Neuropsychiatric adverse events in tenofovir disoproxil fumarate- and tenofovir alafenamide-based HIV therapy and prophylaxis: a systematic review and meta-analysis.

INTRODUCTION: Tenofovir is integral to antiretroviral therapy (ART) and preexposure prophylaxis (PrEP) for HIV, but its neuropsychiatric adverse events (NPAEs) have not been systematically investigated. OBJECTIVES: This systematic review aims to characterize common NPAEs during tenofovir-based ART and PrEP and to assess tenofovir's specific role in their emergence. PATIENTS AND METHODS: Four literature databases and three trial registries were searched up to December 31, 2023, for randomized controlled trials reporting NPAEs in treatment-naïve adults receiving tenofovir-based ART or PrEP. Meta-analyses compared tenofovir (with/without emtricitabine) to placebo and tenofovir alafenamide- to tenofovir disoproxil fumarate-based regimens. RESULTS: Sixty-nine trials (62 on ART, 7 on PrEP) with 29 340 patients on tenofovir-based therapies revealed headache, dizziness, insomnia, and depression as common NPAEs, especially in HIV studies. Meta-analyses of tenofovir (with/without emtricitabine) versus placebo only indicated an increased risk of dizziness (OR 1.32; CI 1.09-1.59; P = 0.004). Comparisons between tenofovir alafenamide and disoproxil fumarate did not reveal significant differences in NPAE risks, although sensitivity analyses suggested a higher risk of headache with tenofovir alafenamide in HIV studies (OR 1.24; CI 1.01-1.52; P = 0.04). CONCLUSIONS: Common NPAEs in tenofovir-based HIV multi-drug regimens highlight the need to screen HIV patients for neuropsychiatric complications. The lack of effect of tenofovir compared to placebo for most analyzable NPAEs suggests that tenofovir itself is mostly safe regarding NPAEs. However, a possible increase in dizziness risk with tenofovir, and a potential rise in headache risk with tenofovir alafenamide- compared to tenofovir disoproxil fumarate-based regimens in HIV therapy, merit further investigation.

Cognitive functioning associated with acute and subacute effects of classic psychedelics and MDMA - a systematic review and meta-analysis.

Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute ("afterglow") window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.

Design of the multicentre randomised controlled BENTO trial to demonstrate patient-relevant benefit of bronchoscopic lung volume reduction using thermal vapour ablation in the German healthcare system for patients with upper lobe emphysema: a study protocol.

INTRODUCTION: Application of vapour ablation as a novel approach to lung volume reduction has positive effects in patients with severe emphysema. The BENTO study is a randomised, controlled, open, multicentre trial, to assess the effects of bronchoscopic thermal vapour ablation (BTVA) in the German healthcare system. METHODS AND ANALYSIS: Patients with bilateral heterogeneous emphysema of the upper lobes in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3/4 will be enrolled in this trial and will receive either standard medical management alone (according to GOLD guidelines) or BTVA treatment with the InterVapor system together with standard medical management. Patients will be randomised in a 2:1 ratio (treatment group:control group). A total of 224 patients will be enrolled at 15 study sites. The primary endpoint is the change in patient-reported disease-specific quality of life, as measured by the St George's Respiratory Questionnaire for chronic obstructive pulmonary disease patients between randomisation and the 9-month follow-up visit. Secondary endpoints include adverse events, mortality, vital status, changes in lung function parameters, exercise capacity and other efficacy measures at 3, 9 and 12 months.The BENTO trial was commissioned by the German Federal Joint Committee, to demonstrate that this approach is an efficient and safe treatment option in the German healthcare system. ETHICS AND DISSEMINATION: The protocol has been approved by the lead ethics committee in Germany (Ethics Committee of the Medical Faculty of Heidelberg) and until present also by the following ethics committees: Ethics Committee of the Medical Faculty of Duisburg-Essen, Ethics Committee of the Medical Faculty of Martin-Luther-University Halle-Wittenberg, Ethics Committee of the State Medical Association of Hessen, Ethics Commission of the State Office for Health and Social Affairs of the State of Berlin, Ethics Committee of the Medical Faculty of Greifswald. The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05717192.

