Favorable Outcome After Single-kidney Transplantation From Small Donors in Children: A Match-controlled CERTAIN Registry Study.

BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 ±â€…6.2 mL/min/1.73 m² compared with a decrease of 6.9 ±â€…5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5 ±â€…25.5 in SDKTx versus 65.7 ±â€…23.1 mL/min/1.73 m² in ADKTx; P = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 ±â€…20.4 versus 104.6 ±â€…35.9; P = 0.043) but superior to ADKTx (68.1 ±â€…23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P = 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Developmental dynamics of homoarginine, ADMA and SDMA plasma levels from birth to adolescence.

Guanidino compounds such as dimethylarginines (SDMA, ADMA) and L-homoarginine ((L-)hArg) can interfere with bioavailability and function of the main NO-donor L-arginine (L-Arg). High ADMA and SDMA but low L-hArg concentrations have been associated with cardio- and cerebrovascular events and mortality in adults. The role of guanidino compounds in paediatric patients remains less clear. We, therefore, compared guanidino compound levels in plasma samples of 57 individuals with chronic kidney disease (CKD) and 141 individuals without CKD from the age of 0 to 17 years, including patients with different comorbidities by correlation and regression analyses. We found highest hArg, SDMA and ADMA concentrations in neonates (Kruskal-Wallis, p < 0.001 for all). From the age of 1 year on, hArg levels increased, whereas SDMA und ADMA levels further decreased in children. SDMA and ADMA are higher in children with CKD independent of GFR (mean factor 1.92 and 1.38, respectively, p < 0.001 for both), and SDMA is strongly correlated with creatinine concentration in children with CKD (Spearman's rho 0.74, p < 0.001). We provide guanidino compound levels in a large sample covering all paediatric age groups for the first time. Our data can be used to assess the role of guanidino compounds such as hArg in disease states, i.e. cerebro- and cardiovascular disorders in childhood and adolescence.

Homoarginine Associates with Carotid Intima-Media Thickness and Atrial Fibrillation and Predicts Adverse Events after Stroke.

Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor -0.68 [95% confidence interval (CI): -1.30, -0.07], -0.14 [95% CI: -0.22, -0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms.

Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial.

BACKGROUND: Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. METHODS: To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants' attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. DISCUSSION: Until today, no study has explored the interplay of pharmacological effects and patients' expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05191277), January 13, 2022.

Effects of remote patient management on self-care behaviour in heart failure patients: results from the randomized TIM-HF2 trial.

AIMS: Remote patient management (RPM) in heart failure (HF) patients has beneficial clinical effects. This analysis investigates the effects of RPM used in the Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial on HF-specific self-care. METHODS AND RESULTS: From 2013 to 2017, 1538 HF outpatients (age 70.3 ± 10.5 years, 70% men, 52%/47% NYHA II/III, 65% LVEF ≤45%) with a recent HF hospitalization were included to the study and randomized to usual care (UC) plus RPM (n = 796) or UC only (n = 775), with a 12-month follow-up. Self-reported self-care behaviour at baseline and at end of study was assessed with the 9-item European Heart Failure Self-care Behaviour Scale (EHFScBS-9), obtaining 1321 patients with valid baseline and follow-up questionnaires for the analysis. EHFScBS-9 sum scores increased in the RPM group (n = 667) from 78.7 ± 17 to 84.5 ± 14 and in the UC group (n = 654) from 79.0 ± 17 to 80.0 ± 16 from baseline to 12 months [difference in means (MD) 4.58 (3.02, 6.14); P < 0.001] with highest improvement [8.66 (3.52; 13.81)] in patients living alone and having an inadequate (<70) baseline EHFScBS-9. There were differences between both groups in item 'I weight myself every day' [MD -1.13 (-1.24, -1.02); P < 0.001] and item 'I take my medication as prescribed' [MD -0.06 (-0.10, -0.01); P = 0.014]. No correlation was found between the EHFScBS-9 score and the efficacy of RPM on the TIM-HF2 primary endpoint of percentage of days lost due to unplanned cardiovascular hospitalization or death of any cause. CONCLUSIONS: RPM improves HF-specific self-care behaviour by achieving a better adherence to recommended HF regimen. REGISTRATION: ClinicalTrials.gov: NCT01878630.

Combined Short-Pulse and Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor.

