Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia.

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.

A cross-species proteomic map reveals neoteny of human synapse development.

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

'Chip'-ing away at morphogenesis - application of organ-on-chip technologies to study tissue morphogenesis.

Emergent cell behaviors that drive tissue morphogenesis are the integrated product of instructions from gene regulatory networks, mechanics and signals from the local tissue microenvironment. How these discrete inputs intersect to coordinate diverse morphogenic events is a critical area of interest. Organ-on-chip technology has revolutionized the ability to construct and manipulate miniaturized human tissues with organotypic three-dimensional architectures in vitro. Applications of organ-on-chip platforms have increasingly transitioned from proof-of-concept tissue engineering to discovery biology, furthering our understanding of molecular and mechanical mechanisms that operate across biological scales to orchestrate tissue morphogenesis. Here, we provide the biological framework to harness organ-on-chip systems to study tissue morphogenesis, and we highlight recent examples where organ-on-chips and associated microphysiological systems have enabled new mechanistic insight in diverse morphogenic settings. We further highlight the use of organ-on-chip platforms as emerging test beds for cell and developmental biology.

Spatial prioritization for widespread invasive species control: Trade-offs between current impact and future spread.

Spatially explicit prioritization of invasive species control is a complex issue, requiring consideration of trade-offs between immediate and future benefits. This study aimed to prioritize management efforts to account for current and future threats from widespread invasions and examine the strength of the trade-off between these different management goals. As a case study, we identified spatially explicit management priorities for the widespread invasion of introduced willow into riparian and wetland habitats across a 102,145-km2 region in eastern Australia. In addition to targeting places where willow threatens biodiversity now, a second set of management goals was to limit reinfestation and further spread that could occur via two different mechanisms (downstream and by wind). A model of likely willow distribution across the region was combined with spatial data for biodiversity (native vegetation, threatened species and communities), ecological conditions, management costs, and two potential dispersal layers. We used systematic conservation planning software (Zonation) to prioritize where willow management should be focussed across more than 100,000 catchments for a range of different scenarios that reflected different weights between management goals. For willow invasion, we found that we could prioritize willow management to reduce the future threat of dispersal downstream with little reduction in the protection of biodiversity. However, accounting for future threats from wind dispersal resulted in a stronger trade-off with protection of threatened biodiversity. The strongest trade-off was observed when both dispersal mechanisms were considered together. This study shows that considering current and future goals together offers the potential to substantially improve conservation outcomes for invasive species management. Our approach also informs land managers about the relative trade-offs among different management goals under different control scenarios, helping to make management decisions more transparent. This approach can be used for other widespread invasive species to help improve invasive species management decisions.

Patisiran, an RNAi therapeutic for hereditary transthyretin-mediated amyloidosis: Sub-analysis in Taiwanese patients from the APOLLO study.

BACKGROUND AND OBJECTIVES: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. METHODS: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. RESULTS: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. CONCLUSIONS: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. TRIAL REGISTRATION INFORMATION: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Asymmetric organelle positioning during epithelial polarization of C. elegans intestinal cells.

While the epithelial cell cortex displays profound asymmetries in protein distribution and morphology along the apico-basal axis, the extent to which the cytoplasm is similarly polarized within epithelial cells remains relatively unexplored. We show that cytoplasmic organelles within C. elegans embryonic intestinal cells develop extensive apico-basal polarity at the time they establish cortical asymmetry. Nuclei and conventional endosomes, including early endosomes, late endosomes, and lysosomes, become polarized apically. Lysosome-related gut granules, yolk platelets, and lipid droplets become basally enriched. Removal of par-3 activity does not disrupt organelle positioning, indicating that cytoplasmic apico-basal asymmetry is independent of the PAR polarity pathway. Blocking the apical migration of nuclei leads to the apical positioning of gut granules and yolk platelets, whereas the asymmetric localization of conventional endosomes and lipid droplets is unaltered. This suggests that nuclear positioning organizes some, but not all, cytoplasmic asymmetries in this cell type. We show that gut granules become apically enriched when WHT-2 and WHT-7 function is disrupted, identifying a novel role for ABCG transporters in gut granule positioning during epithelial polarization. Analysis of WHT-2 and WHT-7 ATPase mutants is consistent with a WHT-2/WHT-7 heterodimer acting as a transporter in gut granule positioning. In wht-2(-) mutants, the polarized distribution of other organelles is not altered and gut granules do not take on characteristics of conventional endosomes that could have explained their apical mispositioning. During epithelial polarization wht-2(-) gut granules exhibit a loss of the Rab32/38 family member GLO-1 and ectopic expression of GLO-1 is sufficient to rescue the basal positioning of wht-2(-) and wht-7(-) gut granules. Furthermore, depletion of GLO-1 causes the mislocalization of the endolysosomal RAB-7 to gut granules and RAB-7 drives the apical mispositioning of gut granules when GLO-1, WHT-2, or WHT-7 function is disrupted. We suggest that ABC transporters residing on gut granules can regulate Rab dynamics to control organelle positioning during epithelial polarization.