Impact of Access Site on Periprocedural Bleeding and Cerebral and Coronary Events in High-Bleeding-Risk Percutaneous Coronary Intervention: Findings from the RIVA-PCI Trial.

INTRODUCTION: The preference for using transradial access (TRA) over transfemoral access (TFA) in patients requiring percutaneous coronary intervention (PCI) is based on evidence suggesting that TRA is associated with less bleeding and fewer vascular complications, shorter hospital stays, improved quality of life, and a potential beneficial effect on mortality. We have limited study data comparing the two access routes in a patient population with atrial fibrillation (AF) undergoing PCI, who have a particular increased risk of bleeding, while AF itself is associated with an increased risk of thromboembolism. METHODS: Using data from the RIVA-PCI registry, which includes patients with AF undergoing PCI, we analyzed a high-bleeding-risk (HBR) cohort. These patients were predominantly on oral anticoagulants (OAC) for AF, and the PCI was performed via radial or femoral access. Endpoints examined were in-hospital bleeding (BARC 2-5), cerebral events (TIA, hemorrhagic or ischemic stroke) and coronary events (stent thrombosis and myocardial infarction). RESULTS: Out of 1636 patients, 854 (52.2%) underwent TFA, while 782 (47.8%) underwent the procedure via TRA, including nine patients with brachial artery puncture. The mean age was 75.5 years. Groups were similar in terms of age, sex distribution, AF type, cardiovascular history, risk factors, and comorbidities, except for a higher incidence of previous bypass surgeries, heart failure, hyperlipidemia, and chronic kidney disease (CKD) with a glomerular filtration rate (GFR) < 60 ml/min in the TFA group. No clinically relevant differences in antithrombotic therapy and combinations were present at the time of PCI. However, upon discharge, transradial PCI patients had a higher rate of triple therapy, while dual therapy was preferred after transfemoral procedures. Radial access was more frequently chosen for non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP) cases (NSTEMI 26.6% vs. 17.0%, p < 0.0001; UAP 21.5% vs. 14.5%, p < 0.001), while femoral access was more common for elective PCI (60.3% vs. 44.1%, p < 0.0001). No differences were observed for ST-segment elevation myocardial infarction (STEMI). Both groups had similar rates of cerebral events (TFA 0.2% vs. TRA 0.3%, p = 0.93), but the TFA group had a higher incidence of bleeding (BARC 2-5) (4.2% vs. 1.5%, p < 0.01), mainly driven by BARC 3 bleeding (1.5% vs. 0.4%, p < 0.05). No significant differences were found for stent thrombosis and myocardial infarction (TFA 0.2% vs. TRA 0.3%, p = 0.93; TFA 0.4% vs. TRA 0.1%, p = 0.36). CONCLUSIONS: In HBR patients with AF undergoing PCI for acute or chronic coronary syndrome, the use of TRA might be associated with a decrease in in-hospital bleeding, while not increasing the risk of embolic or ischemic events compared to femoral access. Further studies are required to confirm these preliminary findings.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

Objective: Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and dopamine D2-receptor occupancy for oral and long-acting injectable (LAI) formulations.Data Sources: Databases were systematically searched for randomized controlled trials (RCTs) and uncontrolled trials concerning blood olanzapine levels in relation to clinical outcomes or D2-receptor occupancy using MEDLINE (PubMed), Web of Science, PsycINFO, and Cochrane Library (March 2021, updated in December 2021). We excluded articles not written in English or German and non-human data. Search terms included olanzapine, blood level, drug monitoring, PET, and SPECT.Study Selection: The process of study selection followed a previously published protocol and PRISMA guidelines. A total of 2,824 articles were identified through database search and 1 article via reference list check. Thirty-four studies were suitable for qualitative synthesis, and 13 studies were included in the quantitative analysis.Data Extraction: Reviewers performed data extraction and quality assessment of the included studies independently following the review protocol.Results: Evidence for a relationship between blood olanzapine level and efficacy/side effects (constipation) is considered low (Level C). In total, 3 studies of moderate quality consistently showed therapeutic thresholds of around 20 ng/mL for olanzapine 12 hours post-dose. This threshold is in line with findings from positron emission tomography (PET) studies that suggest optimal drug efficacy (65%-80% D2-receptor occupancy) between 17 and 44 ng/mL.Conclusions: We suggest a therapeutic reference range of 20-40 ng/mL for olanzapine oral and LAI formulations. In this range, optimal treatment response is expected in patients with schizophrenia and schizophrenia spectrum disorders. Side effects, especially weight gain, may already occur at therapeutic levels. However, higher plasma concentrations are in general well tolerated and should not necessarily require a dose reduction in case of good response and tolerance.

