Oxidation-induced ambiphilicity triggers N-N bond formation and dinitrogen release in octahedral terminal molybdenum(v) nitrido complexes.

Coupling of octahedral, terminal d1 molybdenum(v) nitrido complexes supported by a dianionic pentadentate ligand via N-N bond formation to give µ-dinitrogen complexes was found to be thermodynamically feasible but faces significant kinetic barriers. However, upon oxidation, a kinetically favored nucleophilic/electrophilic N-N bond forming mechanism was enabled to give monocationic µ-dinitrogen dimers. Computational and experimental evidence for this "oxidation-induced ambiphilic nitrido coupling" mechanism is presented. The factors influencing release of dinitrogen from the resulting µ-dinitrogen dimers were also probed and it was found that further oxidation to a dicationic species is required to induce (very rapid) loss of dinitrogen. The mechanistic path discovered for N-N bond formation and dinitrogen release follows an ECECC sequence (E = "electrochemical step"; C = "chemical step"). Experimental evidence for the intermediacy of a highly electrophilic, cationic d0 molybdenum(vi) nitrido in the N-N bond forming mechanism via trapping with an isonitrile reagent is also discussed. Together these results are relevant to the development of molecular catalysts capable of mediating ammonia oxidation to dihydrogen and dinitrogen.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Treatment of Adult Distal Humerus Fracture with Fishtail Deformity: A Case Report.

CASE: We report a single case of a closed intra-articular distal humerus fracture in a 28-year-old man with a preexisting fishtail deformity characterized by concavity of the central trochlea and corresponding deformity of the olecranon. The patient was treated with open reduction and internal fixation. CONCLUSION: The case highlights the diagnosis and challenges of treatment. Conventional fixation choices and imaging techniques may need to be altered when treating a fracture with this deformity.

Finding value in novel antibiotics: How can infectious diseases adopt incremental cost-effectiveness to improve new antibiotic utilization?

Research and development of innovative antimicrobials is paramount to addressing the antimicrobial resistance threat. Although antimicrobial discovery and development has increased, difficulties have emerged in the pharmaceutical industry after market approval. In this minireview, we summarize clinical trial data on recently approved antibiotics, calculate incremental cost-effectiveness ratio (ICER) values, and explore ways to adapt ICER calculations to the limitations of antimicrobial clinical trial design. We provide a systematic review and analysis of randomized, controlled studies of antibiotics approved from 2014 - 2022 and extracted the relevant clinical data. Adapted-ICER (aICER) calculations were conducted using the primary condition-specific outcome that was reported in each study (percent mortality or percent cure rate). The literature search identified 18 studies for the 8 total antibiotics which met inclusion criteria and contained data required for aICER calculation. aICER values ranged from -$17,374 to $4,966 per percent mortality and -$43,931 to $2,529 per percent cure rate. With regards to mortality, ceftolozane/tazobactam and imipenem/cilastatin/relebactam proved cost efficacious, with aICER values of $4,965 per percent mortality and $1,955 per percent mortality respectively. Finding value in novel antibiotic agents is imperative to further justifying their development, and aICER values are the most common method of determining value in healthcare. The current outcomes of clinical trials are difficult to translate to aICER, which most effectively use Quality-Adjusted Life Years (QALY) as the quality standard in other fields such as oncology. Future antimicrobial trials should consider introducing methods of assessing measures of health gain such as QALY to better translate the value of novel antimicrobials in healthcare.

Direct C-H electrophilic borylation with (C6F5)2B-NTf2 to generate B-N dibenzo[a,h]pyrenes.

The borylation of aryl substituted pyridines is an effective way of preparing B-N doped conjugated organic frameworks. Trihaloborane Lewis acids are often employed for this protocol, and may require further functionalization to replace the remaining halides on boron. We report a new, fully characterized, electrophilic borylating agent, (C6F5)2B(κ2-NTf2), that smoothly incorporates a -B(C6F5)2 unit into the model substrate 2-phenylpyridine. To demonstrate its utility in preparing more complex B-N doped structures, we use it to prepare seven examples of the 6a,13a-diaza-7,14-dibora-dibenzo[a,h]pyrene framework, with substituents of varying donor properties. The structural, redox, and photophysical properties of this new family of B-N doped polycyclic hydrocarbon compounds were probed experimentally and computationally.

