Improved inference for MCP-Mod approach using time-to-event endpoints with small sample sizes.

The Multiple Comparison Procedures with Modeling Techniques (MCP-Mod) framework has been recently approved by the U.S. Food, Administration, and European Medicines Agency as fit-for-purpose for phase II studies. Nonetheless, this approach relies on the asymptotic properties of Maximum Likelihood (ML) estimators, which might not be reasonable for small sample sizes. In this paper, we derived improved ML estimators and correction for their covariance matrices in the censored Weibull regression model based on the corrective and preventive approaches. We performed two simulation studies to evaluate ML and improved ML estimators with their covariance matrices in (i) a regression framework (ii) the Multiple Comparison Procedures with Modeling Techniques framework. We have shown that improved ML estimators are less biased than ML estimators yielding Wald-type statistics that controls type I error without loss of power in both frameworks. Therefore, we recommend the use of improved ML estimators in the MCP-Mod approach to control type I error at nominal value for sample sizes ranging from 5 to 25 subjects per dose.

A Novel Functional Electrical Stimulation-Induced Cycling Controller Using Reinforcement Learning to Optimize Online Muscle Activation Pattern.

This study introduces a novel controller based on a Reinforcement Learning (RL) algorithm for real-time adaptation of the stimulation pattern during FES-cycling. Core to our approach is the introduction of an RL agent that interacts with the cycling environment and learns through trial and error how to modulate the electrical charge applied to the stimulated muscle groups according to a predefined policy and while tracking a reference cadence. Instead of a static stimulation pattern to be modified by a control law, we hypothesized that a non-stationary baseline set of parameters would better adjust the amount of injected electrical charge to the time-varying characteristics of the musculature. Overground FES-assisted cycling sessions were performed by a subject with spinal cord injury (SCI AIS-A, T8). For tracking a predefined pedaling cadence, two closed-loop control laws were simultaneously used to modulate the pulse intensity of the stimulation channels responsible for evoking the muscle contractions. First, a Proportional-Integral (PI) controller was used to control the current amplitude of the stimulation channels over an initial parameter setting with predefined pulse amplitude, width and fixed frequency parameters. In parallel, an RL algorithm with a decayed-epsilon-greedy strategy was implemented to randomly explore nine different variations of pulse amplitude and width parameters over the same stimulation setting, aiming to adjust the injected electrical charge according to a predefined policy. The performance of this global control strategy was evaluated in two different RL settings and explored in two different cycling scenarios. The participant was able to pedal overground for distances over 3.5 km, and the results evidenced the RL agent learned to modify the stimulation pattern according to the predefined policy and was simultaneously able to track a predefined pedaling cadence. Despite the simplicity of our approach and the existence of more sophisticated RL algorithms, our method can be used to reduce the time needed to define stimulation patterns. Our results suggest interesting research possibilities to be explored in the future to improve cycling performance since more efficient stimulation cost dynamics can be explored and implemented for the agent to learn.

Development of a High-Power Capacity Open Source Electrical Stimulation System to Enhance Research into FES-Assisted Devices: Validation of FES Cycling.

Since the first Cybathlon 2016, when twelve teams competed in the FES bike race, we have witnessed a global effort towards the development of stimulation and control strategies to improve FES-assisted devices, particularly for cycling, as a means to practice a recreational physical activity. As a result, a set of technical notes and research paved the way for many other studies and the potential behind FES-assisted cycling has been consolidated. However, engineering research needs instrumented devices to support novel developments and enable precise assessment. Therefore, some researchers struggle to develop their own FES-assisted devices or find it challenging to implement their instrumentation using commercial devices, which often limits the implementation of advanced control strategies and the possibility to connect different types of sensor. In this regard, we hypothesize that it would be advantageous for some researchers in our community to enjoy access to an entire open-source FES platform that allows different control strategies to be implemented, offers greater adaptability and power capacity than commercial devices, and can be used to assist different functional activities in addition to cycling. Hence, it appears to be of interest to make our proprietary electrical stimulation system an open-source device and to prove its capabilities by addressing all the aspects necessary to implement a FES cycling system. The high-power capacity stimulation device is based on a constant current topology that allows the creation of biphasic electrical pulses with amplitude, width, and frequency up to 150 mA, 1000 µs, and 100 Hz, respectively. A mobile application (Android) was developed to set and modify the stimulation parameters of up to eight stimulation channels. A proportional-integral controller was implemented for cadence tracking with the aim to improve the overall cycling performance. A volunteer with complete paraplegia participated in the functional testing of the system. He was able to cycle indoors for 45 min, accomplish distances of more than 5 km using a passive cycling trainer, and pedal 2400 m overground in 32 min. The results evidenced the capacity of our FES cycling system to be employed as a cycling tool for individuals with spinal cord injury. The methodological strategies used to improve FES efficiency suggest the possibility of maximizing pedaling duration through more advanced control techniques.