Rational and design of the REMOTE trial: An exploratory, pilot study to analyze REtinal MicrOcirculaTion in wEightlessness.

BACKGROUND: "Spaceflight associated neuro-ocular syndrome" (SANS) represents a challenging health condition in modern space medicine. Forty-eight percent of astronauts are diagnosed with SANS after long-term space missions. The pathophysiological mechanism seems to be multifactorial, and yet remains unknown. In this proof-of-concept study we plan to investigate retinal microcirculatory changes in weightlessness and aim to identify their role in the development of SANS. METHODS AND DESIGN: Healthy individuals will take part in a parabolic flight campaign, which recreates fractioned total weightlessness periods. The airplane is specifically equipped, and designed for the execution of parabolic flight maneuvers and scientific research in microgravity. Retinal microcirculation will be assessed with a modified fundus camera, which allows dynamic vessel analysis. We will additionally measure intra-ocular pressure and hemodynamic changes during each phase of the flight. Blood samples will be analyzed at baseline, one hour and 24 hours after exposure to weightlessness. CONCLUSIONS: This pilot study aims to investigate the feasibility of retinal microcirculation assessment during varying gravity. Results of this study may generate insights whether venous stasis in the eye, surrogated by the dilatation of retinal vessels and increase in intraocular pressure as signs of venous insufficiency, may potentially contribute to the development of SANS.

Rivaroxaban in Patients With Atrial Fibrillation Who Underwent Percutaneous Coronary Intervention in Clinical Practice.

Little is known about the efficacy and safety of rivaroxaban in patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) in clinical practice. We therefore conducted a prospective observational study to determine the rate of ischemic, embolic, and bleeding events in patients with AF and PCI treated with rivaroxaban in a real-world experience. The RIVA-PCI ("rivaroxaban in patients with AF who underwent PCI") (clinicaltrials.gov NCT03315650) is a prospective, noninterventional, multicenter study with a follow-up until 14 months, including patients with AF who underwent PCI discharged with rivaroxaban. Between January 2018 and March 2020, 700 patients with PCI treated with rivaroxaban (elective in 50.1%, non-ST-elevation acute coronary syndrome 43.0%, ST-elevation myocardial infarction in 6.9%) were enrolled at 51 German hospitals. After PCI, a dual antithrombotic therapy consisting of rivaroxaban and a P2Y12 inhibitor was administered in 70.7% and triple antithrombotic therapy in 27.9%, respectively. Follow-up information could be obtained in 695 patients (99.3%). Rivaroxaban has been stopped prematurely in 21.6% of patients. Clinical events under rivaroxaban during the 14-month follow-up compared with those observed in the PIONEER-AF PCI trial included cardiovascular death (2.0% % vs 2.0%), myocardial infarction (0.9% vs 3.0%), stent thrombosis (0.2% vs 0.8%), stroke (1.3% vs 1.3%), International Society on Thrombosis and Haemostasis major (4.2% vs 3.9%), and International Society on Thrombosis and Haemostasis nonmajor clinically relevant bleeding (15.3% vs 12.9%). Therefore, in this real-world experience, rivaroxaban in patients with AF who underwent PCI is associated with ischemic and bleeding event rates comparable with those observed in the randomized PIONEER-AF PCI trial.

Trail Making Test Error Analysis in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Dementia With and Without Depression.