Biochemical and biophysical characterization of the nucleic acid binding properties of the RNA/DNA binding protein EWS.

EWS is a member of the FET family of RNA/DNA binding proteins that regulate crucial phases of nucleic acid metabolism. EWS comprises an N-terminal low-complexity domain (LCD) and a C-terminal RNA-binding domain (RBD). The RBD is further divided into three RG-rich regions, which flank an RNA-recognition motif (RRM) and a zinc finger (ZnF) domain. Recently, EWS was shown to regulate R-loops in Ewing sarcoma, a pediatric bone and soft-tissue cancer in which a chromosomal translocation fuses the N-terminal LCD of EWS to the C-terminal DNA binding domain of the transcription factor FLI1. Though EWS was shown to directly bind R-loops, the binding mechanism was not elucidated. In the current study, the RBD of EWS was divided into several constructs, which were subsequently assayed for binding to various nucleic acid structures expected to form at R-loops, including RNA stem-loops, DNA G-quadruplexes, and RNA:DNA hybrids. EWS interacted with all three nucleic acid structures with varying affinities and multiple domains contributed to binding each substrate. The RRM and RG2 region appear to bind nucleic acids promiscuously while the ZnF displayed more selectivity for single-stranded structures. With these results, the structural underpinnings of EWS recognition and binding of R-loops and other nucleic acid structures is better understood.

Towards a continent-wide ecological site condition database using calibrated expert evaluations.

A cost-effective way of undertaking comprehensive, continental-scale, assessments of ecological condition is needed to support large-scale conservation planning, monitoring, reporting, and decision-making. Currently, cross-jurisdictional inconsistency in assessment methods limits the capacity to scale-up monitoring. Here we present a novel way to build a coherent continent-wide site-level ecological condition dataset, using cross-calibration methods to integrate assessments from many observers. We focus on the use of condition assessments from individual expert observers, a currently untapped resource. Our approach has two components: (1) a simple online tool that captures expert assessments at specific locations; (2) a process of calibrating and rescaling disparate expert evaluations that can be applied to the data to provide a consistent dataset for use in conservation assessments. We describe a pilot study, involving 28 experts, who contributed 314 individual site condition assessments across a wide range of ecosystems and regions throughout continental Australia. A correction factor for each expert was used to rescale the contributed site condition assessment scores, based on a set of 77 photographic images, each scored for their condition by multiple experts, using a linear mixed model. Our approach shows strong promise for delivering the volumes of data required to develop continental-scale reference libraries of site condition assessments. Although developed from expert elicitation, the approach could also be used to harmonize the collation of existing condition datasets. The process we demonstrate can also facilitate online citizen scientists to make site condition assessments that can be cross-calibrated using contributed images.

Use of a Commercial 7-T MRI Scanner for Clinical Brain Imaging: Indications, Protocols, Challenges, and Solutions-A Single-Center Experience.

