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Abstract Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5′ untranslated region (5′UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.

Introduction: Assessing a patient’s risk of scar-based ventricular tachycardia (VT) after myocardial infarction is a challenging task. It can take months to years after infarction for VT to occur. Also, if selected for ablation therapy, success rates are low.Methods: Computational ventricular models have been presented previously to support VT risk assessment and to provide ablation guidance. In this study, an extension to such virtual-heart models is proposed to phenomenologically incorporate tissue remodeling driven by mechanical load. Strain amplitudes in the heart muscle are obtained from simulations of mechanics and are used to adjust the electrical conductivity. Results: The mechanics-driven adaptation of electrophysiology resulted in a more heterogeneous distribution of propagation velocities than that of standard models, which adapt electrophysiology in the structural substrate from medical images only. Moreover, conduction slowing was not only present in such a structural substrate, but extended in the adjacent functional border zone with impaired mechanics. This enlarged the volumes with high repolarization time gradients (≥10 ms/mm). However, maximum gradient values were not significantly affected. The enlarged volumes were localized along the structural substrate border, which lengthened the line of conduction block. The prolonged reentry pathways together with conduction slowing in functional regions increased VT cycle time, such that VT was easier to induce, and the number of recommended ablation sites increased from 3 to 5 locations.Discussion: Sensitivity testing showed an accurate model of strain-dependency to be critical for low ranges of conductivity. The model extension with mechanics-driven tissue remodeling is a potential approach to capture the evolution of the functional substrate and may offer insight into the progression of VT risk over time.

Background and purpose: Microplasty Instrumentation was introduced to improve Oxford Mobile Partial Knee placement and preserve tibial bone in partial knee replacement (PKR). This might therefore reduce revision complexity. We aimed to assess the difference in use of revision total knee replacement (TKR) tibial components in failed Microplasty versus non-Microplasty instrumented PKRs. Patients and methods: Data on 529 conversions to TKR (156 Microplasty instrumented and 373 non-Microplasty instrumented PKRs) from the Dutch Arthroplasty Register (LROI) between 2007 and 2019 was used. The primary outcome was the difference in use of revision TKR tibial components during conversion to TKR, which was calculated with a univariable logistic regression analysis. The secondary outcomes were the 3-year re-revision rate and hazard ratios calculated with Kaplan–Meier and Cox regression analyses. Results: Revision TKR tibial components were used in 29% of the conversions to TKR after failed Microplasty instrumented PKRs and in 24% after failed non-Microplasty instrumented PKRs with an odds ratio of 1.3 (CI 0.86–2.0). The 3-year re-revision rates were 8.4% (CI 4.1–17) after conversion to TKR for failed Microplasty and 11% (CI 7.8–15) for failed non-Microplasty instrumented PKRs with a hazard ratio of 0.77 (CI 0.36–1.7). Conclusion: There was no difference in use of revision tibial components for conversion to TKR or in re-revision rate after failed Microplasty versus non-Microplasty instrumented PKRs nor in the 3-year revision rate.

Abstract Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Background and purpose — Guidelines for managing hip and knee osteoarthritis (OA) advise extensive non-surgical treatment prior to surgery. We evaluated what percentage of hip and knee OA patients received non-surgical treatment prior to arthroplasty, and assessed patient satisfaction regarding alleviation of symptoms and performance of activities. Patients and methods — A multi-center cross-sectional study was performed in 2018 among 186 patients who were listed for hip or knee arthroplasty or had undergone surgery within the previous 6 months in the Netherlands. Questions concerned non-surgical treatments received according to the Stepped Care Strategy and were compared with utilization in 2013. Additionally, satisfaction with treatment effects for pain, swelling, stiffness, and activities of daily life, work, and sports/leisure was questioned. Results — The questionnaire was completed by 175 patients, age 66 years (range 38–84), 57% female, BMI 29 (IQR 25–33). Step 1 treatments, such as acetaminophen and lifestyle advice, were received by 79% and 60% of patients. Step 2 treatments, like exercise-based therapy and diet therapy, were received by 66% and 19%. Step 3—intra-articular injection—was received by 47%. Non-surgical treatment utilization was lower than in 2013. Nearly all treatments showed more satisfied patients regarding pain relief and fewer regarding activities of work/sports/leisure. Hip and knee OA patients were mostly satisfied with NSAIDs for all outcomes, while exercise-based therapy was rated second best. Interpretation — Despite international guideline recommendations, non-surgical treatment for hip and knee OA remains underutilized in the Netherlands. Of the patients referred for arthroplasty, more were satisfied with the effect of non-surgical treatment on pain than on work/sports/leisure participation.

