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Purpose: Many adults with atherosclerotic cardiovascular disease (ASCVD) who are recommended to take a statin, ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) by the 2018 American Heart Association/American College of Cardiology cholesterol guideline do not receive these medications. We estimated the percentage of recurrent ASCVD events potentially prevented with guideline-recommended cholesterol-lowering therapy following a myocardial infarction (MI) hospitalization. Methods: We conducted simulations using data from US adults with government health insurance through Medicare or commercial health insurance in the MarketScan database. We used data from patients with an MI hospitalization in 2018–2019 to estimate the percentage receiving guideline-recommended therapy. We used data from patients with an MI hospitalization in 2013–2016 to estimate the 3-year cumulative incidence of recurrent ASCVD events (i.e., MI, coronary revascularization or ischemic stroke). The low-density lipoprotein cholesterol (LDL-C) reduction with guideline-recommended therapy was derived from trials of statins, ezetimibe and PCSK9i, and the associated ASCVD risk reduction was estimated from a meta-analysis by the Cholesterol-Lowering Treatment Trialists Collaboration. Results: Among 279,395 patients with an MI hospitalization in 2018–2019 (mean age 75 years, mean LDL-C 92 mg/dL), 27.3% were receiving guideline-recommended cholesterol-lowering therapy. With current cholesterol-lowering therapy use, 25.3% (95%CI: 25.2%-25.4%) of patients had an ASCVD event over 3 years. If all patients were to receive guideline-recommended therapy, 19.8% (95%CI: 19.5%-19.9%) were estimated to have an ASCVD event over 3 years, representing a 21.6% (95%CI: 20.5%-23.6%) relative risk reduction. Conclusion: Implementation of guideline-recommended cholesterol-lowering therapy could prevent a substantial percentage of recurrent ASCVD events. [ABSTRACT FROM AUTHOR]

Streptococcus mitis is a leading cause of infective endocarditis (IE). However, our understanding of the genomic epidemiology and pathogenicity of IE-associated S. mitis is hampered by low IE incidence. Here we use whole genome sequencing of 129 S. mitis bloodstream infection (BSI) isolates collected between 2001–2016 from clinically diagnosed IE cases in the UK to investigate genetic diversity, antimicrobial resistance, and pathogenicity. We show high genetic diversity of IE-associated S. mitis with virtually all isolates belonging to distinct lineages indicating no predominance of specific lineages. Additionally, we find a highly variable distribution of known pneumococcal virulence genes among the isolates, some of which are overrepresented in disease when compared to carriage strains. Our findings suggest that S. mitis in patients with clinically diagnosed IE is not primarily caused by specific hypervirulent or antimicrobial resistant lineages, highlighting the accidental pathogenic nature of S. mitis in patients with clinically diagnosed IE. In this genomic analysis, authors observe high genetic diversity among Streptococcus mitis isolates obtained from infective endocarditis cases over 16 years in the United Kingdom and Ireland. [ABSTRACT FROM AUTHOR]

The Midwest Healthcare Case Competition lets graduate trainees gain practical experience and exposure to alternative careers in a condensed time frame without taking away from research commitments. [ABSTRACT FROM AUTHOR]

Evaluating the factors that promote coexistence between ecologically similar species is crucial to understanding the evolution and assembly of herbivore communities. The Jarman–Bell principle presents a trade-off between diet quality and quantity as an axis for dietary niche segregation and has been suggested as a mechanism facilitating species coexistence. This idea holds that larger-bodied herbivores consume greater amounts of relatively low-quality plant resources, while smaller-bodied herbivores typically feed selectively on higher-quality resources. Most studies investigating the Jarman–Bell principle have examined free-living ungulates in African savannas. The diverse ungulate community in Yellowstone National Park, USA offers an opportunity to investigate the applicability of this principle in a temperate North American ecosystem. In this study we use fecal nitrogen (FN) and stable carbon isotope values (δ13C) to examine the relationship between body size and seasonal patterns of dietary niche segregation among five species of wild ungulates. Specifically, we test the predictions that: (1) diet quality decreases with increasing body mass, (2) interspecific differences in diet are greatest between the largest- and smallest-bodied species, and (3) smaller-bodied species have narrower dietary breadth than larger-bodied species. Diet quality, as indicated by digestibility, declined significantly with body mass, consistent with the empirical pattern predicted by the Jarman–Bell hypothesis. Significant interspecific differences in diet quality generally aligned with variation in body mass. When resources were limited during the winter, the relationship between body mass and diet quality was more pronounced, suggesting increased dietary niche segregation during the lean season. The results showed little evidence indicating that dietary breadth scaled allometrically with body mass, as the two species most similar in body mass displayed the greatest and least range of seasonal variation in both FN and δ13C. This study adds to the weight and breadth of evidence that diet quality is negatively correlated with body size in wild ungulate assemblages. Our findings underscore the importance of body size as a factor facilitating dietary niche segregation and promoting coexistence among ecologically similar ungulate species. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the physiology and treatment of vasovagal syncope. Methods: The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope. Results: The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome. Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences. Conclusion: Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope. [ABSTRACT FROM AUTHOR]

