Ruthenium Complexes of a Triphosphorus-Coordinating Pincer Ligand: Ru-P Ligand-Substituent Exchange Reactions Driven by Large Variations of Bond Energies.

The reaction of [(p-cymene)RuCl2]2 with the triphosphine ligand bis(2-di-tert-butylphosphinophenyl)phosphine (tBuPHPP) results in an unusual exchange reaction in which a chloride ligand and a phosphorus-bound H atom are exchanged ("H-P/Ru-Cl exchange") to give the (chlorophosphine)ruthenium hydride complex (tBuPClPP)RuHCl [1Cl-HCl; tBuPClPP = bis(2-di-tert-butylphosphinophenyl)chlorophosphine]. Density functional theory calculations indicate that the presumed initial product of metalation, (tBuPHPP)RuCl2 (1H-Cl2), undergoes an H-P/Ru-Cl exchange via sequential P-to-Ru α-H migration to give the intermediate (tBuPPP)RuHCl2, followed by Ru-to-P α-Cl migration to give the observed product 1Cl-HCl (crystallographically characterized). Dehydrochlorination of 1Cl-HCl under a H2 atmosphere gives (tBuPClPP)RuH4 (1Cl-H4), which then can undergo a second dehydrochlorination and addition of H2 to give (tBuPHPP)RuH4 (1H-H4). This reaction may proceed via the reverse of the intramolecular exchange by 1H-Cl2, i.e., loss of H2 from 1Cl-H4 to give 1Cl-H2, which could undergo Cl-P/Ru-H exchange to give (tBuPHPP)RuHCl (1H-HCl). Accordingly, the thermodynamics of Cl-P/Ru-H exchange are found to be highly dependent on the nature of the ancillary anionic ligand (H or Cl), which is not directly involved in the exchange. The origin of this thermodynamic dependence can be explained in terms of the high stability of complexes (RPXPP)RuHCl (X = H, Cl; R = Me, tBu), in which the hydride is approximately trans to a vacant coordination site and the central phosphine group is approximately trans to the weak-trans-influence chloride ligand. This conclusion has general implications for five-coordinate d6 complexes, both pincer- and nonpincer-ligated.

Reactivity of Iridium Complexes of a Triphosphorus-Pincer Ligand Based on a Secondary Phosphine. Catalytic Alkane Dehydrogenation and the Origin of Extremely High Activity.

The selective functionalization of alkanes and alkyl groups is a major goal of chemical catalysis. Toward this end, a bulky triphosphine with a central secondary phosphino group, bis(2-di-t-butyl-phosphinophenyl)phosphine (tBuPHPP), has been synthesized. When complexed to iridium, it adopts a meridional ("pincer") configuration. The secondary phosphino H atom can undergo migration to iridium to give an anionic phosphido-based-pincer (tBuPPP) complex. Stoichiometric reactions of the (tBuPPP)Ir complexes reflect a distribution of steric bulk around the iridium center in which the coordination site trans to the phosphido group is quite crowded; one coordination site cis to the phosphido is even more crowded; and the remaining site is particularly open. The (tBuPPP)Ir precursors are the most active catalysts reported to date for dehydrogenation of n-alkanes, by about 2 orders of magnitude. The electronic properties of the iridium center are similar to that of well-known analogous (RPCP)Ir catalysts. Accordingly, DFT calculations predict that (tBuPPP)Ir and (tBuPCP)Ir are, intrinsically, comparably active for alkane dehydrogenation. While dehydrogenation by (RPCP)Ir proceeds through an intermediate trans-(PCP)IrH2(alkene), (tBuPPP)Ir follows a pathway proceeding via cis-(PPP)IrH2(alkene), thereby circumventing unfavorable placement of the alkene at the bulky site trans to phosphorus. (tBuPPP)Ir and (tBuPCP)Ir, however, have analogous resting states: square planar (pincer)Ir(alkene). Alkene coordination at the crowded trans site is therefore unavoidable in the resting states. Thus, the resting state of the (tBuPPP)Ir catalyst is destabilized by the architecture of the ligand, and this is largely responsible for its unusually high catalytic activity.

Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice.

Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.

Cannabidiol (CBD): Perspectives from Pinterest.

