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Background: Emergency Medical Services (EMS) studies have shown that prehospital risk stratification and triage decisions in patients with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS) can be improved using clinical risk scores with point-of-care (POC) troponin. In current EMS studies, three different clinical risk scores are used in patients suspected of NSTE-ACS: the prehospital History, ECG, Age, Risk and Troponin (preHEART) score, History, ECG, Age, Risk and Troponin (HEART) score and Troponin-only Manchester Acute Coronary Syndromes (T-MACS). The preHEART score lacks external validation and there exists no prospective comparative analysis of the different risk scores within the prehospital setting. The aim of this analysis is to externally validate the preHEART score and compare the diagnostic performance of the these three clinical risk scores and POC-troponin., Methods: Prespecified analysis from a prospective, multicentre, cohort study in patients with suspected NSTE-ACS who were transported to an ED between April 2021 and December 2022 in the Netherlands. Risk stratification is performed by EMS personnel using preHEART, HEART, T-MACS and POC-troponin. The primary end point was the hospital diagnosis of NSTE-ACS. The diagnostic performance was expressed as area under the receiver operating characteristic (AUROC), sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV)., Results: A total of 823 patients were included for external validation of the preHEART score, final hospital diagnosis of NSTE-ACS was made in 29% (n=235). The preHEART score classified 27% as low risk, with a sensitivity of 92.8% (95% CI 88.7 to 95.7) and NPV of 92.3% (95% CI 88.3 to 95.1). The preHEART classified 9% of the patients as high risk, with a specificity of 98.5% (95% CI 97.1 to 99.3) and PPV of 87.7% (95% CI 78.3 to 93.4). Data for comparing clinical risk scores and POC-troponin were available in 316 patients. No difference was found between the preHEART score and HEART score (AUROC 0.83 (95% CI 0.78 to 0.87) vs AUROC 0.80 (95% CI 0.74 to 0.85), p=0.19), and both were superior compared with T-MACS (AUROC 0.72 (95% CI 0.66 to 0.79), p≤0.001 and p=0.03, respectively) and POC-troponin measurement alone (AUROC 0.71 (95% CI 0.64 to 0.78), p<0.001 and p=0.01, respectively)., Conclusion: On external validation, the preHEART demonstrates good overall diagnostic performance as a prehospital risk stratification tool. Both the preHEART and HEART scores have better overall diagnostic performance compared with T-MACS and sole POC-troponin measurement. These data support the implementation of clinical risk scores in prehospital clinical pathways., Trial Registration Number: NCT05243485., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The validation of objective and easy-to-implement biomarkers that can monitor the effects of fast-acting drugs among Parkinson's disease (PD) patients would benefit antiparkinsonian drug development. We developed composite biomarkers to detect levodopa/carbidopa effects and to estimate PD symptom severity. For this development, we trained machine learning algorithms to select the optimal combination of finger tapping task features to predict treatment effects and disease severity. Data were collected during a placebo-controlled, crossover study with 20 PD patients. The alternate index and middle finger tapping (IMFT), alternative index finger tapping (IFT), and thumb-index finger tapping (TIFT) tasks and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III were performed during treatment. We trained classification algorithms to select features consisting of the MDS-UPDRS III item scores; the individual IMFT, IFT, and TIFT; and all three tapping tasks collectively to classify treatment effects. Furthermore, we trained regression algorithms to estimate the MDS-UPDRS III total score using the tapping task features individually and collectively. The IFT composite biomarker had the best classification performance (83.50% accuracy, 93.95% precision) and outperformed the MDS-UPDRS III composite biomarker (75.75% accuracy, 73.93% precision). It also achieved the best performance when the MDS-UPDRS III total score was estimated (mean absolute error: 7.87, Pearson's correlation: 0.69). We demonstrated that the IFT composite biomarker outperformed the combined tapping tasks and the MDS-UPDRS III composite biomarkers in detecting treatment effects. This provides evidence for adopting the