OBJECTIVE: Novel deep brain stimulation (DBS) systems allow directional and short-pulse stimulation to potentially improve symptoms and reduce side effects. The aim of this study was to investigate the effect of short-pulse and directional stimulation, in addition to a combination of both, in the ventral intermediate thalamus (VIM)/posterior subthalamic area (PSA) on tremor and stimulation-induced side effects in patients with essential tremor. MATERIALS AND METHODS: We recruited 11 patients with essential tremor and VIM/PSA-DBS. Tremor severity (Fahn-Tolosa-Marin), ataxia (International Cooperative Ataxia Rating Scale), and paresthesia (visual analog scale) were assessed with conventional omnidirectional and directional stimulation with pulse width of 60 µs and 30 µs. RESULTS: All stimulation conditions reduced tremor. The best directional stimulation with 60 µs reduced more tremor than did most other stimulation settings. The best directional stimulation, regardless of pulse width, effectively reduced stimulation-induced ataxia compared with the conventional stimulation (ring 60 µs) or worst directional stimulation with 60 µs. All new stimulation modes reduced occurrence of paresthesia, but only the best directional stimulation with 30 µs attenuated paresthesia compared with the conventional stimulation (ring 60 µs) or worst directional stimulation with 60 µs. The best directional stimulation with 30 µs reduced tremor, ataxia, and paresthesia compared with conventional stimulation in most patients. Correlation analyses indicated that more anterior stimulation sites are associated with stronger ataxia reduction with directional 30 µs than with conventional 60 µs stimulation. CONCLUSION: Directional and short-pulse stimulation, and a combination of both, revealed beneficial effects on stimulation-induced adverse effects.

The impact of pharmacists' interventions within the Closed Loop Medication Management process on medication safety: An analysis in a German university hospital.

Background: Single elements of the Closed Loop Medication Management process (CLMM), including electronic prescribing, involvement of clinical pharmacists (CPs), patient individual logistics and digital administration/documentation, have shown to improve medication safety and patient health outcomes. The impact of the complete CLMM on patient safety, as reflected in pharmacists' interventions (PIs), is largely unknown. Aim: To evaluate the extent and characterization of routine PIs performed by hospital-wide CPs at a university hospital with an implemented CLMM. Methods: This single-center study included all interventions documented by CPs on five self-chosen working days within 1 month using the validated online-database DokuPIK (Documentation of Pharmacists' Interventions in the Hospital). Based on different workflows, two groups of CPs were compared. One group operated as a part of the CLMM, the "Closed Loop Clinical Pharmacists" (CL-CPs), while the other group worked less dependent of the CLMM, the "Process Detached Clinical Pharmacists" (PD-CPs). The professional experience and the number of medication reviews were entered in an online survey. Combined pseudonymized datasets were analyzed descriptively after anonymization. Results: A total of 1,329 PIs were documented by nine CPs. Overall CPs intervened in every fifth medication review. The acceptance rate of PIs was 91.9%. The most common reasons were the categories "drugs" (e.g., indication, choice of formulation/drug and documentation/transcription) with 42.7%, followed by "dose" with 29.6%. One-quarter of PIs referred to the therapeutic subgroup "J01 antibacterials for systemic use." Of the 1,329 underlying PIs, 1,295 were classified as medication errors (MEs) and their vast majority (81.5%) was rated as "error, no harm" (NCC MERP categories B-D). Among PIs performed by CL-CPs (n = 1,125), the highest proportion of errors was categorized as B (56.5%), while in the group of PIs from PD-CPs (n = 170) errors categorized as C (68.2%) dominated (p < 0.001). Conclusion: Our study shows that a structured CLMM enables CPs to perform a high number of medication reviews while detecting and solving MEs at an early stage before they can cause harm to the patient. Based on key quality indicators for medication safety, the complete CLMM provides a suitable framework for the efficient medication management of inpatients.

Effectiveness of a complex regional advance care planning intervention to improve care consistency with care preferences: study protocol for a multi-center, cluster-randomized controlled trial focusing on nursing home residents (BEVOR trial).

