Structure, biosynthesis and regulation of the T1 antigen, a phase-variable surface polysaccharide conserved in many Salmonella serovars.

The bacterial genus Salmonella includes diverse isolates with multiple variations in the structure of the main polysaccharide component (O antigen) of membrane lipopolysaccharides. In addition, some isolates produce a transient (T) antigen, such as the T1 polysaccharide identified in the 1960s in an isolate of Salmonella enterica Paratyphi B. The structure and biosynthesis of the T1 antigen have remained enigmatic. Here, we use biophysical, biochemical and genetic methods to show that the T1 antigen is a complex linear glycan containing tandem homopolymeric domains of galactofuranose and ribofuranose, linked to lipid A-core, like a typical O antigen. T1 is a phase-variable antigen, regulated by recombinational inversion of the promoter upstream of the T1 genetic locus through a mechanism not observed for other bacterial O antigens. The T1 locus is conserved across many Salmonella isolates, but is mutated or absent in most typhoidal serovars and in serovar Enteritidis.

Infrared Thermography of the Blowhole as a Potential Diagnostic Tool for Health Assessment in Killer Whales (Orcinus orca).

Killer whales (Orcinus orca) are experiencing increasing environmental pressures, with some ecotypes being identified as endangered, and the development and validation of non-invasive health assessment tools is critical for assessing the well-being of individuals within these endangered populations. Infrared thermography of the blowhole is a non-contact method of temperature measurement that was recently investigated in killer whales in managed care. Two male killer whales presenting with clinical signs at separate institutions had veterinary clinical health assessments performed, which included infrared thermography of the blowhole as well as concurrent rectal temperature measurement. The current case report is aimed at describing the clinical use of infrared thermography of the blowhole as a method to detect elevated body temperature in two killer whales. Both animals exhibited blowhole temperatures above the previously reported values (36.4 °C and 37.6 °C; the mean in healthy whales is reported to be 34.21 ± 1.47 °C) with concurrently elevated rectal temperatures, as well as clinicopathologic findings consistent with a systemic inflammatory response (e.g., neutrophilia, increased fibrinogen and erythrocyte sedimentation rate, hypoferritinemia). Following veterinary intervention, both animals' blowhole and rectal temperatures returned to baseline. Infrared thermography of the blowhole represents a promising tool for the identification of pyrexic animals and with further investigation may be considered as part of conservation health assessments for threatened free-ranging populations.

Transition transferases prime bacterial capsule polymerization.

Capsules are long-chain carbohydrate polymers that envelop the surfaces of many bacteria, protecting them from host immune responses. Capsule biosynthesis enzymes are potential drug targets and valuable biotechnological tools for generating vaccine antigens. Despite their importance, it remains unknown how structurally variable capsule polymers of Gram-negative pathogens are linked to the conserved glycolipid anchoring these virulence factors to the bacterial membrane. Using Actinobacillus pleuropneumoniae as an example, we demonstrate that CpsA and CpsC generate a poly(glycerol-3-phosphate) linker to connect the glycolipid with capsules containing poly(galactosylglycerol-phosphate) backbones. We reconstruct the entire capsule biosynthesis pathway in A. pleuropneumoniae serotypes 3 and 7, solve the X-ray crystal structure of the capsule polymerase CpsD, identify its tetratricopeptide repeat domain as essential for elongating poly(glycerol-3-phosphate) and show that CpsA and CpsC stimulate CpsD to produce longer polymers. We identify the CpsA and CpsC product as a wall teichoic acid homolog, demonstrating similarity between the biosynthesis of Gram-positive wall teichoic acid and Gram-negative capsules.

Genetic predictors of blood pressure traits are associated with preeclampsia.

Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University's BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (ORDBP = 1.10, 95% CI 1.02-1.17, p = 7.68 × 10-3; ORSBP = 1.16, 95% CI 1.09-1.23, p = 2.23 × 10-6; ORPP = 1.14, 95% CI 1.07-1.27, p = 9.86 × 10-5). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.

Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

Adaptive selection at G6PD and disparities in diabetes complications.

Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.

Genomic Insights into Gestational Weight Gain: Uncovering Tissue-Specific Mechanisms and Pathways.

