Prehospital Delta Shock Index Predicts Mortality and Need for Life Saving Interventions in Trauma Patients.

OBJECTIVES: The delta shock index (ΔSI), defined as the change in shock index (SI) over time, is associated with hospital morbidity and mortality, but prehospital studies about ΔSI are limited. We investigate the association of prehospital ΔSI with mortality and resource utilization, hypothesizing that increases in SI among field trauma patients are associated with increased mortality and blood product transfusion. METHODS: We performed a multicenter, retrospective, observational study from the Linking Investigators in Trauma and Emergency Services (LITES) network. We obtained data from January 2017 to June 2021. We fit logistic regression models to evaluate the association between an increase ΔSI > 0.1 and 28-day mortality and blood product transfusion within 4 hours of emergency department (ED) arrival. We used negative binomial models to evaluate the association between ΔSI > 0.1 and days in hospital, intensive care unit (ICU), and on ventilator (up to 28 days). RESULTS: We identified 33,219 prehospital patients. We excluded burn patients and those without documented prehospital or ED heart rate or blood pressure, resulting in 30,511 cases for analysis. In adjusted analysis for the primary outcome of 28-day mortality, patients who had a ΔSI > 0.1 based on initial vital signs were 31% more likely to die (adjusted odds ratio (AOR) of 1.31, 95% CI 1.21-1.41) compared to those patients who had a ΔSI ≤0.1. These patients also spent 16% more days in hospital (adjusted incident rate ratio (AIRR) 1.16, 95% CI 1.14-1.19), 34% more days in ICU (AIRR 1.34, 95% CI 1.28-1.41), and 61% more days on ventilator (ARR 1.61, 95% CI 1.47-1.75). Additionally, patients with a ΔSI > 0.1 had higher odds of receiving blood products (AOR 2.00, 95% CI 1.88-2.12) within 4 hours of ED arrival. Models fit excluding hypotensive patients performed similarly. CONCLUSIONS: An increase of greater than 0.1 in the ΔSI was associated with increased 28-day mortality; increased days in hospital, in ICU, and on ventilator; and increased need for blood product transfusion within 4 hours of ED arrival. This association held true for initially normotensive patients. Validation and implementation are needed to incorporate ΔSI into prehospital and ED triage.

A rare case of symptomatic congenital lobar emphysema in an adolescent female who underwent expectant management of a congenital pulmonary malformation: a case report.

Background: Asymptomatic congenital pulmonary airway malformations (CPAMs) and congenital lobar emphysema (CLE) may safely be observed, though little is known about how many patients later require surgery. The management of these lesions remains controversial, as limited research exists on which patients later require surgery. Notably, there are few reported cases where patients become symptomatic and require definitive treatment beyond childhood. Case Description: We present the rare case of a 17-year-old female who developed dyspnea on exertion associated with pre-syncope, following diagnosis of a CPAM at birth. She had undergone surveillance until 2 years of age. The decision to proceed with a left upper lobectomy via thoracotomy was made, for treatment of her symptoms. During the surgery, one lung ventilation suggested that oxygenation had likely limited to the patient's healthy lung, prior to intervention. The surgery was uncomplicated, and her recovery was uneventful. Pathology revealed CLE. Conclusions: This case highlights that congenital lung malformations should remain in the differential diagnosis of patients presenting in adolescence or adulthood with new onset respiratory symptoms. For patients with a history of untreated congenital lung pathology, it is important to consider the presence of adhesions and loss of domain in perioperative planning. This case also highlights the ongoing need for research on the prognostication of these lesions to better inform surveillance.

Ecofriendly Filtration of Silver Nanoparticles for Ultrasensitive Surface-Enhanced (Resonance) Raman Spectroscopy-Based Detection.

