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Technology in Diabetes Mellitus has been available in the form of insulin pump delivery systems for almost 40 years and glucose sensing technology for over 20 years. It is just the last 10 years there have been broad adoptions of both pumps and personal sensors and more recently integrated delivery systems that are bringing us closer to physiologic dynamic control of diabetes that strives to replicate glucose control similar to persons without diabetes (who have normal glucose control mechanisms). Data from this technology is part of routine clinical practice in anyone caring for persons with diabetes especially in the type 1 space. This is a new avenue for clinical research but also a new area of challenge for providers and staff caring for patients with this technology. There is slowly emerging research that focuses on this clinical data specifically available from personal sensors. This discussion will briefly review what this looks like in clinical practice and a sampling of data from research in this new technology. Then we will discuss how providers, educators, patients, and other stakeholders should work as a team to focus on critical thinking as an essential skill set.

Cardiac 3D printing is mainly performed from magnetic resonance imaging (MRI) and computed tomography (CT) 3D datasets, though anatomic detail of atrioventricular (AV) valves may be limited. 3D echo provides excellent visualization of AV valves. Thus, we tested the feasibility and accuracy of 3D printing from 3D echo in this pilot series of subjects with congenital heart disease (CHD), with a focus on valve anatomy. Five subjects with CHD were identified. 3D echo data were converted to 3D printable files and printed in collaboration with 3D Systems Healthcare (Golden, Colorado). A novel technique for valve modeling was utilized using commercially available software. Two readers (KM, SA) independently measured valve structures from 3D models and compared to source echo images. 3D printing was feasible for all cases. Table 1 shows measurements comparing 2D echo to 3D models. Bland Altman analysis showed close agreement and no significant bias between 2D and digital 3D models (mean difference 0.0, 95% CI 1.1 to − 1.1) or 2D vs printed 3D models, though with wider limits of agreement (mean difference − 0.3, 95% CI 1.9 to − 2.6). Accuracy of 3D models compared to 2D was within

Next-generation sequencing has resulted in an explosion of available data, much of which remains unstudied in terms of biochemical function; yet, experimental characterization of these sequences has the potential to provide unprecedented insight into the evolution of enzyme activity. One way to make inroads into the experimental study of the voluminous data available is to engage students by integrating teaching and research in a college classroom such that eventually hundreds or thousands of enzymes may be characterized. In this study, we capitalize on this potential to focus on SABATH methyltransferase enzymes that have been shown to methylate the important plant hormone, salicylic acid (SA), to form methyl salicylate. We analyze data from 76 enzymes of flowering plant species in 23 orders and 41 families to investigate how widely conserved substrate preference is for SA methyltransferase orthologs. We find a high degree of conservation of substrate preference for SA over the structurally similar metabolite, benzoic acid, with recent switches that appear to be associated with gene duplication and at least three cases of functional compensation by paralogous enzymes. The presence of Met in active site position 150 is a useful predictor of SA methylation preference in SABATH methyltransferases but enzymes with other residues in the homologous position show the same substrate preference. Although our dense and systematic sampling of SABATH enzymes across angiosperms has revealed novel insights, this is merely the “tip of the iceberg” since thousands of sequences remain uncharacterized in this enzyme family alone.

We report a pediatric patient with nonatherosclerotic chronic total occlusion (CTO) of the left main coronary artery (LMCA) leading to complete LMCA atresia which was successfully recanalized via retrograde techniques through a previous internal mammary bypass graft. After the CTO was treated, the artery was found to be anomalous off the right cusp with an intramural coarse and slit-like orifice. The patient's ischemic symptoms resolved after Percutaneous Coronary Intervention (PCI), and she has continued to do well.

