Clear cell meningiomas-case presentation, review of radiographic identifiers, and treatment approaches.

Spinal clear cell meningiomas (CCMs) are a rare histological subtype of meningiomas that pose preoperative diagnostic challenges due to their radiographic similarities with other lesions. They are also more aggressive, exhibiting higher rates of recurrence, particularly in pediatric patients. Overcoming diagnostic challenges of these tumors can improve patient outcomes. In this report, we describe a case of a pediatric patient presenting with a lumbar CCM in whom we were able to obtain gross total resection. Our report reviews previously identified predictors of CCM recurrence, including the Ki-67 proliferation index, number of spinal segments involved, and hormonal influences related to age and sex. We describe the characteristic radiographic features that differentiate spinal CCMs from other tumors to improve pre-operative diagnosis. Furthermore, we provide our rationale for adjuvant therapy for pediatric patients to refine treatment protocols for these rare tumors.

A Case Report of Infant-Type Hemispheric Glioma with a Novel GAB1-ABL2 Kinase Fusion Treated with Dasatinib.

INTRODUCTION: Infant-type hemispheric glioma (IHG) is a rare form of cancer that affects newborns and infants. It is classified as a pediatric-type high-grade glioma and typically harbors receptor tyrosine kinase (RTK) gene fusions. Here, we present the finding of a novel gene fusion IHG treated with a targeted therapy that has yet to be implemented for any other IHG case to date. CASE PRESENTATION: We report the case of a 12-month-old boy with IHG who presented with obstructive hydrocephalus due to a large mass in the right frontal lobe. The patient initially underwent mass resection, but subsequent imaging showed rapid interval progression of the residual tumor. Comprehensive molecular analysis of the tumor tissue revealed a novel GAB1-ABL2 gene fusion, and the patient was started on dasatinib, an ABL kinase inhibitor. Shortly after initiation of dasatinib treatment, there was a significant reduction in tumor size and enhancement, followed by stabilization of disease. DISCUSSION: The patient's robust response to treatment suggests that dasatinib is an effective targeted therapy for IHG harboring a GAB1-ABL2 gene fusion. This finding may inform future investigations into the disease processes of IHG and help guide the diagnosis and treatment of IHG in the absence of previously identified gene fusions, improving clinical management of this vulnerable patient population.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Middle-out sequence confirmation of CRISPR/Cas9 single guide RNA (sgRNA) using DNA primers and ribonuclease T1 digestion.

Accurate sequencing of single guide RNAs (sgRNAs) for CRISPR/Cas9 genome editing is critical for patient safety, as the sgRNA guides the Cas9 nuclease to target site-specific cleavages in DNA. An approach to fully sequence sgRNA using protective DNA primers followed by ribonuclease (RNase) T1 digestion was developed to facilitate the analysis of these larger molecules by hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry (HILIC-HRMS). Without RNase digestion, top-down mass spectrometry alone struggles to properly fragment precursor ions in large RNA oligonucleotides to provide confidence in sequence coverage. With RNase T1 digestion of these larger oligonucleotides, however, bottom-up analysis cannot confirm full sequence coverage due to the presence of short, redundant digestion products. By combining primer protection with RNase T1 digestion, digestion products are large enough to prevent redundancy and small enough to provide base resolution by tandem mass spectrometry to allow for full sgRNA sequence coverage. An investigation into the general requirements for adequate primer protection of specific regions of the RNA was conducted, followed by the development of a generic protection and digestion strategy that may be applied to different sgRNA sequences. This middle-out technique has the potential to expedite accurate sequence confirmation of chemically modified sgRNA oligonucleotides.

A nine-month-old boy with regression of milestones and severe constipation: an unusual case of a large spinal NTRK1 fusion pilocytic astrocytoma.

INTRODUCTION: Pilocytic astrocytoma, a World Health Organization grade 1 tumor, is the most common brain tumor in children between 5 and 14 years of age and the second most common in children younger than 5 and older than 14. Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. Larotrectinib, a selective inhibitor of tropomyosin receptor kinase, has been effective in pediatric tumors with NTRK fusion mutations in children as young as 1-month-old. CASE: We share the case of a 9-month-old boy who presented with a 4-month history of regression of his milestones and severe constipation who was found to have a large spinal pilocytic astrocytoma with multiple intracranial periventricular lesions.

High-Level Data Fusion Enables the Chemoinformatically Guided Discovery of Chiral Disulfonimide Catalysts for Atropselective Iodination of 2-Amino-6-arylpyridines.