The first commercially available 7-T MRI scanner (Magnetom Terra) was approved by the FDA in 2017 for clinical imaging of the brain and knee. After initial protocol development and sequence optimization efforts in volunteers, the 7-T system, in combination with an FDA-approved 1-channel transmit/32-channel receive array head coil, can now be routinely used for clinical brain MRI examinations. The ultrahigh field strength of 7-T MRI has the advantages of improved spatial resolution, increased SNR, and increased CNR but also introduces an array of new technical challenges. The purpose of this article is to describe an institutional experience with the use of the commercially available 7-T MRI scanner for routine clinical brain imaging. Specific clinical indications for which 7-T MRI may be useful for brain imaging include brain tumor evaluation with possible perfusion imaging and/or spectroscopy, radiotherapy planning; evaluation of multiple sclerosis and other demyelinating diseases, evaluation of Parkinson disease and guidance of deep brain stimulator placement, high-detail intracranial MRA and vessel wall imaging, evaluation of pituitary pathology, and evaluation of epilepsy. Detailed protocols, including sequence parameters, for these various indications are presented, and implementation challenges (including artifacts, safety, and side effects) and potential solutions are explored.

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

Assessing central and peripheral respiratory chemoreceptor interaction in humans.

NEW FINDINGS: What is the central question of this study? We investigated the interaction between central and peripheral respiratory chemoreceptors in healthy, awake human participants by using a background of step increases in steady-state normoxic fraction of inspired carbon dioxide to alter central chemoreceptor activation and by using the transient hypoxia test to target the peripheral chemoreceptors. What is the main finding and its importance? Our data suggest that the interaction between central and peripheral respiratory chemoreceptors is additive in minute ventilation and respiratory rate, but hypo-additive in tidal volume. Our study adds important new data in reconciling chemoreceptor interaction in awake healthy humans and is consistent with previous reports of simple addition in intact rodents and humans. ABSTRACT: Arterial blood gas levels are maintained through respiratory chemoreflexes, mediated by central chemoreceptors in the CNS and peripheral chemoreceptors located in the carotid bodies. The interaction between central and peripheral chemoreceptors is controversial, and few studies have investigated this interaction in awake, healthy humans, owing, in part, to methodological challenges. We investigated the interaction between the central and peripheral chemoreceptors in healthy humans using a transient hypoxia test (three consecutive breaths of 100% N2 ; TT-HVR), which targets the temporal domain and stimulus specificity of the peripheral chemoreceptors. The TT-HVRs were superimposed upon three randomized background levels of steady-state inspired fraction of normoxic CO2 ( F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ ; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation ( S cO 2 ${S}_{{\rm{cO}}_{\rm{2}}}$ )] and respiratory variable responses [respiratory rate (RR ), inspired tidal volume (VTI ) and ventilation ( V ̇ I ${{{\dot{V}}}_{\rm{I}}}$ )] were averaged from all three TT-HVR trials at each F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ level. Responses were assessed as: (1) a change (∆) from baseline; and (2) indexed against Δ S cO 2 $\Delta {S}_{{\rm{cO}}_{\rm{2}}}$ . Aside from a significantly lower ∆VTI response in 0.04 F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ (P = 0.01), the hypoxic rate responses (∆RR or ∆RR / Δ S cO 2 $\Delta {S}_{{\rm{cO}}_{\rm{2}}}$ ; P = 0.46 and P = 0.81), hypoxic tidal volume response ( Δ V TI / Δ V TI Δ S cO 2 Δ S cO 2 ${{\Delta {V}_{{\rm{TI}}}} \mathord{/ {\vphantom {{\Delta {V}_{{\rm{TI}}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$ ; P = 0.08) and the hypoxic ventilatory responses ( Δ V ̇ I ${{\Delta {{\dot{V}}}_{\rm{I}}}}$ and Δ V ̇ I / Δ V ̇ I Δ S cO 2 Δ S cO 2 ${{\Delta {{\dot{V}}}_{\rm{I}}} \mathord{/ {\vphantom {{\Delta {{\dot{V}}}_{\rm{I}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$ ; P = 0.09 and P = 0.31) were not significantly different across F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ trials. Our data suggest simple addition between central and peripheral chemoreceptors in V ̇ I ${{{\dot{V}}}_{\rm{I}}}$ , which is mediated through simple addition in RR responses, but hypo-addition in VTI responses. Our study adds important new data in reconciling chemoreceptor interaction in awake, healthy humans and is consistent with previous reports of simple addition in intact rodents and humans.