In this study, a widely used colloid of Creighton AgNPs (ORI, 1-100 nm, mostly ≤ 40 nm, ∼10 µg mL-1) was rapidly manipulated via tangential flow filtration (TFF) for highly reproducible surface-enhanced (resonance) Raman spectroscopy (SE(R)RS) experiments down to the single-molecule (SM) level. The quasi-spherical AgNPs were size-selected, purified, and concentrated in two TFF fractions of a cutoff diameter of ∼40 nm: AgNP ≤ 40 (∼900 µg mL-1) and AgNP ≥ 40 (∼100 µg mL-1). The SE(R)S-based sensing capabilities of the two TFF fractions were then tested under pre-resonance (632.8 nm) and resonance (532.1 nm) excitation conditions for rhodamine 6G (R6G, 10-6-10-15 M). Both TFF isolates, AgNP ≤ 40 and AgNP ≥ 40, were more effective in adsorbing the R6G analyte (≥91%) than the original colloid (≥78%) at submonolayer coverages. Furthermore, the surface enhancement factors (SEF) of the two TFF fractions were markedly superior to those of ORI under all excitation conditions. SERS at 632.8 nm: only AgNP ≥ 40 enabled the detection of R6G at 10-9 M and produced the largest SEF (2.1 × 106). SE(R)RS and SM-SERRS at 532.1 nm: AgNP ≥ 40 gave rise to the largest SEF values (2.5 × 1010) corresponding to the SM regime down to 10-15 M of R6G. Nevertheless, AgNP ≤ 40 compensated for the size-dependence of the electromagnetic enhancements by an increase in the silver concentration, which led to SEF values comparable to those of AgNP ≥ 40 through additional resonance enhancements. TFF resulted into a ∼100-fold increase (AgNP ≤ 40) in the number of negatively charged AgNPs that were available to electrostatically bridge R6G cations and form SERRS "hot-spots" (AgNP-R6G-AgNP) within the focal volume. Evidently, the interplay between AgNP size, AgNP concentration, and excitation wavelength governs the SE(R)RS enhancements. This study demonstrated that TFF can facilitate the ecofriendly isolation of spherical AgNPs of controlled morphological and plasmonic properties for further enhancing their sensing capabilities as SE(R)RS substrates.

Protonophore treatment augments energy expenditure in mice housed at thermoneutrality.

Background: Sub-thermoneutral housing increases facultative thermogenesis in mice, which may mask the pre-clinical efficacy of anti-obesity strategies that target energy expenditure (EE). Here, we quantified the impact of protonophore treatment on whole-body energetics in mice housed at 30°C. Methods: C57BL/6J mice (n = 48, 24M/24F) were housed at 24°C for 2 weeks; 32 (16M/16F) were then transitioned to 30°C for a further 4 weeks. Following 2 weeks acclimation at 30°C, mice (n = 16 per group, 8M/8F) received either normal (0 mg/L; Control) or supplemented (400 mg/L; 2,4-Dinitrophenol [DNP]) drinking water. Mice were singly housed in metabolic cages to determine total EE (TEE) and its components via respiratory gas exchange. Mitochondrial respiratory function of permeabilized liver tissue was determined by high-resolution respirometry. Results: Transitioning mice from 24°C to 30°C reduced TEE and basal EE (BEE) by 16% and 41%, respectively (both P < 0.001). Compared to 30°C controls, TEE was 2.6 kcal/day greater in DNP-treated mice (95% CI: 1.6-3.6 kcal/day, P < 0.001), which was partly due to a 1.2 kcal/day higher BEE in DNP-treated mice (95% CI: 0.6-1.7 kcal/day, P < 0.001). The absolute TEE of 30°C DNP-treated mice was lower than that of mice housed at 24°C in the absence of DNP (DNP: 9.4 ± 0.7 kcal/day vs. 24°C control: 10.4 ± 1.5 kcal/day). DNP treatment reduced overall body fat of females by 2.9 percentage points versus sex-matched controls (95% CI: 1.3%-4.5%, P < 0.001), which was at least partly due to a reduction in inguinal white fat mass. Conclusion: Protonophore treatment markedly increases EE in mice housed at 30°C. The magnitude of change in TEE of mice receiving protonophore treatment at 30°C was smaller than that brought about by transitioning mice from 24°C to 30°C, emphasizing that housing temperature must be considered when assessing anti-obesity strategies that target EE in mice.