Omics-based biomarker technologies, including metabolic profiling (metabolomics/metabonomics) and lipidomics, are making a significant impact on disease understanding, drug development, and translational research. A wide range of patho-physiological processes involve lipids and monitoring changes in lipid abundance can give valuable insights into mechanisms of drug action, off target pharmacology and toxicity. Here we report changes, detected by untargeted LC–MS, in the plasma lipid profiles of male C57Bl/6JRj mice following the PO and IV administration of the epidermal growth factor receptor (EGFR) inhibitor gefitinib. Statistical analysis of the data obtained for both the IV and PO samples showed time-related changes in the amounts of lipids from several different classes. The largest effects were associated with a rapid onset of these changes following gefitinib administration followed by a gradual return by 24 h post dose to the type of lipid profile seen in predose samples. Investigation of the lipids responsible for the variance observed in the data showed that the PI, PC, LPC, PE and TG were subject to the largest disruption with both transient increases and decreases in relative amounts seen in response to administration of the drug. The pattern of the changes in the relative abundances of those lipids subject to variation appeared to be correlated to the pharmacokinetics of gefitinib (and its major metabolites). These observations support the concept of a distinct pharmacolipidodynamic relationship between drug exposure and plasma lipid abundance. [ABSTRACT FROM AUTHOR]

Structure–activity relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates1–3. Here we present an alternative approach in which we convert pyrimidine-containing compounds into various other nitrogen heteroaromatics. Transforming pyrimidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction–reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles4. In effect, this approach allows heterocycle formation on complex molecules, resulting in analogues that would be challenging to obtain by other methods. We anticipate that this deconstruction–reconstruction strategy will extend to other heterocycle classes.We present a synthetic method that transforms complex pyrimidine-containing structures into iminoenamines and then uses de novo heterocycle synthesis to obtain substituted pyrimidine and 1,2-azole analogues. [ABSTRACT FROM AUTHOR]

The usage of digital devices has increased rapidly in recent times due to the expansion of online learning platforms, leading to greater reliance on them. As a result, people forget simple information, dates, and appointments that might lead to digital amnesia. Hence, we aimed to develop and validate a digital amnesia scale (DAS). The study was carried out in two studies. In the first study, we collected data from 616 college students to examine the factor structure of the model and its underlying dimensions for a large pool of items. These analyses showed that the scale formed a three-dimensional structure: digital distraction, digital dependency, and digital detox. In the second study, we collected data from 383 college students to confirm the three-factor structure of the DAS. A satisfactory level of reliability was demonstrated by McDonald's ω value for the dimensions. The test–retest reliability was found to be 0.76. The DAS had satisfactory convergent and discriminant validity. This scale could be useful for both researchers and educators to assess digital amnesia among college students. [ABSTRACT FROM AUTHOR]

Apes possess two sex chromosomes—the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements—owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.Reference assemblies of great ape sex chromosomes show that Y chromosomes are more variable in size and sequence than X chromosomes and provide a resource for studies on human evolution and conservation genetics of non-human apes. [ABSTRACT FROM AUTHOR]

In the U.S., the state of Pennsylvania has proposed lowering its Mn criterion from 1.0 to 0.3 mg/L. An investigation of the feasibility of meeting this standard with passive treatment was conducted. Existing data from 19 full-scale oxic limestone beds were compiled from literature reports to determine current Mn removal effectiveness and rates. The median system decreased Mn from 20 to 1.7 mg/L at a theoretical retention time of 37 h. Only two passive treatment systems produced effluents with < 0.3 mg/L Mn. In order to explore the capabilities of oxic limestone beds to remove Mn, two experimental oxic aggregate beds were installed at conventional AMD treatment plants and used to experimentally treat a portion of each plant's final effluent. The Hollywood unit was marginally effective, decreasing Mn on average from 0.584 to 0.281 mg/L with a theoretical retention time (TRT) of 3.7 h. The Brandy Camp unit was highly effective, decreasing Mn from 5.85 to 0.095 mg/L when operated at a TRT of 2.3 h. Effective removal of Mn by the Brandy Camp unit required 7 weeks of aggregate ripening. Average Mn removal rates for the Brandy Camp unit were 22.7 g/d/m2, 15.7 g/d/mt, and 2.5 mg/L/hr of theoretical retention time. The half-time of Mn removal was 25 min. After one year of operation, hydraulic problems associated with the accumulation of iron solids on the surface of the aggregate forced termination of the Brandy Camp unit. The results indicate that the 0.3 mg/L effluent criterion can be achieved with oxic aggregate beds at very short retention times, as long as aggregate permeability is maintained. [ABSTRACT FROM AUTHOR]