IFT composite biomarker for detecting antiparkinsonian treatment effect in clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Increased leucine-rich repeat kinase 2 (LRRK2) kinase activity is an established risk factor for Parkinson's disease (PD), and several LRRK2 kinase inhibitors are in clinical development as potential novel disease-modifying therapeutics. This biomarker characterization study explored within- and between-subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of the serine 935 (Ser935) residue on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, peripheral blood mononuclear cells [PBMCs], neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase I/II pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (n = 6), idiopathic PD patients (n = 6), and healthy matched control subjects (n = 10) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over 2 days. Within-subject variability (geometric coefficient of variation [CV], %) of these biomarkers was lowest in whole blood and neutrophils (range: 12.64%-51.32%) and considerably higher in PBMCs (range: 34.81%-273.88%). Between-subject variability displayed a similar pattern, with relatively lower variability in neutrophils (range: 61.30%-66.26%) and whole blood (range: 44.94%-123.11%), and considerably higher variability in PBMCs (range: 189.60%-415.19%). Group-level differences were observed with elevated mean pRab10 levels in neutrophils and a reduced mean pS935/tLRRK2 ratio in PBMCs in PD LRRK2-mutation carriers compared to healthy controls. These findings suggest that the evaluated biomarkers and assays could be used to verify pharmacological mechanisms of action and help explore the dose-response of LRRK2 inhibitors in early-phase clinical studies. In addition, comparable α-synuclein aggregation in CSF was observed in LRRK2-mutation carriers compared to idiopathic PD patients., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: In patients with limited peritoneal metastasis (PM) originating from colorectal cancer, cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment option. This combined treatment modality using HIPEC with mitomycin C (MMC) for 90 minutes proved to be superior to systemic chemotherapy alone, but no benefit of adding HIPEC to CRS alone was shown using oxaliplatin-based HIPEC during 30 minutes. We investigated the impact of treatment temperature and duration as relevant HIPEC parameters for these two chemotherapeutic agents in representative preclinical models. The temperature- and duration- dependent efficacy for both oxaliplatin and MMC was evaluated in an in vitro setting and in a representative animal model., Methods: In 130 WAG/Rij rats, PM were established through i.p. injections of rat CC-531 colon carcinoma cells with a signature similar to the dominant treatment-resistant CMS4 type human colorectal PM. Tumor growth was monitored twice per week using ultrasound, and HIPEC was applied when most tumors were 4-6 mm. A semi-open four-inflow HIPEC setup was used to circulate oxaliplatin or MMC through the peritoneum for 30, 60 or 90 minutes with inflow temperatures of 38°C or 42°C to achieve temperatures in the peritoneum of 37°C or 41°C. Tumors, healthy tissue and blood were collected directly or 48 hours after treatment to assess the platinum uptake, level of apoptosis and proliferation and to determine the healthy tissue toxicity., Results: In vitro results show a temperature- and duration- dependent efficacy for both oxaliplatin and MMC in both CC-531 cells and organoids. Temperature distribution throughout the peritoneum of the rats was stable with normothermic and hyperthermic average temperatures in the peritoneum ranging from 36.95-37.63°C and 40.51-41.37°C, respectively. Treatments resulted in minimal body weight decrease (<10%) and only 7/130 rats did not reach the endpoint of 48 hours after treatment., Conclusions: Both elevated temperatures and longer treatment duration resulted in a higher platinum uptake, significantly increased apoptosis and lower proliferation in PM tumor lesions, without enhanced normal tissue toxicity. Our results demonstrated that oxaliplatin- and MMC-based HIPEC procedures are both temperature- and duration-dependent in an in vivo tumor model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor WC declared a past co-authorship with the authors RH, DL, PT, NF, AO, HK and HC., (Copyright © 2023 Helderman, Bokan, van Bochove, Rodermond, Thijssen, Marchal, Torang, Löke, Franken, Kok, Tanis, Crezee and Oei.)

