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Intrathecal therapy has been limited by non-randomized prospective studies, particularly for those suffering from non-cancer. Further, no prospective, randomized studies investigating the efficacy, safety, and utilization of intrathecal polyanalgesic consensus guidelines exist.After IRB approval, patients were enrolled in a 1:1 fashion for intrathecal drug delivery (IDD) or conventional management (CMM), employing standard of care, excluding intrathecal drug delivery, based on the principal investigator's discretion. They were followed 3, 6, 9, and 12 months. Assessments included PROMIS 29, NPRS, and PriceMonkey.Seventy-nine patients were screened, 54 patients were enrolled: 26 to IDD and 28 to CMM. At 3 months, there was no measurable difference in pain improvement in either subgroups within the CMM for chronic pain-related syndromes (CPRS) or failed back and related spine disorders (FBRS). For the IDD, early and maintained benefit from the baseline was statistically achieved. Cost analysis of pump to CMM breakeven was 4.5 months. There were no adverse events related to compounded intrathecal medications.This is the first randomized prospective, multicenter study investigating the safety, cost, and efficacy of off-label medications for intrathecal therapy, as compared to conventional management, and suggests early detection of improvement, cost savings, safety of intrathecal compounded medication use, and safety and efficacy of employing the PACC guidance.

1.AbstractBrain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma-knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER,PR,Herceptin). We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, we used the notion of mutual information, which revealed that the ER-PR-Her2+ and ER-PR-Her2-subtypes showed the smallest amount of mutual information and were most molecularly distinct. Using kernel density estimators, we found a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. BM location maps according to vascular and anatomical distributions using cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. Further characterization of these patterns may have major impacts on treatment or management of cancer patients.SignificanceThe quantitative spatial distribution of breast cancer metastases to the brain, and the effects of breast cancer molecular subtype on distribution frequencies remain poorly understood. We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment.

This work presents a RISC-V system-on-chip (SoC) with eight application cores containing programmable-precision vector accelerators. The SoC is built by using a generator-based design methodology, which enables the integration of open-source and project-specific building blocks to develop differentiated functionality. The digital component generators use Chisel, the analog component generators use the Berkeley Analog Generator (BAG), and the physical design flow is implemented with Hammer. The chip totals 125 M gates and is implemented in a 16-nm finFET process. The vector accelerator achieves peak energy efficiency per task of 209 half-precision, 92 single-precision, and 56 double-precision GFLOPs/W for a matrix multiplication kernel at 0.55 V and 339 MHz.

Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia is an inherited cardiomyopathy, characterized by replacement of the RV muscle wall with fibrofatty tissue. The diagnosis is challenging, due to the absence of a unique presentation and a lack of specific reproducible diagnostic criteria. Materials and methods: Slides and additional clinical information including follow up from 16 cases were reviewed. Pediatric criteria of >30% of muscle replacement was used, instead of >40% as used in adults. Results: All 16 cases were confirmed by genetic testing and show ARVC/D. Applying the adult criteria, 7 cases would not have been categorized as ARVC/D. Conclusion: The modified pediatric criteria for ARVC/D should be used for pediatric patients. Better detection will aid in genetic counseling in order to identify those additional family members susceptible to sudden cardiac deaths so they can be followed optimally.

Earlier variants of SARS-CoV-2 have been associated with plasma hypercoagulability (as judged by thromboelastography) and an extensive formation of fibrin amyloid microclots, which are considered to contribute to the pathology of the coronavirus 2019 disease (COVID-19). The newer Omicron variants appear to be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while the clotting parameters associated with Omicron variants are significantly raised over those of healthy, matched controls, they are only raised to levels significantly lower than those seen with more severe variants such as Beta and Delta. We also observed that individuals infected with Omicron variants manifested less extensive microclot formation in platelet poor plasma compared to those harbouring the more virulent variants. The measurement of clotting effects between the different variants acts as a kind of ‘internal control’ that demonstrates the relationship between the extent of coagulopathies and the virulence of the variant of interest. This adds to the evidence that microclots play an important role in determining the severity of symptoms observed in COVID-19.