Exploring the process of information sharing in an adult intensive care unit: an ethnographic study.

Information sharing, a component of patient and family engagement (PFE), is an important process that may contribute to intensive care unit (ICU) quality of care. Yet, virtually no studies explore how the process of information sharing unfolds in the ICU from the interprofessional team and family member perspectives. To better understand the process of information sharing, we conducted ethnographic fieldwork in a 20-bed medical ICU, focusing on behaviors and interactions of the interprofessional team and family members (May 2016 - October 2016). We completed 17.5 observation hours, 6 shadowing sessions, and 12 semi-structured interviews with 17 total participants. We used thematic content analysis and iterative inductive coding to identify three themes about the information sharing process: 1) family factors (health literacy and past experience with the ICU environment) influence information sharing; 2) clinicians strategies can support engagement in the process of information sharing (assessing families' need for information, understanding a families' hope, using rounds as an opportunity for information sharing); 3) the process of information sharing allows for trust building between families and the ICU team. Our findings suggest that information sharing is a crucial process that may serve as a catalyst for effective patient and family engagement in the ICU.

TWE-PRIL reverse signalling suppresses sympathetic axon growth and tissue innervation.

TWE-PRIL is a naturally occurring fusion protein of components of two TNF superfamily members: the extracellular domain of APRIL; and the intracellular and transmembrane domains of TWEAK with no known function. Here, we show that April-/- mice (which lack APRIL and TWE-PRIL) exhibited overgrowth of sympathetic fibres in vivo, and sympathetic neurons cultured from these mice had significantly longer axons than neurons cultured from wild-type littermates. Enhanced axon growth from sympathetic neurons cultured from April-/- mice was prevented by expressing full-length TWE-PRIL in these neurons but not by treating them with soluble APRIL. Soluble APRIL, however, enhanced axon growth from the sympathetic neurons of wild-type mice. siRNA knockdown of TWE-PRIL but not siRNA knockdown of APRIL alone also enhanced axon growth from wild-type sympathetic neurons. Our work reveals the first and physiologically relevant role for TWE-PRIL and suggests that it mediates reverse signalling.

Radiologic Differentiation of Primary CNS Posttransplant Lymphoproliferative Disorder From Brain Metastasis.

OBJECTIVE. Primary CNS posttransplant lymphoproliferative disorder (PTLD) may present as multiple contrast-enhancing intraaxial lesions, often with central necrosis and surrounding edema. This imaging appearance is similar to the pattern seen in brain metastases. The purpose of this study was to find differences in the radiologic features of primary CNS PTLD lesions and brain metastases. MATERIALS AND METHODS. We retrospectively reviewed the radiologic findings of 51 primary CNS PTLD lesions in 10 patients and 156 metastatic brain lesions in 25 patients. Lesion size, multifocality, location, necrosis, hemorrhage, perilesional vasogenic edema, contrast enhancement, and diffusion and perfusion features were evaluated. We used the chi-square test or Fisher exact test when appropriate to compare the findings between primary CNS PTLD lesions and brain metastases. RESULTS. Primary CNS PTLD lesions occur in the deep gray matter and periventricular locations more frequently than brain metastases (p < 0.0001) and are not present at the gray and white matter junctions and vascular border zones as commonly as brain metastases are (p < 0.0001). Primary CNS PTLD tends to have less frequent hemorrhage (p < 0.0001), more restricted diffusion (p = 0.001), and lower perfusion (p = 0.002) than brain metastases. We did not find statistically significant differences between primary CNS PTLD and brain metastases for lesion size, multifocality, necrosis, and perilesional edema. CONCLUSION. The imaging characteristics of primary CNS PTLD overlap considerably with those of brain metastases, but there are significant differences between primary CNS PTLD lesions and brain metastases in lesion location, diffusion and perfusion features, and tendency to hemorrhage.