Background: Movement Disorder Society-Unified Parkinson's Rating Scale Part III (MDS-UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater-independent measurements would be ideal for future trials., Objectives: To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa-induced changes over time and to determine their correlation and compare their discriminatory power with MDS-UPDRS III., Methods: This was a randomized, double-blind, crossover study in 20 patients with PD receiving levodopa/carbidopa and placebo capsules after overnight medication withdrawal. Pre- and up to 3.5 hours postdose, MDS-UPDRS III and tapping tasks were performed. Tasks included 2 touchscreen-based alternate finger tapping tasks (index finger versus index-middle finger tapping) and a thumb-index finger task using a goniometer., Results: In the alternate index finger tapping task, levodopa/carbidopa compared with placebo resulted in significantly faster (total taps: 12.5 [95% confidence interval, CI, 6.7-18.2]) and less accurate tapping (total spatial error: 240 mm [95% CI, 123-357 mm]) with improved rhythm (intertap interval standard deviation [SD], -16.3% [95% CI, -29.9% to 0.0%]). In the thumb-index finger task, tapping was significantly faster (mean opening velocity, 151 degree/s [64-237 degree/s]), with a higher mean amplitude (8.4 degrees [3.7-13.0 degrees]) and improved rhythm (intertap interval SD, -46.4% [95% CI, -63.7% to -20.9%]). The speed-related endpoints showed a moderate-to-strong correlation with the MDS-UPDRS III ( r  = 0.45-0.70). The effect sizes of total taps and spatial error in the alternate index finger tapping task and opening velocity in the thumb-index finger task were comparable with the MDS-UPDRS III. In contrast, the MDS-UPDRS III performed better than the alternate index-middle finger task., Conclusion: The alternate index finger and the thumb-index finger tapping tasks provide short, rater-independent measurements that are sensitive to levodopa/carbidopa effects with a similar effect size as the MDS-UPDRS III., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are currently transported and admitted to the nearest emergency department (ED) for risk stratification, diagnostic workup and treatment. Although such patients with NSTE-ACS can benefit from direct transfer to a PCI center for early invasive treatment, no reliable prehospital triage tools are available. Recently, the PreHEART score has been validated in the PreHEART study for prehospital triage of patients with suspected NSTE-ACS., Methods: The primary objective of the TRIAGE-ACS study, a prospective cohort study, is to determine whether prehospital triage using the PreHEART score can significantly reduce time from first medical contact to final diagnostics and revascularization in patients in need of coronary revascularization. The first cohort (control cohort; n = 500) is observatory and is used as a reference group for the second cohort. In the second cohort (interventional cohort; n = 500) patients are stratified in the ambulance for direct transfer to either a PCI or a non-PCI center, based on the PreHEART score. These two cohorts will be compared with each other. In total, 1000 patients will be included. Follow-up for endpoints will be performed by reviewing the medical record after 30 days, 1 year, and 2 years., Conclusion: The TRIAGE-ACS study is the first prospective study to investigate the impact of prehospital triage using the PreHEART score on time to final invasive diagnostics and treatment in patients with NSTE-ACS in need of revascularization by transferring high risk patients directly to a PCI center and patients at a low risk of having an NSTE-ACS to a non-PCI center. Such triage strategy could potentially result in optimization of regional care for all ACS patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies., Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study., Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations., Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB-312 dose regimen. The average CSF/serum ratio was 0.2%., Conclusions: UB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath., Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose., Results: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median T max between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment., Conclusion: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD)., Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD., Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose., Results: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg)., Conclusions: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is a progressive neurodegenerative disease that affects almost 2% of the population above the age of 65. To better quantify the effects of new medications, fast and objective methods are needed. Touchscreen-based tapping tasks are simple yet effective tools for quantifying drug effects on PD-related motor symptoms, especially bradykinesia. However, there is no consensus on the optimal task set-up. The present study compares four tapping tasks in 14 healthy participants. In alternate finger tapping (AFT), tapping occurred with the index and middle finger with 2.5 cm between targets, whereas in alternate side tapping (AST) the index finger with 20 cm between targets was used. Both configurations were tested with or without the presence of a visual cue. Moreover, for each tapping task, within- and between-day repeatability and (potential) sensitivity of the calculated parameters were assessed. Visual cueing reduced tapping speed and rhythm, and improved accuracy. This effect was most pronounced for AST. On average, AST had a lower tapping speed with impaired accuracy and improved rhythm compared to AFT. Of all parameters, the total number of taps and mean spatial error had the highest repeatability and sensitivity. The findings suggest against the use of visual cueing because it is crucial that parameters can vary freely to accurately capture medication effects. The choice for AFT or AST depends on the research question, as these tasks assess different aspects of movement. These results encourage further validation of non-cued AFT and AST in PD patients., Competing Interests: The authors declare no competing interests.