Background: Exposure to metals increases risk for pregnancy complications. Extracellular vesicle (EV) miRNA contribute to maternal-fetal communication and are dysregulated in pregnancy complications. However, metal impacts on maternal circulating EV miRNA during pregnancy are unknown. Our objective was to investigate the impact of multiple metal exposures on EV miRNA in maternal circulation during pregnancy in the MADRES Study.Methods: Associations between urinary concentrations of nine metals and 106 EV miRNA in maternal plasma during pregnancy were investigated using robust linear regression (N=231). Primary analyses focused on metal-miRNA associations in early pregnancy (median: 12.3 weeks gestation). In secondary analyses, we investigated associations with late pregnancy miRNA counts in a smaller subset of participants (N=184) with paired data in the third trimester (median: 31.8 weeks gestation). MiRNA associated with three or more metals (PFDR

Interconnect scaling has been identified as one of the key challenges associated with deeply scaled technology nodes because of several reasons. First, the miniaturization of the metal line and via dimensions not only reduces the cross-sectional area for conduction but also leads to an increase in copper (Cu) resistivity due to sidewall scattering and grain-boundary scattering [1] . Second, the highly resistive barrier/liner (TaN/Ta) layers (required to prevent copper (Cu) diffusion into the surrounding dielectrics) further reduce the cross-sectional area of Cu ( Fig. 1 ), aggravating the first issue. Third, the barrier/liner layers are in the path of the vertical conduction through the vias, which significantly increases the via resistance. To address some of these challenges, replacing the conventional TaN/Ta barriers/liners with ultra-thin 2D transition metal dichalcogenide (2D TMD) material such as TaS 2 (which serves as both barrier and liner) has been proposed [2] . With only 0.7nm of TaS 2 (as opposed to 2nm TaN + 2nm Ta), the % volume of Cu in the interconnects can be increased ( Fig. 1 ). However, TaS 2 suffers from higher vertical resistivity compared to Ta/TaN, which deteriorates the via conductivity. Therefore, evaluation of the overall merits and trade-offs of TaS 2 -augmented interconnects mandates extensive device modeling and circuit analysis. In this work, we analyze interconnects with TaS 2 barrier/liner by (a) building a 3D modeling framework for the line metals and vias, (b)integrating the model with the comprehensive circuit simulation flow based on synthesis and place-and-route and (c) evaluating the resistance of different levels of metals (M1-M9) and vias (V1-V8) and the circuit implications of TaS 2 -augmented interconnects in comparison with the conventional interconnects.

Infant birth weight influences numerous health outcomes throughout the life course including childhood obesity and metabolic morbidities. Maternal experience of stress, both before and during pregnancy, has been hypothesized to influence fetal growth and birth outcomes. However, these associations currently are not fully understood, due to conflicting results in the published literature. Salivary cortisol is often used as a biological biomarker to assess the diurnal pattern of the hypothalamic&ndash, pituitary&ndash, adrenal axis (HPA-axis) functioning. Cortisol metrics include both the total cortisol concentration secreted during waking hours, reflected by the area under the curve (AUC), and cortisol dynamics, which include the diurnal cortisol slope (DCS) and the cortisol awakening response (CAR). This study examined the association of these cortisol metrics measured during the third trimester of pregnancy and infant birth weight among 240 mother-infant dyads participating in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort study, which is predominately comprised of Hispanic low-income women. There were no significant associations with the maternal biological stress response and infant birth weight in this study. More research is needed in larger studies to better understand how the biological stress response influences birth weight in populations facing health disparities.

Left ventricular (LV) hypertrophy (LVH) predicts adverse cardiac events in adults. We sought to determine the risk factors and prognostic significance of altered LV geometry in preterm infants. In an echocardiographic, single-center, retrospective case–control study we investigated the risk factors and outcomes in patients with altered LV geometry (either increased left ventricular mass index (LVMI) or increased relative wall thickness (RWT)) from a cohort of 503 preterm infants ≤2 kg. Altered LV geometry was seen in 180 patients and was predicted by postnatal steroids and small for gestational age. Hospital stay was longer in the elevated RWT cases. Altered LV geometry resolved in 129 of the 131 cases with follow-up echocardiogram. Fifteen of 94 patients with elevated RWT died compared to 3/90 controls (P = 0.004). Altered LV geometry in preterm infants is associated with postnatal steroid use and small for gestational age. Elevated RWT is associated with longer hospital stay and increased mortality.

