Use of proxy indicators for automated surveillance of severe acute respiratory infection, the Netherlands, 2017 to 2023: a proof-of-concept study.

BackgroundEffective pandemic preparedness requires robust severe acute respiratory infection (SARI) surveillance. However, identifying SARI patients based on symptoms is time-consuming. Using the number of reverse transcription (RT)-PCR tests or contact and droplet precaution labels as a proxy for SARI could accurately reflect the epidemiology of patients presenting with SARI.AimWe aimed to compare the number of RT-PCR tests, contact and droplet precaution labels and SARI-related International Classification of Disease (ICD)-10 codes and evaluate their use as surveillance indicators.MethodsPatients from all age groups hospitalised at Leiden University Medical Center between 1 January 2017 up to and including 30 April 2023 were eligible for inclusion. We used a clinical data collection tool to extract data from electronic medical records. For each surveillance indicator, we plotted the absolute count for each week, the incidence proportion per week and the correlation between the three surveillance indicators.ResultsWe included 117,404 hospital admissions. The three surveillance indicators generally followed a similar pattern before and during the COVID-19 pandemic. The correlation was highest between contact and droplet precaution labels and ICD-10 diagnostic codes (Pearson correlation coefficient: 0.84). There was a strong increase in the number of RT-PCR tests after the start of the COVID-19 pandemic.DiscussionAll three surveillance indicators have advantages and disadvantages. ICD-10 diagnostic codes are suitable but are subject to reporting delays. Contact and droplet precaution labels are a feasible option for automated SARI surveillance, since these reflect trends in SARI incidence and may be available real-time.

The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant.

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65-80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.

Cannabidiol Increases Psychotropic Effects and Plasma Concentrations of Δ9-Tetrahydrocannabinol Without Improving Its Analgesic Properties.

Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS "Feeling High" by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUClast of THC (AUClast ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUClast ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUClast of 11-OH-THC (AUClast ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUClast ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia.

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy.

INTRODUCTION/AIMS: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). METHODS: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. RESULTS: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. DISCUSSION: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

A Targeted LC-MRM3 Proteomic Approach for the Diagnosis of SARS-CoV-2 Infection in Nasopharyngeal Swabs.

Since its first appearance, severe acute respiratory syndrome coronavirus 2 quickly spread around the world and the lack of adequate PCR testing capacities, especially during the early pandemic, led the scientific community to explore new approaches such as mass spectrometry (MS). We developed a proteomics workflow to target several tryptic peptides of the nucleocapsid protein. A highly selective multiple reaction monitoring-cubed (MRM3) strategy provided a sensitivity increase in comparison to conventional MRM acquisition. Our MRM3 approach was first tested on an Amsterdam public health cohort (alpha-variant, 760 participants) detecting viral nucleocapsid protein peptides from nasopharyngeal swabs samples presenting a cycle threshold value down to 35 with sensitivity and specificity of 94.2% and 100.0%, without immunopurification. A second iteration of the MS-diagnostic test, able to analyze more than 400 samples per day, was clinically validated on a Leiden-Rijswijk public health cohort (delta-variant, 2536 participants) achieving 99.9% specificity and 93.1% sensitivity for patients with cycle threshold values up to 35. In this manuscript, we also developed and brought the first proof of the concept of viral variant monitoring in a complex matrix using targeted MS.

Patients' Perspectives and Feasibility of Home Monitoring in Acute Care: The AcuteCare@Home Flash Mob Study.