Aims: A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers., Methods: In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed., Results: LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. C max , AUC 0-24 and AUC 0-inf increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected., Conclusions: These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Blood-based biomarkers for Alzheimer's disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta (1-42/1-40) , glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity., Methods: We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET-), mild cognitive impairment (26 PET+, 24 PET-), or AD-dementia (132 PET+). Plasma Abeta (1-42/1-40) , GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald's backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman's correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA)., Results: Abeta (1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p < 0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p = 0.001 and p = 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta (1-42/1-40) and GFAP, alongside age and APOE (AUC = 88% (95% CI 83-93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = - 0.40 to - 0.26; NfL: range sβ = - 0.35 to - 0.18; all: p < 0.002), whereas Abeta (1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 - 0.11; all: p < 0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman's rho> 0.33, p < 0.001). Abeta (1-42/1-40) showed a moderate negative correlation with MTA (Spearman's rho = - 0.24, p = 0.001)., Discussion and Conclusions: Combination of plasma Abeta (1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.

Objectives: This study sought to investigate the prevalence of systolic dysfunction using global longitudinal strain (GLS) and its prognostic value in relatives of dilated cardiomyopathy (DCM) patients that had normal left ventricular ejection fraction (LVEF)., Background: DCM relatives are advised to undergo cardiac assessment including echocardiography, irrespective of the genetic status of the index patient. Even though LVEF is normal, the question remains whether this indicates absence of disease or simply normal cardiac volumes. GLS may provide additional information regarding (sub)clinical cardiac abnormalities and thus allow earlier disease detection., Methods: A total of 251 DCM relatives and 251 control subjects with a normal LVEF (≥55%) were screened. Automated software measured the GLS on echocardiographic 2-, 3-, and 4-chamber views. The cutoff value for abnormal strain was >-21.5. Median follow-up was 40 months (interquartile range: 5 to 80 months). Primary outcome was the combination of death and cardiac hospitalization., Results: A total of 120 relatives and 83 control subjects showed abnormal GLS (48% vs. 33%, respectively; p < 0.001). Abnormal GLS was independently associated with DCM relatives and cardiovascular risk factors, rather than genetic mutations. Subjects with abnormal GLS had more frequent cardiac hospitalizations and a higher mortality as compared with subjects with normal GLS (hazard ratio: 3.29; 95% confidence interval: 1.58 to 6.87; p = 0.001). Additionally, follow-up LVEF was measured in a subset of relatives, and it decreased significantly in those with abnormal as compared with normal GLS (p = 0.006)., Conclusions: Relatives of DCM patients had a significantly higher prevalence of systolic dysfunction detected by GLS despite normal LVEF compared with control subjects, independent of age, sex, comorbidities, and genotype. Abnormal GLS was associated with LVEF deterioration, cardiac hospitalization, and death., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Analytical methods based on X-Ray radiation proved to be reliable and sensitive techniques to study activated carbons (ACs). An X-Ray absorption analysis based on digital radiographic images (XRA) is applied for the determination of the exhaustion degree of granular activated carbon (GAC) used in a water purification system for hemodialysis. XRA-method demonstrated the possibility to determine the exhaustion degree at different layers of the GAC filter. The results of the XRA-method were successfully correlated with X-Ray Fluorescence (XRF), TGA, Elemental analysis (EA), SEM, TD-GC/MS, ATR-FTIR, X