Sensitizing methicillin-resistant Staphylococcus aureus (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine.

Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most ß-lactams, the first-line treatment for methicillin-susceptible S. aureus. A phenotype termed "NaHCO3-responsiveness" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care ß-lactams in the presence of physiologically relevant concentrations of NaHCO3, in vitro and ex vivo; moreover, such "NaHCO3-responsive" isolates can be effectively cleared by ß-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO3 exposure on NaHCO3-responsive MRSA is to repress WTA synthesis. This NaHCO3 effect mimics the phenotype of tarO-deficient MRSA, including sensitization to the PBP2-targeting ß-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO3 and/or TCP enhanced susceptibility to CFX in vitro, by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO3-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO3), pre-exposure to TCP prior to infection sensitized the NaHCO3-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific ß-lactam agents.

A mechanistic biomarker investigation of fialuridine hepatotoxicity using the chimeric TK-NOG Hu-liver mouse model and in vitro micropatterned hepatocyte cocultures.

Fialuridine (FIAU) is a nucleoside-based drug that caused liver failure and deaths in a human clinical trial that were not predicted by nonclinical safety studies. A recent report concluded that a TK-NOG humanized liver (hu-liver) mouse model detected human-specific FIAU liver toxicity, and broader use of that model could improve drug safety testing. We further evaluated this model at similar dose levels to assess FIAU sensitivity and potential mechanistic biomarkers. Although we were unable to reproduce the marked acute liver toxicity with two separate studies (including one with a "sensitized" donor), we identified molecular biomarkers reflecting the early stages of FIAU mitochondrial toxicity, which were not seen with its stereoisomer (FIRU). Dose dependent FIAU-induced changes in hu-liver mice included more pronounced reductions in mitochondrial to nuclear DNA (mtDNA/nucDNA) ratios in human hepatocytes compared to mouse hepatocytes and kidneys of the same animals. FIAU treatment also triggered a p53 transcriptional response and opposing changes in transcripts of nuclear- and mitochondrial-encoded mitochondrial proteins. The time dependent accumulation of FIAU into mtDNA is consistent with the ≥9-week latency of liver toxicity observed for FIAU in the clinic. Similar changes were observed in an in vitro micro-patterned hepatocyte coculture system. In addition, FIAU-dependent mtDNA/nucDNA ratio and transcriptional alterations, especially reductions in mitochondrially encoded transcripts, were seen in livers of non-engrafted TK-NOG and CD-1 mice dosed for a shorter period. Conclusion: These mechanistic biomarker findings can be leveraged in an in vitro model and in a more routine preclinical model (CD-1 mice) to identify nucleosides with such a FIAU-like mitochondrial toxicity mechanistic liability potential. Further optimization of the TK-NOG hu-liver mouse model is necessary before broader adoption for drug safety testing.

Development, implementation and impact of an immunoglobulin stewardship programme in Saskatchewan, Canada.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulin (IVIG) is one of the most costly and limited-supply blood products. Judicious use of this therapy is important to ensure a continued supply is available for patients in need. The Saskatchewan IG Stewardship Program was initiated to monitor and reduce inappropriate IG use. MATERIALS AND METHODS: The Program was developed and implemented through the collaborative efforts of a multidisciplinary, inter-organizational team. Funding was provided from provincial organizations to create new positions within the Program and to support stakeholder engagement throughout the process of implementation. Data were collected from local and national databases regarding the amount of IVIG used and appropriateness of orders based on published criteria. RESULTS: Over 20 months, the Program helped to reduce unnecessary IVIG use from pre-intervention levels by more than 20%. Interventions from nurse navigators alone reduced inappropriate IVIG use by 2.6%. During the 20-month period following Program initiation, more than 4 million CAD less was spent on IVIG compared with the previous 20 months. CONCLUSION: The Saskatchewan IG Stewardship Program has led to more appropriate IVIG use across the province, more effective preservation of this limited healthcare resource, and cost savings that more than cover the cost of administering the Program.

Ruthenium polyhydrides supported by rigid PCP pincer ligands: dynamic behaviour and reactions with CO2.

