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Abstract Predictors of rebound after correction of coronal plane deformities using temporary hemiepiphysiodesis (TH) are not well defined. The following research questions were tested: (1) Is the dynamic knee joint load useful to improve rebound prediction accuracy? (2) Does a large initial deformity play a critical role in rebound development? (3) Are BMI and a young age risk factors for rebound? Fifty children and adolescents with idiopathic knee valgus malalignment were included. A deviation of the mechanical femorotibial angle (MFA) of ≥ 3° into valgus between explantation and the one-year follow-up period was chosen to classify a rebound. A rebound was detected in 22 of the 50 patients (44%). Two predictors of rebound were identified: 1. reduced peak lateral knee joint contact force in the first half of the stance phase at the time of explantation (72.7% prediction); 2. minor initial deformity according to the MFA (70.5% prediction). The best prediction (75%) was obtained by including both parameters in the binary logistic regression method. A TH should not be advised in patients with a minor initial deformity of the leg axis. Dynamic knee joint loading using gait analysis and musculoskeletal modeling can be used to determine the optimum time to remove the plates.

Abstract Background Pregnancy is characterized by profound circulatory changes and compensatory adjustments in the renin-angiotensin-aldosterone system (RAAS). Differences in regulatory response may antedate or accompany vascular complicated pregnancy. We performed a systematic review and meta-analysis to delineate the trajectory of active plasma renin concentration (APRC) in healthy pregnancy and compare this to complicated pregnancy. Methods We performed a systematic review and meta-analysis on APRC during normotensive and hypertensive pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. We included only studies reporting measurements during pregnancy together with a nonpregnant reference group measurement. Risk of bias was assessed with QUIPS. Ratio of the mean (ROM) and 95% confidence intervals (CI) of APRC values between pregnant and nonpregnant women were estimated for predefined intervals of gestational age using a random-effects model. Meta-regression was used to analyze APRC over time. Results In total, we included 18 studies. As compared to nonpregnant, APRC significantly increased as early as the first weeks of healthy pregnancy and stayed increased throughout the whole pregnancy (ROM 2.77; 95% CI 2.26–3.39). APRC in hypertensive complicated pregnancy was not significantly different from nonpregnancy (ROM 1.32; 95% CI 0.97–1.80). Conclusion Healthy pregnancy is accompanied by a profound rise in APRC in the first trimester that is maintained until term. In hypertensive complicated pregnancy, this increase in APRC is not observed.

Introduction Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage.Methods and analysis We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at

Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.

Abstract Background Developmental Dysplasia of the Hip (DDH) is one of the most common pediatric orthopedic disorders, affecting 1–3% of all newborns. The optimal treatment of centered DDH is currently under debate. This randomized controlled trial aims to study the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH. Methods This is a multicenter, parallel-group, open-label, non-inferiority randomized controlled trial studying the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH in fourteen hospitals in the Netherlands. In total, 800 infants with centered DDH (Graf IIa-/IIb/IIc), aged 10–16 weeks, will be randomly allocated to the active monitoring or abduction treatment group. Infants will be followed up until the age of 24 months. The primary outcome is the rate of normal hips, defined as an acetabular index lower than 25 degrees on an antero-posterior radiograph, at the age of 12 months. Secondary outcomes are the rate of normal hips at the age of 24 months, complications, time to hip normalization, the relation between baseline patient characteristics and the rate of normal hips, compliance, costs, cost-effectiveness, budget impact, health-related quality of life (HRQoL) of the infant, HRQoL of the parents/caregivers, and parent/caregiver satisfaction with the treatment protocol. Discussion The outcomes of this randomized controlled trial will contribute to improving current care-as-usual for infants with centered DDH. Trial registration Dutch Trial Register, NL9714, registered September 6, 2021. https://clinicaltrialregister.nl/en/trial/29596

Spatiotemporal spike-centered averaging (st-SCA) allows for the visualization of spike-local field potential relationships across both temporal and spatial domains from microelectrode array recordings.