BACKGROUND: According to recent legislation, facilitated advance care planning (ACP) for nursing home (NH) residents is covered by German sickness funds. However, the effects of ACP on patient-relevant outcomes have not been studied in Germany yet. This study investigates whether implementing a complex regional ACP intervention improves care consistency with care preferences in NH residents. METHODS: This is a parallel-group cluster-randomized controlled trial (cRCT) with 48 NHs (≈ 3840 resident beds) between 09/2019 and 02/2023. The intervention group will receive a complex, regional ACP intervention aiming at sustainable systems redesign at all levels (individual, institutional, regional). The intervention comprises comprehensive training of ACP facilitators, implementation of reliable ACP processes, organizational development in the NH and other relevant institutions of the regional healthcare system, and education of health professionals caring for the residents. Control group NHs will deliver care as usual. Primary outcome is the hospitalization rate during the 12-months observation period. Secondary outcomes include the rate of residents whose preferences were known and honored in potentially life-threatening events, hospital days, index treatments like resuscitation and artificial ventilation, advance directives, quality of life, psychological burden on bereaved families, and costs of care. The NHs will provide anonymous, aggregated data of all their residents on the primary outcome and several secondary outcomes (data collection 1). For residents who have given informed consent, we will evaluate care consistency with care preferences and further secondary outcomes, based on chart reviews and short interviews with residents, surrogates, and carers (data collection 2). Process evaluation will aim to explain barriers and facilitators, economic evaluation the cost implications. DISCUSSION: This study has the potential for high-quality evidence on the effects of a complex regional ACP intervention on NH residents, their families and surrogates, NH staff, and health care utilization in Germany. It is the first cRCT investigating a comprehensive regional ACP intervention that aims at improving patient-relevant clinical outcomes, addressing and educating multiple institutions and health care providers, besides qualification of ACP facilitators. Thereby, it can generate evidence on the potential of ACP to effectively promote patient-centered care in the vulnerable population of frail and often chronically ill elderly. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT04333303 . Registered 30 March 2020.

Effective high-density lipoprotein cholesterol is associated with carotid intima-media thickness and vascular events after acute ischemic stroke.

BACKGROUND AND AIMS: Effective high density lipoprotein cholesterol (HDL-C) is a measure of HDL functionality. We evaluated if HDL-C is associated with carotid intima-media thickness (cIMT) and incident major adverse cardiovascular events (MACE) in patients with acute ischemic stroke from two prospective cohort studies. METHODS: In the MARK-STROKE cohort, 299 patients with acute ischemic stroke or TIA were included. Outcome was available in 219 patients during a median follow-up of 294 days. In CIRCULAS, 382 acute ischemic stroke patients were included and a 90-day follow-up was available in 213 patients. HDL-C was calculated based on symmetric dimethylarginine (SDMA) and HDL cholesterol concentrations. Main outcome was incident MACE (death, stroke, and myocardial infarction) and the main measure was cIMT. RESULTS: In both studies, HDL-C was inversely associated with cIMT in linear regression analysis adjusted for age, sex and creatinine. In MARK-STROKE, the adjusted hazard for MACE was significantly reduced for patients with one unit increase (mg/dL) of HDL-C (hazard ratio 0.95 [95% confidence interval (CI): 0.92, 0.99]). In the CIRCULAS cohort, stroke patients with higher HDL-C had less incident MACE during 90 days of follow-up (odds ratio: 0.97 [95% CI: 0.94, 0.99] for one unit increase). Neither SDMA nor HDL cholesterol predicted outcome. CONCLUSIONS: Our findings imply a protective role of biologically effective HDL after acute cerebral ischemia for secondary events and emphasize the relevance of lipoprotein functionality in these patients.

Validation of the German eHealth impact questionnaire for online health information users affected by multiple sclerosis.

