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BACKGROUND AND PURPOSE: Recent reports suggest an association between dural AVFs and cerebral venous thrombosis. We aimed to investigate the specific temporal and anatomic association between the 2 conditions. MATERIALS AND METHODS: A consecutive cohort of adult patients with dural AVFs was seen at Amsterdam University Medical Centers (2007-2020). An experienced neuroradiologist re-evaluated the presence and imaging characteristics of dural AVFs and cerebral venous thrombosis on all available imaging. The temporal (previous/concurrent/subsequent) and anatomic (same/adjacent/unrelated venous sinus or vein) association between dural AVFs and cerebral venous thrombosis was determined. RESULTS: Among 178 patients with dural AVFs, the mean age was 58.3 (SD, 13.2) years and 85 (48%) were women. Of 55 patients (31%) with cerebral venous thrombosis, 34 (62%) were women. Four patients (7%) had cerebral venous thrombosis before the development of a dural AVF, 33 (60%) had cerebral venous thrombosis at the time of dural AVF diagnosis (concurrent), and 18 (33%) developed cerebral venous thrombosis during follow-up after conservative treatment. The incidence rate of cerebral venous thrombosis after a dural AVF was 79 per 1000 person-years (95% CI, 50-124). In 45 (82%) patients with dural AVFs and cerebral venous thrombosis, the thrombosis was located in the same venous sinus as the dural AVF, whereas in 8 (15%) patients, thrombosis occurred in a venous sinus adjacent to the dural AVF. CONCLUSIONS: One-third of patients with a dural AVF in this study were diagnosed with cerebral venous thrombosis. In almost two-thirds of patients, cerebral venous thrombosis was diagnosed prior to or concurrent with the dural AVF. In 97% of patients, there was an anatomic association between the dural AVF and cerebral venous thrombosis. These data support the hypothesis of a bidirectional association between the 2 diseases.

Funding Acknowledgements Type of funding sources: None. Background Atrial Fibrillation (AF) is associated with substantial morbidity, mortality and low quality of life. Obesity is an important risk factor for AF and weight reduction is associated with a decrease in AF burden. Previous studies showed that conventional CR programs lead to insufficient weight reduction in obese patients. The OPTImal CArdiac REhabilitation XL (OPTICARE XL) study was an open label randomized controlled trial (RCT), evaluating effects of a CR program specifically designed for weight reduction in patients with obesity and non-valvular AF. Objective We hypothesize that this novel tailor-made CR program (OPTICARE XL) will lead to reduced AF burden, as compared to conventional CR. Design and setting: Multi-center RCT, conducted between February 2017 and January 2019 in 2 large Dutch CR centers. Patients were randomized to the OPTICARE XL CR intervention-program or a conventional CR-program. Methods The primary endpoint was AF symptom burden, assessed by the Atrial Fibrillation Severity Scale (AFSS). Secondary endpoints were AF symptom number, AF symptom frequency and AF symptom severity. Data were collected at baseline (prior to CR, T0), at the end of the intervention and conventional program (T1) and 1.5 year after inclusion (T2). Results Of 68 included patients, 28 were randomized to conventional CR and 40 to OPTICARE XL CR. Patients were predominantly male (60%), had a mean age of 62.4 ± 10.4 years and a mean BMI of 36.1 ± 4.4 kg/m2. With regards to AF burden, no significant within and between-group differences were observed between T0 and T1, T1 and T2, and T0 and T2 (OPTICARE XL: T0 14.6 ± 4.4, T1 14.1 ± 5.9, T2 14.3 ± 6.9; conventional CR: T0 16.4 ± 6.5, T1 15.3 ± 6.3, T2 15.9 ± 7.6; Figure 1). There was a significant difference (p=0.02) in the AF symptom number at T2 in favor of the intervention group (Figure 2). AF symptom frequency decreased in the intervention group from T0 to T2 (31.5 to 25.8; p=0.027) and in conventional CR from T0 to T1 (32.2 to 28.2; p=0.010). However, for both AF symptom frequency and symptom severity, no significant between-group differences were observed. Conclusion Compared to conventional CR, OPTICARE XL CR did not result in a reduced AF burden. However, it did reduce the AF symptom number at long-term follow-up. Novel CR programs such as OPTICARE XL may have added value in the treatment of obese patients with AF.

Aim In high risk groups such as patients undergoing open abdominal aortic aneurysm (AAA) surgery, the risk of incisional hernia (IH) formation is up to 69%. IH can be prevented through prophylactic mesh augmentation (PMA). Several randomized controlled trials (RCT) have shown a significant decrease in IH formation after PMA. However, due to study design and sample size issues, implementation of PMA into daily practice is lacking. Methods International collaboration will be initiated under the guidance of the European Hernia Society. RCTs studying PMA after open AAA surgery will be identified through a literature search. Corresponding authors of the selected studies will be approached for participation by e-mail, telephone or other means. Where independent patient data (IPD) are available, a suitable data delivery agreement (DDA) will be drafted and signed upon agreement. Pseudonymised or anonymised data sets will be securely transferred and stored, and relevant study parameters will be harmonized. A 1-stage IPD meta-analysis (IPDMA) will be performed, stratified per centre, assessing PMA effectivity according to the intention-to-treat principle. If a 1-stage IPDMA is not feasible, a 2-step IPDMA will be performed, analysing each RCT separately and pooling outcomes. Results will be published in internationally recognized, peer-reviewed journals. This study protocol was registered under PROSPERO number CRD42022347881. Conclusions Gathering IPD across relevant RCTs and performing an IPDMA on the combined data will help to better establish effectiveness of PMA in preventing IH after open AAA surgery. Secondarily, subgroup analyses will allow identification of patients who will benefit from PMA most.