Context: The utility of phenobarbital in the treatment of severe alcohol withdrawal is contentious. Objective: The aim was to conduct a meta-analysis of existing observational and randomized controlled trials investigating the efficacy and safety of phenobarbital versus commonly used benzodiazepine in the setting of severe alcohol withdrawal. Data Sources: A search of PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials published between 1976 and September 2021 was performed using medical subject headings: “severe alcohol withdrawal”, “delirium tremens” (DT), “phenobarbital” (PB), “barbiturate”, “critical care”, “ICU”, “Trial”, “human” and “English”. We selected English-language clinical trials (observational and randomized controlled trials (RCT)) evaluating the efficacy and safety of phenobarbital (PB) compared to benzodiazepine (BZD) for the treatment of severe alcohol withdrawal syndrome (AWS) in the acute care setting. Study Appraisal and synthesis methods: Data extraction and critical appraisal were carried out independently by two authors (EC and YM) using predefined data fields. The outcome variables analyzed included (a) history of DT; (b) initial CIWA-AR score; (c) drug dosages delivered; (d) duration of medical treatment of severe AWS; (e) other adjunct medication use; (f) intensive care unit (ICU) length of stay (LOS); (g) hospital LOS; (h) readmission rate; (i) DT or seizures; (j) other complications including endotracheal intubation and mechanical ventilation. These outcomes were unanimously decided to be important as they influence the practical management of severe AWS within hospitals and institutions. Heterogeneity amongst the outcome variables of these trials was determined by Cochran’s Q statistics and I² index. The meta-analysis was prepared in accordance with PRISMA guidelines. Results: Seven studies consisting of 1 prospective RCT and 6 retrospective trials were identified. Results from all the included studies show similar variables between BZD and PB group: mean age, percentage of patients with previous DT, and median Clinical Institute Withdrawal Assessment for Alcohol Revised (CIWA-AR) scores. There were no statistically significant differences in ICU and hospital LOS when comparing the BZD and PB groups. The prevalence of DT and adjunct medication usage was higher in the BZD group; however, statistically insignificant in the meta-analysis. The pooled prevalence of intubation was similar between the two treatment groups. Lastly, Hawa et al. reported higher alcohol-related re-admission in the BZD group. Conclusions: Based on our findings, the use of PB as the primary treatment, or when used in addition/as adjunct to BZD, offers several advantages in the treatment of severe AWS. These include trend toward improved DT and seizures in severe AWS, shortened ICU and hospital LOS, and less use of adjunct medications. Further RCTs are needed to investigate PB as the primary treatment of AWS that presents with severe features.

