Neural correlates of working memory and its association with metabolic parameters in early-treated adults with phenylketonuria.

BACKGROUND Phenylketonuria (PKU) is an inborn error of metabolism affecting the conversion of phenylalanine (Phe) into tyrosine. Previous research has found cognitive and functional brain alterations in individuals with PKU even if treated early. However, little is known about working memory processing and its association with task performance and metabolic parameters. The aim of the present study was to examine neural correlates of working memory and its association with metabolic parameters in early-treated adults with PKU. METHODS This cross-sectional study included 20 early-treated adults with PKU (mean age: 31.4 years ± 9.0) and 40 healthy controls with comparable age, sex, and education (mean age: 29.8 years ± 8.2). All participants underwent functional magnetic resonance imaging (fMRI) of working memory to evaluate the fronto-parietal working memory network. Fasting blood samples were collected from the individuals with PKU to acquire a concurrent plasma amino acid profile, and retrospective Phe concentrations were obtained to estimate an index of dietary control. RESULTS On a cognitive level, early-treated adults with PKU displayed significantly lower accuracy but comparable reaction time in the working memory task compared to the control group. Whole-brain analyses did not reveal differences in working memory-related neural activation between the groups. Exploratory region-of-interest (ROI) analyses indicated reduced neural activation in the left and right middle frontal gyri and the right superior frontal gyrus in the PKU group compared to the control group. However, none of the ROI analyses survived correction for multiple comparisons. Neural activation was related to concurrent Phe, tyrosine, and tryptophan concentrations but not to retrospective Phe concentrations. CONCLUSION In early-treated adults with PKU, cognitive performance and neural activation are slightly altered, a result that is partly related to metabolic parameters. This study offers a rare insight into the complex interplay between metabolic parameters, neural activation, and cognitive performance in a sample of individuals with PKU

Simultaneous lesion and neuroanatomy segmentation in Multiple Sclerosis using deep neural networks

Segmentation of both white matter lesions and deep grey matter structures is an important task in the quantification of magnetic resonance imaging in multiple sclerosis. Typically these tasks are performed separately: in this paper we present a single segmentation solution based on convolutional neural networks (CNNs) for providing fast, reliable segmentations of multimodal magnetic resonance images into lesion classes and normal-appearing grey- and white-matter structures. We show substantial, statistically significant improvements in both Dice coefficient and in lesion-wise specificity and sensitivity, compared to previous approaches, and agreement with individual human raters in the range of human inter-rater variability. The method is trained on data gathered from a single centre: nonetheless, it performs well on data from centres, scanners and field-strengths not represented in the training dataset. A retrospective study found that the classifier successfully identified lesions missed by the human raters. Lesion labels were provided by human raters, while weak labels for other brain structures (including CSF, cortical grey matter, cortical white matter, cerebellum, amygdala, hippocampus, subcortical GM structures and choroid plexus) were provided by Freesurfer 5.3. The segmentations of these structures compared well, not only with Freesurfer 5.3, but also with FSL-First and Freesurfer 6.0

Attitudes and expectations of patients on home parenteral nutrition towards eHealth: A multicenter survey.

BACKGROUND & AIMS Advances in technology enable patients on home parenteral nutrition (HPN) to manage their treatment more independently and safely. eHealth is a promising application of electronic means in healthcare, aimed at improving and simplifying processes and connecting the different parties involved. A thorough understanding of the attitudes and expectations of patients on HPN towards eHealth is a prerequisite for a successful implementation. However, to the best of our knowledge, such a survey preceding the implementation of HPN specific eHealth care has never been conducted. The objective of this preliminary survey is the acquisition of insights on the attitudes and expectations of patients on HPN towards eHealth. Resulting findings then serve as the basis for the design of an eHealth platform to facilitate communication among those involved in HPN care, improve the HPN management, and safeguard and monitor the treatment. METHODS We conducted a survey on the attitudes and expectations of patients towards an envisioned eHealth platform for HPN. Patients were recruited from large Swiss hospitals by their treating physician or directly by the research team. The surveys were conducted between September 2020 and October 2021 by structured personal interviews based on a questionnaire. RESULTS We included 35 patients on HPN (21 [60%] females) treated in ambulant care of 4 hospitals. They had a median (interquartile range) age of 55 (18) years and a median (interquartile range) duration of parenteral nutrition of 1.3 (3.1) years. Most patients (n = 30, 86%) were equipped with a smartphone, tablet, or computer and 22 (63%) used apps and rated themselves as proficient with the corresponding digital device. A majority of patients rated the following aspects and features of the platform as important: Data collection and storage (n = 29, 83%), checklists for PN, catheter, and infusion pump handling (n = 28, 80%), video instructions (n = 27, 77%), and videoconferencing with physicians (n = 25, 71%). Most patients (n = 26, 74%) were willing to enter data into the platform themselves. The type of data to be entered should be defined on an individual basis. CONCLUSIONS Patients on HPN are open to videoconference consultations and using an eHealth platform. Two-thirds have the necessary technical skills including suitable digital devices for an eHealth care. We identified key features of an eHealth platform to improve HPN management

Compromised white matter is related to lower cognitive performance in adults with phenylketonuria.