Ray Diffraction (XRD) and Nuclear Magnetic Resonance relaxometry (NMR) analyses. It was demonstrated that the XRA-method is a fast and reliable analytical tool to give indirect information on the exhaustion degree of GAC at different layers. It is also demonstrated that XRA results can be correlated with the results of the other analytical techniques, rather dealing with the composition and morphology of GAC at different layers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study was set up to evaluate the costs of a one-stage treatment of chronic osteomyelitis using bioactive glass S53P4 versus a two-stage treatment using gentamicin-loaded PMMA beads. Furthermore, a cost-effectiveness analysis was performed from a hospital's perspective together with the evaluation of clinical outcome. A treatment group ( n = 25) receiving one-stage surgery with bioactive glass was retrospectively compared with a two-stage control group ( n = 25). An assessment was made of all costs included from first outpatient visit until one year after treatment. Bootstrap simulation and sensitivity analyses were performed. The primary endpoint was cost-effectiveness with clinical outcome as the secondary endpoint. The base case analyses shows dominance of the one-stage treatment with bioactive glass S53P4 due to lower costs and a better clinical outcome. Sensitivity analyses confirm these findings. This study is the first in its kind to show one-stage treatment of chronic osteomyelitis with bioactive glass S53P4 to be cost-effective.

Background and Objectives: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are the standard of care for patients diagnosed with colorectal peritoneal surface malignancy (PSM). Despite a clearly defined standardization of CRS, a large variety of HIPEC modalities are still used in clinical practice., Methods: Body surface area (BSA)- and concentration-based HIPEC protocols were clinically and pharmacologically evaluated in a randomized phase III clinical pilot trial. Oxaliplatin dose was 460 mg/m 2 (BSA-based) in 2 L/m 2 carrier solution (concentration-based). Platinum quantification was performed using a validated inductively coupled plasma mass spectrometry method. Three-month morbidity, mortality, and health-related quality of life (HRQOL) were assessed., Results: Thirty-one patients were randomized to either BSA- or concentration-based HIPEC. Toxicity and efficacy were higher (P < 0.001) in patients receiving concentration-based HIPEC. There was no difference in pharmacologic advantage between the two groups. A higher drug concentration in the tumor nodule at the end of HIPEC was found in the HIPEC-concentration group. There was no difference in major morbidity and mortality between the treatment groups. HRQOL was decreased 3 months postoperatively in the HIPEC-concentration group., Conclusion: Concentration-based chemotherapy delivers the drug in the most standardized way to the tumor nodule, resulting in increasing drug concentrations in the tumor nodule without increasing major morbidity., (© 2019 Wiley Periodicals, Inc.)

Silver nanoparticles (AgNPs) belong to the most commercialized nanomaterials, used in both consumer products and medical applications. Despite its omnipresence, in-depth knowledge on the potential toxicity of nanosilver is still lacking, especially for developing organisms. Research on vertebrates is limited due to ethical concerns, and planarians are an ideal invertebrate model to study the effects of AgNPs on stem cells and developing tissues in vivo , as regeneration mimics development by triggering massive stem cell proliferation. Our results revealed a strong interference of AgNPs with tissue- and neuroregeneration which was related to an altered stem cell cycle. The presence of a PVP-coating significantly influenced toxicity outcomes, leading to elevated DNA-damage and decreased stem cell proliferation. Non-coated AgNPs had an inhibiting effect on stem cell and early progeny numbers. Overall, regenerating tissues were more sensitive to AgNP toxicity, and careful handling and appropriate decision making is needed in AgNP applications for healing and developing tissues. We emphasize on the importance of AgNP characterization, as we showed that changes in physicochemical properties influence toxicity.