The Arizona Toad (Anaxyrus microscaphus) is restricted to riverine corridors and adjacent uplands in the arid southwestern United States. As with numerous amphibians worldwide, populations are declining and face various known or suspected threats, from disease to habitat modification resulting from climate change. The Arizona Toad has been petitioned to be listed under the U.S. Endangered Species Act and was considered "warranted but precluded" citing the need for additional information – particularly regarding natural history (e.g., connectivity and dispersal ability). The objectives of this study were to characterize population structure and genetic diversity across the species' range. We used reduced-representation genomic sequencing to genotype 3,601 single nucleotide polymorphisms in 99 Arizona Toads from ten drainages across its range. Multiple analytical methods revealed two distinct genetic groups bisected by the Colorado River; one in the northwestern portion of the range in southwestern Utah and eastern Nevada and the other in the southeastern portion of the range in central and eastern Arizona and New Mexico. We also found subtle substructure within both groups, particularly in central Arizona where toads at lower elevations were less connected than those at higher elevations. The northern and southern parts of the Arizona Toad range are not well connected genetically and could be managed as separate units. Further, these data could be used to identify source populations for assisted migration or translocations to support small or potentially declining populations. [ABSTRACT FROM AUTHOR]

Introduction: The cardiovascular disease risk reduction benefits of proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (PCSK9i mAb) and ezetimibe are dependent on remaining on treatment and being persistent and adherent. We estimated the percentage of patients on therapy, persistent and adherent at 182 and 365 days among US adults with health insurance who initiated a PCSK9i mAb (n = 16,588) or ezetimibe (n = 83,086) between July 2015 and December 2019. Methods: Using pharmacy fill claims, being on therapy was defined as having a day of medication supply in the last 60 of 182 and 365 days following treatment initiation, being persistent was defined as not having a gap of 60 days or more between the last day of supply from one prescription fill and the next fill, and being adherent was defined by having medication available to take on ≥ 80% of the 182 and 365 days following treatment initiation. We estimated multivariable-adjusted risk ratios for being persistent and adherent comparing patients initiating PCSK9i mAb versus ezetimibe using Poisson regression. Results: At 182 days following initiation, 80% and 68% were on therapy and 76% and 64% were persistent among patients who initiated a PCSK9i mAb and ezetimibe, respectively. Among patients who were on therapy and persistent at 182 days following initiation, 88% and 81% of those who initiated a PCSK9i mAb and ezetimibe, respectively, were on therapy at 365 days. Among those on therapy and persistent at 182 days following initiation, being persistent and being adherent at 365 days were each more common among PCSK9i mAb versus ezetimibe initiators (persistent: 82% versus 76%, multivariable-adjusted risk ratio 1.07; 95% confidence interval [CI] 1.06–1.08; adherent: 74% versus 71%, multivariable-adjusted risk ratio 1.02; 95% CI 1.01–1.03). Conclusions: These data suggest approaches to increase persistence and adherence to PCSK9i mAb and ezetimibe should be implemented prior to or within 182 days following treatment initiation. [ABSTRACT FROM AUTHOR]

Purpose: Many survivors of rectal cancer experience persistent bowel dysfunction. There are few evidence-based symptom management interventions to improve bowel control. The purpose of this study is to describe recruitment and pre-randomization baseline sociodemographic, health status, and clinical characteristics for SWOG S1820, a trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention. Methods: SWOG S1820 aimed to determine the preliminary efficacy, feasibility, and acceptability of AIMS-RC, a symptom management intervention for bowel health, comparing intervention to attention control. Survivors with a history of cancers of the rectosigmoid colon or rectum, within 6–24 months of primary treatment completion, with a post-surgical permanent ostomy or anastomosis, and over 18 years of age were enrolled. Outcomes included total bowel function, low anterior resection syndrome, quality of life, motivation for managing bowel health, self-efficacy for managing symptoms, positive and negative affect, and study feasibility and acceptability. Results: The trial completed accrual over a 29-month period and enrolled 117 participants from 34 institutions across 17 states and one US Pacific territory. At baseline, most enrolled participants reported self-imposed diet adjustments after surgery, persistent dietary intolerances, and bowel discomfort post-treatment, with high levels of constipation and diarrhea (grades 1–4). Conclusions: SWOG S1820 was able to recruit, in a timely manner, a study cohort that is demographically representative of US survivors of rectal cancer. Baseline characteristics illustrate the connection between diet/eating and bowel symptoms post-treatment, with many participants reporting diet adjustments and persistent inability to be comfortable with dietary intake. ClinicalTrials.gov registration date: 12/19/2019. ClinicalTrials.gov Identifier: NCT#04205955. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function. [ABSTRACT FROM AUTHOR]