A facile, one pot synthesis of a coordinatively unsaturated ruthenium complex supported by a tripodal, protic bis(N-heterocyclic carbene) phosphine ligand is presented. A number of coordination complexes were discovered en route during this synthesis, revealing some of the unique aspects of complexes ligated by this type of tridentate, protic bis(NHC) ligand. Through a combination of 1D and 2D NMR spectroscopic analysis and single crystal X-ray diffraction, we reveal the intermediacy of phosphine-ligated bisimidazole complexes and show that abstraction of inner-sphere halide ions facilitates conversion to the desired tridentate bis(NHC) coordination mode. Ultimately the use of N-methyl-2-pyrrolidone is shown to enable the use of the extreme temperatures needed to facilitate the direct, thermally activated tautomerization reaction that gives rise to the bis(NHC) motif.

Background: Allogeneic chimeric antigen receptor (CAR) T cell therapy offers the prospect of readily accessible, CD19-directed cellular therapy with assured fitness and effector function for subjects with relapsed or refractory (R/R) B-cell malignancies. Using a single step process, the CD19 CAR is knocked-into the T-cell receptor alpha constant (TRAC) locus after editing with a TRAC-specific ARCUS nuclease, thereby preventing graft-versus-host disease through disruption of the endogenous T-cell receptor. To mitigate rejection of PBCAR0191, an enhanced lymphodepletion (LD) chemotherapy regimen (eLD) was investigated to improve PBCAR expansion and persistence by both deepening and extending the duration of LD without prolonged immune suppression. Here we present results of eLD conditioning in subjects with CD19 + NHL or ALL. Methods: Subjects with measurable CD19 + R/R B-ALL or NHL disease after two or more prior treatment regimens were enrolled; all without CNS disease, recent active infection, or other major medical comorbidities and no active GvHD. Prior autologous (auto) or allogeneic stem cell transplant and/or CD19-directed auto-CAR therapy was permitted. Lymphodepletion consisting of fludarabine 30 mg/m 2/day x 4 days plus cyclophosphamide 1000 mg/m 2/day x 3 days was administered prior to infusion of 3 x 10 6 cells/kg PBCAR0191 CAR T cells on day 0. CAR T cell expansion kinetics were assessed by flow cytometry and RT-PCR. Results: As of July 1, 2021, 21 subjects have been treated including 16 NHL (13 with Day 28 assessment) and 5 B-ALL. Subjects were heavily pretreated (median, 7 lines; max 15) with aggressive and advanced disease (Table 1), including six subjects who had progressed after treatment with an auto-CD19 CAR, and 8 after auto or allogeneic stem cell transplant. Most adverse events were mild. Grade 3 or greater neutropenia occurred in 2 NHL and 2 BALL subjects, and 1 Grade 3 self-limited ICANS with no evidence of Graft versus Host Disease (GvHD). There was 1 non-disease progression, infectious death at day 54 that was deemed possibly related to PBCAR0191 by the investigator. CAR T kinetics were profoundly improved compared to standard LD, with both peak cell expansion and area under the curve increasing 80-fold. Improved CAR T cell kinetics was associated with high rates of objective response. Overall, 15 of 18 (83%) evaluable subjects responded to PBCAR0191, including 11/13 (85%) NHL and 4/5 (80%) ALL subjects, with complete responses (CR/CRi) achieved in 8/13 (62%) NHL and 4 /5 (80%) ALL subjects. To date 3/15 responses are ongoing at > 6 months duration, 1 received consolidation with allo-SCT and 3 additional subjects have not yet reached the 6-month evaluation threshold at the time of abstract submission. Of note, there was no difference in the frequency of response among subjects who were CAR naïve compared to those who received a prior auto-CD19 CAR. Remarkably, among 6 subjects who progressed following an auto-CD19 CAR (5 NHL, 1 ALL), the ORR was 83% (5/6 pts) with 4 (67%) CRs, including an ongoing MRD - CR in an ALL subject of > 6 months. Conclusions: eLD mitigated PBCAR0191 rejection to markedly improve peak CAR T cell expansion and persistence with predictable and manageable toxicity. A single infusion of PBCAR0191 following eLD provided clinical benefit in the majority of subjects, yielding high rates of overall and complete response with promising activity in both CD19 CAR naïve subjects and those who progressed following auto-CD19 CAR therapy. Figure 1 Figure 1. Disclosures Shah: Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Jacobson: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Jain: Beigene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding. Johnson: Precision BioSciences, Inc: Current Employment, Current equity holder in publicly-traded company. Vainorius: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; United Therapeautics: Current equity holder in publicly-traded company. Yu: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company. Heery: Precision BioSciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Arcellx: Current Employment, Current holder of stock options in a privately-held company. List: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Aileron Therapeutics: Consultancy. Reshef: Gilead and Novartis: Honoraria; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy. Akard: Takeda: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Speakers Bureau; Astellas Pharma: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau. Sauter: Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite/Gilead: Consultancy. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Deol: Kite, a Gilead Company: Consultancy.