Background and purpose — Femoral neck fractures are commonly treated with cemented or uncemented hemiarthroplasties (HA). We evaluated differences in mortality and revision rates in this fragile patient group. Patients and methods — From January 1, 2007 until December 31, 2016, 22,356 HA procedures from the Dutch Arthroplasty Register (LROI) were included. For each HA, follow-up until death, revision, or end of follow-up (December 31, 2016) was determined. The crude revision rate was determined by competing risk analysis. Multivariable Cox regression analyses were performed to evaluate the effect of fixation method (cemented vs. uncemented) on death or revision. Age, sex, BMI, Orthopaedic Data Evaluation Panel (ODEP) rating, ASA grade, surgical approach, and previous surgery were included as potential confounders. Results — 1-year mortality rates did not differ between cemented and uncemented HA. 9-year mortality rates were 53% (95% CI 52–54) in cemented HA compared to 56% (CI 54–58) in uncemented HA. Multivariable Cox regression analysis showed similar mortality between cemented and uncemented HA (HR 1.0, CI 0.96–1.1). A statistically significantly lower 9-year revision rate of 3.1% (CI 2.7–3.6) in cemented HA compared with 5.1% (CI 4.2–6.2) in the uncemented HA was found with a lower hazard ratio for revision in cemented compared with uncemented HA (HR 0.56, CI 0.47–0.67). Interpretation — Long-term mortality rates did not differ between patients with a cemented or uncemented HA after an acute femoral neck fracture. Revision rates were lower in cemented compared with uncemented HA.

Background and purpose — Partial knee replacement (PKR) survival rates vary a great deal among registries and cohort studies. These discrepancies can largely be attributed to inappropriate indications of the PKR and low thresholds for revision, but also to the PKR volume. This study used Dutch Arthroplasty Register data to analyze whether absolute PKR or proportional PKR hospital volume is associated with the risk of revision. Patients and methods — 18,134 PKRs were identified in the Dutch Arthroplasty Register from 2007 to 2016. For each year, hospitals were divided into 4 groups based on the quartiles for the absolute volume (< 22, 22–36, 36–58 and > 58 PKRs per year) and the proportional volume (< 8.5, 8.6–14.2, 14.3–25.8 and > 25.8% PKRs). Kaplan–Meier survival analysis was performed to determine survival rates. A multivariable Cox regression adjusted for age category, sex, ASA score, year of surgery, diagnosis, unicondylar side, and type of hospital was used to estimate hazard ratios (HR) for revision. Results and interpretation — Proportional PKR volume did not, but absolute PKR volume did influence the risk of revision. The adjusted HR for hospitals with an absolute volume of 22–36 PKRs per year was 1.04 (95% CI 0.91–1.20), 0.96 (CI 0.83–1.10) for the hospitals with 36–58 PKRs, and 0.74 (CI 0.62–0.89) for hospitals with more than 58 PKRs compared with hospitals that had fewer than 22 PKRs per year. So, patients treated with a PKR in a high absolute volume hospital have a lower risk of revision compared with those treated in a low absolute volume hospital.