BACKGROUND: Pinterest, a widely used social media platform, has shaped how people seek and share health information. Cannabidiol (CBD), a non-psychoactive component of cannabis is marketed as a treatment for many conditions and sales rose to more than 820 million in 2017. Yet CBD is mostly unregulated, legality is murky, and many of the health claims are not scientifically proven. Purpose: This content analysis examined how CBD products were portrayed on Pinterest. Methods: In 2018, using the search terms cannabidiol and CBD, researchers sampled every fifth pin to collect 226 relevant pins. A codebook was developed, pilot tested, and used to code pins. Results: The majority (91.6%) of pins positively portrayed CBD with many claiming a physical or mental benefit including anxiety, depression, pain, and inflammation relief. Most pins did not (98.2%) address potential side effects or recommend dosage. In this sample, user engagement was high with 85.2% of pins being saved and links to commercial sites selling CBD products, personal blogs, and social media accounts. Conclusions: Social media has become a powerful source of health information. This study revealed widespread acceptance of the use of CBD products with minimal information from reliable public health sources represented.

CBD (Cannabidiol) Product Attitudes, Knowledge, and Use Among Young Adults.

Background: Cannabidiol (CBD), a non-psychoactive component of cannabis is marketed as a potential treatment for many conditions and widely available to purchase as a dietary supplement. In 2017, sales of CBD exceeded 820 million dollars despite many unconfirmed health claims, murky legality, and limited product efficacy and safety testing.Purpose/Objectives: This study aims to explore cannabidiol (CBD) knowledge, attitudes, and use among young adults.Methods: The anonymous 36-item survey developed using Qualtrics was distributed via social media from November 2018 to January 2019 with 340 respondents.Results: Of the 340 respondents, 242 reported they had heard of CBD, and 135 reported using CBD products. CBD users were primarily white, female, without children, made less than $25,000 per year, and unmarried. Most commonly used CBD products were edibles (56.30%), tinctures (54.07%), and vape (38.52%). Top reasons for use included stress relief (65.39%), relaxation (54.81%), and sleep improvement (42.22%). Many respondents reported using guesswork to determine dosage, and over half of respondents reported at least one unanticipated side effect.Conclusions/Importance: This study revealed that many users are not responsibly using CBD products, many believe CBD products provide health benefits that are not yet scientifically proven, and they are not knowledgeable about legal and regulatory issues. Until CBD use is more thoroughly researched and has more comprehensive regulation, public health professionals should address alternative stress and anxiety treatment methods.

Elbow Kinematics During Gait Improve With Age in Children With Hemiplegic Cerebral Palsy.

BACKGROUND: Children with hemiplegic cerebral palsy (hCP) exhibit a typical posture of elbow flexion during gait. However, the change in elbow kinematics and symmetry during gait across age span in both hCP and typically developing (TD) children is not well described. The aim of this study was to quantify the change in elbow kinematics and symmetry across age span in hCP children compared with TD children. METHODS: Upper extremity kinematic data were extracted and analyzed from a database for gait studies performed between 2009 and 2015. A total of 35 hCP and 51 TD children between the ages of 4 and 18 (mean age: TD=11.2±0.6, hCP=9.8±0.5) met inclusionary criteria. The groups were further subdivided into 3 age categories: 4 to 7, 8 to 11, 12+ years old. Elbow angles were extracted and peak elbow flexion, overall range of motion during gait, and asymmetry indices were calculated. A 1-way analysis of variance was performed on each group with post hoc Tukey honestly significant difference pairwise comparisons. RESULTS: Peak elbow flexion during gait increased with age in TD children (P<0.05) and decreased with age in hCP children on the affected side (P<0.05). There was no change on the less affected side of hCP children. TD children demonstrated significantly less elbow flexion (mean=51.9±2.1 deg.) compared with the affected side in hCP (mean=82.1±3.8 deg.) across all age categories (P<0.05). There was no change in elbow asymmetry index (0=perfect symmetry) across age in either controls or hCP children; however, there were differences between hCP and TD groups in younger age groups (TD=28, hCP=62, P<0.05) that resolved by adolescence (TD=32, hCP=40). CONCLUSIONS: During gait, hCP children have greater peak elbow flexion on the affected side than do TD children. Peak elbow flexion angle converged between the 2 groups with age, decreasing in hCP children and increasing in TD children. Furthermore, elbow symmetry during gait improves with age in hCP children, approximating symmetry of TD children by adolescence. These findings have implications for both consideration and optimal timing of surgical intervention to improve elbow flexion in children with hCP. LEVEL OF EVIDENCE: Level III-retrospective case-control study.