Endothelin-1- and acetylcholine-mediated effects in human and rat vessels: impact of perivascular adipose tissue, diabetes, angiotensin II, and chemerin.

OBJECTIVE: To study the role of perivascular adipose tissue (PVAT) in the reactivity of rat and human vessels. METHODS: Iliac and mesenteric arteries were obtained from normotensive Sprague-Dawley rats, hypertensive transgenic (mRen2)27 rats overexpressing mouse renin, and (mRen2)27 rats made diabetic with streptozotocin. Human coronary arteries were obtained from donors. Concentration-response curves were constructed to endothelin-1 and acetylcholine with and without PVAT. The contribution of NO and endothelium-dependent hyperpolarization (EDH) were determined making use of the NO synthase inhibitor L-NAME and the EDH inhibitors apamin + TRAM-34. The endothelin type A and type B (ETA, ETB) receptor blockers BQ123 and BQ788, the chemerin inhibitors α-NETA and pravastatin, and the angiotensin receptor blocker losartan were also used. RESULTS: In rat iliac arteries, PVAT diminished endothelin-induced constriction, while the opposite was true in human coronaries. Coronary effects were unaltered by α-NETA, pravastatin, or losartan. ETB receptor-mediated relaxation in iliac arteries occurred only with PVAT, and BQ123 blocked endothelin-1-induced constriction. Diabetes upregulated the anticontractile effects of PVAT. In rat mesenteric arteries, acetylcholine-induced relaxation with PVAT relied on NO, and on NO + EDH without PVAT. Diabetes upregulated the EDH component exclusively with PVAT. CONCLUSION: PVAT modulates ET-1-induced constriction in a vessel type-dependent manner. Its enhancing effects in coronaries involved neither chemerin nor angiotensin II. Its anticontractile effects in rat iliac arteries involved ETB receptor-mediated relaxation. Diabetes upregulated PVAT's anticontractile effects. In mesenteric arteries, PVAT counterbalanced the EDH component of the relaxant effect of acetylcholine. Diabetes reversed this effect by upregulating the EDH component.

What is the context?The role of perivascular adipose tissue (PVAT) in vascular reactivity in pathological conditions is poorly understood.What is the study about?This study investigates the role of PVAT in vascular reactivity in animal and human vessels.What are the results?PVAT has vasoconstrictor and vasorelaxant effects depending on location and tissue. In human coronary arteries, PVAT-mediated vasoconstrictor effects do not involve chemerin or angiotensin II. PVAT's anticontractile effects in rat iliac arteries are mediated through a mechanism involving endothelin type B receptor-dependent relaxation. Moreover, diabetes but not hypertension dysregulates PVAT's anticontractile effects in rat mesenteric vessels.

Mol-ecular structure of tris-[(6-bromo-pyridin-2-yl)meth-yl]amine.

Coordination compounds of polydentate nitro-gen ligands with metals are used extensively in research areas such as catalysis, and as models of complex active sites of enzymes in bioinorganic chemistry. Tris(2-pyridyl-meth-yl)amine (TPA) is a tripodal tetra-dentate ligand that is known to form coordination compounds with metals, including copper, iron and zinc. The related compound, tris-[(6-bromo-pyridin-2-yl)meth-yl]amine (TPABr3), C18H15Br3N4, which possesses a bromine atom on the 6-position of each of the three pyridyl moieties, is also known but has not been heavily investigated. The mol-ecular structure of TPABr3 as determined by X-ray diffraction is reported here. The TPABr3 molecule belongs to the triclinic, P space group and displays interesting intermolecular Br⋯Br interactions that provide a stabilizing influence within the molecule.

Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

Photoredox Oxidation of Alkanes by Monometallic Copper-Oxygen Complexes Using Visible Light Including One Sun Illumination.

Oxygenation of hydrocarbons offers versatile catalytic routes to more valuable compounds, such as alcohols, aldehydes, and ketones. Despite the importance of monometallic copper-oxygen species as hydroxylating agents in biology, few synthetic model compounds are known to react with hydrocarbons, owing to high C-H bond dissociation energies. To overcome this challenge, the photoredox chemistry of monometallic copper (pyrazolyl)borate complexes coordinated by chlorate has been explored in the presence of C1-C6 alkanes with BDEs ≥ 93 kcal/mol. Ethane is photooxidized at room temperature under N2 with yields of 15-30%, which increases to 77% for the most oxidizing tris(3,5-trifluoromethyl-pyrazolyl)borate complex (Cu-3). This complex also promotes the photooxidation of methane to methanol in significant yield (38%) when the photoredox reaction is run under aerobic conditions. Ligand modification alters the reaction selectivity by tuning the redox potential. The ability to activate 1° C-H bonds of C1-C6 alkanes using visible light is consistent with the photogeneration of a powerfully oxidizing copper-oxyl, which is supported by photocrystallographic studies of the tris(3,4,5-tribromopyrazolyl)borate chlorate complex. Mechanistic studies are consistent with the hydrogen atom abstraction of the C-H bond by the copper-oxyl intermediate. We demonstrate for Cu-3 with hexane as an exemplar, that the photoredox chemistry may be achieved under solar conditions of one-sun illumination.

Cytokine profiles and their correlation with clinical and blood parameters in rheumatoid arthritis and systemic lupus erythematosus.

The abnormal biological activity of cytokines and their imbalance are implicated in developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cytokine levels were measured in RA and SLE patients and compared to healthy controls using the Wilcoxon rank sum test and Kruskal-Wallis test. The relationship between cytokine levels and blood and clinical parameters was assessed using Spearman's correlation test. Compared to healthy controls, both RA and SLE patients exhibited elevated levels of GM-CSF, CX3CL1, IFN-α2, IL-12p70, IL-17A, TNF-α, IL-1ß, and IFN-γ, which is evidence of their shared inflammatory signature. IL-2 levels were elevated exclusively in RA patients, while MCP-1 and IL-10 were uniquely increased in SLE patients. Notably, TNF-α showed the most significant increase in SLE patients. IL-4 was elevated in SLE patients with nephritis, correlating with IL-6, IL-10, sCD40L, and IL-8, suggesting B cell involvement in lupus nephritis. The negative correlation between CX3CL1 and TNF-α with HDL in RA and SLE respectively, highlights the potential association of these inflammatory markers with cardiovascular risk. These findings underscore the complex cytokine interplay in RA and SLE. CX3CL1 emerges as a potential therapeutic target for RA, while TNF-α and IL-4 show promise as therapeutic targets for SLE.

Incidence of lymphedema among adults with cerebral palsy.

BACKGROUND: Lymphedema is a chronic and progressive condition but is understudied among adults with cerebral palsy (CP). OBJECTIVE: To compare the 2-year incidence of lymphedema between adults with versus without CP before and after accounting for multimorbidity, cancer diagnosis/treatment, and lymph node/channel surgery. DESIGN: Retrospective cohort study. SETTING: Nationwide commercial claims data from January 1, 2011 to December 31, 2017. PARTICIPANTS: Adults ≥18 years old with and without CP with at least 12 months of continuous health plan enrollment, defined as the baseline period, were included for analysis. The 12-month baseline period was used to establish information on preexisting lymphedema (for exclusion), presence of cancer, including radiation treatment and lymph node surgery, and the Whitney Comorbidity Index (WCI). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The 2-year incidence rate (IR) and IR ratio (IRR) of lymphedema were evaluated. Cox regression estimated the hazard ratio (HR) of 2-year lymphedema after adjusting for age, gender, WCI, cancer diagnosis/treatment, and lymph node/channel surgery. RESULTS: The 2-year IR of lymphedema was 5.73 (95% confidence interval [CI] = 4.59-6.88) for adults with CP (n = 9922) and 1.81 (95% CI = 1.79-1.83) for adults without CP (n = 12,932,288); the IRR was 3.17 (95% CI = 2.59-3.87) and the adjusted HR was 2.43 (95% CI = 1.98-2.98). There was evidence of effect modification by gender, age, and WCI score. All HRs were elevated, but men with versus without CP had higher HRs than women with versus without CP; HRs for adults with versus without CP were higher for younger participants and those with lower WCI scores. CONCLUSIONS: Adults with CP had a higher 2-year rate of lymphedema compared with those without CP. Men with CP had a disproportionately higher rate than women with CP when compared with their gender-based reference cohorts without CP.