Spatial coherence mapping of structured sources: a flexible instrument for solar studies.

We conceptually describe and design, to first order, an instrument to locally map the spatial coherence of extended and structured sources, such as fiber bundles or the Sun, considered as a mosaic of individual solar cells, which is our main motivation. Our solar coherence instrument (SCI) is an instrument for an afocal solar space telescope; the light from its exit pupil dynamically selects one individual solar cell at a time and performs a series of Young-like experiments with different baselines in order to measure the spectral degree of coherence and therefore the effective correlation length that can be assigned for that solar cell. SCI needs flexibility in terms of selective imaging and Young experiments, which is provided by two digital micromirror devices (DMDs), a technology currently under space qualification. SCI is a compact instrument based on retroreflections, and it generates all data required to image the source, to select the cells, and to implement sequentially a series of Young apertures on a re-imaged pupil. It was designed using the (already launched) Hinode solar optical telescope as a baseline, and the first estimation of the SNR, using commercial DMDs and array sensors, while measuring the modulation of Young interference fringes validates our first-order design.

Numerical simulations of spectral shifts in the far-field spectrum of light due to source correlations.

We discuss how to simulate numerically the far-field propagation of the spectrum of light by propagating the cross-spectral density for a planar light source with a given coherence model. To test our approach, we performed simulations for two source models: a Gaussian Schell-model source and a nonuniformly Gaussian-correlated source. We show that our algorithm correctly reproduces the theoretical solutions by Emil Wolf for planar Gaussian Schell-model source, namely, the spectral shifts of spectral lines due to source correlations. Our approach can be used for two-dimensional source models in which the spatial coherence components are frequency independent. It can also be used for nonhomogeneous extended sources of partial coherent light.

Image Quality and Radiation Exposure Comparison of a Double High-Pitch Acquisition for Coronary Computed Tomography Angiography Versus Standard Retrospective Spiral Acquisition in Patients With Atrial Fibrillation.

OBJECTIVE: The aim of this study was to compare image quality and radiation dose of coronary computed tomography (CT) angiography performed with dual-source CT scanner using 2 different protocols in patients with atrial fibrillation. METHODS: Forty-seven patients with AF underwent 2 different acquisition protocols: double high-pitch (DHP) spiral acquisition and retrospective spiral acquisition. The image quality was ranked according to a qualitative score by 2 experts: 1, no evident motion; 2, minimal motion not influencing coronary artery luminal evaluation; and 3, motion with impaired luminal evaluation. A third expert solved any disagreement. RESULTS: A total of 732 segments were evaluated. The DHP group (24 patients, 374 segments) showed more segments classified as score 1 than the retrospective spiral acquisition group (71.3% vs 37.4%). Image quality evaluation agreement was high between observers (κ = 0.8). There was significantly lower radiation exposure for the DHP group (3.65 [1.29] vs 23.57 [10.32] mSv). CONCLUSIONS: In this original direct comparison, a DHP spiral protocol for coronary CT angiography acquisition in patients with atrial fibrillation resulted in lower radiation exposure and superior image quality compared with conventional spiral retrospective acquisition.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion.

Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease-causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub-phenotypes.

Functional impact of global rare copy number variation in autism spectrum disorders.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Use of Autogenous Tricorticocancellous Iliac Crest Graft for Large Hill-Sachs Lesion Associated with Anterior Glenohumeral Dislocation: A Case Report.

Introduction: Although Hill-Sachs lesions are frequently associated with recurrent anterior glenohumeral dislocation, understanding of biomechanics and the importance of having an engaging or non-engaging lesion has only been recently studied at more depth. It is now widely accepted that engaging lesions benefit from surgery due to the high risk of symptom recurrence if left untreated. Techniques that have been described include capsular shift procedures, rotational osteotomies of the humeral head, or even femoral or humeral head allografts. The authors describe an alternative treatment which involves autogenous tricorticocancellous iliac crest graft to treat the bony defect in a patient with recurrent anterior glenohumeral dislocation and a large, engaging Hill-Sachs lesion. Case Report: A 33-year-old male with clinical history of two anterior-inferior dislocations of the left shoulder presented with chronic instability and a large Hill-Sachs defect (about 30% of the humeral head) with an anterior labrum lesion but no glenoid bony lesion. The defect was treated with a tailored autogenous tricorticocancellous iliac crest graft and fixed with headless compression screws. The patient returned to every-day activities at 5 months postoperatively and has a complete range of motion no complications were observed. Conclusion: This appears to be a safe and painless technique with excellent functional results, that should, however, be validated in the future with prospective randomized controlled trials.