Increasing gestational weight gain (GWG) is linked to adverse outcomes in pregnant persons and their children. The Early Growth Genetics (EGG) Consortium identified previously genetic variants that could contribute to early, late, and total GWG from fetal and maternal genomes. However, the biologic mechanisms and tissue-Specificity of these variants in GWG is unknown. We evaluated the association between genetically predicted gene expression in five relevant maternal (subcutaneous and visceral adipose, breast, uterus, and whole blood) from GTEx (v7) and fetal (placenta) tissues and early, late, and total GWG using S-PrediXcan. We tested enrichment of pre-defined biological pathways for nominally (P < 0.05) significant associations using the GENE2FUNC module from Functional Mapping and Annotation of Genome-Wide Association Studies. After multiple testing correction, we did not find significant associations between maternal and fetal gene expression and early, late, or total GWG. There was significant enrichment of several biological pathways, including metabolic processes, secretion, and intracellular transport, among nominally significant genes from the maternal analyses (false discovery rate p-values: 0.016 to 9.37×10). Enriched biological pathways varied across pregnancy. Though additional research is necessary, these results indicate that diverse biological pathways are likely to impact GWG, with their influence varying by tissue and weeks of gestation.

POMC neurons control fertility through differential signaling of MC4R in Kisspeptin neurons.

Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of MC4RKO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations; the Kiss1ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeN neurons controlling the preovulatory LH surge. Here, we show that Mc4r expressed in Kiss1 neurons is required for fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion of Mc4r in Kiss1 neurons of MC4R null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of MC4R on Kiss1ARH vs Kiss1AVPV/PeN neurons and show that MC4R activation excites Kiss1ARH neurons through direct synaptic actions. In contrast, Kiss1AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMCARH neurons acting through MC4R, directly regulate reproductive function in females by stimulating the "pulse generator" activity of Kiss1ARH neurons and restricting the activation of Kiss1AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.

Three-component systems represent a common pathway for extracytoplasmic addition of pentofuranose sugars into bacterial glycans.

Cell surface glycans are major drivers of antigenic diversity in bacteria. The biochemistry and molecular biology underpinning their synthesis are important in understanding host-pathogen interactions and for vaccine development with emerging chemoenzymatic and glycoengineering approaches. Structural diversity in glycostructures arises from the action of glycosyltransferases (GTs) that use an immense catalog of activated sugar donors to build the repeating unit and modifying enzymes that add further heterogeneity. Classical Leloir GTs incorporate α- or ß-linked sugars by inverting or retaining mechanisms, depending on the nucleotide sugar donor. In contrast, the mechanism of known ribofuranosyltransferases is confined to ß-linkages, so the existence of α-linked ribofuranose in some glycans dictates an alternative strategy. Here, we use Citrobacter youngae O1 and O2 lipopolysaccharide O antigens as prototypes to describe a widespread, versatile pathway for incorporating side-chain α-linked pentofuranoses by extracytoplasmic postpolymerization glycosylation. The pathway requires a polyprenyl phosphoribose synthase to generate a lipid-linked donor, a MATE-family flippase to transport the donor to the periplasm, and a GT-C type GT (founding the GT136 family) that performs the final glycosylation reaction. The characterized system shares similarities, but also fundamental differences, with both cell wall arabinan biosynthesis in mycobacteria, and periplasmic glucosylation of O antigens first discovered in Salmonella and Shigella. The participation of auxiliary epimerases allows the diversification of incorporated pentofuranoses. The results offer insight into a broad concept in microbial glycobiology and provide prototype systems and bioinformatic guides that facilitate discovery of further examples from diverse species, some in currently unknown glycans.

Protocol for the Prone and Oscillation Pediatric Clinical Trial (PROSpect).

