma.

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.

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).

A prospective study on living related kidney donors' quality of life in the first year: choosing appropriate reference data.

Prospective studies on living kidney donors' quality of life (QoL) are still rare. Most existing studies compare healthy donors with the general population, including subjects with diseases. This is the first prospective study comparing living donors' QoL with reference data of both the general population and healthy individuals. We investigated QoL, anxiety, and depression in living kidney donors (n = 79) before donation and at two post-operative data points (three months and one yr). Subsequently, data from the donors were compared with the reference data. Our results show an impaired physical QoL three months post-donation. One yr after surgery, physical QoL had returned to the pre-operative level. Neither mental QoL nor anxiety or depression showed major changes across time. Pre-operative QoL was comparable to that of healthy individuals and higher than that in the general population. Donors' perception of the recipient's health showed moderate correlations with donors' mental outcome three months after donation. In conclusion, the impact on physical QoL seems to persist for at least three months after kidney donation. It could be demonstrated that in the context of living donation, healthy individuals provide more adequate reference data. Future research needs to determine the length and the nature of the post-operative QoL impairment and further explore possible influencing factors.

High serum adiponectin concentration in children with chronic kidney disease.

Adiponectin (ADPN) counteracts the inflammatory response of the endothelium, which plays an important role in the development of atherosclerosis in patients with chronic kidney disease (CKD). Data in children with CKD are scarce. We examined serum ADPN concentration in 90 children with various renal disorders: 28 with CKD on conservative treatment (CKD), 21 on regular dialysis treatment (D), and 41 after kidney transplantation (Tx); 27 age-matched healthy children served as controls (C). Body mass index (BMI), estimated glomerular filtration rate (eGFR), lipids, homocysteine, high sensitivity CRP (hsCRP), and systolic blood pressure (SBP) were also measured. Mean serum ADPN concentration was significantly higher in patients with CKD (27.3 µg/ml ±15.0), on D (34.2 µg/ml ±14.9), and after Tx (23.6 µg/ml ±9.5) compared with ADPN levels in C (13.5 µg/ml ±6.1) (p < 0.0001). Serum ADPN concentration was inversely related to BMI (p = 0.001) and SBP (p = 0.004). In the multiple linear regression analysis, only SBP remained independently associated with ADPN plasma levels. Data show that children with CKD have significantly higher serum ADPN, even after Tx. The protective antiarthrosclerotic effect of ADPN may be mediated by lower SBP, a finding that deserves further study.

Prediction of volume responsiveness using pleth variability index in patients undergoing cardiac surgery after cardiopulmonary bypass.

BACKGROUND: The pleth variability index (PVI) is derived from analysis of the plethysmographic curve and is considered to be a noninvasive parameter for prediction of volume responsiveness. The aim of our prospective clinical study was to evaluate if volume responsiveness can be predicted by PVI in patients undergoing cardiac surgery after cardiopulmonary bypass. METHODS: Eighteen patients were prospectively studied. Directly after cardiac surgery, PVI, stroke volume variation (SVV), and cardiac index (CI) were recorded. Colloid infusion (4 ml/kg body weight) was used for volume loading, and volume responsiveness was defined as increase of CI more than 10 %. RESULTS: SVV and PVI measures were found to be highly correlated at r = 0.80 (p < 0.001). Receiver operating characteristics curve (ROC) analysis resulted in an area under the curve of 0.87 for SVV and 0.95 for PVI, which values did not differ statistically significant from each other (p > 0.05). The optimal threshold value given by ROC analysis was ≥11 % for SVV with a sensitivity and specificity of 100 % and 72.2 %. For PVI, optimal threshold value was ≥16 % with a sensitivity and specificity of 100 % and 88.9 %. Positive and negative predictive values estimating an increase of CI ≥10 % for SVV were 44.4 % and 100 % and 66.7 % and 100 % for PVI. CONCLUSIONS: For consideration of fluid responsiveness PVI is as accurate as SVV in patients after cardiopulmonary bypass. Methodological limitations such as instable cardiac rhythm after cardiopulmonary bypass and right- or left ventricular impairment seem to be responsible for low specificity and positive predictive values in both parameters PVI and SVV.

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.

Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells.

Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.

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.