Despite increasing knowledge about the effects of phenylketonuria on brain structure and function, it is uncertain whether white matter microstructure is affected and if it is linked to patients' metabolic control or cognitive performance. Thus, we quantitatively assessed white matter characteristics in adults with phenylketonuria and assessed their relationship to concurrent brain and blood phenylalanine levels, historical metabolic control and cognitive performance. Diffusion tensor imaging and 1H spectroscopy were performed in 30 adults with early-treated classical phenylketonuria (median age 35.5 years) and 54 healthy controls (median age 29.3 years). Fractional anisotropy and mean, axial and radial diffusivity were investigated using tract-based spatial statistics, and white matter lesion load was evaluated. Brain phenylalanine levels were measured with 1H spectroscopy whereas concurrent plasma phenylalanine levels were assessed after an overnight fast. Retrospective phenylalanine levels were collected to estimate historical metabolic control, and a neuropsychological evaluation assessed the performance in executive functions, attention and processing speed. Widespread reductions in mean diffusivity, axial diffusivity and fractional anisotropy occurred in patients compared to controls. Mean diffusivity and axial diffusivity were decreased in several white matter tracts and were most restricted in the optic radiation (effect size rrb = 0.66 to 0.78, P < 0.001) and posterior corona radiata (rrb = 0.83 to 0.90, P < 0.001). Lower fractional anisotropy was found in the optic radiation and posterior corona radiata (rrb = 0.43 to 0.49, P < 0.001). White matter microstructure in patients was significantly associated with cognition. Specifically, inhibition was related to axial diffusivity in the external capsule (rs = -0.69, P < 0.001) and the superior (rs = -0.58, P < 0.001) and inferior longitudinal fasciculi (rs = -0.60, P < 0.001). Cognitive flexibility was associated with mean diffusivity of the posterior limb of the internal capsule (rs = -0.62, P < 0.001), and divided attention correlated with fractional anisotropy of the external capsule (rs = -0.61, P < 0.001). Neither concurrent nor historical metabolic control was significantly associated with white matter microstructure. White matter lesions were present in 29 out of 30 patients (96.7%), most often in the parietal and occipital lobes. However, total white matter lesion load scores were unrelated to patients' cognitive performance and metabolic control. In conclusion, our findings demonstrate that white matter alterations in early-treated phenylketonuria persist into adulthood, are most prominent in the posterior white matter and are likely to be driven by axonal damage. Furthermore, diffusion tensor imaging metrics in adults with phenylketonuria were related to performance in attention and executive functions

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial.

BACKGROUND The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain. METHODS The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial. PARTICIPANTS Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life. INTERVENTION The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. OBJECTIVES The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland. RANDOMIZATION Central randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician. Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment. DISCUSSION Using a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed. TRIAL REGISTRATION The study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO

Correction to: Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial.

amendment to https://boris.unibe.ch/14072

The impact of rapid on-site evaluation (ROSE) on the quality and diagnostic value of thyroid nodule fine-needle aspirations.

BACKGROUND Ultrasound-guided fine-needle aspiration (FNA) is the preferred method to evaluate the dignity of thyroid nodules. Nevertheless, the often-reported high non-diagnostic rate burdens affected patients and the healthcare system. Rapid on-site evaluation (ROSE) constitutes an addition to the thyroid FNA procedure, with various studies showing its beneficial effect on the Bethesda I non-diagnostic rate. We aimed to assess whether ROSE may reduce the rate of Bethesda categories III and V. Additionally, we examined the influence of ROSE on specimen quality. METHODS We performed a retrospective cohort study, comparing Bethesda categorization and specimen quality in specimens subject to ROSE compared to those not subject to ROSE. We also evaluated aspects of specimen quality that differed according to the use of ROSE. We subcategorized Bethesda I into insufficient cellularity or artifacts, and Bethesda categories III and V into cellular without artifacts, sparsely cellular, or artifacts. RESULTS We evaluated 5030 thyroid FNAs. ROSE was performed in 1304 (25.9%) cases, and ROSE was not utilized for 3726 (74.1%) specimens. The rate of Bethesda I non-diagnostic and Bethesda III categories was reduced in specimens subject to ROSE (4.3%, 56/1304), compared to non-ROSE (39.9%, 1487/3726, p<.001). The rate of both benign Bethesda II and malignant Bethesda VI diagnoses was 91.6% (1194/1270) in ROSE specimens, compared to 56.6% (1999/3530) in non-ROSE (p<.001). This was reflected by a significant improvement in diagnostic accuracy with ROSE (AUCnon-ROSE=0.811, AUCROSE=0.895, p=.004). The overall rate of specimens flawed by sparse cellularity in Bethesda categories III and V was 0.1% (1/1304) in ROSE specimens compared to 1.2% (45/3726) in non-ROSE (p<.001). The overall artifact rate was 0.3% (4/1304) for ROSE specimens and 2.5% (92/3726) for non-ROSE (p<.001). CONCLUSIONS ROSE significantly increased diagnostic accuracy by improving FNA specimens quantitatively and qualitatively. We suggest considering ROSE as standard of care for thyroid FNAs