Influence of acute and chronic streptozotocin-induced diabetes on the rat tendon extracellular matrix and mechanical properties.

Diabetes is a major risk factor for tendinopathy, and tendon abnormalities are common in diabetic patients. The purpose of the present study was to evaluate the effect of streptozotocin (60 mg/kg)-induced diabetes and insulin therapy on tendon mechanical and cellular properties. Sprague-Dawley rats (n = 40) were divided into the following four groups: nondiabetic (control), 1 wk of diabetes (acute), 10 wk of diabetes (chronic), and 10 wk of diabetes with insulin treatment (insulin). After 10 wk, Achilles tendon and tail fascicle mechanical properties were similar between groups (P > 0.05). Cell density in the Achilles tendon was greater in the chronic group compared with the control and acute groups (control group: 7.8 ± 0.5 cells/100 µm(2), acute group: 8.3 ± 0.4 cells/100 µm(2), chronic group: 10.9 ± 0.9 cells/100 µm(2), and insulin group: 9.2 ± 0.8 cells/100 µm(2), P < 0.05). The density of proliferating cells in the Achilles tendon was greater in the chronic group compared with all other groups (control group: 0.025 ± 0.009 cells/100 µm(2), acute group: 0.019 ± 0.005 cells/100 µm(2), chronic group: 0.067 ± 0.015, and insulin group: 0.004 ± 0.004 cells/100 µm(2), P < 0.05). Patellar tendon collagen content was ∼32% greater in the chronic and acute groups compared with the control or insulin groups (control group: 681 ± 63 µg collagen/mg dry wt, acute group: 938 ± 21 µg collagen/mg dry wt, chronic: 951 ± 52 µg collagen/mg dry wt, and insulin group: 596 ± 84 µg collagen/mg dry wt, P < 0.05). In contrast, patellar tendon hydroxylysyl pyridinoline cross linking and collagen fibril organization were unchanged by diabetes or insulin (P > 0.05). Our findings suggest that 10 wk of streptozotocin-induced diabetes does not alter rat tendon mechanical properties even with an increase in collagen content. Future studies could attempt to further address the mechanisms contributing to the increase in tendon problems noted in diabetic patients, especially since our data suggest that hyperglycemia per se does not alter tendon mechanical properties.

Genomic medicine for cancer diagnosis.

Genomic diagnostics in cancer has evolved since the completion of the Human Genome Project and the advancements made in diagnosis and therapy in chronic myelogenous leukemia. Among the diseases to achieve limited success or potentially benefit from diagnostic genetic testing are thyroid cancer, Burkitt's lymphoma, gastrointestinal stromal tumors, adrenocortical carcinoma, and colorectal cancer. With increased understanding of genomics, genetic tests should improve diagnosis and help guide medical and surgical management.

The effects of exercise training on the traditional lipid profile and beyond.

The purpose of this review is to provide up-to-date information regarding the effects of aerobic and resistance exercise training on the traditional blood lipid and lipoprotein profile. In addition, emerging coronary artery disease (CAD) risk factors, such as postprandial lipemia (PPL) and metabolic syndrome (MetS), are reviewed. Numerous studies report that aerobic exercise combined with weight loss significantly reduces blood cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG) while improving high-density lipoprotein cholesterol (HDL-C). Both aerobic and resistance training demonstrated a reduction in non-HDL-C independent of changes in body weight. Transient beneficial effects of a single session of aerobic exercise are observed for PPL. Nonetheless further research is needed to provide a better understanding of the potential mechanisms for reducing PPL. Exercise as an intervention for patients with MetS leads to improved CAD risk factors including atherogenic dyslipidemia, blood pressure, body composition, insulin sensitivity, and fat metabolism.

The Relationship between Physical Activity, Physical Fitness, Cognition, and Academic Outcomes in School-Aged Latino Children: A Scoping Review.

This scoping review provides an overview of the relationship between physical activity, physical fitness, cognition, and academic outcomes in Latino school-aged children and identifies areas for future research. A primary search was conducted in PubMed, PsycINFO, Web of Science, and ERIC for original-research articles meeting the inclusion criteria; the search results were uploaded into PICO Portal and assessed by two independent reviewers. Of the 488 initial search results, 50 articles were eligible for full-text review, and 38 were included in this review. Most studies were cross-sectional, conducted in the United States or Chile, and included children 5-18 years old. Overall, the majority of articles reported positive associations between physical activity or physical fitness and cognitive outcomes (n = 11/12; 91.7%), and physical activity or physical fitness and academic outcomes (n = 22/28; 78.6%). In sum, this review provided consistent evidence for higher amounts of physical activity and greater physical fitness to be associated with various positive cognitive and academic outcomes in a school-aged Latino population. This scoping review also elucidated a substantial gap in the research regarding study design, with a discernible lack of interventional efforts. Future studies should test physical activity interventional strategies to optimize cognitive and academic outcomes in school-aged Latino populations.

Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model.

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis.

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, cyclosporine, or colectomy. Fewer data are available for the use of TDM of infliximab in ASUC. The pharmacokinetics of ASUC make TDM in this population more complex. High inflammatory burden is associated with increased infliximab clearance, which is associated with lower infliximab drug concentrations. Observational data support the association between increased serum infliximab concentrations, lower clearance, and favorable clinical and endoscopic outcomes, as well as decreased rates of colectomy. Data regarding the benefit of accelerated or intensified dosing strategies of infliximab-as well as target drug concentration thresholds-in ASUC patients remain more equivocal, though limited by their observational nature. Studies are underway to further evaluate optimal dosing and TDM targets in this population. This review examines the evidence for TDM in patients with ASUC, with a focus on infliximab.

The seminal odorant binding protein Obp56g is required for mating plug formation and male fertility in Drosophila melanogaster.

In Drosophila melanogaster and other insects, the seminal fluid proteins (SFPs) and male sex pheromones that enter the female with sperm during mating are essential for fertility and induce profound post-mating effects on female physiology and behavior. The SFPs in D. melanogaster and other taxa include several members of the large gene family known as odorant binding proteins (Obps). Previous work in Drosophila has shown that some Obp genes are highly expressed in the antennae and can mediate behavioral responses to odorants, potentially by binding and carrying these molecules to odorant receptors. These observations have led to the hypothesis that the seminal Obps might act as molecular carriers for pheromones or other compounds important for male fertility in the ejaculate, though functional evidence in any species is lacking. Here, we used RNAi and CRISPR/Cas9 generated mutants to test the role of the seven seminal Obps in D. melanogaster fertility and the post-mating response (PMR). We found that Obp56g is required for male fertility and the induction of the PMR, whereas the other six genes had no effect on fertility when mutated individually. Obp56g is expressed in the male's ejaculatory bulb, an important tissue in the reproductive tract that synthesizes components of the mating plug. We found males lacking Obp56g fail to form a mating plug in the mated female's reproductive tract, leading to ejaculate loss and reduced sperm storage. We also examined the evolutionary history of these seminal Obp genes, as several studies have documented rapid evolution and turnover of SFP genes across taxa. We found extensive lability in gene copy number and evidence of positive selection acting on two genes, Obp22a and Obp51a. Comparative RNAseq data from the male reproductive tract of multiple Drosophila species revealed that Obp56g shows high male reproductive tract expression only in species of the melanogaster and obscura groups, though conserved head expression in all species tested. Together, these functional and expression data suggest that Obp56g may have been co-opted for a reproductive function over evolutionary time.

The seminal odorant binding protein Obp56g is required for mating plug formation and male fertility in Drosophila melanogaster.

In Drosophila melanogaster and other insects, the seminal fluid proteins (SFPs) and male sex pheromones that enter the female with sperm during mating are essential for fertility and induce profound post-mating effects on female physiology. The SFPs in D. melanogaster and other taxa include several members of the large gene family known as odorant binding proteins (Obps). Work in Drosophila has shown that some Obp genes are highly expressed in the antennae and can mediate behavioral responses to odorants, potentially by binding and carrying these molecules to odorant receptors. These observations have led to the hypothesis that the seminal Obps might act as molecular carriers for pheromones or other compounds important for male fertility, though functional evidence in any species is lacking. Here, we used functional genetics to test the role of the seven seminal Obps in D. melanogaster fertility and the post-mating response (PMR). We found that Obp56g is required for male fertility and the induction of the PMR, whereas the other six genes are dispensable. We found males lacking Obp56g fail to form a mating plug in the mated female's reproductive tract, leading to ejaculate loss and reduced sperm storage, likely due to its expression in the male ejaculatory bulb. We also examined the evolutionary history of these seminal Obp genes, as several studies have documented rapid evolution and turnover of SFP genes across taxa. We found extensive lability in gene copy number and evidence of positive selection acting on two genes, Obp22a and Obp51a. Comparative RNAseq data from the male reproductive tract of multiple Drosophila species revealed that Obp56g shows high male reproductive tract expression in a subset of taxa, though conserved head expression across the phylogeny. Together, these functional and expression data suggest that Obp56g may have been co-opted for a reproductive function over evolutionary time.