Subtyping of acute myeloid leukaemia (AML) has made significant progress, exemplified by the recent classification updates by the World Health Organization and International Consensus Classification. AML subclassification is predominantly genetics-based, despite research showing the benefits of transcriptomic profiling on top of known genetic markers. However, a comprehensive survey of subtypes in AML defined by gene expression has yet to be performed. To this end, we integrated mRNAseq data from 1337 patients and five studies, with corresponding biological and clinical data. We defined 19 gene expression-based subtypes, further stratifying AML. We found that KMT2A leukaemias with fusion partners MLLT3, MLLT10 and MLLT1 clustered together, while KMT2A-MLLT4 displayed a distinct gene expression pattern, suggesting differences in their aetiology. We discovered a transcriptional CEBPA subtype, of which only 40% had a CEBPA bZIP indel. Regardless of mutation status, all patients within this CEBPA cluster had the same favourable outcome. We found four NPM1- enriched transcriptomic subtypes, each with distinct co-mutation patterns and associated ex-vivo drug responses. Similarly, we identified nine AML with myelodysplasia-related changes (AML-MRC) subtypes, dividing a subtype making up one-third of the AML patients into novel groups with different outcomes and drug response profiles. In conclusion, we provide an unprecedented overview of the transcriptomic subtypes in AML and illustrate their potential for AML diagnostics.

Pharmacogenomics (PGx)-guided drug treatment is one of the cornerstones of personalized medicine. However, the genes involved in drug response are highly complex and known to carry many (rare) variants. Current technologies (short-read sequencing and SNP panels) are limited in their ability to resolve these genes and characterize all variants. Moreover, these technologies cannot always phase variants to their allele of origin. Recent advance in long-read sequencing technologies have shown promise in resolving these problems. Here we present a long-read sequencing panel-based approach for PGx using PacBio HiFi sequencing.A capture based approach was developed using a custom panel of clinically-relevant pharmacogenes including up- and downstream regions. A total of 27 samples were sequenced and panel accuracy was determined using benchmarking variant calls for 3 Genome in a Bottle samples and GeT-RM star(*)-allele calls for 21 samples..The coverage was uniform for all samples with an average of 94% of bases covered at >30×. When compared to benchmarking results, accuracy was high with an average F1 score of 0.89 for INDELs and 0.98 for SNPs. Phasing was good with an average of 68% the target region phased (compared to ~20% for short-reads) and an average phased haploblock size of 6.6kbp. Using Aldy 4, we compared our variant calls to GeT-RM data for 8 genes (CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, TPMT), and observed highly accurate star(*)-allele calling with 98.2% concordance (165/168 calls), with only one discordance inCYP2C9leading to a different predicted phenotype.We have shown that our long-read panel-based approach results in high accuracy and target phasing for SNVs as well as for clinical star(*)-alleles.

Background Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this “off-hours effect” also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. Methods Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009–2015, EVT: 2014–2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. Results In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7–4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI − 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. Conclusion Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Contains fulltext : 252064.pdf (Publisher’s version ) (Open Access) PURPOSE: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs. MATERIALS AND METHODS: Data from the National-Intensive-Care-Evaluation-registry of COVID-19 patients admitted between February 15th and January 1th 2021 and other viral pneumonia patients admitted between January 1st 2017 and January 1st 2020 were used. Patients' characteristics, the unadjusted, and adjusted in-hospital mortality were compared. RESULTS: 6343 COVID-19 and 2256 other viral pneumonia patients from 79 ICUs were included. The COVID-19 patients included more male (71.3 vs 49.8%), had a higher Body-Mass-Index (28.1 vs 25.5), less comorbidities (42.2 vs 72.7%), and a prolonged hospital length of stay (19 vs 9 days). The COVID-19 patients had a significantly higher crude in-hospital mortality rate (Odds ratio (OR) = 1.80), after adjustment for patient characteristics and ICU occupancy rate the OR was respectively 3.62 and 3.58. CONCLUSION: Higher mortality among COVID-19 patients could not be explained by patient characteristics and higher ICU occupancy rates, indicating that COVID-19 is more severe compared to other viral pneumonia. Our findings confirm earlier warnings of a high need of ICU capacity and high mortality rates among relatively healthy COVID-19 patients as this may lead to a higher mental workload for the staff.

