How to inform at-risk relatives?:Attitudes of 1379 Dutch patients, relatives, and members of the general population

The uptake of predictive DNA testing in families with a hereditary disease is <50%. Current practice often relies on the proband to inform relatives about the possibility of predictive DNA testing, but not all relatives are informed adequately. To enable informed decision-making concerning predictive DNA testing, the approach used to inform at-risk relatives needs to be optimized. This study investigated the preferences of patients, relatives, and the general population from the Netherlands on how to inform relatives at risk of autosomal dominant diseases. Online surveys were sent to people with autosomal dominant neuro-, onco-, or cardiogenetic diseases and their relatives via patient organizations (n = 379), and to members of the general population via a commercial panel (n = 1,000). Attitudes of the patient and population samples generally corresponded. A majority believed that initially only first-degree relatives should be informed, following the principles of a cascade screening approach. Most participants also thought that probands and healthcare professionals (HCPs) should be involved in informing relatives, and a large proportion believed that HCPs should contact relatives directly in cases where patients are unwilling to inform, both for untreatable and treatable conditions. Participants from the patient sample were of the opinion that HCPs should actively offer support. Our findings show that both patients and HCPs should be involved in informing at-risk relatives of autosomal dominant diseases and suggest that relatives' 'right to know' was considered a dominant issue by the majority of participants. Further research is needed on how to increase proactive support in informing of at-risk relatives

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders.</p

Comparative pharmacokinetics and allometric scaling of carboplatin in different avian species

The use of chemotherapeutics as a possible treatment strategy in avian oncology is steadily increasing over the last years. Despite this, literature reports regarding dosing strategies and pharmacokinetic behaviour of chemotherapeutics in avian species are lacking. The aim of the present study was to investigate the pharmacokinetics of carboplatin in a representative species of the order of Galliformes, Anseriformes, Columbiformes and Psittaciformes. Eight chickens, ducks and pigeons and twenty-eight parakeets were administered carboplatin intravenously (5 mg/kg body weight). A specific and sensitive liquid chromatographytandem mass spectrometry method was developed and validated for quantification of the free carboplatin in plasma of the four birds species (limit of quantification: 20 ng/mL for chicken and duck, 50 ng/mL for pigeon and 100 ng/mL for parakeets). Non-compartmental pharmacokinetic analysis and allometric scaling demonstrated a significant correlation (R²=0.9769) between body weight (BW) and elimination half-life (T1/2el). T1/2el ranged from 0.41h in parakeets (BW: 61 ± 8 g) to 1.16 h chickens (BW: 1909 ± 619 g). T1/2el is a good parameter for dose optimization of carboplatin in other avian species, since also the previously reported T1/2el in cockatoos (average BW: 769 ± 68 g) of 1.00 h corresponds to the results obtained in the present study

Prospective GIRF-based RF phase cycling to reduce eddy current-induced steady-state disruption in bSSFP imaging

PURPOSE: To propose an explicit Balanced steady-state free precession (bSSFP) signal model that predicts eddy current-induced steady-state disruptions and to provide a prospective, practical, and general eddy current compensation method. THEORY AND METHODS: Gradient impulse response functions (GIRF) were used to simulate trajectory-specific eddy current-induced phase errors at the end of a repetition block. These phase errors were included in bloch simulations to establish a bSSFP signal model to predict steady-state disruptions and their corresponding image artifacts. The signal model was embedded in the MR system and used to compensate the phase errors by prospectively modifying the phase cycling scheme of the RF pulse. The signal model and eddy current compensation method were validated in phantom and in vivo experiments. In addition, the signal model was used to analyze pre-existing eddy current mitigation methods, such as 2D tiny golden angle radial and 3D paired phase encoded Cartesian acquisitions. RESULTS: The signal model predicted eddy current-induced image artifacts, with the zeroth-order GIRF being the primary factor to predict the steady-state disruption. Prospective RF phase cycling schemes were automatically computed online and considerably reduced eddy current-induced image artifacts. The signal model provides a direct relationship for the smoothness of k-space trajectories, which explains the effectiveness of phase encode pairing and tiny golden angle trajectory. CONCLUSIONS: The proposed signal model can accurately predict eddy current-induced steady-state disruptions for bSSFP imaging. The signal model can be used to derive the eddy current-induced phase errors required for trajectory-specific RF phase cycling schemes, which considerably reduce eddy current-induced image artifacts

Current practice of first-trimester ultrasound screening for structural fetal anomalies in developed countries