Abstract Compressive knee joint contact force during walking is thought to be related to initiation and progression of knee osteoarthritis. However, joint loading is often evaluated with surrogate measures, like the external knee adduction moment, due to the complexity of computing joint contact forces. Statistical models have shown promising correlations between medial knee joint contact forces and knee adduction moments in particularly in individuals with knee osteoarthritis or after total knee replacements (R 2 = 0.44–0.60). The purpose of this study was to evaluate how accurately model-based predictions of peak medial and lateral knee joint contact forces during walking could be estimated by linear mixed-effects models including joint moments for children and adolescents with and without valgus malalignment. Peak knee joint moments were strongly correlated (R 2 > 0.85, p

Iatrogenic preterm premature rupture of fetal membranes (iPPROM) after fetal surgery remains a strong trigger for premature birth. As fetal membrane defects do not heal spontaneously and amniotic fluid leakage and chorioamniotic membrane separation may occur, we developed a biocompatible, fetoscopically-applicable collagen plug with shape memory to prevent leakage. This plug expands directly upon employment and seals fetal membranes, hence preventing amniotic fluid leakage and potentially iPPROM.Lyophilized type I collagen plugs were given shape memory and crimped to fit through a fetoscopic cannula (Ø 3 mm). Expansion of the plug was examined in phosphate buffered saline (PBS). Its sealing capacity was studied ex vivo using human fetal membranes, and in situ in a porcine bladder model.The crimped plug with shape memory expanded and tripled in diameter within 1 min when placed into PBS, whereas a crimped plug without shape memory did not. In both human fetal membranes and porcine bladder, the plug expanded in the defect, secured itself and sealed the defect without membrane rupture.In conclusion, collagen plugs with shape memory are promising as medical device for rapid sealing of fetoscopic defects in fetal membranes at the endoscopic entry point.

Abstract Neuroscientific analyses balance between capturing the brain’s complexity and expressing that complexity in meaningful and understandable ways. Here we present a novel approach that fully characterizes neural network activity and does so by uniquely transforming raw signals into easily interpretable and biologically relevant metrics of network behavior. We first prove that third-order (triple) correlation describes network activity in its entirety using the triple correlation uniqueness theorem. Triple correlation quantifies the relationships among three events separated by spatial and temporal lags, which are triplet motifs. Classifying these motifs by their event sequencing leads to fourteen qualitatively distinct motif classes that embody well-studied network behaviors including synchrony, feedback, feedforward, convergence, and divergence. Within these motif classes, the summed triple correlations provide novel metrics of network behavior, as well as being inclusive of commonly used analyses. We demonstrate the power of this approach on a range of networks with increasingly obscured signals, from ideal noiseless simulations to noisy experimental data. This approach can be easily applied to any recording modality, so existing neural datasets are ripe for reanalysis. Triple correlation is an accessible signal processing tool with a solid theoretical foundation capable of revealing previously elusive information within recordings of neural networks.

This study aimed to evaluate the effectiveness of glasses that emit blue light in reducing the need for recovery, general fatigue, and stress levels in security guards who work night shifts. Light manipulation is seen as a promising strategy to mitigate complaints related to shift work, such as sleepiness and impaired cognitive performance. In a randomized controlled cross-over study design, 86 Dutch security guards used light-emitting glasses (exposure duration: 30 min) during night shifts in a five week period versus a five week control period without glasses. Measurements (Need for Recovery Scale; Checklist Individual Strength; stress level assessed by a fitness tracker) were performed at baseline, at five weeks, and again at 11 weeks. The chronotype was measured at baseline as a potential covariate. A mixed model for repeated measure analyses showed no significant reduction in the need for recovery, nor a reduction in general fatigue scores, during the intervention period. Paired Samples T-Test analyses showed no significant changes in stress levels for the intervention period. Conclusively, blue light exposure using light-emitting glasses for security guards during night shifts showed no directly measurable effect on the reduced need for recovery, overall fatigue, and stress levels.

Marleen MHJ van Gelder,1 Pim Beekers,1,2 Yrea RJ van Rijt-Weetink,3 Joris van Drongelen,4 Nel Roeleveld,1 Luc JM Smits5 1Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 2National Health Care Institute, Diemen, the Netherlands; 3Netherlands Pharmacovigilance Centre Lareb,‘s-Hertogenbosch, the Netherlands; 4Department of Obstetrics & Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands; 5Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, the NetherlandsCorrespondence: Marleen MHJ van Gelder, Department for Health Evidence (HP 133), Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, the Netherlands, Tel +31 24 3615305, Fax +31 24 3613505, Email Marleen.vanGelder@radboudumc.nlPurpose: Preeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥ 34 weeks of gestation), taking into account dosage and timing of use.Patients and Methods: We included 9058 pregnant women participating in the PRIDE Study (2012– 2019) or The Dutch Pregnancy Drug Register (2014– 2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237.Results: Late-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9– 1.6]) or PPIs (RR 1.4 [95% CI 0.8– 2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0– 16 (< 1 g/day; RR 1.8 [95% CI 1.1– 2.9]) and any use of PPIs in gestational weeks 17– 33 (RR 1.6 [95% CI 1.0– 2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6– 1.5]) and PPIs (HR 1.4 [95% CI 0.7– 2.9]) after gestational day 237.Conclusion: In this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia.Keywords: extended Cox models, gestational hypertension, gastroesophageal reflux disease, longitudinal clustering methods, PRIDE study, The Dutch Pregnancy Drug Register