Background Cardiac rehabilitation (CR) has favourable effects on cardiovascular mortality and morbidity. Therefore, it might reasonable to expect that incomplete CR participation will result in suboptimal patient outcomes. Methods We studied the 914 post-acute coronary syndrome patients who participated in the OPTImal CArdiac REhabilitation (OPTICARE) trial. They all started a ‘standard’ CR programme, with physical exercises (group sessions) twice a week for 12 weeks. Incomplete CR was defined as participation in Results A total of 142 (16%) patients had incomplete CR. They had a higher incidence of MACE than their counterparts who completed CR (11.3% versus 3.8%, adjusted hazard ratio [aHR] 2.86 and 95% confidence interval [CI] 1.47–5.26). Furthermore, the incidence of any cardiac event, including MACE and coronary revascularisation, was higher (20.4% versus 11.0%, aHR 1.54; 95% CI 0.98–2.44). Patients with incomplete CR were more often persistent smokers than those who completed CR (31.7% versus 11.5%), but clinical characteristics were similar otherwise. Conclusion Post-ACS patients who did not complete a ‘standard’ 12-week CR programme had a higher incidence of adverse cardiac events during long-term follow-up than those who completed the programme. Since CR is proven beneficial, further research is needed to understand the reasons why patients terminate prematurely.

Patients with subarachnoid hemorrhage (SAH) who are using antiplatelet drugs prior to their hemorrhage, often receive platelet transfusions to reverse antiplatelet effects prior to life-saving surgical interventions. However, little is known about the effect of platelet transfusion on patient outcome in these patients. The aim of this study is to investigate the effect of platelet transfusion on clinical outcome in patients with aneurysmal SAH (aSAH) who use antiplatelet agents. Consecutive adult patients with an aSAH admitted between 2011 and 2015 to the Academic Medical Center (Amsterdam, the Netherlands) were included. Demographic characteristics and in-hospital complications were compared and clinical outcome was assessed after six months. Multivariable logistic regression analysis was performed to correct for confounding variables. A total of 364 patients with an aSAH were included. Thirty-eight (10%) patients underwent platelet transfusion during admission. Patients receiving platelet transfusion had worse clinical outcome (modified Rankin Scale score 4–6) at six months compared to patients without platelet transfusion (65% versus 32%, odds ratio 4.0, 95% confidence interval:1.9–8.1). Multivariable logistic regression analysis showed that platelet transfusion during admission was associated with unfavorable clinical outcome after six months; adjusted for age, treatment modality, modified Fisher and WFNS on admission (adjusted odds ratio 3.3, 95% confidence interval: 1.3–8.4). In this observational study, platelet transfusion was associated with poor clinical outcome at six months after correcting for confounding influences. In aSAH patients who need surgical treatment at low risk of bleeding, the indication for platelet transfusion needs careful weighing of the risk-benefit-balance.

Pediatric patients with myelopathy expressing intradural spinal vascular ectasia without arteriovenous shunting were studied at four tertiary referral neuropediatric centers. Patients were identified by retrospective review of institutional records and excluded if spinal vascular pathology could be classified into a previously described category of spinal vascular malformation. Four patients meeting the study criteria were enrolled in the study. Clinical, magnetic resonance imaging, catheter-directed angiography, laboratory, histological and genetic data were analyzed to characterize the disease process and elucidate underlying pathomechanisms. Our study revealed a highly lethal, progressive multi-segmental myelopathy associated with a unique form of non-inflammatory spinal angiopathy featuring diffuse enlargement and tortuosity of spinal cord arteries, spinal cord hyperemia, and spinal cord edema (Arterioectatic Spinal Angiopathy of Childhood). The condition was shown to mimic venous congestive myelopathy associated with pediatric spinal cord arteriovenous shunts on MRI but to have distinct pathognomonic findings on catheter-directed angiography. Clinicopathological, genetic, and neuroimaging features, which are described in detail, closely overlap with those of mitochondrial disease.

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control., This study presents an anatomical, neurophysiological and functional characterization of four distinct prefrontal populations that project to striatal and thalamic sub-regions. The authors show that each of these populations have a discrete role in the regulation of cognitive control.

Since the discovery of cosmic radiation by Victor Hess in 1912, when he reported a significant increase in radiation as altitude increases, concerns about radiation effects on human bodies and equipment have grown over the years. The secondary and tertiary particles which result from the interaction of primary cosmic rays with atmospheric particles and commercial aircraft components, are the primary cause of the radiation dose deposited in human bodies and in electronic equipment (avionics) during aircraft flights. At an altitude of about 10 km (or higher) above sea level, the dose received by frequent flyers, and especially flight crew, is a serious concern. Also of concern is the possible failure of sensitive equipment on board commercial aircrafts as a result of flying through this mixed radiation field. Monitoring radiation in the atmosphere is therefore very important. Here we report on the first measurements by the High Altitude Radiation Monitor (HARM) detector during a commercial flight from Johannesburg (O.R. Tambo International Airport) to Windhoek (Hosea Kutako International Airport). As part of a public awareness activity, the HARM detector was placed on a high-altitude balloon, and these measurements are also shown here. Model calculations (estimations) of radiation levels for the commercial aircraft flight are shown and the results are used to interpret our measurements. Significance: Measurements of the Regener–Pfotzer maximum in South Africa and dosimetric measurements on board a commercial flight are presented. These radiation measurements are compared to model calculations which can be used to predict the radiation dose during commercial flights. This study also aims to raise public awareness about the atmospheric radiation environment from ground level to the Regener–Pfotzer peak at high altitude.