Objective: To determine patients' perspectives on home monitoring at emergency department (ED) presentation and shortly after admission and compare these with their physicians' perspectives. Methods: Forty Dutch hospitals participated in this prospective flash mob study. Adult patients with acute medical conditions, treated by internal medicine specialties, presenting at the ED or admitted at the admission ward within the previous 24 h were included. The primary outcome was the proportion of patients who were able and willing to undergo home monitoring. Secondary outcomes included identifying barriers to home monitoring, patient's prerequisites, and assessing the agreement between the perspectives of patients and treating physicians. Results: On February 2, 2023, in total 665 patients [median age 69 (interquartile range: 55-78) years; 95.5% community dwelling; 29.3% Modified Early Warning Score ≥3; 29.5% clinical frailty score ≥5] were included. In total, 19.6% of ED patients were admitted and 26% of ward patients preferred home monitoring as continuation of care. Guaranteed readmission (87.8%), ability to contact the hospital 24/7 (77.3%), and a family caregiver at home (55.7%) were the most often reported prerequisites. Barriers for home monitoring were feeling too severely ill (78.8%) and inability to receive the required treatment at home (64.4%). The agreement between patients and physicians was fair (Cohens kappa coefficient 0.26). Conclusions: A substantial proportion of acutely ill patients stated that they were willing and able to be monitored at home. Guaranteed readmission, availability of a treatment team (24/7), and a home support system are needed for successful implementation of home monitoring in acute care.

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 µg or 300/300/300 µg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 µg and 300/300/300 µg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov: NCT04075318 .

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia.

BACKGROUND: Staphylococcus aureus bacteraemia (SAB) is a clinically heterogeneous disease. The ability to identify sub-groups of patients with shared traits (sub-phenotypes) is an unmet need that could allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically-relevant sub-phenotypes can be reproducibly identified amongst patients with SAB. METHODS: We studied three cohorts of hospitalised adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n=458), the UK ARREST randomised trial (n=758), and the Spanish SAFO randomised trial (n=214). Latent class analysis was used to identify sub-phenotypes using routinely-collected clinical data, without considering outcomes. Mortality and microbiologic outcomes were then compared between sub-phenotypes. RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366/1430,95.5%). We identified five distinct, reproducible clinical sub-phenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the sub-phenotypes. 84-day mortality was highest in sub-phenotype A, and lowest in B and E. Microbiologic outcomes were worse in sub-phenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased 84-day mortality in sub-phenotype B and improved microbiologic outcomes in sub-phenotype C. CONCLUSIONS: We have identified reproducible and clinically-relevant sub-phenotypes within SAB, and provide proof-of-principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these sub-phenotypes could contribute to a personalised medicine approach to SAB.

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies.

AIMS: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. METHODS: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. RESULTS: In rats, BI 474121 was associated with a dose-dependent increase (71% at the highest dose tested [3.0 mg kg-1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum-measured concentration CSF-to-plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose-adjusted geometric mean: 8.96% overall). BI 474121 2.5-40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure-related change from baseline ratio, BI 474121: 1.44-2.20 vs. placebo: 1.26). The most common treatment-emergent adverse event (AE) was mild-to-moderate post-lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. CONCLUSIONS: BI 474121 crosses the blood-brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. CLINICALTRIALS: gov number (NCT04672954).

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

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.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Evaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity.

Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the [Formula: see text] ratio. Because of the ceiling effect in oxyhaemoglobin saturation, [Formula: see text] ratio ceases to reflect pulmonary oxygenation function at high [Formula: see text] values. We found that the correlation of [Formula: see text] with the reference standard ([Formula: see text]/[Formula: see text] ratio) improves substantially when excluding [Formula: see text] and refer to this measure as [Formula: see text]. Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that [Formula: see text] is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using [Formula: see text]. We demonstrate that [Formula: see text] is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power.

A smartphone- and wearable-based biomarker for the estimation of unipolar depression severity.

Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely monitored self-reported assessments and objectively measured activities with depression severity assessments often applied in clinical trials. 30 unipolar depressed patients and 29 age- and gender-matched healthy controls were enrolled in this study. Each participant's daily physiological, physical, and social activity were monitored using a smartphone-based application (CHDR MORE™) for 3 weeks continuously. Self-reported depression anxiety stress scale-21 (DASS-21) and positive and negative affect schedule (PANAS) were administered via smartphone weekly and daily respectively. The structured interview guide for the Hamilton depression scale and inventory of depressive symptomatology-clinical rated (SIGHD-IDSC) was administered in-clinic weekly. Nested cross-validated linear mixed-effects models were used to identify the correlation between the CHDR MORE™ features with the weekly in-clinic SIGHD-IDSC scores. The SIGHD-IDSC regression model demonstrated an explained variance (R2) of 0.80, and a Root Mean Square Error (RMSE) of ± 15 points. The SIGHD-IDSC total scores were positively correlated with the DASS and mean steps-per-minute, and negatively correlated with the travel duration. Unobtrusive, remotely monitored behavior and self-reported outcomes are correlated with depression severity. While these features cannot replace the SIGHD-IDSC for estimating depression severity, it can serve as a complementary approach for assessing depression and drug effects outside the clinic.