Humoral and cellular immune responses in vaccinated and unvaccinated children following SARS-CoV-2 Omicron infection.

Objectives: The immune response in children elicited by SARS-CoV-2 Omicron infection alone or in combination with COVID-19 vaccination (hybrid immunity) is poorly understood. We examined the humoral and cellular immune response following SARS-CoV-2 Omicron infection in unvaccinated children and children who were previously vaccinated with COVID-19 mRNA vaccine. Methods: Participants were recruited as part of a household cohort study conducted during the Omicron predominant wave (Jan to July 2022) in Victoria, Australia. Blood samples were collected at 1, 3, 6 and 12 months following COVID-19 diagnosis. Humoral immune responses to SARS-CoV-2 Spike proteins from Wuhan, Omicron BA.1, BA.4/5 and JN.1, as well as cellular immune responses to Wuhan and BA.1 were assessed. Results: A total of 43 children and 113 samples were included in the analysis. Following Omicron infection, unvaccinated children generated low antibody responses but elicited Spike-specific CD4 and CD8 T-cell responses. In contrast, vaccinated children infected with the Omicron variant mounted robust humoral and cellular immune responses to both ancestral strain and Omicron subvariants. Hybrid immunity persisted for at least 6 months post infection, with cellular immune memory characterised by the generation of Spike-specific polyfunctional CD8 T-cell responses. Conclusion: SARS-CoV-2 hybrid immunity in children is characterised by persisting SARS-CoV-2 antibodies and robust CD4 and CD8 T-cell activation and polyfunctional responses. Our findings contribute to understanding hybrid immunity in children and may have implications regarding COVID-19 vaccination and SARS-CoV-2 re-infections.

Imaging Strain-Controlled Magnetic Reversal in Thin CrSBr.

Two-dimensional materials are extraordinarily sensitive to external stimuli, making them ideal for studying fundamental properties and for engineering devices with new functionalities. One such stimulus, strain, affects the magnetic properties of the layered magnetic semiconductor CrSBr to such a degree that it can induce a reversible antiferromagnetic-to-ferromagnetic phase transition. Using scanning SQUID-on-lever microscopy, we directly image the effects of spatially inhomogeneous strain on the magnetization of layered CrSBr, as it is polarized by a field applied along its easy axis. The evolution of this magnetization and the formation of domains is reproduced by a micromagnetic model, which incorporates the spatially varying strain and the corresponding changes in the local interlayer exchange stiffness. The observed sensitivity to small strain gradients along with similar images of a nominally unstrained CrSBr sample suggest that unintentional strain inhomogeneity influences the magnetic behavior of exfoliated samples.

Inhalable Dry Powders for Lung mRNA Delivery.