OBJECTIVE: Standard evaluation of the Trail Making Test (TMT) only incorporates completion times. However, the analysis of different error types may provide more insight into underlying cognitive processes and could also increase diagnostic accuracy. This cross-sectional observational study compared three different TMT error types and assessed their diagnostic utility in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) with or without depression. METHOD: We evaluated 618 outpatients of a memory clinic with SCD (N = 190), MCI (N = 210), or AD (N = 218). Of these, 157 had comorbid depression. TMT completion times, total error rates, and the three error types "sequencing error," "perseverative error," and "proximity error" were examined. RESULTS: Results indicated that patients with MCI or AD committed more errors on TMT B, and specifically more perseverative errors than patients with SCD (p < 0.001). Depression was not associated with any TMT error type. Including TMT errors in models predicting diagnosis group by TMT completion times did not increase predictive accuracy, measured by areas under the curve. CONCLUSIONS: The findings do not indicate any impact of comorbid depression on TMT errors. Moreover, TMT error analysis does not seem to provide additional diagnostic utility for SCD, MCI, and AD diagnoses.

Current status of antithrombotic therapy and in-hospital outcomes in patients with atrial fibrillation undergoing percutaneous coronary intervention in Germany.

BACKGROUND: Little is known about current patterns of antithrombotic therapy in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) in clinical practice in Germany. METHODS: The RIVA-PCI is a prospective, non-interventional, multicenter study with follow-up until hospital discharge including consecutive patients with AF undergoing PCI. RESULTS: Between January 2018 and March 2020, 1636 patients (elective in 52.6%, non-ST elevation acute coronary syndrome [NSTE-ACS] in 39.3%, ST-elevation myocardial infarction in 8.2%) from 51 German hospitals were enrolled in the study. After PCI a dual antithrombotic therapy (DAT) consisting of OAC and a P2Y12 inhibitor was given to 66.0%, triple antithrombotic therapy (TAT) to 26.0%, dual antiplatelet therapy to 5.5%, and a mono-therapy to 2.5% of the patients. Non-vitamin K antagonist oral anticoagulants (NOACs) were given to 82.4% and vitamin K antagonists to 11.5% of the patients. In-hospital events included death in 12 cases (0.7%), myocardial infarction, stent thrombosis, and ischemic stroke in four (0.2%) patients each, while 2.8% of patients had bleeding complications. The recommended durations for DAT or TAT at discharge were 1 month (1.5%), 3 months (2.1%), 6 months (43.1%), and 12 months (45.6%), with a 6-month course of DAT (47.7%) most often recommended after elective PCI and a 12-month course of DAT (40.1%) after ACS. CONCLUSION: The preferred therapy after PCI in patients with AF is DAT with a NOAC and clopidogrel. In-hospital ischemic and bleeding events were rare. The recommended durations for combination therapy vary considerably.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis.

RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

Quality of life of patients with coronary heart disease treated with the bioresorbable vascular scaffold (ABSORB™): 2-year results from the GABI-R-registry.

BACKGROUND: Numerous studies have reported clinical endpoints following coronary revascularization using bioresorbable vascular scaffolds (BVS), while information about the impact on health-related quality of life is sparse. In this analysis of the German-Austrian ABSORB RegIstRy, the 2 year results concerning quality of life development in a large cohort of patients treated with BVS were reported. METHODS: Data were collected at baseline as well as 30 days, 6 and 24 months after coronary revascularization using BVS. The EQ-5D score, EQ visual analogue scale (VAS) and Seattle Angina Questionnaire (SAQ) were determined for each time point. Patients were categorized according to the indication for coronary revascularization [acute coronary syndrome (ACS), stable angina pectoris (SAP), silent myocardial ischemia (SMI), or other]. Binary logistic regression analysis was performed to determine factors that predict above-average scores two years after implantation. RESULTS: Data from 1317 patients in 88 centres were included. Reasons for revascularization were: ACS (n = 643), SAP (n = 443), SMI (n = 52), and other (n = 179). Mean EQ-5D was significantly increased after six months, while a value comparable to baseline was found two years after implantation. EQ VAS and four of five dimensions of SAQ were significantly improved over baseline at all follow-up surveys. Particularly strong improvements were seen in SAQ scores angina frequency and quality of life. Binary regressions showed different statistically significant predictors in the respective models. CONCLUSIONS: Following coronary revascularization with BVS strong decrease in self-reported angina frequency and increase of self-reported quality of life were observed with continuous improvements over two years of follow-up. Trial registration ClinicalTrials.gov Identifier: NCT02066623.