BackgroundPresence of vertebral corner inflammation (VCI) increases the likelihood of a new syndesmophyte in the same vertebral corner (VC) in patients with r-axSpA. It was suggested that subsequent vertebral corner fat deposition (VCFD) partially explains this effect. However, this has not been formally tested.ObjectivesTo determine how much of the effect of VCI on the development of new syndesmophytes is explained by new VCFD.MethodsTwo datasets (SIAS cohort, ASSERT clinical trial) were analyzed. Patients with r-axSpA were assessed at baseline (T0), an intermediate visit (T1) (SIAS: 1 year; ASSERT: 24 weeks) and the end of follow-up (T2) (SIAS: 2 years; ASSERT: 102 weeks). Syndesmophytes were assessed on whole spine low dose CT (SIAS) or spinal radiographs (ASSERT) at T0 and T2 and considered present if seen by 2 of 2 readers. VCI (T0) and VCFD (T0 and T1) on spinal MRI were present if seen by ≥2 of 3 readers (SIAS) or 2 of 2 readers (ASSERT). VCs with VCFD or a syndesmophyte at baseline were excluded. We used the counterfactual approach1 to decompose the total effect of VCI at T0 (binary exposure) on the formation of a new syndesmophyte in the same VC at T2 (binary outcome) into the effect that is explained (natural indirect effect, NIE) and the effect that is not explained (natural direct effect, NDE) by new VCFD (binary mediator) at T1. Because there was no interaction between the exposure and mediator (p=0.88 for SIAS; p=0.82 for ASSERT), the average NIE (aNIE) and average NDE (aNDE) are reported. The aNIE, aNDE and total effect, expressed as absolute increase in risk, were estimated in R using the ‘mediation’ package, which takes into account the 2-level structure of the data (VCs nested within patients).ResultsIn total, 49 patients (2,667 corners) in SIAS and 168 patients (2,918 corners) in ASSERT were included. A new syndesmophyte occurred at T2 in 124/2,667 (5%) corners in SIAS and 91/2,918 (3%) corners in ASSERT (Table 1). New VCFD at T1 was also uncommon (SIAS: 4%; ASSERT: 2%), but occurred more often in corners with (SIAS: 12%; ASSERT: 18%) than without VCI at T0 (SIAS: 3%; ASSERT: 1%). Applying the mediation formula, in SIAS, the presence of VCI at T0 increased the probability of a new syndesmophyte in the same VC at T2 by 9.3% [total effect (95% CI)=9.3% (4.5; 15.0)]. There was only a 0.2% increase in this probability that was mediated by the formation of new VCFDs at T1 [aNIE=0.2% (-0.4; 1.0)]. In contrast, 9.1% of the increase in probability remained unexplained [aNDE=9.1 (4.3; 15.0)]. This means that only 2% (0.2/9.3) of the total effect of VCI on the formation of new syndesmophytes was explained by new VCFD [% mediated=2.0% (-4.1; 13)]. In ASSERT, the total effect was somewhat lower than in SIAS [total effect=7.3% (2.0; 16.0)], and again the aNIE was small [aNIE=0.8% (-0.2; 3.0)], and the aNDE composed most of the total effect [aNDE=6.5% (1.3; 14.0)]. The proportion of the total effect explained by VCFD (0.8/7.3=10% (-3.1;44)) was larger than in SIAS but still non-significant.Table 1.Marginal and conditional probabilitiesSIASVCI T0New VCFD T1New SYND T2nP (SYND|VCI, VCFD)P(VCFD|VCI)0002302P (SYND|0,0) =90/2392= 0.038P(VCFD|0) = 74/2466=0.0300019001070P (SYND|0,1) =4/74 = 0.0540114100152P (SYND|1,0) = 25/177 = 0.141P(VCFD|1) = 24/201 =0.1191012511019P (SYND|1,1) = 5/24 = 0.2081115ASSERTVCI T0New VCFD T1New SYND T2nP (SYND|VCI, VCFD)P(VCFD|VCI)0002660P (SYND|0,0) = 76/2736= 0.028P(VCFD|0) = 35/2771 =0.0130017601034P (SYND|0,1) =1/35= 0.0290111100112P (SYND|1,0) = 9/121= 0.074P(VCFD|1) = 26/147 =0.177101911021P (SYND|1,1) = 5/26 = 0.1921115VCI, vertebral corner inflammation; VCFD, vertebral corner fat deposition; Synd, syndesmophytes; T0, baseline; T1, intermediate visit; T2, end of follow-up; n, number of vertebral corners; P, probabilityConclusionIn these two datasets we see that VCI only infrequently leads to syndesmophyte formation via visible VCFD.References[1]Pearl, The mediation formula, 2011Figure 1.The pathways under study. VCI, vertebral corner inflammation; VCFD, vertebral corner fat depositionDisclosure of InterestsRosalinde Stal: None declared, Alexandre Sepriano Speakers bureau: Novartis, Consultant of: UCB, Sofia Ramiro Speakers bureau: Eli Lilly, MSD, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB, Sanofi, Grant/research support from: AbbVi, Galapagos, MSD, Novartis, Pfizer, UCB, Floris A. van Gaalen Consultant of: Novartis, MSD, AbbVie, Bristol Myers Squibb, Eli Lilly, Grant/research support from: Stichting vrienden van Sole Mio, Stichting ASAS, Jacobus Stichting, Novartis, UCB, Pedro Machado Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Xenofon Baraliakos: None declared, Rosaline van den Berg: None declared, Monique Reijnierse Grant/research support from: reader for ASAS CLASSIC study, Juergen Braun: None declared, Robert B.M. Landewé Consultant of: AbbVie, Amgen, BMS, GSK, Janssen, Eli Lilly, Novartis, Pfizer, UCB, Désirée van der Heijde Consultant of: AbbVie, Gilead, Glaxo-Smith-Kline, Lilly, Novartis, UCB Pharma, Grant/research support from: Dutch Rheumatism Association