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for colorectal peritoneal surface malignancy (PSM) treatment. Although, there is an acknowledged standardization regarding the CRS, we are still lacking a much-needed standardization amongst the various intraperitoneal (IP) chemotherapy protocols, including the HIPEC dosing regimen. We should rely on pharmacologic evidence building towards such a standardization. The current IP chemotherapy dosing regimens can be divided into body surface area (BSA)-based and concentration-based protocols. A preclinical animal study was designed to evaluate pharmacologic advantage (PA), efficacy and survival. WAG/Rij rats were IP injected with the rat colonic carcinoma cell line CC-531. Animals were randomized into three groups: CRS alone or CRS combined with oxaliplatin-based HIPEC (either BSA- or concentration-based). There was no difference in PA between the two groups (p=0.283). Platinum concentration in the tumor nodule was significantly higher in the concentration-based group ( p <0.001). Median survival did not differ between the treatment groups ( p <0.250). This preclinical study, in contrast to previous thinking, clearly demonstrates that the PA does not provide any information about the true efficacy of the drug and emphasizes the importance of the tumor nodule as pharmacologic endpoint., Competing Interests: CONFLICTS OF INTEREST The authors have no conflict of interest to disclose.

Oxaliplatin is a platinum (Pt) 1 containing antineoplastic agent that is applied in current clinical practice for the treatment of colon and appendiceal neoplasms. A fully validated, highly sensitive, high throughput inductively coupled plasma mass spectrometry (ICP-MS) method is provided to quantify the total Pt content in plasma, plasma ultrafiltrate, urine and peritoneal fluid. In this ICP-MS approach, the only step of sample preparation is a 1000-fold dilution in 0.5% nitric acid, allowing the analysis of 17 samples per hour. Detection of Pt was achieved over a linear range of 0.01-100 ng/mL. The limit of quantification was 18.0 ng/mL Pt in plasma, 8.0 ng/mL in ultrafiltrate and 6.1 ng/mL in urine and peritoneal fluid. The ICP-MS method was further validated for inter-and intraday precision and accuracy (≤15%), recovery, robustness and stability. Short-term storage of the biofluids, for 14 days, can be performed at -4 °C, -24 °C and -80 °C. As to long-term stability, up to 5 months, storage at -80 °C is encouraged. Furthermore, a timeline assessing the total and unbound Pt fraction in plasma and ultrafiltrate over a period of 45 h is provided. Following an incubation period of 5 h at 37 °C, 19-21% of Pt was recovered in the ultrafiltrate, emphasizing the extensive and rapid binding of oxaliplatin-derived Pt to plasma proteins. The described method can easily be implemented in a routine setting for pharmacokinetic studies in patients treated with oxaliplatin-based hyperthermic intraperitoneal perioperative chemotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

OA is a degenerative joint disease characterized by articular cartilage degradation, osteophyte formation, synovitis, and subchondral bone sclerosis. One of OAs main risk factors is obesity. To date, it is not fully understood how obesity results in OA. Historically, this link was ascribed to excessive joint loading as a result of increased body weight. However, the association between obesity and OA in non-weight-bearing joints suggests a more complex aetiology for obesity-induced OA. In the present review, the link between obesity and OA is discussed. First, the historical view of altered joint loading leading to wear and tear of the joint is addressed. Subsequently, the effects of a disturbed lipid metabolism, low-grade inflammation, and adipokines on joint tissues are discussed and linked to OA. Taken together, inflamed adipose tissue and dyslipidaemia play pivotal roles in obesity-induced OA. It becomes increasingly clear that the link between obesity and OA transcends excessive loading., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The NVVC guideline on ST-elevation myocardial infarction forms the basis for the regional prehospital triage (PHT) project in Zuidoost Brabant. In this project diagnosis and treatment strategies are determined in the ambulance., Aim: To summarise quality assessment and clinical results after one year., Methods: We evaluated the protocol and patient record form, the patient's call, assignment of tasks, diagnosis, treatment, time intervals, information to hospitals, cooperation and data transmission. Time delays were compared with time delays in a regional dry run before the start of the project and with time delays reported in the literature., Results: Patients still wait over one hour before seeking medical attention. The GP received the majority (65%) of patient calls. In half of all cases (51%), GPs call the ambulance centre only after they have seen the patient. When the patient calls the ambulance centre (35%), information to the GP is either prompt or absent. In 77% of calls to 112 it remains unclear whether the GP was informed at all. The treatment strategy was correct in 97% of cases. Time between symptoms and call decreased in comparison with our local preliminary investigation. Quality assessment after one year shows protocol deviations that are either logical procedural improvements or correctable flaws with no substantial negative influence., Conclusion: Short-term clinical results are good, but structured follow-up is needed to reduce mortality in the long term, especially after thrombolysis. A guideline is a snapshot of a dynamic process. The PHT project allows rapid adaptations to be made to new paradigms.