Prevalence and factors associated with vitamin C deficiency in inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are prone to several nutritional deficiencies. However, data are lacking on vitamin C deficiency in Crohn's disease (CD) and ulcerative colitis (UC) patients, as well as the impact of clinical, biomarker and endoscopic disease severity on the development of vitamin C deficiency. AIM: To determine proportions and factors associated with vitamin C deficiency in CD and UC patients. METHODS: In this retrospective study, we obtained clinical, laboratory and endoscopic data from CD and UC patients presenting to the IBD clinic at a single tertiary care center from 2014 to 2019. All patients had an available plasma vitamin C level. Of 353 subjects who met initial search criteria using a cohort discovery tool, 301 ultimately met criteria for inclusion in the study. The primary aim described vitamin C deficiency (≤ 11.4 µmol/L) rates in IBD. Secondary analyses compared proportions with deficiency between active and inactive IBD. Multivariate logistic regression analysis evaluated factors associated with deficiency. RESULTS: Of 301 IBD patients, 21.6% had deficiency, including 24.4% of CD patients and 16.0% of UC patients. Patients with elevated C-reactive protein (CRP) (39.1% vs 16.9%, P < 0.001) and fecal calprotectin (50.0% vs 20.0%, P = 0.009) had significantly higher proportions of deficiency compared to those without. Penetrating disease (P = 0.03), obesity (P = 0.02) and current biologic use (P = 0.006) were also associated with deficiency on univariate analysis. On multivariate analysis, the objective inflammatory marker utilized for analysis (elevated CRP) was the only factor associated with deficiency (odds ratio = 3.1, 95% confidence interval: 1.5-6.6, P = 0.003). There was no difference in the presence of clinical symptoms of scurvy in those with vitamin C deficiency and those without. CONCLUSION: Vitamin C deficiency was common in IBD. Patients with elevated inflammatory markers and penetrating disease had higher rates of vitamin C deficiency.

Synoptic reporting accuracy for computed tomography pulmonary arteriography among patients suspected of pulmonary embolism.

Background: Structured reporting is an efficient and replicable method of presenting diagnostic results that eliminates variability inherent in narrative descriptive reporting and may improve clinical decisions. Synoptic element reporting can generate discrete coded data that then may inform clinical decision support and trigger downstream actions in computerized electronic health records. Objective: Limited evidence exists for use of synoptic reporting for computed tomography pulmonary arteriography (CTPA) among patients suspected of pulmonary embolism. We reported the accuracy of synoptic reporting for the outcome of pulmonary embolism among patients who presented to an integrated health care system with CTPA performed for suspected pulmonary embolism. Methods: Structured radiology reports with embedded synoptic elements were implemented for all CTPA examinations on March 1, 2018. Four hundred CTPA reports between January 4, 2019 and July 30, 2020 (200 reports each for which synoptic reporting recorded the presence or absence of pulmonary embolism [PE]) were selected at random. One non-diagnostic study was excluded from analysis. We then assessed the accuracy of synoptic reporting compared with the gold standard of manual chart review. Results: Synoptic reporting and manual review agreed in 99.2% of patients undergoing CTPA for suspected PE, agreed on the presence of PE in 196 of 199 (98.5%) cases, the absence of PE in 200 of 200 (100%) cases with a sensitivity of 87.6% (76.1-96.1) a specificity of 99.9% (99.7%-100%), a positive predictive value of 99.5% (98.1-100), and a negative predictive value of 98% (95.7%-99.5%). Conclusion: The overall rate of agreement was 99.2%, but we observed an unacceptable false-negative rate for clinical reliance on synoptic element reporting in isolation from dictated reports.

CheXED: Comparison of a Deep Learning Model to a Clinical Decision Support System for Pneumonia in the Emergency Department.