Background And Purpose: In patients with SAH, the amount of blood is strongly associated with clinical outcome. However, it is commonly estimated with a coarse grading scale, potentially limiting its predictive value. Therefore, we aimed to develop and externally validate prediction models for clinical outcome, including quantified blood volumes, as candidate predictors. Materials And Methods: Clinical and radiologic candidate predictors were included in a logistic regression model. Unfavorable outcome was defined as a modified Rankin Scale score of 4-6. An automatic hemorrhage-quantification algorithm calculated the total blood volume. Blood was manually classified as cisternal, intraventricular, or intraparenchymal. The model was selected with bootstrapped backward selection and validated with the R 2, C-statistic, and calibration plots. If total blood volume remained in the final model, its performance was compared with models including location-specific blood volumes or the modified Fisher scale. Results: The total blood volume, neurologic condition, age, aneurysm size, and history of cardiovascular disease remained in the final models after selection. The externally validated predictive accuracy and discriminative power were high (R 2= 56% ± 1.8%; mean C-statistic = 0.89 ± 0.01). The location-specific volume models showed a similar performance (R 2= 56% ± 1%, P=.8; mean C-statistic = 0.89 ± 0.00, P=.4). The modified Fisher models were significantly less accurate (R 2= 45% ± 3%, P < .001; mean C-statistic = 0.85 ± 0.01, P=.03). Conclusions: The total blood volume-based prediction model for clinical outcome in patients with SAH showed a high predictive accuracy, higher than a prediction model including the commonly used modified Fisher scale.

A large European multi-country Salmonella enterica serovar Enteritidis outbreak associated with Polish eggs was characterized by whole-genome sequencing (WGS)-based analysis, with various European institutes using different analysis workflows to identify isolates potentially related to the outbreak. The objective of our study was to compare the output of six of these different typing workflows (distance matrices of either SNP-based or allele-based workflows) in terms of cluster detection and concordance. To this end, we analysed a set of 180 isolates coming from confirmed and probable outbreak cases, which were representative of the genetic variation within the outbreak, supplemented with 22 unrelated contemporaneous S . enterica serovar Enteritidis isolates. Since the definition of a cluster cut-off based on genetic distance requires prior knowledge on the evolutionary processes that govern the bacterial populations in question, we used a variety of hierarchical clustering methods (single, average and complete) and selected the optimal number of clusters based on the consensus of the silhouette, Dunn2, and McClain–Rao internal validation indices. External validation was done by calculating the concordance with the WGS-based case definition (SNP-address) for this outbreak using the Fowlkes–Mallows index. Our analysis indicates that with complete-linkage hierarchical clustering combined with the optimal number of clusters, as defined by three internal validity indices, the six different allele- and SNP-based typing workflows generate clusters with similar compositions. Furthermore, we show that even in the absence of coordinated typing procedures, but by using an unsupervised machine learning methodology for cluster delineation, the various workflows that are currently in use by six European public-health authorities can identify concordant clusters of genetically related S . enterica serovar Enteritidis isolates; thus, providing public-health researchers with comparable tools for detection of infectious-disease outbreaks.

SUMMARYStem-cell derived in vitro systems, such as organoids or embryoids, hold great potential for modeling in vivo biology and engineering living systems with novel functions. To unlock that potential, we need new ways to elicit higher-level organization. Here we show that adding extraembryonic endoderm (XEN) cells to mouse gastruloids leads to the formation of neural epithelia. By single-cell RNA-seq, imaging and differentiation experiments, we demonstrate the neural characteristics and spatial patterning of the epithelial tissue. We further show that the XEN cells differentiate reciprocally to a visceral endoderm-like state. Finally, we demonstrate that local inhibition of WNT signaling and production of a basement membrane by the XEN cells underlie the formation of the neuroepithelial tissue. In summary, we establish “XEN Enhanced Gastruloids” (XEGs) to explore heterotypic cellular interactions as a means to achieve complex, tissue-level organization in vitro.