The atropselective iodination of 2-amino-6-arylpyridines catalyzed by chiral disulfonimides (DSIs) is described. Key to the development of this transformation was the use of a chemoinformatically guided workflow for the curation of a structurally diverse training set of DSI catalysts. Utilization of this catalyst training set in the atropselective iodination across a variety 2-aminopyridine substrates allowed for the recommendation of statistically higher-performing DSIs for this reaction. Data Fusion techniques were implemented to successfully predict the performance of catalysts when classical linear regression analysis failed to provide suitable models. This effort identified a privileged class of 3,3'-alkynyl-DSI catalysts which were effective in catalyzing the iodination of a variety of 2-amino-6-arylpyridines with high stereoselectivity and generality. Subsequent preparative-scale demonstrations highlighted the utility of this reaction by providing iodinated pyridines >90:10 er and in good chemical yield.

Protocol for a multi-site randomized controlled trial of a stepped-care intervention for emergency department patients with panic-related anxiety.

BACKGROUND: Approximately 40% of Emergency Department (ED) patients with chest pain meet diagnostic criteria for panic-related anxiety, but only 1-2% are correctly diagnosed and appropriately managed in the ED. A stepped-care model, which focuses on providing evidence-based interventions in a resource-efficient manner, is the state-of-the art for treating panic disorder patients in medical settings such as primary care. Stepped-care has yet to be tested in the ED setting, which is the first point of contact with the healthcare system for most patients with panic symptoms. METHODS: This multi-site randomized controlled trial (RCT) aims to evaluate the clinical, patient-centred, and economic effectiveness of a stepped-care intervention in a sample of 212 patients with panic-related anxiety presenting to the ED of Singapore's largest public healthcare group. Participants will be randomly assigned to either: 1) an enhanced care arm consisting of a stepped-care intervention for panic-related anxiety; or 2) a control arm consisting of screening for panic attacks and panic disorder. Screening will be followed by baseline assessments and blocked randomization in a 1:1 ratio. Masked follow-up assessments will be conducted at 1, 3, 6, and 12 months. Clinical outcomes will be panic symptom severity and rates of panic disorder. Patient-centred outcomes will be health-related quality of life, daily functioning, psychiatric comorbidity, and health services utilization. Economic effectiveness outcomes will be the incremental cost-effectiveness ratio of the stepped-care intervention relative to screening alone. DISCUSSION: This trial will examine the impact of early intervention for patients with panic-related anxiety in the ED setting. The results will be used to propose a clinically-meaningful and cost-effective model of care for ED patients with panic-related anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03632356. Retrospectively registered 15 August 2018.

Infant-Family Mental Health in the NICU: A Mixed-Methods Study Exploring Referral Pathways and Family Engagement.

Parents and infants in the neonatal intensive care unit (NICU) are exposed to considerable stress, and infant-family mental health (IFMH) services foster emotional well-being in the context of the parent-infant relationship. This mixed-methods study examined the role of an IFMH program introduced in a level 4 NICU. The study included (1) retrospective medical record review of NICU patients who were referred to the IFMH program and (2) qualitative interviews with NICU nurse managers, neonatologists, and medical social workers to explore their understanding of the IFMH program, explore the referral pathways and factors that supported family engagement, and identify specific recommendations for program improvement. Of the 311 infant-parent dyads referred to the IFMH program, 62% had at least one session and Spanish-speaking families were more likely to engage. Of those families receiving services, about one-third had brief intervention, one-third had 4 to 10 sessions, and one-third had long-term services, including in-home after-discharge services. Qualitative interviews with health providers identified unique qualities of the IFMH program and why families were and were not referred to the program. Recommendations centered on adding a full-time IFMH mental health provider to the NICU and increasing communication and integration between the IFMH program and the medical team.

The implementation of a culturally grounded, school-based, drug prevention curriculum in rural Hawai'i.

This article describes the process of infusing implementation strategies in the development of a school-based drug prevention curriculum for rural Native Hawaiian youth. The curriculum (Ho'ouna Pono) is a video-enhanced, teacher-implemented curriculum developed using a culturally grounded and community-based participatory research approach. Throughout the development of the curriculum, strategies reflective of the domains of the Consolidated Framework for Implementation Research (CFIR) were integrated into the teacher training manual, to promote the implementation, adoption, and sustainability of the curriculum in rural Hawai'i. These strategies were validated through qualitative data across two interrelated studies with community stakeholders in rural Hawai'i. Implications for prevention, community, and educational practices are described in this article.

Utility of Spatial Point-Pattern Analysis Using Residential and Workplace Geospatial Information to Localize Potential Outbreak Sources.