To validate the correlation between the signal intensity gradient (SIG) from time-of-flight magnetic resonance angiography (TOF-MRA) and wall shear stress (WSS) determined by phase contrast magnetic resonance (PC-MR), we conducted both experimental and human studies. In the experimental study, we measured WSS in four tubes of different sizes with variable flow rates using PC-MR and TOF-MRA. The flow rates of water in the experimental study ranged from 0.06 to 12.75 mL/s, resulting in PC-WSS values between 0.1 and 1.6 dyne/cm2. The correlation between PC-WSS and SIG was statistically significant, showing a coefficient of 0.86 (P < 0.001, R2 = 0.75). The line fit provided the conversion equation as Y = 1.6287X − 1.1563 (Y = PC-WSS, X = SIG). For the human study, 28 subjects underwent TOF-MRA and PC-MR examinations of carotid and vertebral arteries. Arterial PC-WSS and SIG were determined in the same segment for each subject. The arterial PC-WSS ranged from 1.9 to 21.0 dyne/cm2. Both carotid and vertebral arteries showed significant correlations between PC-WSS and SIG, with coefficients of 0.85, 0.86, 0.91, and 0.81 in the right and left carotid and vertebral arteries, respectively. Our results show that SIG from TOF-MRA and SIG-WSS derived from the conversion equation provide concurrent in vivo hemodynamic information on arterial shear stress. This study was registered on ClinicalTrials.gov with the identifier NCT04585971 on October 14, 2020. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic led to 231,841 deaths and 940,243 hospitalisations in England, by the end of March 2023. This paper calculates the real-time infection hospitalisation risk (IHR) and infection fatality risk (IFR) using the Office for National Statistics Coronavirus Infection Survey (ONS CIS) and the Real-time Assessment of Community Transmission Survey between November 2020 to March 2023. The IHR and the IFR in England peaked in January 2021 at 3.39% (95% Credible Intervals (CrI): 2.79, 3.97) and 0.97% (95% CrI: 0.62, 1.36), respectively. After this time, there was a rapid decline in the severity from infection, with the lowest estimated IHR of 0.32% (95% CrI: 0.27, 0.39) in December 2022 and IFR of 0.06% (95% CrI: 0.04, 0.08) in April 2022. We found infection severity to vary more markedly between regions early in the pandemic however, the absolute heterogeneity has since reduced. The risk from infection of SARS-CoV-2 has changed substantially throughout the COVID-19 pandemic with a decline of 86.03% (80.86, 89.35) and 89.67% (80.18, 93.93) in the IHR and IFR, respectively, since early 2021. From April 2022 until March 2023, the end of the ONS CIS study, we found fluctuating patterns in the severity of infection with the resumption of more normative mixing, resurgent epidemic waves, patterns of waning immunity, and emerging variants that have shown signs of convergent evolution. The severity of SARS-CoV-2 infection varied over the course of the pandemic due to factors such as changes in variant characteristics and population immunity from previous infection or vaccination. Here, the authors estimate infection hospitalisation and infection fatality rates in England over time from the start of the pandemic until March 2023. [ABSTRACT FROM AUTHOR]

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions. Many natural products exist as families of structurally similar molecules, and therefore developing skeletal modifications of common intermediates offers flexible and powerful approaches for target synthesis. Here, the authors report a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners. [ABSTRACT FROM AUTHOR]