Creation and Testing of a Deep Learning Algorithm to Automatically Identify and Label Vessels, Nerves, Tendons, and Bones on Cross-sectional Point-of-Care Ultrasound Scans for Peripheral Intravenous Catheter Placement by Novices.

OBJECTIVES: We sought to create a deep learning (DL) algorithm to identify vessels, bones, nerves, and tendons on transverse upper extremity (UE) ultrasound (US) images to enable providers new to US-guided peripheral vascular access to identify anatomy. METHODS: We used publicly available DL architecture (YOLOv3) and deidentified transverse US videos of the UE for algorithm development. Vessels, bones, tendons, and nerves were labeled with bounding boxes. A total of 203,966 images were generated from videos, with corresponding label box coordinates in a YOLOv3 format. Training accuracy, losses, and learning curves were tracked. As a final real-world test, 50 randomly selected images from unrelated UE US videos were used to test the DL algorithm. Four different versions of the YOLOv3 algorithm were tested with varied amounts of training and sensitivity settings. The same 50 images were labeled by 2 blinded point-of-care ultrasound (POCUS) experts. The area under the curve (AUC) was calculated for the DL algorithm and POCUS expert performance. RESULTS: The algorithm outperformed POCUS experts in detection of all structures in the UE, with an AUC of 0.78 versus 0.69 and 0.71, respectively. When considering vessels, only one of the POCUS experts attained an AUC of 0.85, just ahead of the DL algorithm, with an AUC of 0.83. CONCLUSIONS: Our DL algorithm proved accurate at identifying 4 common structures on cross-sectional US imaging of the UE, which would allow novice POCUS providers to more confidently and accurately target vessels for cannulation, avoiding other structures. Overall, the algorithm outperformed 2 blinded POCUS experts.

Accuracy analysis of fMRI and MEG activations determined by intraoperative mapping.

OBJECTIVE: By looking at how the accuracy of preoperative brain mapping methods vary according to differences in the distance from the activation clusters used for the analysis, the present study aimed to elucidate how preoperative functional neuroimaging may be used in such a way that maximizes the mapping accuracy. METHODS: The eloquent function of 19 patients with a brain tumor or cavernoma was mapped prior to resection with both functional MRI (fMRI) and magnetoencephalography (MEG). The mapping results were then validated using direct cortical stimulation mapping performed immediately after craniotomy and prior to resection. The subset of patients with equivalent MEG and fMRI tasks performed for motor (n = 14) and language (n = 12) were evaluated as both individual and combined predictions. Furthermore, the distance resulting in the maximum accuracy, as evaluated by the J statistic, was determined by plotting the sensitivities and specificities against a linearly increasing distance threshold. RESULTS: fMRI showed a maximum mapping accuracy at 5 mm for both motor and language mapping. MEG showed a maximum mapping accuracy at 40 mm for motor and 15 mm for language mapping. At the standard 10-mm distance used in the literature, MEG showed a greater specificity than fMRI for both motor and language mapping but a lower sensitivity for motor mapping. Combining MEG and fMRI showed a maximum accuracy at 15 mm and 5 mm-MEG and fMRI distances, respectively-for motor mapping and at a 10-mm distance for both MEG and fMRI for language mapping. For motor mapping, combining MEG and fMRI at the optimal distances resulted in a greater accuracy than the maximum accuracy of the individual predictions. CONCLUSIONS: This study demonstrates that the accuracy of language and motor mapping for both fMRI and MEG is heavily dependent on the distance threshold used in the analysis. Furthermore, combining MEG and fMRI showed the potential for increased motor mapping accuracy compared to when using the modalities separately.Clinical trial registration no.: NCT01535430 (clinicaltrials.gov).

Donor human leukocyte antigen-G single nucleotide polymorphisms are associated with post-lung transplant mortality.