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARγ), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARγ expression, and determine RARγ regulatory mechanisms.RARGshRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARγ levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARγ cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARγ to regulate androgen signaling, RARγ knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARγ down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARγ expression and function Capture of the miR-96 targetome by biotin-miR96 identified that RARγ and a number of RARγ interacting co-factors includingTACC1were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels ofRARGandTACC1and upper quartile miR-96, compared to the reverse, identified a gene network including several RARγ target genes (e.g.SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARγ network to govern AR signaling, PCa progression and disease outcome.Conflict of interest:The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.FUNDINGLESCacknowledges support, in part, of Roswell Park Comprehensive Cancer Center-University of Pittsburg Cancer Institute Ovarian Cancer Specialized Program of Research Excellence National Institutes of Health [P50CA159981-01A1].MDLacknowledges support of Molecular Pharmacology and Experimental Therapeutics NRSA T32 program [T32CA009072] held at Roswell Park Comprehensive Cancer Center.MJCandDJSacknowledges support in part from the Prostate program of the Department of Defense Congressionally Directed Medical Research Programs [W81XWH-14-1-0608, W81XWH-11-2-0033] and the National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Genomic Shared Resource.MJC, GL, AR, HWandPvdBacknowledges support from the European Union-United States Atlantis Program [P116J090011].MJCandLESCacknowledge support from the National Cancer Institute (NCI) grant P30CA016056 involving the use of OSUCCC The James, CCSG P30CA016058

PURPOSE: To study whether clinical outcome data from our patient cohort could give support to the new recommendation in the AHA/ASA guidelines for the management of aneurysmal subarachnoid hemorrhage that states "that microsurgical clipping may receive increased consideration in patients with ruptured middle cerebral artery (MCA) aneurysms and large (>50 mL) intraparenchymal hematomas", while clinical outcome data supporting this recommendation are sparse.METHODS: We reviewed the clinical and radiological data of 81 consecutive patients with MCA aneurysms and concomitant hematomas admitted between January 2006 and December 2015. The relation between (semi-automatically quantified) hematoma volume (< or > 50 ml), neurological condition on admission (poor: GCS RESULTS: Clinical outcome data were available for 76 patients. A significant difference in favorable outcome (17 vs 68%) was seen when comparing patients with poor and good neurological condition on admission (p 50 ml had similar outcomes for coiling and clipping, all underwent decompression. Patients with hematomas CONCLUSION: Poor neurological condition on admission, and not large intraparenchymal hematoma volume, was associated with poor clinical outcome. Therefore, even in patients with large hematomas, the neurological condition on admission and the aneurysm configuration seem to be equally important factors to determine the most appropriate treatment strategy.

Objectives Rapid diagnostic tests targeting virus-specific antigen could significantly enhance the diagnostic capacity for chikungunya virus infections. We evaluated the accuracy of an immunochromatographic antigen test for diagnosis of chikungunya in a reference laboratory for arboviruses. Methods An immunochromatographic rapid test that uses mouse monoclonal antibodies as a tracer against the E1-envelope protein of chikungunya (ARKRAY, Inc. Kyoto, Japan) was evaluated. Sensitivity was tested in sera from travellers with RT-PCR confirmed chikungunya virus infection (Eastern/Central/Southern African (ECSA) genotype) ( n =9) and from patients diagnosed during the 2014-2015 chikungunya outbreak on Aruba (Asian genotype, n =30). Samples from patients with other febrile and non-febrile illnesses ( n =26), sera spiked with Flavivirus and Alphavirus reference strains ( n =13, including non-spiked serum), and samples containing other selected pathogens ( n =20) were used to test specificity of the E1-antigen test. Results Sensitivity of the E1-antigen test was 8/9 (88.9%, 95% CI 56.5–98.0) for the ECSA genotype, but only 10/30 (33.3%, 95% CI 19.2-51.2) for the Asian genotype. Overall diagnostic specificity was 49/59 (83.1%, 95% CI 71.5-90.5). Conclusions The E1-antigen test we evaluated had fair diagnostic sensitivity for ECSA genotype chikungunya, but low sensitivity for Asian genotype, and poor overall specificity. Antibodies that react across genotypes will be required for further development of a rapid test for chikungunya. Performance of new tests should be evaluated against different chikungunya genotypes.

BACKGROUND CONTEXT About 85% of the patients with low back pain seeking medical care have nonspecific low back pain (NsLBP), implying that no definitive cause can be identified. Nonspecific low back pain is defined as low back pain and disability which cannot be linked to an underlying pathology, such as cancer, spinal osteomyelitis, fracture, spinal stenosis, cauda equine, ankylosing spondylitis, and visceral-referred pain. Many pain conditions are linked with elevated serum levels of pro-inflammatory biomarkers. Outcomes of interest are NsLBP and the level of pro-inflammatory biomarkers. PURPOSE To unravel the etiology and get better insight in the prognosis of NsLBP, the aim of this study was to assess the association between pro-inflammatory biomarkers and the presence and severity of NsLBP. STUDY DESIGN A systematic literature search was made in Embase, Medline, Cinahl, Webof-science, and Google scholar up to January 19th 2017. METHODS Included were cross-sectional and cohort studies reporting on patients aged over 18 years with NsLBP, in which one or more pro-inflammatory biomarkers were measured in blood plasma. The methodological quality of the included studies was assessed using the Newcastle Ottawa Scale. A best-evidence synthesis was used to summarize the results from the individual studies, meaning that the included studies were ranked according to the consistency of the findings and according to their methodological quality score using the Newcastle Ottawa Scale. RESULTS Included were 10 studies which assessed four different pro-inflammatory biomarkers. For the association between the presence of NsLBP and C-reactive protein (CRP), interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α limited, conflicting and moderate evidence, respectively, was found. For the association between the severity of NsLBP and CRP and IL-6, moderate evidence was found. For the association between the severity of NsLBP and TNF-α and RANTES Regulated on Activation, Normal T Cell Expressed and Secreted conflicting and limited evidence, respectively, was found. CONCLUSIONS This study found moderate evidence for (i) a positive association between the pro-inflammatory biomarkers CRP and IL-6 and the severity of NsLBP, and (ii) a positive association between TNF-α and the presence of NsLBP. Conflicting and limited evidence was found for the association between TNF-α and Regulated on Activation, Normal T Cell Expressed and Secreted and severity of NsLBP, respectively.