Abstract Infraslow activity (ISA) is a biomarker that has recently become of interest in the characterization of seizure recordings. Recent data from a small number of studies have suggested that the epileptogenic zone may be identified by the presence of ISA. Investigation of low frequency activity in clinical seizure recordings, however, has been hampered by technical limitations. EEG systems necessarily include a high-pass filter early in the measurement chain to remove large artifactual drifts that can saturate recording elements such as the amplifier. This filter, unfortunately, attenuates legitimately seizure-related low frequencies, making ISA difficult to study in clinical EEG recordings. In this study, we present a deconvolution-based digital inverse filter that allows recovery of attenuated low frequency activity in intracranial recordings of temporal lobe epilepsy patients. First, we show that the unit impulse response (UIR) of an EEG system can be characterized by differentiation of the system’s step response. As proof of method, we present several examples that show that the low frequency component of a high-pass filtered signal can be restored by deconvolution with the UIR. We then demonstrate that this method can be applied to biologically relevant signals including clinical EEG recordings obtained from seizure patients. Finally, we discuss how this method can be applied to study ISA to identify and assess the seizure onset zone.

In the presence of IFN-γ, a short DRB1*03:01-encoded allelic epitope is found to activate a characteristic lupus transcriptome in macrophages and trigger a cascade of systemic lupus erythematosus-associated cellular aberrations.

Introduction: Correction of knee malalignment by guided growth using a tension-band plate is a common therapy to prevent knee osteoarthritis among other things. This approach is based on the Hueter-Volkmann law stating that the length growth of bones is inhibited by compression and stimulated by tension. How the locally varying mechanical loading of the growth plate is influenced by the implant has not yet been investigated. This study combines load cases from the gait cycle with personalized geometry in order to investigate the mechanical influence of the tension-band plates.Methods: Personalized finite element models of four distal femoral epiphyses of three individuals, that had undergone guided growth, were generated. Load cases from the gait cycles and musculoskeletal modelling were simulated with and without implant. Morphological features of the growth plates were obtained from radiographs. 3D geometries were completed using non-individual Magnetic Resonance Images of age-matched individuals. Boundary conditions for the models were obtained from instrumented gait analyses.Results: The stress distribution in the growth plate was heterogenous and depended on the geometry. In the insertion region, the implants locally induced static stress and reduced the cyclic loading and unloading. Both factors that reduce the growth rate. On the contralateral side of the growth plate, increased tension stress was observed, which stimulates growth.Discussion: Personalized finite element models are able to estimate the changes of local static and cyclic loading of the growth plate induced by the implant. In future, this knowledge can help to better control growth modulation and avoid the return of the malalignment after the treatment. However, this requires models that are completely participant-specific in terms of load cases and 3D geometry.

Osteoarthritis of the hip is a common condition that affects older adults. Total hip replacement is the end-stage treatment to relief pain and improve joint function. Little is known about the mechanical load distribution during the activity of bipedal stance, which is an important daily activity for older adults who need to rest more frequently. This study investigated the distribution of the hip and knee joint moments during bipedal stance in patients with unilateral hip osteoarthritis and how the distribution changed 1 year after total hip replacement. Kinematic and kinetic data from bipedal stance were recorded. External hip and knee adduction moments were calculated and load distribution over both limbs was calculated using the symmetry angle. Preoperatively, the non-affected limb carried 10% more body weight than the affected limb when standing on two legs. Moreover, the mean external hip and knee adduction moments of the non-affected limb were increased compared to the affected limb. At follow-up no significant differences were observed between the patients’ limbs. Preoperative and postoperative changes in hip adduction moment were mainly explained by the combination of the vertical ground reaction force and the hip adduction angle. Stance width also explained changes in the hip and knee adduction moments of the affected leg. Furthermore, as with walking, bipedal standing also showed an asymmetric mechanical load distribution in patients with unilateral hip osteoarthritis. Overall, the findings suggest the need for preventive therapy concepts that focus not only on walking but also on optimizing stance towards a balanced load distribution of both legs.