PURPOSE: Patients with pneumonia often present to the emergency department (ED) and require prompt diagnosis and treatment. Clinical decision support systems for the diagnosis and management of pneumonia are commonly utilized in EDs to improve patient care. The purpose of this study is to investigate whether a deep learning model for detecting radiographic pneumonia and pleural effusions can improve functionality of a clinical decision support system (CDSS) for pneumonia management (ePNa) operating in 20 EDs. MATERIALS AND METHODS: In this retrospective cohort study, a dataset of 7434 prior chest radiographic studies from 6551 ED patients was used to develop and validate a deep learning model to identify radiographic pneumonia, pleural effusions, and evidence of multilobar pneumonia. Model performance was evaluated against 3 radiologists' adjudicated interpretation and compared with performance of the natural language processing of radiology reports used by ePNa. RESULTS: The deep learning model achieved an area under the receiver operating characteristic curve of 0.833 (95% confidence interval [CI]: 0.795, 0.868) for detecting radiographic pneumonia, 0.939 (95% CI: 0.911, 0.962) for detecting pleural effusions and 0.847 (95% CI: 0.800, 0.890) for identifying multilobar pneumonia. On all 3 tasks, the model achieved higher agreement with the adjudicated radiologist interpretation compared with ePNa. CONCLUSIONS: A deep learning model demonstrated higher agreement with radiologists than the ePNa CDSS in detecting radiographic pneumonia and related findings. Incorporating deep learning models into pneumonia CDSS could enhance diagnostic performance and improve pneumonia management.

Blood pressure-lowering efficacy of a 6-week multi-modal isometric exercise intervention.

Isometric exercise training (IET) is an effective method for reducing resting blood pressure (BP). To date, no research studies have been conducted using multiple exercises within an IET intervention. Previous research has suggested that varied exercise programmes may have a positive effect on adherence. Therefore, this randomized controlled study aimed to investigate the BP-lowering efficacy of a multi-modal IET (MIET) intervention in healthy young adults. Twenty healthy participants were randomized to an MIET [n = 10; four women; SBP 117.9 ± 6.9 mmHg; DBP 66.3 ± 5.1 mmHg] or control (CON) group (n = 10; five women; SBP, 123.3 ± 10.4 mmHg; DBP, 77.3 ± 6.7 mmHg). The MIET group completed three sessions per week of 4, 2-min isometric contractions, with a 1-min rest between each contraction, for 6 weeks. Resting BP and heart rate (HR) were measured at baseline and post-intervention. Pre-to-post intervention within-group reductions in resting BP were observed (SBP: 5.3 ± 6.1 mmHg, DBP: 3.4 ± 3.7 mmHg, MAP: 4.0 ± 3.9 mmHg, HR: 4.8 ±6 .6 bpm), although clinically relevant (≥2 mmHg), these changes were not statistically significant. Significant (p < 0.05) between-group differences were found between the intervention and control groups, indicating that the MIET intervention has a greater BP-lowering effect compared to control. The clinically relevant post-training reductions in resting BP suggest that MIET may be a promising additional IET method for hypertension prevention. These findings; however, must be interpreted with caution due to the small sample size and the non-clinical cohort.

Symbiodinium-invertebrate symbioses and the role of metabolomics.

Symbioses play an important role within the marine environment. Among the most well known of these symbioses is that between coral and the photosynthetic dinoflagellate, Symbiodinium spp. Understanding the metabolic relationships between the host and the symbiont is of the utmost importance in order to gain insight into how this symbiosis may be disrupted due to environmental stressors. Here we summarize the metabolites related to nutritional roles, diel cycles and the common metabolites associated with the invertebrate-Symbiodinium relationship. We also review the more obscure metabolites and toxins that have been identified through natural products and biomarker research. Finally, we discuss the key role that metabolomics and functional genomics will play in understanding these important symbioses.

The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines.

Breast cancer affects roughly one in eight women over their lifetime and is a leading cause of cancer-related death in women. While outcomes have improved in recent years, prognosis remains poor for patients who present with either disseminated disease or aggressive molecular subtypes. Cancer immunotherapy has revolutionized the treatment of several cancers, with therapeutic vaccines aiming to direct the cytotoxic immune program against tumor cells showing particular promise. However, these results have yet to translate to breast cancer, which remains largely refractory from such approaches. Recent evidence suggests that the breast tumor microenvironment (TME) is an important and long understudied barrier to the efficacy of therapeutic vaccines. Through an improved understanding of the complex and biologically diverse breast TME, it may be possible to advance new combination strategies to render breast carcinomas sensitive to the effects of therapeutic vaccines. Here, we discuss past and present efforts to advance therapeutic vaccines in the treatment of breast cancer, the molecular mechanisms through which the TME contributes to the failure of such approaches, as well as the potential means through which these can be overcome.