Introduction: CD19-directed autologous CAR-T products induce high response rates in adults with R/R B-ALL, yet many patients relapse within the first year. Additionally, cell manufacturing timelines, and poor t-cell fitness may imperil efficacy, especially among those with proliferative disease. This makes access to a donor-derived, readily available CAR-T product of great interest in this patient population, particularly when consolidation with allogeneic stem cell transplant (allo-SCT) is possible. We report preliminary safety, efficacy, and correlative data for the R/R B-ALL patients dosed with at least 3 x 10 6 CAR-T cells/kg of PBCAR0191, an allogeneic 'off-the-shelf' CD19-directed CAR-T. Methods: Subjects were 18 years or older with CD19+ R/R B-ALL after at least 2 prior lines of therapy. Patients were required to have adequate organ function and no active GvHD, CNS disease, active infections, or other active medical issues. Prior allo-SCT and/or autologous CAR-T therapy were allowed. Subjects received either standard (sLD; 30mg/m2/day and 500mg/m2/day x 3 days fludarabine and cyclophosphamide, respectively) or enhanced (eLD; 30mg/m2/day x 4 days flu and 1000mg/m2/day x 3 days cy) lymphodepletion preceding PBCAR0191 infusion. Correlative laboratory samples were taken for CAR-T expansion, persistence, molecular response to treatment and safety assessments. Results: As of August 2, 2021, 15 subjects with R/R CD19+ B-ALL have been dosed with dose Dose level 3/4a (3 X 10 6 CAR-T cells/kg or equivalent, n=11) or a Dose level 4b (flat dose of 5 X 10 8 CAR-T cells, n=4). Demographics, baseline disease, and prior treatment data are presented in the table. Most of the Adverse events (AE) reported to date were mild, with no cases of GvHD, no Grade ≥3 CRS and 1 case of Grade 3 ICANS which resolved within 48 hours. 67% of subjects treated (10/15) experienced PBCAR0191 related AEs, with 60% (9/15) of subjects experiencing serious AEs (one related to PBCAR0191, ICANS Grade 3). The complete response (CR) or CRi (incomplete marrow recovery) rate at Day ≥28 is 33% (2/6) in DL3/4a and sLD, 80% (4/5) in DL3/4a with eLD and 75% (3/4) in DL4b with sLD. Importantly, 4/15 (27%) responding subjects underwent allo-SCT, with one additional subject not able to receive transplant due to eligibility yet maintaining an MRD- CR for >250 days, and one refusing to proceed with transplant. Product accessibility was evident compared to autologous CAR-T products, with median time from screening completion to PBCAR0191 infusion of 7 days (median of 1 day until start of LD) and all eligible subjects receiving PBCAR0191 infusion. Conclusion: PBCAR0191 has demonstrated a manageable safety profile and high complete response rate at day 28 or later, providing an adequate window for potential bridge to allo-SCT. Figure 1 Figure 1. Disclosures Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Pfizer: Research Funding; Janssen: Honoraria; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kantarjian: KAHR Medical Ltd: Honoraria; Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Heery: Precision BioSciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Arcellx: Current Employment, Current holder of stock options in a privately-held company. List: Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; CTI Biosciences: Consultancy; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Johnson: Precision BioSciences, Inc: Current Employment, Current equity holder in publicly-traded company. Lou: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company. Vainorius: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; United Therapeautics: Current equity holder in publicly-traded company. Olszewski: Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genmab: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Shah: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other. OffLabel Disclosure: PBCAR0191 is not FDA approved