Two rigid ß-elimination immune PCcarbeneP pincer ligands, differing in their electron donor properties by variation of the substitution pattern on the aromatic linker arms, were complexed to ruthenium to form the dichlorides LRRuCl2 (R = H or NMe2). These compounds were converted to hydrido chlorides by treatment with dihydrogen (H2) and a base. By converting to tert-butoxide derivatives in situ under an atmosphere of H2, the poly hydride PCalkylP complexes LHRRu(H)3 compounds were generated. In these complexes, H2 has added across the RuC bond in the PCcarbeneP starting materials. The polyhydrides are dynamic in solution and extensive NMR studies helped to elucidate the speciation and fluxional processes operative in this dynamic system. The polyhydride complexes react rapidly with CO2 to give the PCcarbeneP formato hydride complexes LRRu(H)-κ2-O2CH. For R = H, the 1,2-hydride shift from the anchoring alkyl of the PCalkylP carbon to the metal is reversible, but for R = NMe2 it is irreversible. The CO2 incorporated into the formato ligand of these compounds exchanges with free CO2via a bimolecular mechanism that is more rapid for R = NMe2 than for R = H; plausible explanations for this observation are proffered. Experiments designed to evaluate the efficacy of the R = NMe2 formato hydride complex as a catalyst precursor for CO2 hydrogenation to formate salts reveal poor performance in comparison to state-of-the-art ruthenium-based catalysts. This is due primarily to the precipitation of a dimeric µ-κ2-κ1-CO3 carbonate complex that is not an active catalyst for the reaction.

Genomic and Transcriptomic Comparisons of the Twig Blight Pathogen, Passalora sequoiae, with Mycosphaerellaceae Foliar and Conifer Pathogens.

Passalora sequoiae is a foliar pathogen to conifer tree species. In this study, we conducted whole-genome and transcriptome analyses on isolates of P. sequoiae collected from symptomatic Leyland cypress leaves from a Christmas tree farm in Mississippi. The objectives for this research were to elucidate the pathogenicity mechanisms of P. sequoiae by characterizing the genome and transcriptome and possibly identify unique and shared predicted genes in comparison with non-conifer/canker and foliar pathogens in the family Mycosphaerellaceae. P. sequoiae was found to be similar to other foliar Mycosphaerellaceae pathogens and likely represents a hemibiotrophic lifestyle based on comparisons across pathogens. The genome and in planta transcriptome highlighted some unique features of P. sequoiae: the significant presence of chitin synthases and fructose-degrading carbohydrate-degrading enzymes, trans-AT PKS genes, and antibiotic gene clusters that were unique to P. sequoiae compared with the other Mycosphaerellaceae species genomes. Several transcripts that were highly expressed in planta were identified as effectors, yet the functions were not characterized. These targets provide ample resources to continue to characterize pathogen-conifer host interactions in conifer foliar pathogens. Furthermore, this research helps build genomic resources for an important plant pathogen on Leyland cypress that will further our ability to develop novel management practices that could begin with breeding for resistance.

Essential gene knockdowns reveal genetic vulnerabilities and antibiotic sensitivities in Acinetobacter baumannii.

The emergence of multidrug-resistant Gram-negative bacteria underscores the need to define genetic vulnerabilities that can be therapeutically exploited. The Gram-negative pathogen, Acinetobacter baumannii, is considered an urgent threat due to its propensity to evade antibiotic treatments. Essential cellular processes are the target of existing antibiotics and a likely source of new vulnerabilities. Although A. baumannii essential genes have been identified by transposon sequencing, they have not been prioritized by sensitivity to knockdown or antibiotics. Here, we take a systems biology approach to comprehensively characterize A. baumannii essential genes using CRISPR interference (CRISPRi). We show that certain essential genes and pathways are acutely sensitive to knockdown, providing a set of vulnerable targets for future therapeutic investigation. Screening our CRISPRi library against last-resort antibiotics uncovered genes and pathways that modulate beta-lactam sensitivity, an unexpected link between NADH dehydrogenase activity and growth inhibition by polymyxins, and anticorrelated phenotypes that may explain synergy between polymyxins and rifamycins. Our study demonstrates the power of systematic genetic approaches to identify vulnerabilities in Gram-negative pathogens and uncovers antibiotic-essential gene interactions that better inform combination therapies.IMPORTANCEAcinetobacter baumannii is a hospital-acquired pathogen that is resistant to many common antibiotic treatments. To combat resistant A. baumannii infections, we need to identify promising therapeutic targets and effective antibiotic combinations. In this study, we comprehensively characterize the genes and pathways that are critical for A. baumannii viability. We show that genes involved in aerobic metabolism are central to A. baumannii physiology and may represent appealing drug targets. We also find antibiotic-gene interactions that may impact the efficacy of carbapenems, rifamycins, and polymyxins, providing a new window into how these antibiotics function in mono- and combination therapies. Our studies offer a useful approach for characterizing interactions between drugs and essential genes in pathogens to inform future therapies.