OBJECTIVES: Respiratory management for pediatric acute respiratory distress syndrome (PARDS) remains largely supportive without data to support one approach over another, including supine versus prone positioning (PP) and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV). DESIGN: We present the research methodology of a global, multicenter, two-by-two factorial, response-adaptive, randomized controlled trial of supine versus PP and CMV versus HFOV in high moderate-severe PARDS, the Prone and Oscillation Pediatric Clinical Trial (PROSpect, www.ClinicalTrials.gov, NCT03896763). SETTING: Approximately 60 PICUs with on-site extracorporeal membrane oxygenation support in North and South America, Europe, Asia, and Oceania with experience using PP and HFOV in the care of patients with PARDS. PATIENTS: Eligible pediatric patients (2 wk old or older and younger than 21 yr) are randomized within 48 h of meeting eligibility criteria occurring within 96 h of endotracheal intubation. INTERVENTIONS: One of four arms, including supine/CMV, prone/CMV, supine/HFOV, or prone/HFOV. We hypothesize that children with high moderate-severe PARDS treated with PP or HFOV will demonstrate greater than or equal to 2 additional ventilator-free days (VFD). MEASUREMENTS AND MAIN RESULTS: The primary outcome is VFD through day 28; nonsurvivors receive zero VFD. Secondary and exploratory outcomes include nonpulmonary organ failure-free days, interaction effects of PP with HFOV on VFD, 90-day in-hospital mortality, and among survivors, duration of mechanical ventilation, PICU and hospital length of stay, and post-PICU functional status and health-related quality of life. Up to 600 patients will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur 28 days after 300 patients are randomized and every 100 patients thereafter. At these randomization updates, new allocation probabilities will be computed based on intention-to-treat trial results, increasing allocation to well-performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol for primary, secondary, and exploratory analyses. CONCLUSIONS: PROSpect will provide clinicians with data to inform the practice of PP and HFOV in PARDS.

Klebsiella pneumoniae O-polysaccharide biosynthesis highlights the diverse organization of catalytic modules in ABC transporter-dependent glycan assembly.

Klebsiella pneumoniae provides influential prototypes for lipopolysaccharide O antigen (OPS) biosynthesis in Gram-negative bacteria. Sequences of OPS-biosynthesis gene clusters in serotypes O4 and O7 suggest fundamental differences in the organization of required enzyme modules compared to other serotypes. Furthermore, some required activities were not assigned by homology shared with characterized enzymes. The goal of this study was therefore to resolve the serotype O4 and O7 pathways to expand our broader understanding of glycan polymerization and chain termination processes. The O4 and O7 antigens were produced from cloned genetic loci in recombinant Escherichia coli. Systematic in vivo and in vitro approaches were then applied to assign each enzyme in each of the pathways, defining the necessary components for polymerization and chain termination. OPS assembly is accomplished by multiprotein complexes formed by interactions between polymerase components variably distributed in single and multimodule proteins. In each complex, a terminator function is present in a protein containing a characteristic coiled-coil molecular ruler, which determines glycan chain length. In serotype O4, we discovered a CMP-α-3-deoxy-ᴅ-manno-octulosonic acid-dependent chain-terminating glycosyltransferase that is the founding member of a new glycosyltransferase family (GT137) and potentially identifies a new glycosyltransferase fold. The O7 OPS is terminated by a methylphosphate moiety, like the K. pneumoniae O3 antigen, but the methyltransferase-kinase enzyme pairs responsible for termination in these serotypes differ in sequence and predicted structures. Together, the characterization of O4 and O7 has established unique enzyme activities and provided new insight into glycan-assembly strategies that are widely distributed in bacteria.

Emergency Ultrasound Unveils Intermediate-High Risk Saddle Pulmonary Embolism with Extensive Bilateral Clot Burden, Masquerading as Micturition Syncope: A Case Report.

BACKGROUND: Isolated syncope as the manifestation of pulmonary embolism (PE) is a rare and diagnostically challenging presentation that often leads to delayed or missed diagnosis, increasing morbidity and mortality. In spite of emphasizing cardiovascular etiologies of syncope, current guidelines offer essentially no guidance in establishing a diagnostic workup for PE in these patients. By performing bedside echocardiography, emergency physicians can accurately identify concerning features suggestive of PE in patients with syncope. CASE REPORT: A 78-year-old man, receiving ertapenem via a peripherally inserted central catheter for treatment of extended spectrum ß-lactamase urinary tract infection, presented to the emergency department for isolated syncope with collapse while urinating. Arriving asymptomatic with normal vital signs and a benign physical examination, a presumptive diagnosis of micturition syncope was made. However, subtle vital sign changes on reassessment prompted performance of a point-of-care echocardiogram, which revealed signs of right heart strain. A computed tomography angiogram confirmed a saddle PE with extensive bilateral clot burden. Catheter-directed thrombectomy was performed via interventional radiology, with successful removal of pulmonary emboli. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pulmonary embolism presenting as isolated syncope represents a daunting diagnostic dilemma, as emergency physicians may not consider it, or anchor on more benign etiologies of syncope. Although lacking sufficient sensitivity to rule out PE, point-of-care echocardiography to evaluate for signs of right heart strain can quickly and effectively point toward the diagnosis, while also assessing for other emergent cardiovascular causes of syncope. Given the lack of evidence-based guidance concerning PE presenting as syncope, bedside echocardiography should be highly considered as a part of the emergency physician's diagnostic workup, especially in patients with abnormal vital signs.