We developed and optimized a new modified amplified fragment length polymorphism (AFLP) typing method to obtain a multibanding fingerprint that can be separated by agarose gel electrophoresis. Both to maximize the discriminatory power and to facilitate the computer-assisted analysis, bacterial DNA was digested with four different restriction enzymes. After ligation of adaptors to the DNA fragments, PCR testing of various single primers was performed. Two single primers that gave optimal results with regard to band resolution and discriminatory power were selected and combined. The computer-assisted analysis of fingerprint patterns was performed with Pearson's product-moment correlation values of densitometric curves, without assigning bands to peaks. Thus, the analysis is not subject to human interpretation errors. With this method, we investigated two outbreaks of multiresistant Klebsiella pneumoniae in an intensive care unit and various sporadic isolates of K. pneumoniae and Klebsiella oxytoca. Cluster analysis of isolates analyzed in different experiments and on different gels showed that fingerprint patterns clustered correctly according to subspecies or to the outbreaks. Multienzyme multiplex PCR AFLP revealed that the first outbreak was caused by two different types of strains. Outbreak two was caused by yet another strain of K. pneumoniae. In conclusion, the typing method used here is easy to perform and highly reproducible, and due to generation of complex banding patterns, it has a higher discriminatory power. Furthermore, the multienzyme multiplex PCR fingerprints are easy to analyze, and a reliable database can be stored in the computer to facilitate comparison of future isolates of Klebsiella spp. The method can be performed in every clinical microbiology laboratory.

Between September 1988 and February 1993, 14 patients whose ages ranged from 3 months to 16 years (mean 11.1 +/- 4.3 years) underwent replacement of the aortic root with the autologous pulmonary root for aortic valve disease. The follow-up was 4 years (cumulative total of 25.2 patient-years). There was no early mortality. Late mortality (one patient) was 7.1% (95% confidence limits 0% to 21%). This patient had juvenile rheumatoid arthritis and died of consequent congestive heart failure with autograft failure 6 months after operation. Event-free survival after 4 years was 78.6% (95% confidence limits 50% to 95%). One patient was reoperated on because of autograft failure caused by a relapse of rheumatic fever. One patient operated on for critical neonatal aortic stenosis has subnormal exercise tolerance because of restrictive cardiomyopathy and pulmonary homograft regurgitation. The other 12 patients were in New York Heart Association functional class I at the end of follow-up. There was no prevalence of bacterial endocarditis. There were no signs of primary structural degeneration of the pulmonary autograft. During follow-up, in eight patients, increased anulus diameter of the pulmonary autograft could be demonstrated by precordial two-dimensional echocardiography, suggesting growth of the autograft. Our experience shows that aortic root replacement with the pulmonary autograft can be done with low mortality and morbidity in children with aortic valve disease. The operation seems to be contraindicated in children with juvenile rheumatoid arthritis because of the risk of recurrence of rheumatic disease in the autograft. The pulmonary autograft has also been shown to be susceptible to recurrence of rheumatic inflammation in children with a history of acute rheumatic fever. Despite pulmonary autograft replacement of the aortic valve in infants with critical valvular aortic stenosis and endocardial fibroelastosis, clinical results may be poor. Growth of the autograft is suggested by echocardiographic follow-up. We consider aortic root replacement with the pulmonary autograft the procedure of choice in children who require aortic valve replacement.