Despite great promise, application of mRNA therapeutics in the lung has proven challenging. Many groups have reported success instilling liquid mRNA formulations in animal models, but direct intratracheal administration of large liquid quantities to the human lung presents significant safety and distribution concerns. To accomplish safe and effective mRNA delivery to the lung, formulations must be prepared for dosing via inhalation. An inhaled mRNA delivery system for the lung must be both robust enough to survive inhalation conditions and potent enough to deliver mRNA upon reaching the lung. In this work dry powder lipid nanoparticle formulations are developed, using spray-freeze-drying, to produce stable, biologically active, inhalable dry powders for mRNA delivery. The final powders have suitable aerosolization properties, with mean mass aerodynamic diameter (MMAD) of 3-4 microns, and fine particle fraction (FPF) ≈40%, allowing for efficient mRNA delivery to the deep lung following inhalation. Importantly, the formulations developed here are suitable for use with different ionizable lipids. Four different ionizable lipid-based formulations are evaluated as powders, and all exhibit in vivo pulmonary mRNA delivery equal to that of instilled liquid formulations. These results lay promising groundwork for the eventual development of an inhalable mRNA dry powder therapeutic.

An International, Expert-Based Delphi Consensus Document on Controversial Issues about TransCarotid Artery Revascularization (TCAR).

OBJECTIVE: TransCarotid Artery Revascularization (TCAR) has emerged as an alternative therapeutic modality to carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS) for the management of patients with carotid artery stenosis. However, certain issues regarding the indications and contraindications of TCAR remain unanswered or unresolved. The aim of this international, expert-based Delphi Consensus document was to attempt to provide some guidance on these topics. METHODS: A 3-Round Delphi Consensus process was performed including 29 experts. The aim of Round 1 was to investigate the differing views and opinions of the participants. Round 2 was carried out after the results from the literature on each topic were provided to the participants. During Round 3, the participants had the opportunity to finalize their vote. RESULTS: Most participants agreed that TCAR can/can probably/possibly be performed within 14 days of a cerebrovascular event, but it is best to avoid it in the first 48 hours. It was felt that TCAR cannot/should not replace TFCAS or CEA, as each procedure has specific indications and contraindications. Symptomatic patients >80 years should probably be treated with TCAR rather than with TFCAS. TCAR can/can probably be used for the treatment of restenosis following CEA/TFCAS. Finally, there is a need for a randomized controlled trial to provide better evidence for the unresolved issues. CONCLUSIONS: This Delphi Consensus document attempted to assist the decision-making of physicians/interventionalists/vascular surgeons involved in the management of carotid stenosis patients. Furthermore, areas requiring additional research were identified. Future studies and randomized controlled trials should provide more evidence to address the unanswered questions regarding TCAR.

Regulation of the gap junction interplay during postnatal development in the rat epididymis.

During postnatal development of the rat epididymis, a change in the expression of gap junction proteins, or connexins (Cxs), occurs, in which Gjb2 (Cx26) and Gja1 (Cx43) levels in the proximal epididymis are decreased, while Gjb1 (Cx32), Gjb4 (Cx30.3) and Gjb5 (Cx31.1) levels increase. The mechanism(s) responsible for the switch in Cx expression is unknown. The aim of this study is to identify the mechanisms responsible for the decrease in GJB2 protein levels and the increase in other Cxs during postnatal development. Results indicate that decreased Gjb2 expression for 48 h does not alter the expression of other Cxs in RCE-1 principal cells, suggesting a lack of compensatory expression. Sequence analysis of both Gjb2 and Gjb1 promoters identified common multiple response elements to steroid hormones. Using RCE-1 cells, we observed that dexamethasone increased Gjb2 mRNA levels by twofold after 48 h, while estradiol had no effect. Orchidectomy in rats resulted in a significant increase in GJB2 and decreased GJB1 in the caput and corpus epididymidis. Changes in Cxs protein levels were prevented by testosterone in orchidectomized rats. Similar results were observed in the prostate, another androgen-receptive organ. LNCaP cells, which are androgen-responsive, showed that exogenous dihydrotestosterone (DHT) decreased Gjb2 mRNA levels by approximately 50% concomitant with a 1.5-fold increase in Gjb1 levels. Using a GJB1 promoter construct we showed that DHT could induce transactivation of the luciferase transgene, while transactivation of two GJB2 promoters were unaltered. Results indicate that androgens and glucocorticoids regulate the expression of epididymal Cxs.