Objectives To assess the learning curve of the direct superior approach (DSA) for total hip arthroplasty (THA) and to compare surgical, clinical, and radiological results with a matched control group using the mini posterior approach (MPA). Methods A prospective cohort study was performed from October 2016 to May 2017 including our first 52 patients undergoing THA using the DSA. Patients with primary osteoarthritis or osteonecrosis and a body mass index (BMI)

Abstract Background CLN3 disease is a disorder of lysosomal homeostasis predominantly affecting the retina and the brain. The severity of the underlying mutations in CLN3 particularly determines onset and course of neurological deterioration. Given the highly conserved start codon code among eukaryotic species, we expected a variant in the start codon of CLN3 to give rise to the classical, that is, severe, phenotype. Case series We present three patients with an identical CLN3 genotype (compound heterozygosity for the common 1 kb deletion in combination with a c.1A > C start codon variant) who all displayed a more attenuated phenotype than expected. While their retinal phenotype was similar to as expected in classical CLN3 disease, their neurological phenotype was delayed. Two patients had an early onset of cognitive impairment, but a particularly slow deterioration afterwards without any obvious motor impairment. The third patient also had a late onset of cognitive impairment. Conclusions Contrasting our initial expectations, patients with a start codon variant in CLN3 may display a protracted phenotype. Future work will have to reveal the exact mechanism behind the assumed residual protein synthesis, and determine whether this may be eligible to start codon targeted therapy.

Background and purpose — The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) was analyzed to determine trends in use of primary total elbow arthroplasty (TEA), the types of prostheses used, primary diagnoses, reasons for and types of revision, and whether the primary diagnosis or prosthesis design influenced the revision rate. Patients and methods — During 2008–2018, 1,220 primary TEA procedures were reported of which 140 TEAs were revised. Kaplan–Meier estimates of survivorship were used to describe the time to first revision and hazard ratios (HR) from Cox proportional hazard models, adjusted for age and sex, were used to compare revision rates. Results — The annual number of TEAs performed remained constant. The 3 most common diagnoses for primary TEA were fracture/dislocation (trauma) (36%), osteoarthritis (OA) (34%), and rheumatoid arthritis (RA) (26%). The cumulative percentage revision for all TEAs undertaken for any reason was 10%, 15%, and 19% at 3, 6, and 9 years. TEAs undertaken for OA had a higher revision rate compared with TEAs for trauma (HR = 1.8, 95% CI 1.1–3.0) and RA (HR = 2.0, CI 1.3–3.1). The Coonrad-Morrey (50%), Latitude (30%), Nexel (10%), and Discovery (9%) were the most used prosthesis designs. There was no difference in revision rates when these 4 designs were compared. The most common reasons for revision were infection (35%) and aseptic loosening (34%). Interpretation — The indications for primary and revision TEA in Australia are similar to those reported for other registries. Revision for trauma is lower than previously reported.

Abstract Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X‐linked disorders. Parenteral hydroxocobalamin (P‐OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long‐term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1‐3; cblA: patient 4; cblX: patient 5) following daily P‐OHCbl dose intensification (DI). In patient 4, P‐OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P‐OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P‐OHCbl doses. After age 36 months, patients 1‐3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P‐OHCbl‐DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P‐OHCbl‐DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P‐OHCbl doses were administrated to improve tolerability.

Abstract Background In the treatment of Lateral Epicondylitis (LE) no single intervention concerning injection therapies has been proven to be the most effective with regard to pain reduction. In this trial 3 injection therapies (perforation with application of autologous blood, perforation with application of dextrose and perforation only) will be compared in a standardized and ultrasound guided way. The objective is to assess the effectiveness of these 3 injection therapies on pain, quality of life and functional recovery. By conducting this study, we hope to make a statement on the effectiveness of injection therapy in the treatment of LE. Hereby, unnecessary treatments can be avoided, a more universal method of treatment can be established and the quality of the treatment can be improved. Methods/design A multicenter, randomized controlled trial with a superiority design and 12 months follow-up will be conducted in four Dutch hospitals. One hundred sixty five patients will be recruited in the age of 18 to 65 years, with chronic symptomatic lateral epicondylitis lasting longer than 6 weeks, which have concordant pain during physical examination. Patients will be randomized by block randomization to one of the three treatment arms. The treatment will be blinded for patients and outcome assessors. The following three injection therapies are compared: perforation with application of autologous blood, perforation with application of dextrose and perforation only. Injections will be performed ultrasound guided in a standardized and automated way. The primary endpoint is: pain (change in ‘Visual Analogue Scale’). Secondary endpoints are quality of life and functional recovery. These measurements are collected at baseline, 8 weeks, 5 months and 1 year after treatment. Discussion When completed, this trial will provide evidence on the effectiveness of injection therapy in the treatment of lateral epicondylitis on pain, quality of life and functional recovery. In current literature proper comparison of the effectiveness of injectables for LE is questionable, due to the lack of standardization of the treatment. This study will overcome bias due to manually performed injection therapy. Trial registration This study is registered in the Trial Register (www.trialregister.nl) of the Dutch Cochrane centre. Trial ID; NTR4569. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4569