Human leukocyte antigen (HLA)-G is a non-classical HLA that inhibits immune responses. Its expression is modified by single nucleotide polymorphisms (SNPs), which are associated with transplant outcomes. Our aim was to investigate the association of donor and recipient HLA-G SNPs with chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation.In this single-centre study, we examined 11 HLA-G SNPs in 345 consecutive recipients and 297 donors of a first bilateral lung transplant. A multivariable Cox proportional hazards model assessed associations of SNPs with death and CLAD. Transbronchial biopsies (TBBx) and bronchoalveolar lavage (BAL) samples were examined using quantitative PCR, ELISA and immunofluorescence.Over a median of 4.75 years, 142 patients (41%) developed CLAD; 170 (49%) died. Multivariable analysis revealed donor SNP +3142 (GG+CG versus CC) was associated with increased mortality (hazard ratio 1.78, 95% CI 1.12-2.84; p=0.015). In contrast, five donor SNPs, -201(CC), -716(TT), -56(CC), G*01:03(AA) and 14 bp INDEL, conferred reduced mortality risk. Specific donor-recipient SNP pairings reduced CLAD risk. Predominantly epithelial HLA-G expression was observed on TBBx without rejection. Soluble HLA-G was present in higher concentrations in the BAL samples of patients who later developed CLAD.Specific donor SNPs were associated with mortality risk after lung transplantation, while certain donor-recipient SNP pairings modulated CLAD risk. TBBx demonstrated predominantly epithelial, and therefore presumably donor-derived, HLA-G expression in keeping with these observations. This study is the first to demonstrate an effect of donor HLA-G SNPs on lung transplantation outcome.

Photoconductive Properties of Dibenzotetrathiafulvalene-Tetracyanoquinodimethane (DBTTF-TCNQ) Nanorods Prepared by the Reprecipitation Method.

Charge-transfer complex crystals have been extensively studied because of their metallic conductivity, photoconductivity, ambipolar charge transport, and high career mobility. Numerous studies of their applications for organic electric devices such as organic field effect transistors and solar cells have reported. However, bulky single crystals of charge-transfer complexes are difficult to handle, specifically to be made into a form of a thin film. Recently, nano/micro crystallization of charge-transfer crystal is attracted to realize thin film applications. In this paper, charge transfer complex nanorods composed of dibenzotetrathiafulvalene-tetracyanoquinodimethane (DBTTF-TCNQ) were prepared by the reprecipitation method. The as-formed nanorods possess a kinetically metastable crystal structure different from the thermodynamically stable bulk crystal prepared by slow evaporation of the solvent. From photoconductive measurement, nanorod stacks show a significant photosensitivity (354.57 µA/W) on par with bulk crystal (417.14 µA/W). These results suggest dibenzotetrathiafulvalene-tetracyanoquinodimethane (DBTTF-TCNQ) nanorods have a favorable crystal structure for carrier transport due to the difference of molecular stacking assembly.

Family-Based Crisis Intervention With Suicidal Adolescents: A Randomized Clinical Trial.

OBJECTIVE: In current practice, treatment as usual (TAU) for suicidal adolescents includes evaluation, with little or no intervention provided in the emergency department (ED), and disposition, usually to an inpatient psychiatry unit. The family-based crisis intervention (FBCI) is an emergency psychiatry intervention designed to sufficiently stabilize suicidal adolescents within a single ED visit so that they may return home safely with their families. The objective of this article is to report efficacy outcomes related to FBCI for suicidal adolescents and their families. METHODS: A total of 142 suicidal adolescents (age, 13-18 years) and their families presenting for psychiatric evaluation to a large pediatric ED were randomized to receive FBCI or TAU. Patients and caregivers completed self-report measures of suicidality, family empowerment, and satisfaction with care provided at pretest, posttest, and 3 follow-up time points over a 1-month period. RESULTS: Patients randomized to FBCI were significantly more likely to be discharged home with outpatient follow-up care compared with their TAU counterparts (P < 0.001). Families randomized to the FBCI condition reported significantly higher levels of family empowerment and client satisfaction with care at posttest compared with their TAU counterparts. Gains were maintained over the follow-up period. No completed suicides were reported during the study period in either condition. CONCLUSIONS: Family-based crisis intervention is a model of care for suicidal adolescents that may be a viable alternative to traditional ED care that involves inpatient psychiatric hospitalization.