Abstract Background Twin reversed arterial perfusion sequence is a rare complication of monochorionic multifetal pregnancies. In this syndrome, the acardiac twin has a nonfunctional heart, while the other twin, the pump twin, has normal development. The pump twin perfuses the acardiac twin and is therefore at risk for cardiac decompensation. In monoamniotic cases, the normal co-twin is also at risk of sudden death due to cord entanglement. Treatment consists of coagulation and transection of the acardiac’s umbilical cord. We report the first intrauterine use in pregnancy of a Ho:yttrium aluminum garnet laser to safely and successfully transect the umbilical cord after Nd:yttrium aluminum garnet coagulation. Case presentation A 30-year-old Caucasian woman was referred to our fetal–maternal medicine unit at 9 weeks gestation with a monochorionic–monoamniotic twin pregnancy complicated by an acardiac twin. After counseling, she opted for an elective intervention to minimize the risks to the pump twin. At 16 weeks, fetoscopy was performed using a single 2-mm entry port. Through this port, a 1.0-mm fetoscope and a 0.365-mm laser fiber were introduced. Under fetoscopic sight and ultrasound (Doppler) guidance, the umbilical cord of the acardiac twin was first coagulated by laser energy using a Nd:yttrium aluminum garnet laser and then, using the same fiber, transected using a Ho:yttrium aluminum garnet laser. The patient underwent cesarean section at 38 weeks and delivered a healthy baby. Conclusions We present the first report on intrauterine use of an Ho:yttrium aluminum garnet laser in human pregnancy. Ho:yttrium aluminum garnet laser energy can be successfully and safely used for umbilical cord transection and carries fewer risks than other methods of transection.

Objective: To evaluate the diagnostic yield of exome sequencing (ES) in fetuses and neonates with prenatally detected congenital diaphragmatic hernia (CDH) and normal copy number variant (CNV) analysis. Methods: We conducted a retrospective cohort study of prenatally diagnosed CDH cases seen between 2019 and 2022. All cases who underwent prenatal or postnatal genetic testing were reviewed. The results from the ES analysis that identified pathogenic or likely pathogenic single nucleotide variants are described. Results: In total, 133 fetuses with CDH were seen, of whom 98 (74%) had an isolated CDH and 35 (26%) had a complex CDH (associated structural anomalies) on prenatal examination. ES was performed in 68 cases, and eight pathogenic or likely pathogenic variants were found, accounting for a 12% diagnostic yield (10% [5/50] in isolated cases and 17% [3/18] in complex CDH). Conclusions: In 12% of fetuses and neonates with CDH and normal CNV analysis results, pathogenic or likely pathogenic variants were identified with ES. These data indicate that there is a substantial diagnostic yield when offering ES in prenatally detected CDH, both in complex and isolated cases. Key points: What's already known about this topic? More than 100 syndromes are reportedly associated with congenital diaphragmatic hernia (CDH) that impact the prognosis of survival and long‐term morbidity.In the prenatal setting, advances in genetic testing have made routine implementation of exome sequencing (ES) possible to identify monogenic disorders. What does this study add? This is the first study performed in a clinical setting describing the added diagnostic yield of ES in prenatally isolated CDH or complex CDH (associated structural anomalies).In 10% of isolated CDH cases and 17% of complex CDH cases, we observed pathogenic or likely pathogenic single nucleotide variants.These findings support the broader use of ES in CDH, even in fetuses or neonates with CDH as an apparently isolated anomaly. [ABSTRACT FROM AUTHOR]

We report on nanoscale order-disorder transitions of hard segments and their domains composed of 4,4′-methylenebis(phenyl isocyanate) - 1,4-butanediol (MDI-BD), in polycaprolactone-based (Mn = 2000 g/mol) polyurethanes (PCL-PUs), when the free surface is pre-oriented by cryo-microtoming of the material. Morphological variations of the hard domains as a function of temperature and the anisotropy of surface morphology features are captured by employing Atomic Force Microscopy (AFM) stiffness imaging by PeakForce Quantitative Nanomechanical Mapping (PF-QNM). The AFM imaging is supported by WAXS, SAXS, FTIR, and DSC measurements. The experimental results show that hard domains initially grown at the surface break apart at elevated temperatures (65 °C) and cannot be re-grown upon cooling. They require new microtoming to repeat the growth scenario. The detailed step-by-step submicron scale observations of the surfaces serve to show importance of the influence that microtoming and the time after its completion have on surface morphology, and that these shall be considered when studying polymer materials microscopically.