In this article an exploratory study into a national exercise program for people of 55 years and older is reported. In order to gain more insight in the various characteristics of the participants, a questionnaire was completed by a sample of 839 persons. The studied aspects are background characteristics, medical characteristics, characteristics of daily activities, risk behaviour, way of acquaintance with and motive for participation in the program. The results of the research are, if possible, compared with a reference group. A comparison between the participants of the various types of the movement program, shows similarities on the dimensions ADL-problems and bad health. Differences are found on the dimensions gender, age and education. The conclusion is that the choice of the type of the movement program is probably made on the ground of these three characteristics. The comparison between the participants of the exercise program and the reference group shows that a selection within the population of people of 55 years and older is very likely. The majority of the participants is 65 to 74 years old (43%), female (80%) and of low educational level (85%). Positive differences in favour of the exercise participants are found on the variables hypertension, medicine usage. ADL problems and risk behaviour (smoking and drinking). It is, however, unclear whether these differences are the result of an effect of the program or the result of selection in the program population. A combination of these two factors is also not ruled out. An effect-study can give more evidence for one of the factors involved.

We investigated contractile responses of the isolated human coronary artery to 5-hydroxytryptamine (5-HT), washed human platelets, sumatriptan and ergotamine. 5-HT (pD2: 6.8 +/- 0.1, Emax: 47.7 +/- 6.8 mN) and platelets (effect 14.4 +/- 2.8 mN with 3.10(10) platelets/l) caused contractile responses which were attenuated by ketanserin (1 microM). In the presence of ketanserin (1 microM), both rauwolscine (1 and 10 microM) and cyanopindolol (1 and 10 microM) caused concentration-dependent additional antagonism against contractions induced by low (< or = 1 microM) concentrations of 5-HT. Sumatriptan-induced contractions (pD2: 6.2 +/- 0.1; Emax: 10.7 +/- 2.4 mN) were antagonized to a similar extent by both rauwolscine (1 microM) and cyanopindolol (1 microM) (pKB: 6.5 +/- 0.1 and 6.4 +/- 0.1, respectively) and also by metergoline (0.1 microM; pKB: 7.2 +/- 0.1). The order of potency of antagonists against sumatriptan resembles the order reported for the human saphenous vein 5-HT1D-like receptor. No significant additional antagonism by cyanopindolol (1 microM) or rauwolscine (1 microM) against platelet-induced contractile responses was observed. Ergotamine caused potent contractile responses (pD2: 8.4 +/- 0.3, Emax: 19.4 +/- 2.4 mN). It is concluded that although 5-HT2 receptors predominantly mediate 5-HT-induced contractions, the 5-HT1-like receptor seems to play a role in coronary vasospasm caused by low concentrations of 5-HT.

Allograft heart valves obtained from donor hearts have been cryopreserved in the Heart Valve Bank in Rotterdam for transplantation purposes. In contrast to hepatitis B screening of organ donors, which consists of only a rapid HBV surface antigen (HBsAg) assay, tissue donors can be screened more completely for hepatitis B virus (HBV) by HBsAg and antibodies against HBV core antigen (anti-HBc) tests, and when necessary, anti-HBs and HBV-DNA tests. The value of this complete HBV screening was investigated by evaluation of the HBV screening results of 676 donor sera. HBsAg was positive in 1 serum. Anti-HBc was positive in 63 sera, of which 52 also had positive antibodies against HBV surface antigen (anti-HBs) tests (no risk of transmission) and 10 had negative anti-HBs tests. In 3 cases with a negative anti-HBs test the HBV-DNA test was positive (risk of transmission). In 3 cases not enough serum was available to perform all tests, resulting in a total of 7 rejected donors. Single HBsAg testing would have resulted in the rejection of only 1 donor. In the presented group of selected donors, approximately 0.5% of the HBsAg-negative donors were lower-level chronic carriers of hepatitis B. Complete HBV screening decreases the risk of transmission of hepatitis B in allograft heart valve transplantation.