BACKGROUND: Persons with multiple sclerosis (MS) are confronted by an overwhelming amount of online health information, which can be valuable but also vary in quality and aim. Therefore, it is of great importance for developers and providers of eHealth information to understand its impact on the users. The eHealth Impact Questionnaire (eHIQ) has been developed in the United Kingdom to measure the potential effects of health and experimental information websites. This contains user's general attitudes towards using the internet to gain health information and attitudes towards a specific health related website. The self-complete questionnaire is divided into two independently administered and scored parts: the 11-item eHIQ part 1 and the 26-item eHIQ part 2. This study aimed to validate the psychometric properties of the German version of the eHealth Impact Questionnaire (eHIQ-G). METHODS: 162 people with multiple sclerosis browsed one of two possible websites containing information on MS and completed an online survey. Internal consistency was assessed by Cronbach's alpha and structural validity by Confirmatory Factor Analysis. Construct validity was examined by assessing correlations with the reference instruments eHealth Literacy Questionnaire and the General Self-Efficacy Scale measuring related, but dissimilar constructs. Moreover, we investigated the mean difference of the eHIQ-G score between the two websites. Data were analyzed using SPSS and AMOS software. RESULTS: The eHIQ-G subscales showed high internal consistency with Cronbach's alpha from 0.833 to 0.885. The 2-factor model of eHIQ part 1 achieved acceptable levels of goodness-of-fit indices, whereas the fit for the 3-factor model of eHIQ part 2 was poor and likewise for the alternative modified models. The correlations with the reference instruments were 0.08-0.62 and as expected. Older age was related with lower eHIQ part 1 score, whereas no significant effect was found for education on eHIQ part 1. Although not significant, the website 'AMSEL' reached higher mean scores on eHIQ part 2. CONCLUSIONS: The eHIQ-G has good internal consistency, and sufficient structural and construct validity. This instrument will facilitate the measurement of the potential impact of eHealth tools.

Left Ventricular Diastolic Dysfunction Is Not Associated With Pulmonary Edema in Septic Patients. A Prospective Observational Cohort Study.

Purpose: We aimed to investigate whether left ventricular diastolic dysfunction (LVDD) is associated with pulmonary edema in septic patients. Methods: We conducted a prospective cohort study in adult septic patients between October 2018 and May 2019. We performed repeated echocardiography and lung ultrasound examinations within the first 7 days after diagnosis of sepsis. We defined LVDD according to the 2016 recommendations of the American Society of Echocardiography and-for sensitivity analysis-according to an algorithm which has been validated in septic patients. We quantified pulmonary edema using the lung ultrasound score (LUSS), counting B-lines in four intercostal spaces. Results: We included 54 patients. LVDD was present in 51 (42%) of 122 echocardiography examinations. The mean (±SD) LUSS was 11 ± 6. There was no clinically meaningful association of LVDD with LUSS (B = 0.55 [95%CI: -1.38; 2.47]; p = 0.571). Pneumonia was significantly associated with higher LUSS (B = 4.42 [95%CI: 0.38; 8.5]; p = 0.033). Conclusion: The lack of a clinically meaningful association of LVDD with LUSS suggests that LVDD is not a major contributor to pulmonary edema in septic patients. Trial Registration: NCT03768752, ClinicalTrials.gov, November 30th, 2018 - retrospectively registered.

Diabetes, Glycated Hemoglobin (HbA1c), and Neuroaxonal Damage in Parkinson's Disease (MARK-PD Study).

BACKGROUND: Diabetes is associated with incidence and prevalence of Parkinson's disease (PD). Furthermore, glycated hemoglobin (HbA1c) levels have been linked with motor function and progression. OBJECTIVES: We evaluated the relationship between prevalent diabetes and HbA1c levels with serum neurofilament light chain (NfL) levels as marker of neuroaxonal damage. METHODS: NfL concentrations were analyzed with Simoa in serum of 195 PD patients with available HbA1c values. Motor (MDS-UPDRS III, Hoehn & Yahr [H&Y]) and cognitive (Montreal Cognitive Assessment [MoCA]) function was assessed and vascular comorbidities were documented from medical records. RESULTS: PD patients with prevalent diabetes had higher serum NfL levels and lower MoCA scores independent of age, body mass index (BMI), and vascular risk factors. Furthermore, diabetes was associated with higher H&Y stages in unadjusted and age/BMI-adjusted models. Higher HbA1c levels were associated with increased NfL in unadjusted and age/BMI-adjusted models. CONCLUSIONS: In PD patients, diabetes and high HbA1c are associated with increased neuroaxonal damage and cognitive impairment. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Serum neurofilament light chain and postural instability/gait difficulty (PIGD) subtypes of Parkinson's disease in the MARK-PD study.