SummaryObjective The objective of this study is to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) for improvements in body composition in overweight and obese adults. Methods Trials comparing HIIT and MICT in overweight or obese participants aged 18–45 years were included. Direct measures (e.g. whole-body fat mass) and indirect measures (e.g. waist circumference) were examined. Results From 1,334 articles initially screened, 13 were included. Studies averaged 10 weeks × 3 sessions per week training. Both HIIT and MICT elicited significant (p

Song et al. used an allelic reporter approach to show super-enhancers allelic DNA methylation dynamics underlies locus-specific heterogeneity, which functionally impacts transcription and cellular states of mouse embryonic stem cells., NIH (Grants HD045022, 1U19AI131135, 5R01MH104610, and 1R01GM114864)

BACKGROUND AND PURPOSE Aneurysm hemodynamics play an important role in aneurysm growth and subsequent rupture. Within the available hemodynamic characteristics, particle residence time (PRT) is relatively unexplored. However, some studies have shown that PRT is related to thrombus formation and inflammation. The goal of this study is to evaluate the association between PRT and aneurysm rupture and morphology. METHODS We determined the PRT for 113 aneurysms (61 unruptured, 53 ruptured) based on computational fluid dynamic models. Virtual particles were injected into the parent vessel and followed during multiple cardiac cycles. PRT was defined as the time needed for 99% of the particles that entered an aneurysm to leave the aneurysm. Subsequently, we evaluated the association between PRT, rupture, and morphology (aneurysm type, presence of blebs, or multiple lobulations). RESULTS PRT showed no significant difference between unruptured (1.1 seconds interquartile range [IQR .39‐2.0 seconds]) and ruptured aneurysms (1.2 seconds [IQR .47‐2.3 seconds]). PRT was influenced by aneurysm morphology. Longer PRTs were seen in bifurcation aneurysms (1.3 seconds [IQR .54‐2.4 seconds], P = .01) and aneurysms with blebs or multiple lobulations (1.92 seconds [IQR .94‐2.8 seconds], P < .001). Four of five partially thrombosed aneurysms had a long residence time (>1.9 seconds). CONCLUSIONS Our study shows an influence of aneurysm morphology on PRT. Nevertheless, it suggests that PRT cannot be used to differentiate unruptured and ruptured aneurysms.

Multidrug-resistant Salmonella enterica serovar Heidelberg isolates are frequently recovered in the Netherlands from poultry meat imported from South America. Our aim was to retrospectively assess the characteristics of the antimicrobial determinants, gene content and the clonal relatedness of 122 unique S. Heidelberg isolates from chicken meat from Brazil (n = 119) and Argentina (n = 3) that were imported between 2010 and 2015. These isolates were subjected to antimicrobial susceptibility testing, PCR and Illumina HiSeq2500 whole genome sequencing. Draft genomes were assembled to assess the gene content, and the phylogenetic relationships between isolates were determined using single nucleotide polymorphisms. Ciprofloxacin-resistance was identified in 98.4% of the isolates and 83.7% isolates showed resistance to the extended-spectrum cephalosporins cefotaxime and ceftazidime (83.6% and 82.8% respectively). Of the latter, 97.1% exhibited an AmpC phenotype and contained blaCMY-2, whereas the remaining three isolates contained an extended spectrum beta-lactamase. Of the 99 extended-spectrum cephalosporins-resistant isolates harboring CMY-2 plasmids, 56.6% contained the incompatibility group I1 replicon. Phylogenetic cluster analysis showed that all isolates from Brazil clustered together, with 49% occurring in clusters larger than 5 isolates that revealed intra-cluster similarities based on geographical location and/or resistance profiles. The remaining isolates were classified in smaller clusters or as singletons, highlighting the large diversity of S. Heidelberg in the poultry chain in Brazil that was revealed by this study. Considering the potential public health risk associated with multidrug-resistant S. Heidelberg in imported poultry, collaborative whole genome sequencing-based surveillance is needed to monitor the spread, pathogenic properties and epidemiological distribution of these isolates.