Objectives This study describes the biochemical changes – also known as the storage lesion – that occur in canine packed red blood cells during ex vivo storage. Materials and Methods Ten 125-mL units of non-leuco-reduced packed red blood cells in citrate phosphate dextrose adenine were obtained from a commercial blood bank within 24 hours of donation. Samples were aseptically collected on days 1, 4, 7, 14, 28, 35 and 42 for measurement of sodium, potassium, chloride, lactate, glucose, pH and ammonia concentrations. All units were cultured on day 42. Friedman's repeated measures test with Dunn's multiple comparison test was used for non-parametric data. A repeated-measures analysis of variance with Tukey's multiple comparison test was used for parametric data. Alpha was set to 0·05. Results All analytes changed significantly during storage. The mean ammonia on day 1 (58·14 g/dL) was significantly lower (P

Fine-needle aspiration and cytologic examination should be a component of the diagnostic workup of skin masses. Cytologic examination may allow veterinarians to categorize neoplasms of the skin as epithelial, mesenchymal, or round cell and to determine the malignancy potential of the tumor. These results should provide veterinarians the ability to discuss with their clients the subsequent diagnostic considerations and appropriate treatment options for these tumors.

The concept of the "Golden Hour" has been a time-honored tenet of prehospital trauma care, despite a paucity of data to substantiate its validity. Non-compressible torso hemorrhage has been demonstrated to be a significant cause of mortality in both military and civilian settings. We sought to characterize the impact of prehospital time and torso injury severity on survival. Furthermore, we hypothesized that time would be a significant determinant of mortality in patients with higher Abbreviated Injury Scale (AIS) grades of torso injury (AIS ≥ 4) and field hypotension (prehospital SBP ≤ 110 mmHg) as these injuries are commonly associated with hemorrhage.Data for this analysis was generated from a registry of 2,523,394 injured patients entered into the National Trauma Data Bank Research Data Set from 2012 to 2014. Patients with torso injury were identified utilizing Abbreviated Injury Scale (AIS) for body regions 4 (Thorax) and 5 (Abdomen). Specific inclusion criteria for this study included pre-hospital time, prehospital SBP ≤110 mmHg, torso injury qualified by AIS and mortality. Patients with non-survivable torso injury (AIS = 6), severe head injuries (AIS ≥ 3), no signs of life in the field (SBP = 0), interfacility transfers, or those with any missing data elements were excluded. This classification methodology identified a composite cohort of 42,135 adult patients for analysis.The overall mortality rate of the study population was 7.9% (3326/42,135); Torso AIS and prehospital time were noted to be strong independent predictors of patient mortality in all population strata of the analysis (P 0.05). The data demonstrated a profound incremental increase in mortality in the early time course after injury associated with torso AIS ≥4.In patients with high-grade torso injury, AIS grades ≥4, the degree anatomic disruption is associated with significant hemorrhage. In our study, a precipitous rise in patient mortality was exhibited in this high-grade injury group at prehospital times30 min. Our data highlight the critical nature of prehospital time in patients with non-compressible torso hemorrhage. However, realizing that evacuation times ≤30 min may not be realistic, particularly in rural or austere environments, future efforts should be directed toward the development of therapies to increase the window of survival in the prehospital environment.

A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors.