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.

D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

Abstract Background The elbow is prone to stiffness after trauma. To regain functional elbow motion several conservative- and surgical treatment options are available. Conservative treatment includes physical therapy, intra-articular injections with corticosteroids and a static progressive or dynamic splinting program. If conservative treatment fails, an operative release of the posttraumatic stiff elbow is often performed. The best Evidence-Based rehabilitation protocol for patients after an operative release is unknown to date and differs per surgeon, hospital and country. Options include early- or delayed motion supervised by a physical therapist, immediate continuous passive motion (CPM), (night) splinting and a static progressive or dynamic splinting program. Methods/design The SET-Study (Stiff Elbow Trial) is a single-centre, prospective, randomized controlled trial. The primary objective of this study is to compare the active Range of Motion (ROM) (flexion arc and rotational arc) twelve months after surgery between three groups. The first group will receive in-hospital CPM in combination with early motion Physical Therapy (PT) supervised by a physical therapist, the second group will receive only in-hospital early motion PT supervised by a physical therapist and the third group will receive outpatient supervised PT from postoperative day seven till ten. Secondary outcome measures will be Patient Reported Outcome Measures (PROMs) including the Mayo Elbow Performance Score (MEPS), the Oxford Elbow Score (OES), the quick Disabilities of Arm, Shoulder and Hand (qDASH) score, Visual Analogue pain Scale in rest and activity (VAS), Pain Catastrophizing Scale (PCS), the Short Form (SF)-36, the Centre for Epidemiological Studies Depression Scale Revised (CESD-R) and the Work Rehabilitation Questionnaire (WORQ) for the upper limb. Discussion A successful completion of this trial will provide evidence on the best rehabilitation protocol in order to (re)gain optimal motion after surgical release of the stiff elbow. Trial registration The trial is registered at the Dutch Trial Register: NTR6067 , 31–8-2016.

Background and purpose — Radiostereometric analysis (RSA) is an accurate method for measurement of early migration of implants. Since a relation has been shown between early migration and future loosening of total knee and hip prostheses, RSA plays an important role in the development and evaluation of prostheses. However, there have been few RSA studies of the upper limb, and the value of RSA of the upper limb is not yet clear. We therefore performed a systematic review to investigate the accuracy and precision of RSA of the upper limb. Patients and methods — PRISMA guidelines were followed and the protocol for this review was published online at PROSPERO under registration number CRD42016042014. A systematic search of the literature was performed in the databases Embase, Medline, Cochrane, Web of Science, Scopus, Cinahl, and Google Scholar on April 25, 2015 based on the keywords radiostereometric analysis, shoulder prosthesis, elbow prosthesis, wrist prosthesis, trapeziometacarpal joint prosthesis, humerus, ulna, radius, carpus. Articles concerning RSA for the analysis of early migration of prostheses of the upper limb were included. Quality assessment was performed using the MINORS score, Downs and Black checklist, and the ISO RSA Results — 23 studies were included. Precision values were in the 0.06–0.88 mm and 0.05–10.7° range for the shoulder, the 0.05–0.34 mm and 0.16–0.76° range for the elbow, and the 0.16–1.83 mm and 11–124° range for the TMC joint. Accuracy data from marker- and model-based RSA were not reported in the studies included. Interpretation — RSA is a highly precise method for measurement of early migration of orthopedic implants in the upper limb. However, the precision of rotation measurement is poor in some components. Challenges with RSA in the upper limb include the symmetrical shape of prostheses and the limited size of surrounding bone, leading to over-projection of the markers by the prosthesis. We recommend higher adherence to RSA guidelines and encourage investigators to publish long-term follow-up RSA studies.