EVOLUTION OF DIAGNOSTIC DELAY IN PEDIATRIC INFLAMMATORY BOWEL DISEASE AND THE IMPACT OF THE COVID-19 PANDEMIC.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) is increasingly prevalent, but diagnosis can still be challenging. Diagnostic delay is particularly deleterious in this age group. OBJECTIVE: This study explores the evolution of diagnostic delay in pediatric IBD and the influence of the COVID-19 pandemic. METHODS: Retrospective study including all pediatric IBD patients diagnosed during 2014, 2019 and 2020 in a tertiary hospital. Diagnostic delay, time to first medical visit, time to pediatric gastroenterologist (PG) visit and time to diagnosis were calculated and compared within a gap of five years (2019 and 2014) and with the year of onset of the pandemic (2020 and 2019). RESULTS: A total of 93 participants were included (2014: 32, 2019: 30, 2020: 31). No significant differences were observed in diagnostic delay, time to first medical visit in Crohn's disease (CD), time to PG visit and time to diagnosis when comparing 2019-2014 and 2020-2019. Time to first visit in ulcerative colitis (UC) and Undetermined-IBD increased in 2019 (P=0.03), with new decrease in 2020 (P=0.04). Diagnostic delay was longer in DC compared to UC plus Undetermined-IBD. CONCLUSION: Diagnostic delay is still an important matter in pediatric IBD, with no significant change over the last years. The time to the first PG visit and the time for diagnosis seem to have the greatest impact on diagnostic delay. Thus, strategies to enhance recognition of IBD symptoms among first-line physicians and to improve communication, facilitating referral, are of utmost importance. Despite the restraints in the health care system caused by the pandemic, time to diagnosis in pediatric IBD was not impaired during 2020 in our center.

Microscopic Inspection of the Adhesive Interface of Composite Onlays after Cementation on Low Loading: An In Vitro Study.

PURPOSE: This study aimed to assess the layer thickness and microstructure of traditional resin-matrix cements and flowable resin-matrix composites at dentin and enamel to composite onlay interfaces after cementation on low loading magnitude. MATERIALS AND METHODS: Twenty teeth were prepared and conditioned with an adhesive system for restoration with resin-matrix composite onlays manufactured by CAD-CAM. On cementation, tooth-to-onlay assemblies were distributed into four groups, including two traditional resin-matrix cements (groups M and B), one flowable resin-matrix composite (group G), and one thermally induced flowable composite (group V). After the cementation procedure, assemblies were cross-sectioned for inspection by optical microscopy at different magnification up to ×1000. RESULTS: The layer thickness of resin-matrix cementation showed the highest mean values at around 405 µm for a traditional resin-matrix cement (group B). The thermally induced flowable resin-matrix composites showed the lowest layer thickness values. The resin-matrix layer thickness revealed statistical differences between traditional resin cement (groups M and B) and flowable resin-matrix composites (groups V and G) (p < 0.05). However, the groups of flowable resin-matrix composites did not reveal statistical differences (p < 0.05). The thickness of the adhesive system layer at around 7 µm and 12 µm was lower at the interfaces with flowable resin-matrix composites when compared to the adhesive layer at resin-matrix cements, which ranged from 12 µm up to 40 µm. CONCLUSIONS: The flowable resin-matrix composites showed adequate flowing even though the loading on cementation was performed at low magnitude. Nevertheless, significant variation in thickness of the cementation layer was noticed for flowable resin-matrix composites and traditional resin-matrix cements that can occur in chair-side procedures due to the clinical sensitivity and differences in rheological properties of the materials.

Giant Right Atrium: An Extreme Structural Damage Case Due to Rheumatic Heart Disease.

Giant right atrium (RA) is a rare finding in adults. We report a case of a 53-year-old female with rheumatic heart disease (RHD) previously submitted to two mitral valve replacements. She presented at the emergency room with signs of heart failure. Image studies revealed gross cardiomegaly. Transthoracic echocardiogram showed torrential tricuspid regurgitation, with right chambers enlargement. At chest tomography, the estimated right atrium volume was 1,200 mL. The patient was treated with intravenous diuretics and multiple paracentesis, as well as referred to heart transplantation. Physicians should be aware of this extreme outcome, which can lead to life-threatening complications such as atrial fibrillation and thromboembolism.