The design of microelectronic systems requires integration and cooperation across multiple disciplines, but most curriculum is taught in unconnected pieces. This makes the creation of manageable projects that reflect the design experience very difficult. The System-on-a-Chip Extension Technologies (SoCET) group is an undergraduate design group modelled after industry. SoCET is a multi-semester project of primarily undergraduate students in the process of iteratively improving, prototyping, fabricating, and testing an SoC. The group recently taped out its fourth iteration of the SoC and submitted it for fabrication. Students on the SoCET team are divided into smaller groups which focus on specific SoC design tasks. These tasks are connected by a near industry grade design flow forcing students to address system and design flow integration issues. This framework enables students to approach engineering as an integrative process and learn relationships between seemingly separate disciplines.

Rare heterozygous variants in SMAD6 have been identified as a significant genetic contributor to bicuspid aortic valve-associated thoracic aortic aneurysm on one hand and non-syndromic midline craniosynostosis on the other. In this study, we report two individuals with biallelic missense variants in SMAD6 and a complex cardiac phenotype. Trio exome sequencing in Proband 1, a male who had aortic isthmus stenosis, revealed the homozygous SMAD6 variant p.(Ile466Thr). He also had mild intellectual disability and radio-ulnar synostosis. Proband 2 is a female who presented with a more severe cardiac phenotype with a dysplastic and stenotic pulmonary valve and dilated cardiomyopathy. In addition, she had vascular anomalies, including a stenotic left main coronary artery requiring a bypass procedure, narrowing of the proximal left pulmonary artery and a venous anomaly in the brain. Proband 2 has compound heterozygous SMAD6 missense variants, p.(Phe357Ile) and p.(Ser483Pro). Absence of these SMAD6 variants in the general population and high pathogenicity prediction scores suggest that these variants caused the probands' phenotypes. This is further corroborated by cardiovascular anomalies and appendicular skeletal defects in Smad6-deficient mice. SMAD6 acts as an inhibitory SMAD and preferentially inhibits bone morphogenetic protein (BMP)-induced signaling. Our data suggest that biallelic variants in SMAD6 may affect the inhibitory activity of SMAD6 and cause enhanced BMP signaling underlying the cardiovascular anomalies and possibly other clinical features in the two probands.

Little is known about patients' electronic cigarette use, interest in and use of smoking cessation treatments, and providers' attitude towards such treatment. We assessed patients (N = 231) and providers (45 psychiatrists, 97 case workers) in four Community Mental Health Centers. Interestingly, 50% of smokers reported interest in using electronic cigarettes to quit smoking, and 22% reported current use. While 82% of smokers reported wanting to quit or reduce smoking, 91% of psychiatrists and 84% of case workers reported that patients were not interested in quitting as the lead barrier, limiting the provision of cessation interventions. Providers' assumption of low patient interest in treatment may account for the low rate of smoking cessation treatment. In contrast, patients report interest and active use of electronic cigarettes to quit smoking. This study highlights the need for interventions targeting different phases of smoking cessation in these patients suffering disproportionately from tobacco dependence.

On a muggy southern summer Monday afternoon, with thunderstorm clouds looming in the not-so-distant horizon, thousands of adults, teenagers, and children; men and women; black, white, and brown; st...

Across the United States, a counter-network of teacher activists is engaged in the development of grassroots organizing structures to advocate for social justice, resist the privatization of public...

In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population.Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale (CGI-I).One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 ± 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 ± 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or "much improved."These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.

Objective To describe the biochemical changes that occur during storage of feline packed red blood cells. Methods Feline packed red blood cells were obtained from the manufacturer via overnight delivery immediately following collection. Bag spikes were placed using aseptic technique and samples were drawn on days 1, 4, 7, 14, 21, 28 and 35. Sodium, potassium, chloride, glucose, lactate, pH and ammonia were measured at each time point. Aerobic and anaerobic bacterial cultures were submitted following collection on day 35. Results There were statistically significant increases in the median concentrations of lactate and ammonia within the first 2 weeks of storage to a concentration of 12·38 mmol/L and 447·96 µmol/L, respectively. Glucose concentrations decreased significantly by day 28 to a mean of 1·86 mmol/L. Median sodium and chloride concentrations increased throughout the course of storage to a concentration of 158·20 and 131·00 mmol/L, respectively. Mean potassium concentrations decreased to a concentration of 2·40 mmol/L. Clinical significance These results show that biochemical derangements within feline packed red blood cells are progressive, with some alterations, such as lactate and ammonia, occurring early within the storage periods, while others, including glucose and electrolytes, are slower to develop. Additional prospective research evaluating the clinical effects of these biochemical alterations is required.