The current understanding of mammalian kidney development is largely based on mouse models. Recent landmark studies revealed pervasive differences in renal embryogenesis between mouse and human. The scarcity of detailed gene expression data in humans therefore hampers a thorough understanding of human kidney development and the possible developmental origin of kidney diseases. In this paper, we present a single-cell transcriptomics study of the human fetal kidney. We identified 22 cell types and a host of marker genes. Comparison of samples from different developmental ages revealed continuous gene expression changes in podocytes. To demonstrate the usefulness of our data set, we explored the heterogeneity of the nephrogenic niche, localized podocyte precursors, and confirmed disease-associated marker genes. With close to 18,000 renal cells from five different developmental ages, this study provides a rich resource for the elucidation of human kidney development, easily accessible through an interactive web application., A detailed transcriptomic characterization of the human fetal kidney at the single-cell level allows the identification of 22 cell types and a host of novel marker genes, revealing heterogeneity in the nephrogenic niche and localized podocyte precursors., Author summary Regenerative medicine offers an exciting avenue to potential cures of kidney disease. However, a detailed knowledge of the structure and embryonic development of the kidney is crucial, both for stimulating regeneration in the body and for growing healthy kidney tissue in a dish. Most of such knowledge has been obtained from mice, whose development differs in crucial ways from that of humans. We therefore studied the composition of human fetal kidney tissue from five developmental ages, using a technique that can measure gene expression in individual cells. Our measurements revealed 22 distinguishable cell types, some of which we localized in the tissue by fluorescence microscopy. We found several subpopulations of nephron progenitors—cells that give rise to the nephron, the functional unit of the kidney. Our study also focused on the development of podocytes, a cell type that is crucial for the filtration function of the kidney, and our results might inform attempts to recreate these cells in a dish. We hope that our data set, made conveniently accessible through a web application, will help scientists develop new regenerative medicine approaches to kidney disease.

Supraphysiological doses of biotin are being tested in patients with multiple sclerosis. Biotin can cause interference with laboratory assessment of thyroid function, and therefore give a false suggestion of thyrotoxicosis.A 64-year-old patient was referred for assessment of thyrotoxicosis, due to Graves' disease. Antithyroid medication was started, but there was no effect on laboratory results. In addition, he developed symptoms which subsequently could be attributed to iatrogenic hypothyroidism. Biotin interference, when assaying TSH and thyroxin, was suspected. Upon further investigation, the patient revealed to use high doses of biotin. After discontinuation of the biotin treatment, the thyroid function test normalized.It is expected that in the future, patients with multiple sclerosis will use biotin more often. Therefore, it is important for healthcare professionals to be aware that biotin can interfere with immunoassays for thyroid hormones, to avoid misdiagnosis and unnecessary treatment for hyperthyroidism.

Background:In radiographic axial spondyloarthritis (r-axSpA), spinal damage manifests as syndesmophytes and facet joint ankylosis (FJA).Objectives:Explore whether syndesmophytes and FJA seem to have a preferential order of development.Methods:Data were used from the Sensitive Imaging in Ankylosing Spondylitis cohort from Leiden and Herne. Patients underwent low-dose Computed Tomography (ldCT) at baseline and two-years. LdCT images were scored independently by two trained readers. Vertebrae were scored according to the Computed Tomography Syndesmophyte Score (CTSS) for presence and size of syndesmophytes; facet joints were scored as not-ankylosed and ankylosed. Analyses were performed on the vertebral unit (VU) level and using individual-reader data (Figure 1). Two hypotheses were tested: 1) presence of bridging syndesmophyte(s) is associated with FJA on the same VU two years later, and 2) presence of FJA is associated with syndesmophyte(s) on the same VU two years later. Generalized Estimating Equations (GEE) models were used to take into account the correlations between VUs from the same patient and adjusting for reader to account for individual reader scores. Two models were tested per hypothesis using different outcomes. Model 1 uses the presence of syndesmophytes or FJA as outcome adjusting for the outcome at baseline. Model 2 uses development of new syndesmophytes or FJA at two years plus an increase in the number of syndesmophytes or FJA.Results:In total, 50 patients were included (mean age 49, 84% male, 82% HLA-B27+). At baseline, there was a higher percentage of bridging syndesmophytes (range: 10-60%) than FJA (range: 8-36%) considering all VUs and both readers (Figure 1). In both models, presence of bridging syndesmophytes was associated with development of FJA two years later (OR (95%CI) Model 1: 3.35 (2.18-5.14); Model 2: 2.23 (1.19-4.16)) while presence of FJA at baseline did not have a statistically significant association with development of syndesmophytes two years later (Table 1).Conclusion:The data showed a higher occurrence of bridging syndesmophytes than FJA at baseline and showed significantly increased odds to develop FJA when bridging syndesmophyte(s) are present on the same VU two years prior. This mechanism did not hold true for the other direction. These results cautiously imply that bridging syndesmophytes precede FJA, rather than FJA preceding syndesmophytes.Figure 1.Percentage of occurrence of syndesmophytes and facet joint ankylosis per vertebral unit and per reader at baseline.Figure 1 displaying percentages of patients with a bridging syndesmophyte and with facet joint ankylosis at baseline, per reader. The image on the left illustrates the vertebral unit level (VU) at which analyses were performed. Seven VUs are illustrated in dashed boxes as example. Synd, syndesmophyte; FJA, facet joint ankylosis; BL, baseline.Table 1.Associations between facet joint ankylosis and syndesmophytesModel 1: development of new FJA/syndesmophytes at FUOR (95% CI)Model 2: development and/or increase FJA/syndesmophytes at FUOR (95% CI)Hypothesis 1Presence bridging syndesmophytes at BL on development of FJA at FU3.35 (2.18-5.14)2.23 (1.19-4.16)Hypothesis 2Presence FJA at BL on development of syndesmophytes at FU1.60 (0.88-2.91)1.12 (0.76-1.66)Disclosure of Interests:None declared.