Overcome the Limitation of Phenome-Wide Association Studies (PheWAS): Extension of PheWAS to Efficient and Robust Large-Scale ICD Codes Analysis.

The Phenome-wide association studies (PheWAS) have become widely used for efficient, high-throughput evaluation of relationship between a genetic factor and a large number of disease phenotypes, typically extracted from a DNA biobank linked with electronic medical records (EMR). Phecodes, billing code-derived disease case-control status, are usually used as outcome variables in PheWAS and logistic regression has been the standard choice of analysis method. Since the clinical diagnoses in EMR are often inaccurate with errors which can lead to biases in the odds ratio estimates, much effort has been put to accurately define the cases and controls to ensure an accurate analysis. Specifically in order to correctly classify controls in the population, an exclusion criteria list for each Phecode was manually compiled to obtain unbiased odds ratios. However, the accuracy of the list cannot be guaranteed without extensive data curation process. The costly curation process limits the efficiency of large-scale analyses that take full advantage of all structured phenotypic information available in EMR. Here, we proposed to estimate relative risks (RR) instead. We first demonstrated the desired nature of RR that overcomes the inaccuracy in the controls via theoretical formula. With simulation and real data application, we further confirmed that RR is unbiased without compiling exclusion criteria lists. With RR as estimates, we are able to efficiently extend PheWAS to a larger-scale, phenome construction agnostic analysis of phenotypes, using ICD 9/10 codes, which preserve much more disease-related clinical information than Phecodes.

Safety and efficacy of endovenous ablation in patients with a history of deep vein thrombosis.

OBJECTIVE: Endovenous ablation is the standard of care for patients with symptomatic superficial venous insufficiency. For patients with a history of deep vein thrombosis (DVT), concern exists for an increased risk of postprocedural complications, particularly venous thromboembolism. The objective of this study was to evaluate the safety and efficacy of endovenous thermal ablation in patients with a history of DVT. METHODS: The national Vascular Quality Initiative Varicose Vein Registry was queried for superficial venous procedures performed from January 2014 to July 2021. Limbs treated with radiofrequency or laser ablation were compared between patients with and without a DVT history. The primary safety end point was incident DVT or endothermal heat-induced thrombosis (EHIT) II-IV in the treated limb at <3 months of follow-up. The secondary safety end points included any proximal thrombus extension (ie, EHIT I-IV), major bleeding, hematoma, pulmonary embolism, and death due to the procedure. The primary efficacy end point was technical failure (ie, recanalization at <1 week of follow-up). Secondary efficacy end points included the risk of recanalization over time and the postprocedural change in quality-of-life measures. Outcomes stratified by preoperative use of anticoagulation (AC) were also compared among those with prior DVT. RESULTS: Among 33,892 endovenous thermal ablations performed on 23,572 individual patients aged 13 to 90 years, 1698 patients (7.2%) had a history of DVT. Patients with prior DVT were older (P < .001), had a higher body mass index (P < .001), were more likely to be male at birth (P < .001) and Black/African American (P < .001), and had greater CEAP classifications (P < .001). A history of DVT conferred a higher risk of new DVT (1.4% vs 0.8%; P = .03), proximal thrombus extension (2.3% vs 1.6%; P = .045), and bleeding (0.2% vs 0.04%; P = .03). EHIT II-IV, pulmonary embolism, and hematoma risk did not differ by DVT history (P = NS). No deaths from treatment occurred in either group. Continuing preoperative AC in patients with prior DVT did not change the risk of any complications after endovenous ablation (P = NS) but did confer an increased hematoma risk among all endovenous thermal ablations and surgeries (P = .001). Technical failure was similar between groups (2.0% vs 1.2%; P = .07), although a history of DVT conferred an increased recanalization risk over time (hazard ratio, 1.90; 95% confidence interval, 1.46, 2.46; P < .001). The groups had comparable improvements in postprocedural venous clinical severity scores and Heaviness, Aching, Swelling, Throbbing, and Itching scores (P = NS). CONCLUSIONS: Endovenous thermal ablation for patients with a history of DVT was effective. However, appropriate patient counseling regarding a heightened DVT risk, albeit still low, is critical. The decision to continue or withhold AC preoperatively should be tailored on a case-by-case basis.