Feasibility of thin-slice, low noise images created using multi-kernel synthesis to replace multiple image series in head CT.

BACKGROUND: SynthesiZed Improved Resolution and Concurrent nOise reductioN (ZIRCON) is a multi-kernel synthesis method that creates a single series of thin-slice computed tomography (CT) images displaying low noise and high spatial resolution, increasing reader efficiency and minimizing partial volume averaging. PURPOSE: To compare the diagnostic performance of a single set of ZIRCON images to two routine clinical image series using conventional CT head and bone reconstruction kernels for diagnosing intracranial findings and fractures in patients with trauma or suspected acute neurologic deficit. MATERIAL AND METHODS: In total, 50 patients underwent clinically indicated head CT in the ER (15 normal, 35 abnormal cases). A non-reader neuroradiologist established the reference standard. Three neuroradiologists reviewed two routine clinical series (head and bone kernels) and a single ZIRCON series, detecting intracranial findings or fractures and rating confidence (0-100). Sensitivity, specificity, and jackknife free-response receiver operating characteristic (JAFROC) figure of merit (FOM) were compared (limit of non-inferiority: -0.10). RESULTS: ZIRCON and conventional images demonstrated comparable performance for fractures (sensitivity: 51.5% vs. 54.5%; specificity: 40.2% vs. 34.2%) and intracranial findings (sensitivity: 88.2% vs. 91.4%; specificity: 77.2% vs. 73.7%).The estimated difference of JAFROC FOM demonstrated ZIRCON non-inferiority for acute pathologies overall (0.003 [95% CI=-0.051-0.057]) and fractures (0.048 [95% CI=-0.050-0.145]) but not for intracranial findings alone (-0.024 [95% CI=-0.100-0.052]). CONCLUSION: Thin-slice, low noise, and high spatial resolution images can be created to display intracranial findings and fractures replacing multiple images series in head CT with similar performance. Future studies in more patients and further algorithmic development are warranted.

2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N3CDP.

Ribonucleotide reductases (RNRs) reduce ribonucleotides to deoxyribonucleotides using radical-based chemistry. For class Ia RNRs, the radical species is stored in a separate subunit (ß2) from the subunit housing the active site (α2), requiring the formation of a short-lived α2ß2 complex and long-range radical transfer (RT). RT occurs via proton-coupled electron transfer (PCET) over a long distance (~32-Å) and involves the formation and decay of multiple amino acid radical species. Here, we use cryogenic-electron microscopy and a mechanism-based inhibitor 2'-azido-2'-deoxycytidine-5'-diphosphate (N 3 CDP) to trap a wild-type α2ß2 complex of E. coli class Ia RNR. We find that one α subunit has turned over and that the other is trapped, bound to ß in a mid-turnover state. Instead of N 3 CDP in the active site, forward RT has resulted in N 2 loss, migration of the third nitrogen from the ribose C2' to C3' positions, and attachment of this nitrogen to the sulfur of cysteine-225. To the best of our knowledge, this is the first time an inhibitor has been visualized as an adduct to an RNR. Additionally, this structure reveals the positions of PCET residues following forward RT, complementing the previous structure that depicted a pre-turnover PCET pathway and suggesting how PCET is gated at the α-ß interface. This N 3 CDP-trapped structure is also of sufficient resolution (2.6 Å) to visualize water molecules, allowing us to evaluate the proposal that water molecules are proton acceptors and donors as part of the PCET process. Significance Statement: Several FDA-approved cancer drugs target human ribonucleotide reductase (RNR), a radical enzyme that produces the requisite deoxyribonucleotides for DNA biosynthesis and repair. Human RNR is a class Ia enzyme that requires radical transfer (RT) from a ß2 subunit to an α2 subunit on every round of turnover. Long-range RT is both a remarkable feature and an Achilles heel, given that inhibitors can intercept the radical species. Here we present a cryogenic electron microscopy (cryo-EM) structure of the best studied class Ia RNR, the enzyme from E. coli , in which α2 and ß2 subunits have been trapped together using a mechanism-based inhibitor. This structure provides insight into both the mechanism of RNR inhibition and the mechanism of long-range RT.