Objectives: First-trimester ultrasound screening is increasingly performed to detect fetal anomalies early in pregnancy, aiming to enhance reproductive autonomy for future parents. This study aims to display the current practice of first-trimester ultrasound screening in developed countries. Method: An online survey among 47 prenatal screening experts in developed countries. Results: First-trimester structural anomaly screening is available in 30 of the 33 countries and is mostly offered to all women with generally high uptakes. National protocols are available in 23/30 (76.7%) countries, but the extent of anatomy assessment varies. Monitoring of scan quality occurs in 43.3% of the countries. 23/43 (53.5%) of the respondents considered the quality of first-trimester ultrasound screening unequal in different regions of their country. Conclusions: First-trimester screening for structural fetal anomalies is widely offered in developed countries, but large differences are reported in availability and use of screening protocols, the extent of anatomy assessment, training and experience of sonographers and quality monitoring systems. Consequently, this results in an unequal offer to parents in developed countries, sometimes even within the same country. Furthermore, as offer and execution differ widely, this has to be taken into account when results of screening policies are scientifically published or compared.</p

Deep learning-based image reconstruction and motion estimation from undersampled radial k-space for real-time MRI-guided radiotherapy

To enable magnetic resonance imaging (MRI)-guided radiotherapy with real-time adaptation, motion must be quickly estimated with low latency. The motion estimate is used to adapt the radiation beam to the current anatomy, yielding a more conformal dose distribution. As the MR acquisition is the largest component of latency, deep learning (DL) may reduce the total latency by enabling much higher undersampling factors compared to conventional reconstruction and motion estimation methods. The benefit of DL on image reconstruction and motion estimation was investigated for obtaining accurate deformation vector fields (DVFs) with high temporal resolution and minimal latency. 2D cine MRI acquired at 1.5 T from 135 abdominal cancer patients were retrospectively included in this study. Undersampled radial golden angle acquisitions were retrospectively simulated. DVFs were computed using different combinations of conventional- and DL-based methods for image reconstruction and motion estimation, allowing a comparison of four approaches to achieve real-time motion estimation. The four approaches were evaluated based on the end-point-error and root-mean-square error compared to a ground-truth optical flow estimate on fully-sampled images, the structural similarity (SSIM) after registration and time necessary to acquire k-space, reconstruct an image and estimate motion. The lowest DVF error and highest SSIM were obtained using conventional methods up to. For undersampling factors, the lowest DVF error and highest SSIM were obtained using conventional image reconstruction and DL-based motion estimation. We have found that, with this combination, accurate DVFs can be obtained up to with an average root-mean-square error up to 1 millimeter and an SSIM greater than 0.8 after registration, taking 60 milliseconds. High-quality 2D DVFs from highly undersampled k-space can be obtained with a high temporal resolution with conventional image reconstruction and a deep learning-based motion estimation approach for real-time adaptive MRI-guided radiotherapy

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p

Multiparametric renal MRI: an intrasubject test-retest repeatability study

Background: Renal multiparametric magnetic resonance imaging (MRI) is a promising tool for diagnosis, prognosis, and treatment monitoring in kidney disease.Purpose: To determine intrasubject test-retest repeatability of renal MRI measurements.Study Type: Prospective.Population: Nineteen healthy subjects aged over 40 years.Field Strength/Sequences: T-1 and T-2 mapping, R-2* mapping or blood oxygenation level-dependent (BOLD) MRI, diffusion tensor imaging (DTI), and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI), 2D phase contrast, arterial spin labelling (ASL), dynamic contrast enhanced (DCE) MRI, and quantitative Dixon for fat quantification at 3T.Assessment: Subjects were scanned twice with similar to 1 week between visits. Total scan time was similar to 1 hour. Postprocessing included motion correction, semiautomated segmentation of cortex and medulla, and fitting of the appropriate signal model. Statistical Test: To assess the repeatability, a Bland-Altman analysis was performed and coefficients of variation (CoVs), repeatability coefficients, and intraclass correlation coefficients were calculated.Results: CoVs for relaxometry (T-1, T-2, R-2*/BOLD) were below 6.1%, with the lowest CoVs for T-2 maps and highest for R-2*/BOLD. CoVs for all diffusion analyses were below 7.2%, except for perfusion fraction (FP), with CoVs ranging from 18-24%. The CoV for renal sinus fat volume and percentage were both around 9%. Perfusion measurements were most repeatable with ASL (cortical perfusion only) and 2D phase contrast with CoVs of 10% and 13%, respectively. DCE perfusion had a CoV of 16%, while single kidney glomerular filtration rate (GFR) had a CoV of 13%. Repeatability coefficients (RCs) ranged from 7.7-87% (lowest/highest values for medullary mean diffusivity and cortical FP, respectively) and intraclass correlation coefficients (ICCs) ranged from -0.01 to 0.98 (lowest/highest values for cortical FP and renal sinus fat volume, respectively).Data Conclusion: CoVs of most MRI measures of renal function and structure (with the exception of FP and perfusion as measured by DCE) were below 13%, which is comparable to standard clinical tests in nephrology.Cardiovascular Aspects of Radiolog

Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder:results of a prospective multicenter clinical utility study in the Netherlands

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p &lt; 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.</p