A novel, reverse-phase-shifting, thermoreversible foaming hydrogel containing antibiotics for the treatment of thermal burns in a swine model - A pilot study.

BACKGROUND: This study compared a novel topical hydrogel burn dressing (CI-PRJ012) to standard of care (silver sulfadiazine) and to untreated control in a swine thermal burn model, to assess for wound healing properties both in the presence and absence of concomitant bacterial inoculation. METHODS: Eight equal burn wounds were created on six Yorkshire swine. Half the wounds were randomized to post-burn bacterial inoculation. Wounds were subsequently randomized to three treatments groups: no intervention, CI-PRJ012, or silver sulfadiazine cream. At study end, a blinded pathologist evaluated wounds for necrosis and bacterial colonization. RESULTS: When comparing CI-PRJ012 and silver sulfadiazine cream to no treatment, both agents significantly reduced the amount of necrosis and bacteria at 7 days after wound creation (p < 0.01, independently for both). Further, CI-PRJ012 was found to be significantly better than silver sulfadiazine (p < 0.02) in reducing bacterial colonization. For wound necrosis, no significant difference was found between silver sulfadiazine cream and CI-PRJ012 (p = 0.33). CONCLUSIONS: CI-PRJ012 decreases necrosis and bacterial colonization compared to no treatment in a swine model. CI-PRJ012 appeared to perform comparably to silver sulfadiazine. CI-PRJ012, which is easily removed with the application of room-temperature water, may provide clinical advantages over silver sulfadiazine.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

LGBQ-affirming clinical recommendations for compulsive sexual behavior disorder.

Background and aims: Since the inclusion of Compulsive Sexual Behavior Disorder (CSBD) in the International Classification of Diseases (11th ed.), there has been little effort placed into developing clinical recommendations for lesbian, gay, bisexual, and queer (LGBQ) clients with this condition. Thus, we develop preliminary clinical recommendations for mental health professionals working with LGBQ clients who may be struggling with CSBD. Methods: The present paper synthesizes the CSBD literature with advances in LGBQ-affirming care to develop assessment and treatment recommendations. These recommendations are discussed within the context of minority stress theory, which provides an empirically supported explanation for how anti-LGBQ stigma may contribute to the development of mental health conditions in LGBQ populations. Results: Assessment recommendations are designed to assist mental health professionals in distinguishing aspects of an LGBQ client's sociocultural context from CSBD symptomology, given recent concerns that these constructs may be wrongly conflated and result in misdiagnosis. The treatment recommendations consist of broadly applicable, evidence-based principles that can be leveraged by mental health professionals of various theoretical orientations to provide LGBQ-affirming treatment for CSBD. Discussion and Conclusions: The present article provides theoretically and empirically supported recommendations for mental health professionals who want to provide LGBQ-affirming care for CSBD. Given the preliminary nature of these recommendations, future research is needed to investigate their clinical applicability and efficacy.

A new test for trait mean and variance detects unreported loci for blood-pressure variation.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Exploring a De Novo Route to Bradyrhizose: Synthesis and Isomeric Equilibrium of Bradyrhizose Diastereomers≠.

A de novo asymmetric strategy for the synthesis of d-bradyrhizose diastereomers from an achiral ketoenolester precursor is described. Key transformations used in the stereodivergent approach include two Noyori asymmetric reductions, an Achmatowicz rearrangement, diastereoselective alkene oxidations, and the first example of a palladium(0)-catalyzed glycosylation of a vinylogous pyranone. The isomeric composition of the bicyclic reducing sugars obtained was analyzed and their behaviour was compared to the natural product, revealing key stereocentres that impact the overall distribution.