The association between fracture and short-term adverse health outcomes among children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) have a high risk of fracture; yet, little is known about their post-fracture health outcomes. A fracture is an unplanned event in contrast to surgeries or procedures where there is a pre-operative period to optimize body composition and health and planned post-operative follow-up care. Fractures may be associated with significant outcomes due to the unplannable nature and reactionary care. The objective of this study was to determine if fractures were associated with an increased rate of short-term adverse health outcomes among children with CP, and if these associations were dependent on age. METHODS: This retrospective cohort study used commercial claims from 01/01/2001-12/31/2018. The primary cohort was children 2-18 years old with CP and an incident fracture (CP + Fx). Comparison cohorts were propensity score matched 1:1 to CP + Fx on demographic and health-related indicators: CP without fractures (CPw/oFx); without CP with (w/oCP + Fx) or without (w/oCPw/oFx) a fracture. The incidence rate (IR) and IR ratios (IRR) of 30-day and 31-90-day pneumonia and 90-day emergency department (ED) visit were estimated. Cox regression tested for effect modification by age and sex. RESULTS: The CP + Fx cohort (n = 1670) had higher IRs of 30-day pneumonia (IRR range, 1.53-4.54) and 90-day ED visit (IRR range, 1.45-2.37) (all P < 0.05), and higher IRs of 31-90-day pneumonia but this did not reach statistical significance (IRR, 1.41 to 2.32, all P > 0.05). Notably, there was evidence of effect modification by age. The rate of 30-day pneumonia became more problematic for CP + Fx with older age relative to comparison cohorts and for 90-day ED visit compared to CPw/oFx. The rate of 90-day ED visit for CP + Fx was more problematic at younger ages compared to w/oCP + Fx. CONCLUSIONS: Fractures among children with CP were associated with an increased rate of short-term pneumonia and ED visit, which was more problematic with older age.

Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. OBJECTIVES: The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. METHODS: In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate <0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling. RESULTS: The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings. CONCLUSIONS: The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.

Performance Evaluation of the Two-Input Buck Converter as a Visible Light Communication High-Brightness LED Driver Based on Split Power.

This work proposes a high-efficiency High-Brightness LED (HB-LED) driver for Visible Light Communication (VLC) based on a Two-Input Buck (TIBuck) DC/DC converter. This solution not only outperforms previous approaches based on Buck DC/DC converters, but also simplifies previous proposals for VLC drivers that use the split power technique with two DC/DC converters: one is in charge of the communication tasks and the other controls the biasing of the HB-LED (i.e., lighting tasks). The real implementation of this scheme requires either two input voltage sources, one of which is isolated, or one DC/DC converter with galvanic isolation. The proposed implementation of splitting the power is based on a TIBuck DC/DC converter that avoids the isolation requirement, overcoming the major drawback of this technique, keeping high-efficiency and high communication capability thanks to the lower voltage stress both across the switches and at the switching node. This fact allows for the operation at very high frequency for communication purposes, minimizing switching power losses, achieving high efficiency and providing lower filtering effort. Moreover, the duty ratio range can also be adapted to the useful voltage range of the HB-LED load to maximize the resolution on the tracking of the output volage. The power is split by means of an auxiliary Buck DC/DC converter operating at low switching frequency, which generates the secondary voltage source needed by the TIBuck DC/DC converter. This defines a natural split of power by only processing the power delivered for communications purposes at high frequency. A 7 W output-power experimental prototype of the proposed VLC driver was built and tested. Based on the experimental results, the prototype achieved 94% efficiency, reproducing a 64-QAM digital modulation scheme and achieving a bit rate of 1.5 Mbps with error in communication of 12%.