Predicting Significant Coronary Obstruction in a Population with Suspected Coronary Disease and Absence of Coronary Calcium: CORE-64 / CORE320 Studies. / Predição de Obstrução Coronariana Significativa em População com Suspeita de Doença Coronariana e Ausência de Cálcio Coronariano: CORE-64 e CORE320.

BACKGROUND: Coronary artery calcium (CAC) scanning can be performed using non-contrast computed tomography to predict cardiovascular events, but has less value for risk stratification in symptomatic patients. OBJECTIVE: To identify and validate predictors of significant coronary obstruction (SCO) in symptomatic patients without coronary artery calcification. METHODS: A total of 4,258 participants were screened from the CORE64 and CORE320 studies that enrolled patients referred for invasive angiography, and from the Quanta Registry that included patients referred for coronary computed tomography angiography (CTA). Logistic regression models evaluated associations between cardiovascular risk factors, CAC, and SCO. An algorithm to assess the risk of SCO was proposed for patients without CAC. Significance level of 5% was used in the analyses. RESULTS: Of the 509 participants of the CORE study, 117 (23%) had zero coronary calcium score; 13 (11%) patients without CAC had SCO. Zero calcium score was related to younger age, female gender, lower body mass index, no diabetes, and no dyslipidemia. Being a current smoker increased ~3.5 fold the probability of SCO and other CV risk factors were not significantly associated. Considering the clinical findings, an algorithm to further stratify zero calcium score patients was proposed and had a limited performance in the validation cohort (AUC 58; 95%CI 43, 72). CONCLUSION: A lower cardiovascular risk profile is associated with zero calcium score in a setting of high-risk patients. Smoking is the strongest predictor of SCO in patients without CAC.

FUNDAMENTO: A avaliação do Escore de Cálcio Coronariano (ECC) pode ser realizada por tomografia computadorizada sem contraste para prever eventos cardiovasculares, mas tem menor valor na estratificação de risco em pacientes sintomáticos. OBJETIVO: Identificar e validar preditores de obstrução coronariana significativa (OCS) em pacientes sintomáticos sem calcificação da artéria coronária. MÉTODOS: Um total de 4258 participantes foram rastreados dos estudos CORE64 e CORE 320, nos quais foram avaliados pacientes encaminhados para angiografia invasiva, e do Quanta Registry que incluiu pacientes encaminhados para angiotomografia. Modelos de regressão logística avaliaram associações entre fatores de risco cardiovascular, ECC e OCS. Um nível de significância de 5% foi usado nas análises. RESULTADOS: Dos 509 participantes do estudo CORE, 117 (23%) apresentaram um ECC igual a zero; 13 (11%) pacientes sem cálcio coronariano apresentaram OCS. A ausência de cálcio coronariano correlacionou-se com idade mais jovem, sexo feminino, índice de massa corporal mais baixo, ausência de diabetes, e ausência de dislipidemia. O fato de ser fumante atual aumentou em 3,5 vezes a probabilidade de OCS e outros fatores de risco cardiovasculares não apresentaram associação significativa. Considerando os achados clínicos, um algoritmo para estratificar os pacientes com ECC igual a zero foi proposto, e tiveram desempenho limitado na coorte de validação (AUC 58; IC95% 43, 72). CONCLUSÃO: Um perfil de risco cardiovascular mais baixo está associado a um ECC igual a zero em pacientes de alto risco. Tabagismo é o preditor mais forte de OCS em pacientes com ausência de cálcio coronariano.

A genome-wide scan for common alleles affecting risk for autism.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Large congenital pulmonary airway malformation with mucinous cell clusters - a case report.

We report the clinical case of a 38 weeks gestational age neonate, antenatally diagnosed with a left large macrocystic pulmonary malformation conditioning dextrocardia. At birth, he presented with respiratory distress requiring non-invasive ventilation with high-flow nasal cannula (HFNC). A left inferior lobectomy was performed via thoracotomy on day 21 of life. Histological features of the lesion were compatible with congenital pulmonary airway malformation (CPAM) type I with muci- nous cell clusters. No surgical complications were reported and the neonate was discharged six days after surgery. Follow-up two months after surgery was unremarkable.

A Unique Shunt For Treatment Of A Postoperative Chylothorax.

Postoperative chylothorax can be a serious complication. We report on the case of a neonate who had a postoperative chylothorax immediately after esophageal surgery that did not respond to conservative measures or the first two attempts of surgical management of chylothorax. Lastly, a successful pleuroperitoneal shunt was placed and the patient was discharge at 3-months-old. A pleuroperitoneal shunt is usually the last surgical option but may be a curative measure.