Optic disc blood perfusion and oxygenation in glaucoma.

PURPOSE: To investigate the haemoglobin concentration and oxygenation in the optic disc in glaucoma patients vs. controls. METHODS: Thirty-one eyes of primary open angle glaucoma patients (mean age: 64.9 ± 2.1 years) and 31 eyes of 31 healthy controls (65.5 ± 2.0 years) were included. Perimetry, optical coherence tomography (OCT), and OCT angiography were performed. Multispectral imaging was used to record the optic disc reflectance at wavelengths 522 nm, 548 nm, 555 nm, 586 nm, and 610 nm, and haemoglobin concentration and oxygenation (SO2) were calculated from these measures. This was done in the rest and under stimulation of neuronal activity by flicker light. RESULTS: The haemoglobin concentration was significantly lower (p < 0.001) in the rim (40.0 ± 6.3) and the excavation (35.7 ± 8.0) of the glaucoma patients' discs than in controls (45.7 ± 7.5). SO2 was not different in general, but lower in a subgroup of 18 glaucoma patients with ischaemic disc rims than in non-ischaemic ones (median 26.8%, interquartile range (IQR): 29.5% vs. 51.9%, IQR 32.0%, p = 0.02) as well as in controls (41.0%, IQR 30.6%, p = 0.01). Flicker light stimulation significantly increased the haemoglobin concentration in the controls (+ 1.3 ± 3.6, p = 0.048) as well as in the rim of glaucoma discs (+ 2.6 ± 5.0, p = 0.006) and SO2 in the controls only (+ 15.4 ± 23.6%, p = 0.001). The haemoglobin concentration was significantly correlated with the perimetric mean defect, retinal nerve fibre layer (RNFL) thickness and para-papillary perfusion density. CONCLUSIONS: The optic disc haemoglobin concentration and oxygenation are quantifiable from multispectral imaging and reduced in glaucoma. The correlation of haemoglobin concentration with perfusion density, RNFL thickness and visual field loss indicates its implication in glaucoma pathology.

Is Therapeutic Drug Monitoring Relevant for Antidepressant Drug Therapy? Implications From a Systematic Review and Meta-Analysis With Focus on Moderating Factors.

Inter-individual differences in antidepressant drug concentrations attained in blood may limit the efficacy of pharmacological treatment of depressive disorders. Therapeutic drug monitoring (TDM) enables to determine drug concentrations in blood and adjust antidepressant dosage accordingly. However, research on the underlying assumption of TDM, association between concentration and clinical effect, has yielded ambiguous results for antidepressants. It has been proposed that this ambiguity may be caused by methodological shortcomings in studies investigating the concentration-effect relationship. Guidelines recommend the use of TDM in antidepressant treatment as expert opinion. This reflects the lack of research, particularly systematic reviews and meta-analyses of randomized controlled trials, on the relationship between concentration and effect as well as on the benefits of the use of TDM in clinical practice. In this study, a systematic review and meta-analysis of randomized controlled trials has been performed to investigate the relationship between antidepressant concentration, efficacy, and side effects. It is the first meta-analytical approach to this subject and additionally considers methodological properties of primary studies as moderators of effect in quantitative analysis. Our results identified methodological shortcomings, namely the use of a flexible dose design and the exclusion of concentrations in lower- or subtherapeutic ranges, which significantly moderate the relationship between antidepressant concentration and efficacy. Such shortcomings obscure the evidence base of using TDM in clinical practice to guide antidepressant drug therapy. Further research should consider these findings to determine the relationship between concentration and efficacy and safety of antidepressant treatments, especially for newer antidepressants. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246149, identifier: CRD42021246149.

Comprehensive Quantitative and Calibration-Free Evaluation of Hyperpolarized Xenon-Host Interaction by Multiparametric NMR.