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment.

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates. Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease. Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants: This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions: Two doses of IT GLA-SE (5 µg and 10 µg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures: Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results: Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance: In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02180698.

Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity: In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project.

Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.

Essential Gene Knockdowns Reveal Genetic Vulnerabilities and Antibiotic Sensitivities in Acinetobacter baumannii.

The emergence of multidrug-resistant Gram-negative bacteria underscores the need to define genetic vulnerabilities that can be therapeutically exploited. The Gram-negative pathogen, Acinetobacter baumannii, is considered an urgent threat due to its propensity to evade antibiotic treatments. Essential cellular processes are the target of existing antibiotics and a likely source of new vulnerabilities. Although A. baumannii essential genes have been identified by transposon sequencing (Tn-seq), they have not been prioritized by sensitivity to knockdown or antibiotics. Here, we take a systems biology approach to comprehensively characterize A. baumannii essential genes using CRISPR interference (CRISPRi). We show that certain essential genes and pathways are acutely sensitive to knockdown, providing a set of vulnerable targets for future therapeutic investigation. Screening our CRISPRi library against last-resort antibiotics uncovered genes and pathways that modulate beta-lactam sensitivity, an unexpected link between NADH dehydrogenase activity and growth inhibition by polymyxins, and anticorrelated phenotypes that underpin synergy between polymyxins and rifamycins. Our study demonstrates the power of systematic genetic approaches to identify vulnerabilities in Gram-negative pathogens and uncovers antibiotic-essential gene interactions that better inform combination therapies.

Geometrical Doping at the Atomic Scale in Oxide Quantum Materials.

Chemical dopants enabling a plethora of emergent physical properties have been treated as randomly and uniformly distributed in the frame of a three-dimensional doped system. However, in nanostructured architectures, the location of dopants relative to the interface or boundary can greatly influence device performance. This observation suggests that chemical dopants need to be considered as discrete defects, meaning that geometric control of chemical dopants becomes a critical aspect as the physical size of materials scales down into the nanotechnology regime. Here we show that geometrical control of dopants at the atomic scale is another fundamental parameter in chemical doping, extending beyond the kind and amount of dopants conventionally used. The geometrical control of dopants extends the class of geometrically controlled structures into an unexplored dimensionality, between 2D and 3D. It is well understood that in the middle of the progressive dimensionality change from 3D to 2D, the electronic state of doped SrTiO3 is altered from a highly symmetric charged fluid to a charge disproportionated insulating state. Our results introduce a geometrical control of dopants, namely, geometrical doping, as another axis to provide a variety of emergent electronic states via tuning of the electronic properties of the solid state.

The inconclusive category, entropy, and forensic firearm identification.

There has been extensive recent discussion of the difficulty in estimating meaningful error rates in forensic firearms examinations, and other areas of pattern evidence. The 2016 President's Council of Advisors on Science and Technology (PCAST) report was clear in criticizing many forensic disciplines as lacking the types of studies that would provide error rate measurements seen in other scientific fields. However, there is a substantial lack of consensus on the approach to measuring an "error rate" for fields such as forensic firearm examination that include in the conclusion scale the "inconclusive" category, as occurs in the Association of Firearm and Tool Mark Examiners (AFTE) Range of Conclusions and many other such fields. Many authors appear to assume the error rate calculated in the binary decision model is the only appropriate way to report errors, but there have been attempts made to adapt the error rate from the binary decision model to scientific fields in which the inconclusive category is viewed as a meaningful outcome of the examination process. In this study we present three neural networks of differing complexity and performance trained to classify the outlines of ejector marks on cartridge cases fired from different firearm models, as a model system for examining the performance of various metrics of error in systems using the inconclusive category. We also discuss an entropy, or information, based method to assess the similarity of classifications to ground truth that is applicable to range of conclusion scales, even when the inconclusive category is used.