Next-generation sequencing and next-generation metabolic screening are, independently, increasingly applied in clinical diagnostics of inborn errors of metabolism (IEM). Integrated into a single bioinformatic method, these two –omics technologies can potentially further improve the diagnostic yield for IEM. Here, we present cross-omics: a method that uses untargeted metabolomics results of patient’s dried blood spots (DBSs), indicated by Z-scores and mapped onto human metabolic pathways, to prioritize potentially affected genes. We demonstrate the optimization of three parameters: (1) maximum distance to the primary reaction of the affected protein, (2) an extension stringency threshold reflecting in how many reactions a metabolite can participate, to be able to extend the metabolite set associated with a certain gene, and (3) a biochemical stringency threshold reflecting paired Z-score thresholds for untargeted metabolomics results. Patients with known IEMs were included. We performed untargeted metabolomics on 168 DBSs of 97 patients with 46 different disease-causing genes, and we simulated their whole-exome sequencing results in silico. We showed that for accurate prioritization of disease-causing genes in IEM, it is essential to take into account not only the primary reaction of the affected protein but a larger network of potentially affected metabolites, multiple steps away from the primary reaction.

Although much attention has been given to the global three-dimensional aspect of adolescent idiopathic scoliosis (AIS), the accurate three-dimensional morphology of the primary and compensatory curves, as well as the intervening junctional segments, in the scoliotic spine has not been described before.A unique series of 77 AIS patients with high-resolution CT scans of the spine, acquired for surgical planning purposes, were included and compared to 22 healthy controls. Non-idiopathic curves were excluded. Endplate segmentation and local longitudinal axis in endplate plane enabled semi-automatic geometric analysis of the complete three-dimensional morphology of the spine, taking inter-vertebral rotation, intra-vertebral torsion and coronal and sagittal tilt into account. Intraclass correlation coefficients for interobserver reliability were 0.98-1.00. Coronal deviation, axial rotation and the exact length discrepancies in the reconstructed sagittal plane, as defined per vertebra and disc, were analyzed for each primary and compensatory curve as well as for the junctional segments in-between.The anterior-posterior difference of spinal length, based on "true" anterior and posterior points on endplates, was +3.8% for thoracic and +9.4% for (thoraco)lumbar curves, while the junctional segments were almost straight. This differed significantly from control group thoracic kyphosis (-4.1%; P

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2-4% of Western-European children). Complex febrile seizures are associated with an increased risk to develop temporal lobe epilepsy. To investigate short- and long-term effects of experimental febrile seizures (eFS), we induced eFS in highly febrile convulsion-susceptible C57BL/6J mice at post-natal day 10 by exposure to hyperthermia (HT) and compared them to normotherm-exposed (NT) mice. We detected structural re-organization in the hippocampus 14 days after eFS. To identify molecular candidates, which entrain this structural re-organization, we investigated temporal changes in mRNA expression profiles eFS 1 hour to 56 days after eFS. We identified 931 regulated genes and profiled several candidates using in situ hybridization and histology at 3 and 14 days after eFS. This is the first study to report genome-wide transcriptome analysis after eFS in mice. We identify temporal regulation of multiple processes, such as stress-, immune- and inflammatory responses, glia activation, glutamate-glutamine cycle and myelination. Identification of the short- and long-term changes after eFS is important to elucidate the mechanisms contributing to epileptogenesis.

IntroductionLacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden.MethodsWithin the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning.ResultsVoxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden.ConclusionThese findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.

