Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Evaporation-induced alterations in oscillation and flow characteristics of a sessile droplet on a rose-mimetic surface.

Strategic control of evaporation dynamics can help control oscillation modes and internal flow field in an oscillating sessile droplet. This article presents the study of an oscillating droplet on a bio-inspired "sticky" surface to better understand the nexus between the modes of evaporation and oscillation. Oscillation in droplets can be characterized by the number of nodes forming on the surface and is referred to as the mode of oscillation. An evaporating sessile droplet under constant periodic perturbation naturally self-tunes between different oscillation modes depending on its geometry. The droplet geometry evolves according to the mode of evaporation controlled by substrate topography. We use a bio-inspired, rose patterned, "sticky" hydrophobic substrate to perpetually pin the contact line of the droplet in order to hence achieve a single mode of evaporation for most of the droplet's lifetime. This allows the prediction of experimentally observed oscillation mode transitions at different excitation frequencies. We present simple scaling arguments to predict the velocity of the internal flow induced by the oscillation. The findings are beneficial to applications which seek to tailor energy and mass transfer rates across liquid droplets by using bio-inspired surfaces.

Engineering Interfacial Processes at Mini-Micro-Nano Scales Using Sessile Droplet Architecture.

Evaporating sessile functional droplets act as the fundamental building block that controls the cumulative outcome of many industrial and biological applications such as surface patterning, 3D printing, photonic crystals, and DNA sequencing, to name a few. Additionally, a drying single sessile droplet forms a high-throughput processing technique using low material volume which is especially suitable for medical diagnosis. A sessile droplet also provides an elementary platform to study and analyze fundamental interfacial processes at various length scales ranging from macroscopically observable wetting and evaporation to microfluidic transport to interparticle forces operating at a nanometric length scale. As an example, to ascertain the quality of 3D printing we must understand the fundamental interfacial processes at the droplet scale. In this article, we review the coupled physics of evaporation flow-contact-line-driven particle transport in sessile colloidal droplets and provide methodologies to control the same. Through natural alterations in droplet vaporization, one can change the evaporative pattern and contact line dynamics leading to internal flow which will modulate the final particle assembly in a nontrivial fashion. We further show that control over particle transport can also be exerted by external stimuli which can be thermal, mechanical oscillations, vapor confinement (walled or a fellow droplet), or chemical (surfactant-induced) in nature. For example, significant augmentation of an otherwise evaporation-driven particle transport in sessile droplets can be brought about simply through controlled interfacial oscillations. The ability to control the final morphologies by manipulating the governing interfacial mechanisms in the precursor stages of droplet drying makes it perfectly suitable for fabrication-, mixing-, and diagnostic-based applications.

Confinement-induced alterations in the evaporation dynamics of sessile droplets.

Evaporation of sessile droplets has been a topic of extensive research. However, the effect of confinement on the underlying dynamics has not been well explored. Here, we report the evaporation dynamics of a sessile droplet in a confined fluidic environment. Our findings reveal that an increase in the channel length delays the completion of the evaporation process and leads to unique spatio-temporal evaporation flux and internal flow. The evaporation modes (constant contact angle and constant contact radius) during the droplet lifetime however exhibit global similarity when normalized by appropriate length and timescales. These results are explained in light of an increase in vapor concentration inside the channel due to greater accumulation of water vapor on account of increased channel length. We have formulated a theoretical framework which introduces two key parameters namely an enhanced concentration of the vapor field in the vicinity of the confined droplet and a corresponding accumulation lengthscale over which the accumulated vapor relaxes to the ambient concentration. Using these two parameters and modified diffusion based evaporation we are able to show that confined droplets exhibit a universal behavior in terms of the temporal evolution of each evaporation mode irrespective of the channel length. These results may turn out to be of profound importance in a wide variety of applications, ranging from surface patterning to microfluidic technology.

PET hypermetabolism in medically resistant childhood epilepsy: Incidence, associations, and surgical outcome.