The probing of microscopic environments by hyperpolarized xenon NMR has spurred investigations in supramolecular chemistry as well as important biosensing and molecular imaging applications. While xenon exchange with host structures at micromolar concentrations and below can be readily detected, a quantitative analysis is limited, requiring complementary experimentation by different methodologies and thus lacking completeness and compromising the validity and comparability of numerical results. Here, a new NMR measurement and data analysis approach is introduced for the comprehensive characterization of the host-xenon binding dynamics. The application of chemical exchange saturation transfer of hyperpolarized 129Xe under parametric modulation of the saturation RF amplitude and xenon gas saturation of the solution enables a delineation of exchange mechanisms and, through modeling, a numerical estimation of the various reaction rate constants (and thus magnetization exchange rate constants), the xenon affinity, and the total host molecule concentration. Only the numerical xenon solubility is additionally required for input, a quantity that has a low impact on the measurement uncertainty and is derivable from metrological data collections. Signal calibration by a reference material may thus be avoided, qualifying the method as calibration-free. For demonstration a xenon exchange with the host cucurbit[6]uril at low concentration is investigated, with the numerical results being validated by standard quantitative NMR data obtained at high concentration. The readiness to evaluate xenon exchange for the one sample at hand and in a single experimental attempt by the proposed method may allow comprehensive quantitative studies in supramolecular chemistry, biomacromolecular structure and dynamics, and sensing.

No Difference in 30-Day Outcome and Quality of Life in Transradial Versus Transfemoral Access - Results From the German Austrian ABSORB Registry (GABI-R).

BACKGROUND: Radial (RA) instead of femoral access (FA) for coronary interventions has become a European Society of Cardiology Class-IA guideline recommendation. But when the decision on the access site is left to the discretion of the operator, differences in adverse event rates mitigate. METHODS: We compared the 30-day outcome for RA and FA in all patients recruited for the observational German Austrian ABSORB Registry (GABI-R) in regard to all-cause mortality, stroke, myocardial infarction (MI), TIMI major bleedings (TMB) and quality of life (QoL). All patients were treated with a bioresorbable vascular scaffold. Access site was left to the discretion of the operator. RESULTS: In total, 3137 patients included by 92 centers received percutaneous coronary interventions (PCI) for acute MI in 51.5% and non-acute settings in 48.5%. RA was performed in 47.8% and had a higher median radiation exposure (3896 vs. 3082 cGycm2, p < 0.001). There was no difference in the amount of contrast used. There was also no difference in all-cause mortality (0.53% vs. 0.49%, p = 0.86), the combination of death, MI and stroke (1.87% vs. 1.83%, p = 0.94), but a trend towards more TMB (0.47% vs. 1.04%, p = 0.07) with FA. These outcomes were consistent across the subgroups of patients with ST-elevation MI, non-ST-elevation-ACS and stable coronary artery disease. Finally, QoL did not differ between RA and FA. CONCLUSIONS: In this contemporary GABI-R cohort, in which access site was left to the discretion of the operator, both access routes were safe and equal concerning QoL (ClinicalTrials.gov; NCT02066623).

Outcomes of 10,312 patients treated with everolimus-eluting bioresorbable scaffolds during daily clinical practice - results from the European Absorb Consortium.

OBJECTIVES: To asses mid-term clinical outcomes of bioresorbable vascular scaffolds (BVS) for the treatment of coronary artery disease in a large-scale all-comers population. BACKGROUND: Several clinical settings are underrepresented in randomized studies investigating BVS against drug-eluting stents. Whether their results can be translated into the heterogeny patient population seen during daily routine requires further investigation. METHODS: The European ABSORB Consortium comprises the following European registries: GABI-R, ABSORB UK Registry, ABSORB France, BVS RAI Registry, and REPARA BVS Registry, which all prospectively collected patient-level data regarding outcomes following unrestricted BVS implantation. The primary endpoint of target lesion failure (TLF) includes cardiac death, target-vessel myocardial infarction (TVMI) and target-lesion revascularisation (TLR) at 12 months. The incidence of scaffold thrombosis (ST) according to ARC criteria was also assessed. Multivariable analysis was used to adjust for differences in patient and lesion characteristics. RESULTS: A total of 10,312 patients (mean age 58.4 ± 11.4 y) underwent BVS implantation during routine practice. The 12-month follow-up was complete in 95.5% of patients. At 12 months, the primary endpoint of TLF occurred in 3.6%; its components cardiac death, TVMI and TLR were documented in 1.2%, 1.8%, and 2.6%, respectively. The definite/probable ST rate was 1.7%. Absence of predilatation, discontinuation of DAPT and scaffold diameter below 3 mm were independent predictors of ST. CONCLUSIONS: The EAC demonstrates reasonable real-world clinical outcome data after BVS implantation. However, the rate of scaffold thrombosis remains high.