Determining the validity of non-invasive spot-check hemoglobin co-oximetry testing to detect anemia in postpartum women at a tertiary care centre, a prospective cohort study.

BACKGROUND: Spot-check hemoglobin co-oximetry analyzers measure hemoglobin transcutaneously and offer the benefit of a hemoglobin measurement without phlebotomy. The objective of this study was to determine the validity of non-invasive spot-check hemoglobin co-oximetry testing for the detection of postpartum anemia (hemoglobin < 10 g/dL). METHODS: Five hundred eighty-four women aged 18 and over were recruited on postpartum day one following a singleton delivery. Two non-invasive spot-check hemoglobin co-oximetry monitors, Masimo Pronto Pulse CO-Oximeter (Pronto) and Masimo Rad-67 Pulse CO-Oximeter (Rad-67), were evaluated and compared to the postpartum phlebotomy hemoglobin value. RESULTS: Of 584 participants, 31% (181) had postpartum anemia by phlebotomy hemoglobin measurement. Bland-Altman plots determined a bias of + 2.4 (± 1.2) g/dL with the Pronto and + 2.2 (± 1.1) g/dL with the Rad-67. Low sensitivity was observed: 15% for the Pronto and 16% for the Rad-67. Adjusting for the fixed bias, the Pronto demonstrated a sensitivity of 68% and specificity of 84%, while the Rad-67 demonstrated a sensitivity of 78% and specificity of 88%. CONCLUSION: A consistent overestimation of hemoglobin by the non-invasive spot-check hemoglobin co-oximetry monitors compared to phlebotomy hemoglobin result was observed. Even after adjusting for the fixed bias, the sensitivity for detecting postpartum anemia was low. Detection of postpartum anemia should not be based on these devices alone.

Rib Fractures With Concomitant Spinal Fractures May Benefit From Surgical Stabilization.

Surgical stabilization of rib fractures has demonstrated benefits in patients with complex thoracic injuries. Limited information exists regarding patients with thoracic injuries and concomitant spinal injuries. We hypothesized that patients who suffer both thoracic cage and spinal fractures and undergo surgical fixation (FIX) will have improved outcomes compared to non-fixation (NFIX) patients. In our retrospective review, adult patients with rib injuries from 2015 to 2019 were pooled from the National Trauma Data Bank. Mortality with FIX rib fractures with spinal fractures decreased by 6.1% vs the NFIX group. Mortality of FIX of rib fractures without spinal fractures decreased by 2.2% vs the NFIX group. Patients with rib fractures with concomitant spinal fracture (RFWSF) are more likely to receive rib FIX than those with rib fractures without spinal fractures. Rib FIX in patients with RFWSF vs those with RFWO facilitates less ventilators days and shorter ICU and hospital length of stay (LOS) as well as decreases mortality.

Chromosome-length genome assembly and karyotype of the endangered black-footed ferret (Mustela nigripes).

The black-footed ferret (Mustela nigripes) narrowly avoided extinction to become an oft-cited example of the benefits of intensive management, research, and collaboration to save a species through ex situ conservation breeding and reintroduction into its former range. However, the species remains at risk due to possible inbreeding, disease susceptibility, and multiple fertility challenges. Here, we report the de novo genome assembly of a male black-footed ferret generated through a combination of linked-read sequencing, optical mapping, and Hi-C proximity ligation. In addition, we report the karyotype for this species, which was used to anchor and assign chromosome numbers to the chromosome-length scaffolds. The draft assembly was ~2.5 Gb in length, with 95.6% of it anchored to 19 chromosome-length scaffolds, corresponding to the 2n = 38 chromosomes revealed by the karyotype. The assembly has contig and scaffold N50 values of 148.8 kbp and 145.4 Mbp, respectively, and is up to 96% complete based on BUSCO analyses. Annotation of the assembly, including evidence from RNA-seq data, identified 21,406 protein-coding genes and a repeat content of 37.35%. Phylogenomic analyses indicated that the black-footed ferret diverged from the European polecat/domestic ferret lineage 1.6 million yr ago. This assembly will enable research on the conservation genomics of black-footed ferrets and thereby aid in the further restoration of this endangered species.