[Prehospital triage of undifferentiated syndromes in the ambulance]. / Prehospitale triage op basis van onduidelijke symptomen.

Increasing complexity due to an ageing population, a shortage of healthcare professionals and the rising costs are major concerns for the acute care in the coming years. Innovative triage methods in the ambulance could improve appropriate care for patients with subacute undifferentiated syndromes. A proportion of these patients should not be transferred to an emergency department. We conducted a systematic literature search on prehospital triage in the ambulance and evaluated the results relevant to the Dutch acute care system. Consultation of primary care or hospital physicians by paramedics to decide on the optimal strategy for the individual patient seems promising. Adding a video connection could increase the potential benefits. Point-of-care testing in well-defined syndromes does improve prehospital triage and may therefore be of benefit in undifferentiated syndromes. Both techniques may keep ambulances away from presenting specific patients on emergency departments, enabling appropriate use of scarce acute care facilities.

[Influenza vaccination as secondary prevention for cardiovascular disease]. / Influenzavaccinatie bij hartpatiënten voorkomt cardiale complicaties.

Influenza infection increases the risk of cardiovascular complications and mortality in patients with heart disease. In patients with coronary artery disease influenza vaccination has been shown to reduce cardiovascular mortality, but high-quality evidence was missing. New trial data from a RCT in patients shortly after myocardial infarction has confirmed the significant reduction of the risk of major adverse cardiovascular events (MACE) and cardiovascular death after influenza vaccination. Also in patients with heart failure the first published RCT in heart failure shows a clinical benefit of influenza vaccination versus placebo during the influenza season, confirming preceding observational studies. Meta-analyses from the study data estimate that after influenza vaccination a risk reduction of MACE of at least 25% is possible in patients with heart disease. The current underutilization of influenza vaccines in heart patients should be addressed because influenza vaccination has proven to be an effective and safe instrument for secondary prevention.

Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine.

BACKGROUND: Oliceridine (Olinvyk) is a µ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. METHODS: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. RESULTS: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. CONCLUSIONS: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Randomized placebo-controlled crossover study to assess tolerability and pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator, in healthy elderly.

AIMS: Dysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. METHODS: In this randomized crossover study, 24 healthy participants aged ≥65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. RESULTS: Twenty-four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well-tolerated and penetrated the blood-brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. CONCLUSION: Zagociguat was well-tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.

Treatment Detection and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III Estimation Using Finger Tapping Tasks.

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.

Machine Learning Techniques for Developing Remotely Monitored Central Nervous System Biomarkers Using Wearable Sensors: A Narrative Literature Review.

BACKGROUND: Central nervous system (CNS) disorders benefit from ongoing monitoring to assess disease progression and treatment efficacy. Mobile health (mHealth) technologies offer a means for the remote and continuous symptom monitoring of patients. Machine Learning (ML) techniques can process and engineer mHealth data into a precise and multidimensional biomarker of disease activity. OBJECTIVE: This narrative literature review aims to provide an overview of the current landscape of biomarker development using mHealth technologies and ML. Additionally, it proposes recommendations to ensure the accuracy, reliability, and interpretability of these biomarkers. METHODS: This review extracted relevant publications from databases such as PubMed, IEEE, and CTTI. The ML methods employed across the selected publications were then extracted, aggregated, and reviewed. RESULTS: This review synthesized and presented the diverse approaches of 66 publications that address creating mHealth-based biomarkers using ML. The reviewed publications provide a foundation for effective biomarker development and offer recommendations for creating representative, reproducible, and interpretable biomarkers for future clinical trials. CONCLUSION: mHealth-based and ML-derived biomarkers have great potential for the remote monitoring of CNS disorders. However, further research and standardization of study designs are needed to advance this field. With continued innovation, mHealth-based biomarkers hold promise for improving the monitoring of CNS disorders.