Background: NF1 (neurofibromin type 1) encodes neurofibromin, and is commonly altered in many cancers, including breast cancer. NF1 suppresses breast cancer by not only negatively regulating RAS signaling but also by independently acting as a transcriptional co-repressor of the estrogen receptor (ER). In this study, we analyzed the genomic landscape of patients with NF1 alterations from a large genomic database to define what unique patient characteristics were associated with NF1 alterations. Methods: Retrospective analysis of the Guardant Health database based on samples from the commercially available Guardant360® plasma-based circulating tumor DNA (ctDNA) assay. Samples were queried between June 2020-June 2022 for patients with any detected NF1 alteration and breast cancer diagnosis. NF1 synonymous alterations were excluded from this study. Statistics were conducted using a two-sided Fisher’s exact test. Results: NF1 alterations were found in 895 patients with breast cancer over 1156 samples, typically in female patients (98.2%) diagnosed with breast carcinoma (99.4%). The average age of patients was 66 years old (23-93), with a median of 1.4 serial tests (1-19). The common nonsynonymous NF1 alterations are missense mutations (56.5%), nonsense mutations (23.5%), indels (22.3%), and aberrant splicing mutations (8.2%). There were significant differences in NF1 alteration frequency between younger (< 55 y/o) vs. older (≤55 y/o) patients, with older patients demonstrating an increase in NF1 alterations (p< 0.0001) across all mutation types except for splice mutations. There was also a significant difference in NF1 alterations between female vs. male patients, with male patients trending toward a higher frequency in NF1 missense alterations. Mutations affecting genes encoding the receptor tyrosine kinase (e.g., HER2) and the Ras-MAP kinase pathways (e.g., several RAS and RAF genes) co-occur with NF1 mutations. In contrast, there is no evidence of co-occurrence with mutations in the ESR1 gene, which encodes ER. The blood tumor mutational burden (bTMB) score was evaluable in 848 patients with an average score of 26.1 mut/Mb (range 1.16-447.7). In addition, mutations affecting genes controlling the cell cycle were also found to co-occur with NF1 mutations. Conclusions: Plasma-based liquid biopsy via G360 can efficiently identify NF1 alterations illustrating that such genetic alterations are common in this metastatic breast cancer cohort. Analysis of co-occurrent mutations supports our model that a key role of NF1 is to act as an ER transcriptional co-repressor, such that its loss is functionally redundant with acquiring ESR1 mutations. Oncogenic activation of the RTK-Ras pathways is needed for efficient progression to metastasis by additional mutations in this pathway. Mutational co-occurrence may also identify collaborating molecular events that collaborate with NF1 loss to promote treatment relapse and metastasis. Citation Format: Eric Chang, Jill Tsai, Bora Lim. Characterization of the genomic landscape of breast carcinoma patients with NF1 alterations using comprehensive cell-free tumor DNA next-generation sequencing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-03.

We present a bang-bang phase-locked loop (PLL) generator that encapsulates design methodologies for its circuit blocks and the complete PLL system. The generator is fully automated and parameterized, producing the layout and schematic based on process characterization and top-level specifications. Three 14GHz PLLs are instantiated in TSMC 16nm, GF 14nm and Intel 22nm technologies, demonstrating the process portability. The rapid generation time of less than four days enables fast PLL design and technology porting. The PLL design fabricated in TSMC 16nm shows RMS jitter of 565.4fs and power of 6.64mW from a 0.9V supply.

Background Cornelia de Lange syndrome (CdLS) is characterized by slow growth with short stature, intellectual disability with developmental delays, distinctive facial features, and limb defects. Various genetic mutations have been associated with CdLS, with approximately 60% of cases having a mutation in the NIPBL gene. There are few published reports of endocrine disorders in individuals affected by CdLS. Clinical Case A four month old female was admitted for hypoglycemic seizures. She had previously undergone workup for CHARGE syndrome. Physical exam was remarkable for acrocephaly, malar hypoplasia, hypertelorism with downslanting eyes, hirsutism, and bradydactyly. During her hospitalization, she remained persistently hypoglycemic despite repeated dextrose boluses, prompting a scheduled fasting test. Results indicated severe hypoglycemia (37 mg/dL) with inappropriate suppression of beta-hydroxybutyrate (0. 08 mmol/L) and negative urine ketones. Her glucagon stimulation test result showed an exaggerated increase of the glucose greater than 30 mg/dL after glucagon administration (glucose was 31 mg/dL at the start of the test; peak glucose was 77 mg/dL after receiving 0. 03 mg/kg of glucagon), indicating excessive glycogen stores. These findings were consistent with hyperinsulinism. Furthermore, she was found to have an undetectable cortisol ( Conclusion There are very few clinical reports that mention either hyperinsulinism or hypopituitarism in an individual affected by CdLS. This patient is a rare documented case of CdLS presenting with both hyperinsulinism and hypopituitarism. Further understanding of the different genetic mutations seen with CdLS could help identify atypical forms of CdLS associated with endocrinopathies and more clearly direct unifying treatment. Presentation: No date and time listed