The PIGD (postural instability / gait difficulty) subtype of Parkinson´s disease (PD) is associated with faster cognitive and motor decline. So far, there are no quantifiable biomarkers to aid clinical subtyping. Neurofilament light chain (NfL) is a highly specific marker of neuro-axonal damage and can be assessed in blood. Here, we investigated if serum NfL concentrations are associated with PIGD subtype and PIGD scores in PD patients at advanced disease stages. Furthermore, we evaluated if serum NfL is associated with motor and cognitive function assessed with MDS-UPDRS part III and Montreal cognitive assessment (MoCA). Serum NfL levels were analyzed with Single Molecule Assays (Simoa) in blood of 223 PD patients from the bioMARKers in Parkinson's Disease (MARK-PD) study. Serum NfL concentrations were higher in PIGD patients independent of age, sex and disease duration. In linear regression analysis, serum NfL levels were associated with MoCA, MDS-UPDRS III and PIGD scores in unadjusted models, but remained significant after adjustment only with PIGD scores. In conclusion, increased serum NfL levels were associated with PIGD subtype and PIGD scores in patients with advanced PD.

Fra-2 overexpression upregulates pro-metastatic cell-adhesion molecules, promotes pulmonary metastasis, and reduces survival in a spontaneous xenograft model of human breast cancer.

PURPOSE: The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P-selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model. METHODS: The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA MB231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin-deficient scid mice. RESULTS: Fra-2 overexpression leads to a significantly shorter overall survival and a higher amount of spontaneous lung metastases not only in scid mice, but also in E- and P-deficient mice, indicating that it regulates not only selectin ligands, but also selectin-independent adhesion processes. CONCLUSION: Thus, Fra-2 expression influences the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells in a breast cancer xenograft model.

Clinical pharmacists' interventions across German hospitals: results from a repetitive cross-sectional study.

Background Pharmacists' interventions (PI) are suitable to improve medication safety and optimise patient outcome. However, in Germany, clinical pharmacy services are not yet available nationwide. Aim To gain prospective data on the extent and the composition of routine PI with special focus on intervention rates among German hospital pharmacists during two intervention weeks. Methods Within a repetitive cross-sectional study, clinical pharmacists documented all PIs on five days during a one-month period (intervention week) in 2017 and 2019 using the validated online-database ADKA-DokuPIK. Additionally, data regarding the supply structure/level of medical care, the extent of clinical pharmacy services and their professional experience were collected. All data were anonymised before analysis. Results In total, 2,282 PI from 62 pharmacists (2017) and 2578 PI from 52 pharmacists (2019) were entered. Intervention rate increased from 27.5 PI/100 patient days in 2017 to 38.5 PI/100 patient days in 2019 (p = 0.0097). Frequency of clinical pharmacy services on a daily basis significantly increased from 60% (2017) to 83% (2019). Reasons for PIs from the categories "drugs" (e.g. indication, choice, documentation/transcription) and "dose" were most common in both intervention weeks. The vast majority of underlying medication errors in both intervention weeks were categorised as "error, no harm" (80.3 vs. 78.6%), while the proportion of errors which did not reach the patient, doubled to 39.8% in IW-2019. Conclusion Regular and daily clinical pharmacy services become more established in Germany and clinical pharmacists are increasingly involved in solving drug related problems proactively and early during the medication management process.

Ten Years of Improving Acute Stroke Management in a Metropolitan Area: A Population-Based Quantification of Quality Indicators.

BACKGROUND AND PURPOSE: Rapid access to acute stroke treatment improves clinical outcomes in patients with ischemic stroke. We aimed to shorten the time to admission and to acute stroke treatment for patients with acute stroke in the Hamburg metropolitan area by collaborative multilevel measures involving all hospitals with stroke units, the Emergency Medical Services (EMS), and health-care authorities. METHODS: In 2007, an area-wide stroke care quality project was initiated. The project included mandatory admission of all stroke patients in Hamburg exclusively to hospitals with stroke units, harmonized acute treatment algorithms among all hospitals, repeated training of the EMS staff, a multimedia educational campaign, and a mandatory stroke care quality monitoring system based on structured data assessment and quality indicators for procedural measures. We analyzed data of all patients with acute stroke who received inhospital treatment in the city of Hamburg during the evaluation period from the quality assurance database data and evaluated trends of key quality indicators over time. RESULTS: From 2007 to 2016, a total of 83,395 patients with acute stroke were registered. During this period, the proportion of patients admitted within ≤3 h from symptom onset increased over time from 27.8% in 2007 to 35.2% in 2016 (p < 0.001). The proportion of patients who received rapid thrombolysis (within ≤30 min after admission) increased from 7.7 to 54.1% (p < 0.001). CONCLUSIONS: Collaborative stroke care quality projects are suitable and effective to improve acute stroke care.

Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH): an investigator-initiated, randomised, double-blinded, placebo-controlled, multicentre trial.

BACKGROUND: Cardiogenic shock has a high mortality on optimal therapy. Adrenomedullin is released during cardiogenic shock and is involved in its pathophysiological processes. This study assessed treatment with the humanised, monoclonal, non-neutralising, adrenomedullin antibody adrecizumab, increasing circulating concentrations of adrenomedullin in cardiogenic shock. METHODS: In this investigator-initiated, placebo-controlled, double-blind, multicentre, randomised trial (ACCOST-HH), patients were recruited from four university hospitals in Germany. Patients were eligible if they were 18 years old or older and hospitalised for cardiogenic shock within the last 48 h. Exclusion criteria were resuscitation for longer than 60 min and cardiogenic shock due to sustained ventricular tachycardia or bradycardia. Adult patients in cardiogenic shock were randomly assigned (1:1) to intravenous adrecizumab (8 mg/kg bodyweight) or placebo using an internet-based software. A block randomisation procedure was applied with stratification by age (older vs younger than 65 years), sex (male vs female), and type of underlying cardiogenic shock (acute myocardial infarction vs other entities). Investigators, patients, and medical staff involved in patient care were masked to group assignment. The primary endpoint was number of days up to day 30 without the need for cardiovascular organ support, defined as vasopressor therapy, inotropes, or mechanical circulatory support (or both) assessed in the intention-to-treat population. Safety outcomes included therapy-emergent serious adverse events, severe adverse events, adverse events, suspected unexpected serious adverse reactions, study drug-related mortality, and total mortality. The trial was registered at ClinicalTrials.gov, NCT03989531, and EudraCT, 2018-002824-17, and is now complete. FINDINGS: Between April 5, 2019, and Jan 13, 2021, 150 patients were enrolled: 77 (51%) were randomly assigned to adrecizumab and 73 (49%) to placebo. All patients received the allocated treatment. The number of days without the need for cardiovascular organ support was not different between patients receiving adrecizumab or placebo (12·37 days [95% CI 9·80-14·94] vs 14·05 [11·41-16·69]; adjusted mean difference -1·69 days [-5·37 to 2·00]; p=0·37). Serious adverse events occurred in 59 patients receiving adrecizumab and in 57 receiving placebo (odds ratio 0·92 [95% CI 0·43-1·98]; p=0·83). Mortality was not different between groups at 30 days (hazard ratio 0·99 [95% CI 0·60-1·65]; p=0·98) or 90 days (1·10 [0·68-1·77]; p=0·71). INTERPRETATION: Adrecizumab was well tolerated in patients with cardiogenic shock but did not reduce the need for cardiovascular organ support or improve survival at days 30 and 90. FUNDING: Adrenomed AG and University Hospital of Hamburg.

Mandibular condyle morphology among patients with mucopolysaccharidosis: An observational study of panoramic radiographs.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare metabolic diseases characterized by a wide spectrum of symptoms including progressive condylar resorption. AIM: The aim of this study was to quantify the severity of condylar involvement in MPS I individuals in comparison with a group of non-MPS individuals and to describe how condylar changes may vary among the different types of MPS. DESIGN: Fifty panoramic radiographs of MPS patients (13.4 ± 6.2 years) with MPS I (n = 14), MPS II (n = 2), MPS IV (n = 8) and MPS VI (n = 2) were compared with forty panoramic radiographs of non-MPS individuals. The severity of condylar resorption was evaluated using a qualitative score (grades 0-3) and using the ratio of condylar height to ramus height (CH: RH). RESULTS: All MPS I and VI individuals showed pronounced bilateral degenerative condylar resorption. In contrast, individuals with MPS II and IV exhibited heterogeneous findings. The quantification of condylar height to ramus height revealed that CH: RH was significantly decreased in MPS I as compared to that of non-MPS individuals (P < .001). In contrast, the CH: RH ratios of MPS II and IV showed great variability. CONCLUSION: Mucopolysaccharidoses subtypes differ with regard to the severity of condylar resorption.