Therapeutic Reference Ranges for Psychotropic Drugs: A Protocol for Systematic Reviews.

Background: For many psychotropic drugs, monitoring of drug concentrations in the blood (Therapeutic Drug Monitoring; TDM) has been proven useful to individualize treatments and optimize drug effects. Clinicians hereby compare individual drug concentrations to population-based reference ranges for a titration of prescribed doses. Thus, established reference ranges are pre-requisite for TDM. For psychotropic drugs, guideline-based ranges are mostly expert recommendations derived from a conglomerate of cohort and cross-sectional studies. A systematic approach for identifying therapeutic reference ranges has not been published yet. This paper describes how to search, evaluate and grade the available literature and validate published therapeutic reference ranges for psychotropic drugs. Methods/Results: Following PRISMA guidelines, relevant databases have to be systematically searched using search terms for the specific psychotropic drug, blood concentrations, drug monitoring, positron emission tomography (PET) and single photon emission computed tomography (SPECT). The search should be restricted to humans, and diagnoses should be pre-specified. Therapeutic references ranges will not only base upon studies that report blood concentrations in relation to clinical effects, but will also include implications from neuroimaging studies on target engagement. Furthermore, studies reporting concentrations in representative patient populations are used to support identified ranges. Each range will be assigned a level of underlying evidence according to a systematic grading system. Discussion: Following this protocol allows a comprehensive overview of TDM literature that supports a certain reference range for a psychotropic drug. The assigned level of evidence reflects the validity of a reported range rather than experts' opinions.

Neuropsychological Functioning in Users of Serotonergic Psychedelics - A Systematic Review and Meta-Analysis.

Background: Serotonergic psychedelics (SPs) like LSD, psilocybin, DMT, and mescaline are a heterogeneous group of substances that share agonism at 5-HT2a receptors. Besides the ability of these substances to facilitate profoundly altered states of consciousness, persisting psychological effects have been reported after single administrations, which outlast the acute psychedelic effects. In this review and meta-analysis, we investigated if repeated SP use associates with a characteristic neuropsychological profile indicating persisting effects on neuropsychological function. Methods: We conducted a systematic review of studies investigating the neuropsychological performance in SP users, searching studies in Medline, Web of Science, embase, ClinicalTrials.gov, and EudraCT. Studies were included if they reported at least one neuropsychological measurement in users of SPs. Studies comparing SP users and non-users that reported mean scores and standard deviations were included in an exploratory meta-analysis. Results: 13 studies (N = 539) published between 1969 and 2020 were included in this systematic review. Overall, we found that only three SPs were specifically investigated: ayahuasca (6 studies, n = 343), LSD (5 studies, n = 135), and peyote (1 study, n = 61). However, heterogeneity of the methodological quality was high across studies, with matching problems representing the most important limitation. Across all SPs, no uniform pattern of neuropsychological impairment was identified. Rather, the individual SPs seemed to be associated with distinct neuropsychological profiles. For instance, one study (n = 42) found LSD users to perform worse in trials A and B of the Trail-Making task, whereas meta-analytic assessment (5 studies, n = 352) of eleven individual neuropsychological measures indicated a better performance of ayahuasca users in the Stroop incongruent task (p = 0.03) and no differences in the others (all p > 0.05). Conclusion: The majority of the included studies were not completely successful in controlling for confounders such as differences in non-psychedelic substance use between SP-users and non-users. Our analysis suggests that LSD, ayahuasca and peyote may have different neuropsychological consequences associated with their use. While LSD users showed reduced executive functioning and peyote users showed no differences across domains, there is some evidence that ayahuasca use is associated with increased executive functioning.