BACKGROUND: Diffusion weighted MR imaging (DWI) plays an important role in the diagnosis of perinatal arterial ischemic stroke (PAIS) during the acute phase. Its derived apparent diffusion coefficient (ADC) can be used to quantify the diffusion restriction. Aim of the current study was to identify the changes in ADC values in the acute phase following PAIS. METHODS: A cohort of 36 infants with a confirmed PAIS who were examined once during the first ten days of life was studied. ADC values in the core of the ischemic tissue (iADC) were determined and correlated with postnatal age. ADC ratios (rADC) were calculated by dividing the iADC value by the ADC value of the corresponding area in the contralateral 'healthy' hemisphere. RESULTS: Infants were scanned between days two and ten. A non-linear increase in iADC and rADC values was observed over time and large middle cerebral artery strokes resulted in lower iADC and rADC values. Normalisation of rADC values was observed after day seven. rADC values were lower when compared to previously published rADC values of infants with hypoxic ischemic encephalopathy, suggesting more severe injury. CONCLUSIONS: Following PAIS, DWI showed decreased ADC values with a non-linear increase during the first week, and pseudonormalization after day 7, which limits the use of DWI to assess PAIS to the first week. Compared to previous studies, ADC values were lower when compared to infants with hypoxic ischemic encephalopathy, most likely due to more severe injury.

Cerebral microbleeds are associated with vascular disease and dementia. They can be detected on MRI and receive increasing attention. Visual rating is the current standard for microbleed detection, but is rater dependent, has limited reproducibility, modest sensitivity, and can be time-consuming. The goal of the current study is to present a tool for semi-automated detection of microbleeds that can assist human raters in the rating procedure. The radial symmetry transform is originally a technique to highlight circular-shaped objects in two-dimensional images. In the current study, the three-dimensional radial symmetry transform was adapted to detect spherical microbleeds in a series of 72 patients from our hospital, for whom a ground truth visual rating was made by four raters. Potential microbleeds were automatically identified on T2*-weighted 3.0 T MRI scans and the results were visually checked to identify microbleeds. Final ratings of the radial symmetry transform were compared to human ratings. After implementing and optimizing the radial symmetry transform, the method achieved a high sensitivity, while maintaining a modest number of false positives. Depending on the settings, sensitivities ranged from 65%-84% compared to the ground truth rating. Rating of the processed images required 1-2 minutes per participant, in which 20-96 false positive locations per participant were censored. Sensitivities of individual raters ranged from 39%-86% compared to the ground truth and required 5-10 minutes per participant per rater. The sensitivities that were achieved by the radial symmetry transform are similar to those of individual experienced human raters, demonstrating its feasibility and usefulness for semi-automated microbleed detection.

Objectives. Mechanisms influencing the course of physical and mental functioning after an atherosclerotic event are unclear. We examined effects of white matter lesion (WML) activity on changes in functioning in patients with symptomatic atherosclerotic disease. Methods. In 486 patients (58±9 years) of the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, volumetric WML measurements on 1.5T MRI were performed at baseline and 3.9±0.4 years followup. Functioning was assessed with the modified Short-Form 12 (SF-12) questionnaire. Associations of WML progression with changes in functioning were adjusted for age, sex, and vascular risk factors. Results. Physical functioning (baseline: 44, 10th–90th percentile 29–55) improved, whereas mental functioning (baseline: 51, 10th–90th percentile 32–60) declined during followup. WML progression (highest quartile versus rest) contributed to a stronger decline in mental functioning (B=−1.76, 95% CI −3.11 to −0.42), but did not influence changes in physical functioning. Conclusions. Progression of WML volume contributes to a decline in mental functioning in patients with symptomatic atherosclerotic disease.

Rationale and objectivesRadiology expertise is dependent on the use of efficient search strategies. The aim of this study is to investigate the effect of teaching search strategies on trainee's accuracy in detecting lung nodules at computed tomography.Materials and methodsTwo search strategies, "scanning" and "drilling," were tested with a randomized crossover design. Nineteen junior radiology residents were randomized into two groups. Both groups first completed a baseline lung nodule detection test allowing a free search strategy, followed by a test after scanning instruction and drilling instruction or vice versa. True positive (TP) and false positive (FP) scores and scroll behavior were registered. A mixed-design analysis of variance was applied to compare the three search conditions.ResultsSearch strategy instruction had a significant effect on scroll behavior, F(1.3) = 54.2, P

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.