This 2017 Politics of Education Yearbook focuses on the power of policymaking networks to set agendas and shape education policy. As the yearbook title suggests, we present a series of case studies...

Left ventricular (LV) hypertrophy (LVH) predicts adverse cardiac events in adults. We sought to determine the risk factors and prognostic significance of altered LV geometry in preterm infants.In an echocardiographic, single-center, retrospective case-control study we investigated the risk factors and outcomes in patients with altered LV geometry (either increased left ventricular mass index (LVMI) or increased relative wall thickness (RWT)) from a cohort of 503 preterm infants ≤2 kg.Altered LV geometry was seen in 180 patients and was predicted by postnatal steroids and small for gestational age. Hospital stay was longer in the elevated RWT cases. Altered LV geometry resolved in 129 of the 131 cases with follow-up echocardiogram. Fifteen of 94 patients with elevated RWT died compared to 3/90 controls (P = 0.004).Altered LV geometry in preterm infants is associated with postnatal steroid use and small for gestational age. Elevated RWT is associated with longer hospital stay and increased mortality.

From September 9, 2016 through October 15, 2016, over 2000 citizens of Indiana carried an unusual torch through all 92 counties. A map updated in real time indicated the current location of the torch and social media sites featured photos and videos taken a short time before using the torch. This torch was the result of many student projects and a challenging integration and production process. This paper will provide you with insight into some of what was required to make this happen along with lessons learned and observations on ways that this project went beyond what is practiced in most student projects or even industry sponsored projects.

The development of FPGA-based digital signal processing devices has been gaining attention. Researchers seek to reduce power consumption and enhance signal processing quality in these devices with given resources and spatial limits. Hence, there is a need to investigate both the capability and the power consumption associated with the various digital filtering schemes commonly used in FPGA-based devices. We carry out a set of performance and power consumption measurements of interpolation filters using an FPGA and other basic signal processing building blocks. We compare the signal processing performance with theoretical prediction, and measure the power consumed by the filters. Our experimental measurements also confirm the accuracy of the numerical tools used for predicting FPGA power consumption. This paper is aimed at providing a framework to accurately test basic signal processing across various interpolation schemes and compare the respective schemes’ software-side contributions to power consumption and filtering quality.

IL-35 is a recently identified cytokine exhibiting potent immunosuppressive properties. The therapeutic potential and effects of IL-35 on pathogenic T effector (Teff) cells and Foxp3+ Treg cells, however, are ill-defined. We tested the capacity of IL-35 to suppress ongoing autoimmunity in NOD mice. For this purpose, an adeno-associated virus vector in which IL-35 transgene expression is selectively targeted to β cells via an insulin promoter (AAV8mIP-IL35) was used. AAV8mIP-IL35 vaccination of NOD mice at a late preclinical stage of type 1 diabetes (T1D) suppressed β-cell autoimmunity and prevented diabetes onset. Numbers of islet-resident conventional CD4+ and CD8+ T cells, and DCs were reduced within 4 weeks of AAV8mIP-IL35 treatment. The diminished islet T-cell pool correlated with suppressed proliferation, and a decreased frequency of IFN-γ-expressing Teff cells. Ectopic IL-35 also reduced islet Foxp3+ Treg-cell numbers and proliferation, and protection was independent of induction/expansion of adaptive islet immunoregulatory T cells. These findings demonstrate that IL-35-mediated suppression is sufficiently robust to block established β-cell autoimmunity, and support the use of IL-35 to treat T1D and other T-cell-mediated autoimmune diseases.