Identifying the source of an outbreak facilitates its control. Spatial methods are not optimally used in outbreak investigation, due to a mix of the complexities involved (e.g., methods requiring additional parameter selection), imperfect performance, and lack of confidence in existing options. We simulated 30 mock outbreaks and compared 5 simple methods that do not require parameter selection but could select between mock cases' residential and workplace addresses to localize the source. Each category of site had a unique spatial distribution; residential and workplace address were visually and statistically clustered around the residential neighborhood and city center sites respectively, suggesting that the value of workplace addresses is tied to the location where an outbreak might originate. A modification to centrographic statistics that we propose-the center of minimum geometric distance with address selection-was able to localize the mock outbreak source to within a 500 m radius in almost all instances when using workplace in combination with residential addresses. In the sensitivity analysis, when given sufficient workplace data, the method performed well in various scenarios with only 10 cases. It was also successful when applied to past outbreaks, except for a multisite outbreak from a common food supplier.

Cell separation using tilted-angle standing surface acoustic waves.

Separation of cells is a critical process for studying cell properties, disease diagnostics, and therapeutics. Cell sorting by acoustic waves offers a means to separate cells on the basis of their size and physical properties in a label-free, contactless, and biocompatible manner. The separation sensitivity and efficiency of currently available acoustic-based approaches, however, are limited, thereby restricting their widespread application in research and health diagnostics. In this work, we introduce a unique configuration of tilted-angle standing surface acoustic waves (taSSAW), which are oriented at an optimally designed inclination to the flow direction in the microfluidic channel. We demonstrate that this design significantly improves the efficiency and sensitivity of acoustic separation techniques. To optimize our device design, we carried out systematic simulations of cell trajectories, matching closely with experimental results. Using numerically optimized design of taSSAW, we successfully separated 2- and 10-µm-diameter polystyrene beads with a separation efficiency of ∼ 99%, and separated 7.3- and 9.9-µm-polystyrene beads with an efficiency of ∼ 97%. We illustrate that taSSAW is capable of effectively separating particles-cells of approximately the same size and density but different compressibility. Finally, we demonstrate the effectiveness of the present technique for biological-biomedical applications by sorting MCF-7 human breast cancer cells from nonmalignant leukocytes, while preserving the integrity of the separated cells. The method introduced here thus offers a unique route for separating circulating tumor cells, and for label-free cell separation with potential applications in biological research, disease diagnostics, and clinical practice.

On-chip manipulation of single microparticles, cells, and organisms using surface acoustic waves.

Techniques that can dexterously manipulate single particles, cells, and organisms are invaluable for many applications in biology, chemistry, engineering, and physics. Here, we demonstrate standing surface acoustic wave based "acoustic tweezers" that can trap and manipulate single microparticles, cells, and entire organisms (i.e., Caenorhabditis elegans) in a single-layer microfluidic chip. Our acoustic tweezers utilize the wide resonance band of chirped interdigital transducers to achieve real-time control of a standing surface acoustic wave field, which enables flexible manipulation of most known microparticles. The power density required by our acoustic device is significantly lower than its optical counterparts (10,000,000 times less than optical tweezers and 100 times less than optoelectronic tweezers), which renders the technique more biocompatible and amenable to miniaturization. Cell-viability tests were conducted to verify the tweezers' compatibility with biological objects. With its advantages in biocompatibility, miniaturization, and versatility, the acoustic tweezers presented here will become a powerful tool for many disciplines of science and engineering.

Inter-rater reliability of J-point location and measurement of the magnitude of ST segment elevation at the J-point on ECGs of STEMI patients by emergency department doctors.

INTRODUCTION AND OBJECTIVES: Identification of the J-point and measurement of ST segment elevation at the J-point are important for the diagnosis of ST-elevation myocardial infarction (STEMI). We conducted a study to determine the inter-rater reliability (IRR) of J-point location and measurement of the magnitude of ST elevation at the J-point on ECGs of patients with STEMI by emergency department (ED) doctors. SUBJECTS AND METHODS: Each participant examined 20 STEMI ECGs during a 1-month period in 2013. The participants were required to locate the J-point by selecting the small 1 mm square within which the J-point is located and measure the magnitude of ST elevation at the J-point identified (rounded up to the nearest 0.5 mm). The intraclass correlation coefficient (ICC) was calculated to assess the IRR. RESULTS: Thirty doctors participated. The ICC assessing the degree to which all participants provided agreement in their assessment of the location of J-points across ECGs was 0.85 (95% CI 0.75 to 0.93), which is in the excellent range. The ICC for assessing the magnitude of ST elevation was 0.97 (95% CI 0.94 to 0.98), indicating excellent agreement as well. CONCLUSIONS: ED doctors show a high level of agreement when determining the location of J-points and measuring the magnitude of ST elevation at those J-points on ECGs of patients with STEMI. The findings support the measurement of ST segment elevation at the J-point in STEMI cases and should be regarded as a consistent standard to avoid confusion.

Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.

We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.

Comparison of the effects of surgical dissection devices on the rabbit liver.

PURPOSE: Multiple energy-based surgical dissection and coagulation modalities are available to facilitate surgical dissection and hemostasis, but there is limited information regarding the acute tissue effects of these devices. Our objective was to compare the functional characteristics and tissue effects of four energy-based surgical dissection and coagulation modalities on the rabbit liver. METHODS: Linear incisions were created in the rabbit liver using monopolar electrocautery, a harmonic scalpel, a PlasmaBlade and a new ferromagnetic induction loop device. Subjective cutting and coagulation characteristics for each device were recorded, and the histological tissue effects were evaluated. RESULTS: Each of the modalities successfully incised the liver tissue. The PlasmaBlade and the ferromagnetic induction loop exhibited significantly less perceived tissue drag during the incision, significantly less collateral tissue damage and significantly better margin uniformity than the monopolar electrocautery device. Each device showed comparable subjective hemostasis. The harmonic scalpel did not demonstrate a significant difference compared with any of the other devices in any of the parameters examined. The histological analysis revealed that the least lateral thermal damage resulted when the PlasmaBlade, harmonic scalpel and ferromagnetic induction loop were used, and the most damage occurred with the use of monopolar electrocautery. CONCLUSIONS: Each of the newer energy-based surgical tools showed improvement over monopolar electrocautery with regard to lateral thermal injury, and the ferromagnetic induction device and the PlasmaBlade demonstrated superior surgical tissue handling characteristics to the monopolar electrocautery device.

Proximate factors associated with speech intelligibility in children with cochlear implants: A preliminary study.

The purpose of this descriptive pilot study was to examine possible relationships among speech intelligibility and structural characteristics of speech in children who use cochlear implants. The Beginners Intelligibility Test (BIT) was administered to 10 children with cochlear implants, and the intelligibility of the words in the sentences was judged by panels of naïve adult listeners. Additionally, several qualitative and quantitative measures of word omission, segment correctness, duration, and intonation variability were applied to the sentences used to assess intelligibility. Correlational analyses were conducted to determine if BIT scores and the other speech parameters were related. There was a significant correlation between BIT score and percent words omitted, but no other variables correlated significantly with BIT score. The correlation between intelligibility and word omission may be task-specific as well as reflective of memory limitations.

Automated online deconjugation of antibody-drug conjugate for small molecule drug profiling.

Antibody-drug conjugates (ADCs) are designed by chemically linking highly potent cytotoxic small molecule drugs to monoclonal antibodies of unique specificity for targeted destruction of cancer cells. This innovative class of molecules incurs unique developmental challenges due to its structural complexity of having both small molecule and protein components. The stability of the small molecule payload on the ADC is a critical attribute as it directly relates to product efficacy and patient safety. This study describes the use of an end-to-end automated workflow for effective and robust characterization of the small molecule drug while it is conjugated to the antibody. In this approach, online deconjugation was accomplished by an autosampler user defined program and 1D size exclusion chromatography was utilized to provide separation between small molecule and protein species. The small molecule portion was then trapped and sent to the 2D for separation and quantification by reversed-phase liquid chromatography with identification of impurities and degradants by mass spectrometry. The feasibility of this system was demonstrated on an ADC with a disulfide-based linker. This fully automated approach avoids tedious sample preparation that may lead to sample loss and large assay variability. Under optimized conditions, the method was shown to have excellent specificity, sensitivity (LOD of 0.036 µg/mL and LOQ of 0.144 µg/mL), linearity (0.04-72.1 µg/mL), precision (system precision %RSD of 1.7 and method precision %RSD of 3.4), accuracy (97.4 % recovery), stability-indicating nature, and was successfully exploited to analyze the small molecule drug on a panel of stressed ADC samples. Overall, the workflow established here offers a powerful analytical tool for profiling the in-situ properties of small molecule drugs conjugated to antibodies and the obtained information could be of great significance for guiding process/formulation development and understanding pharmacokinetic/pharmacodynamic behavior of ADCs.