OBJECTIVE: We observed several children with medically resistant epilepsy demonstrating focal positron emission tomography (PET) hypermetabolism, a finding rarely reported and of questionable significance. We therefore retrospectively reviewed the incidence of hypermetabolic PET, and its relationship to electroencephalography (EEG) and magnetic resonance imaging (MRI) findings, and to the outcome of epilepsy surgery. METHODS: We retrospectively reviewed 498 PET brain studies in patients with medically resistant childhood epilepsy for evidence of hypermetabolism. In patients with PET hypermetabolism, we correlated metabolic abnormality with the scalp EEG and MRI findings. In a subset of patients who underwent surgical resection, we further correlated the PET findings with histopathologic and surgical outcomes. RESULTS: Focal PET hypermetabolism was identified in 33 (6.6%) of 498 studies. The region of hypermetabolism correlated with a spike count of ≥10 per minute in 26 of 32 concomitant scalp EEG studies and 18 of 21 lesions evident on MRI. In 17 patients who underwent surgical resection, PET hypermetabolism further correlated with regions revealing almost continuous epileptiform discharges on the intracranial EEG and with histopathologically malformative tissue. At a minimum follow-up of 1 year postsurgery (median 33 months), 7 (50%) of 14 patients had Engel's class I outcome, 4 patients had class II, and 2 had class III outcome, whereas one patient was unchanged. At last follow-up, seizure freedom was noted in five of seven patients with focal PET hypermetabolism alone versus three of eight patients with PET hypometabolism. SIGNIFICANCE: Focal PET hypermetabolism is associated with high spike frequency on scalp EEG and can occur in the absence of ictal events during the peri-injection period. Correlation with intracranial EEG usually corroborates the highly epileptogenic pathophysiologic state. Cortical malformations constitute the most common pathologic substrate, and resection of the hypermetabolic PET region may facilitate favorable outcomes. These observations indicate that focal PET hypermetabolism is an important marker of the epileptogenic zone and may represent its epicenter.

Insights into Vapor-Mediated Interactions in a Nanocolloidal Droplet System: Evaporation Dynamics and Affects on Self-Assembly Topologies on Macro- to Microscales.

Particle-laden droplet-based systems ranging from micro- to nanoscale have become increasingly popular in applications such as inkjet printing, pharmaceutics, nanoelectronics, and surface patterning. All such applications involve multidroplet arrays in which vapor-mediated interactions can significantly affect the evaporation dynamics and morphological topology of precipitates. A fundamental study was conducted on nanocolloidal paired droplets (droplets kept adjacent to each other as in an array) to understand the physics related to the evaporation dynamics, internal flow pattern, particle transport, and nanoparticle self-assembly, primarily using optical diagnostic techniques [such as micro-particle image velocimetry (µPIV)]. Paired droplets exhibit contact angle asymmetry, inhomogeneous contact line slip, and unique single-toroid microscale flow, which are unobserved in single droplets. Furthermore, nanoparticles self-assemble (at the nanoscale) to form a unique variable-thickness (microscale) tilted dome-shaped structure that eventually ruptures at an angle because of evaporation at a nanopore scale to form cavities (miniscale). The geometry and morphology of the dome can be further fine-tuned at a macro- to microscale by varying the initial particle concentration and substrate properties. This concept has been extended to a linear array of droplets to showcase how to custom design two-dimensional drop arrangements to create controlled surface patterns at multiple length scales.

Towards universal buckling dynamics in nanocolloidal sessile droplets: the effect of hydrophilic to superhydrophobic substrates and evaporation modes.

The evaporation of a nanocolloidal sessile droplet exhibits preferential particle assembly, nanoporous shell formation and buckling to form cavities with unique morphological features. Here, we have established many universal trends that explain the buckling dynamics under one umbrella irrespective of hydrophobicity, evaporation mode and particle loading. We provide a regime map explaining the droplet morphology and buckling characteristics for droplet evaporation on various substrates. Specifically, we find that the final droplet volume and the radius of curvature at the buckling onset are universal functions of particle concentration. Furthermore, we establish that post-buckling cavity growth is evaporation driven regardless of the substrate.

Seven-core erbium-doped double-clad fiber amplifier pumped simultaneously by side-coupled multimode fiber.

We demonstrate a seven-core erbium-doped fiber amplifier in which all the cores were pumped simultaneously by a side-coupled tapered multimode fiber. The amplifier has multicore (MC) MC inputs and MC outputs, which can be readily spliced to MC transmission fiber for amplifying space division multiplexed signals. Gain over 25 dB was obtained in each of the cores over a 40-nm bandwidth covering the C-band.

Efficacy and Tolerability of Ultra Rapid Duty Cycling Vagus Nerve Stimulation for Medically Refractory Absence Seizures.

BACKGROUND: Significant knowledge gap exists on vagus nerve stimulation (VNS) efficacy and tolerability in medically refractory absence seizures (MRAS). This retrospective review of patients with MRAS aims to narrow this knowledge gap by comparing ultra rapid duty cycling ([URDC] ON time seven seconds, OFF time 0.2 minutes) with less frequent stimulations of rapid duty cycling (RDC, OFF time <1.1 minutes) and normal duty cycling (NDC, OFF time ≥1.1 minutes). METHODS: Patients with MRAS aged less than 21 years who underwent VNS implantation were identified. Patient demographics, antiepileptic medications, seizure types, frequency, VNS parameters, outcomes of seizure reduction rate (SRR), and seizure freedom were extracted and compared among NDC, RDC, and URDC patient cohorts. RESULTS: Thirty-six patients with MRAS were identified. After a mean follow-up of 32.6 months, responder rate ([RR], SRR ≥50%) for URDC was 80% for absence seizures and 80% for all seizure types versus 66.67% and 66.77% for NDC and 78.57% and 57.14% for RDC, respectively. Six of 10 patients (60%) on URDC achieved complete seizure freedom. A higher rate of subjective improvement in academic performance, attention, and developmental gain was noted in the URDC group. Patients on URDC tolerated higher output current (mean 3.025 mA) with minimal side effects but required a battery change sooner. CONCLUSIONS: VNS is a safe and effective nonpharmacologic management choice in patients with MRAS. The data presented demonstrate that the combination of URDC and high output current provides better RR and seizure freedom. Apart from a reduced battery life, this parameter modality seems to be well-tolerated.

Solid Pseudopapillary Neoplasm - Case Series and Review of Literature.

Solid-pseudopapillary neoplasm (SPN) is a variety of solid and cystic tumors of the pancreas. It was first described by Frantz in 1959. It is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, which accounts for about 0.17 to 2.7% of all pancreatic tumors. Here, we are describing 5 cases of pancreatic solid pseudopapillary neoplasm, out of 180 pancreatic tumors, operated in our institution in the 5-year period (2015-2020). Also, we have reviewed all available case series (from 2006 to 2020) in the literature, of pancreatic pseudopapillary neoplasm, for demographic information, etiopathogenesis, diagnosis, and extent of operation to establish the optimal management of this condition. Retrospective analysis of pancreatic tumors was carried out from February 2015 to January 2020. A total of 180 patients underwent pancreatic resection in this period for pancreatic tumor, out of which, the solid pseudopapillary neoplasm was confirmed in 5 cases (2.76%). Among these 5 cases, 4 cases (80%) were female and one (20%) male, with age group range from 14 to 45 years (mean age - 28 years). Abdominal pain was the most frequent presenting symptom (60%). Mean tumor diameter was 6.9 cm (range, 2-18 cm). Two patients were diagnosed preoperatively by CECT and MRI findings, and three patients were diagnosed preoperatively by percutaneous/USG-guided and CT-guided FNA cytology. Two patients underwent pancreatoduodenectomy; one patient underwent enucleation; and two patients underwent spleen preserving distal pancreatectomy. Four patients are alive and on regular follow-up, while one patient died on the 5th post-operative day due to post-operative sepsis.