Summary: Patients who sustain a contralateral hip fracture experience significantly inferior outcomes; however, the incidence and predictors of contralateral hip fracture remain poorly understood. In the present study, 2.5% of patients sustained a contralateral hip fracture within 12 months, and socioeconomic deprivation was associated with reduced risk of contralateral hip fracture. Introduction: Hip fractures are associated with high morbidity and mortality, and patients that sustain a subsequent contralateral fracture experience inferior outcomes. The risk of contralateral fracture is highest within the first year; however, the incidence and associated factors remain poorly understood. The aims were to investigate (i) the incidence of a subsequent contralateral hip fracture within the first year, (ii) identify factors associated with an increased risk of contralateral fracture and (iii) compare early mortality risk after index versus contralateral hip fracture. Methods: This study included all patients aged over 50 years admitted to NHS hospitals in Scotland between 1st March 2020 and 31st December 2020 (n = 5566) as routine activity of the Scottish Hip Fracture Audit (SHFA). Multivariate logistic regression was used to examine factors associated with 30-day mortality, and cox regression was used to identify factors associated with a contralateral fracture. Results: During the study period 2.5% (138/5566) of patients sustained a contralateral hip fracture within 12 months of the index hip fracture. Socioeconomic deprivation was inversely associated with increased risk of contralateral fracture (odds ratio 2.64, p < 0.001), whilst advancing age (p = 0.427) and sex (p = 0.265) were not. After adjusting for significant cofounders, there was no significant difference in 30-day mortality following contralateral fracture compared to index fracture (OR 1.22, p = 0.433). Conclusion: One in 40 (2.5%) hip fracture patients sustained a contralateral fracture within 12 months of their index fracture, and deprivation was associated with a reduced risk of contralateral fracture. No difference in 30-day mortality was found. [ABSTRACT FROM AUTHOR]

Purpose of Review: Targeting traditional cardiovascular risk factors is effective in reducing recurrent cardiovascular events, yet the presence of residual cardiovascular risk due to underlying systemic inflammation is a largely unaddressed opportunity. This review aims to comprehensively assess the evolving role of colchicine as a therapeutic approach targeting residual inflammatory risk in the context of those with coronary artery disease (CAD). Recent Findings: Inflammation plays a significant role in promoting atherosclerosis, and targeting anti-inflammatory pathways has the potential to decrease cardiovascular events. Low-dose colchicine (0.5 mg/day orally), when added to guideline-directed medical care for CAD, safely decreases major adverse cardiovascular events (MACE) by 31% in stable atherosclerosis patients and 23% in those after recent myocardial infarctions. Meta-analyses of recent randomized control trials further support both the efficacy and safety of colchicine, particularly when added to other standard cardiovascular therapies, including statin therapy. The European Society of Cardiology and other national guidelines endorse the use of low-dose colchicine in patients across the spectrum of CAD. Recently, colchicine was FDA-approved in the United States as the first anti-inflammatory therapy for the reduction of cardiovascular events. In a period of a rising incidence of CAD across the globe, colchicine represents a unique opportunity to decrease MACE due to its large magnitude of benefits and general affordability. However, challenges with drug interactions must be addressed, especially in those regions where HIV, hepatitis, and tuberculosis are prevalent. Summary: Colchicine is safe and effective at reducing cardiovascular events across a broad spectrum of coronary syndromes. The ability to simultaneously target traditional risk factors and mitigate residual inflammatory risk marks a substantial advancement in cardiovascular prevention strategies, heralding a new era in the global battle against CAD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Although rare, the development of mechanical complications following an acute myocardial infarction is associated with a high morbidity and mortality. Here, we review the clinical features, diagnostic strategy, and treatment options for each of the mechanical complications, with a focus on the role of echocardiography. Recent Findings: The growth of percutaneous structural interventions worldwide has given rise to new non-surgical options for management of mechanical complications. As such, select patients may benefit from a novel use of these established treatment methods. Summary: A thorough understanding of the two-dimensional, three-dimensional, color Doppler, and spectral Doppler findings for each mechanical complication is essential in recognizing major causes of hemodynamic decompensation after an acute myocardial infarction. Thereafter, echocardiography can aid in the selection and maintenance of mechanical circulatory support and potentially facilitate the use of a percutaneous intervention. [ABSTRACT FROM AUTHOR]

This article presents a model that combines financial analysis with macroeconomics to study society's asset allocation problem. The model considers the effects of technological changes and policy decisions on equilibrium, as well as the impact of financialization on optimal asset allocation. The model posits a capital allocation plane where agents allocate wealth between consumption and investment to maximize social utility. The article also discusses the project availability incline, which represents different combinations of projects based on their capital requirement, expected risk, and expected return. Exogenous changes, such as technological progress and government regulation, can affect capital allocation. The article suggests that further investigation is needed to understand the impact of financialization on the allocation of capital. [Extracted from the article]

Introduction: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging. Objective: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality. Methods: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) – the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact. Results: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-l-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased. Conclusion: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

ZnO/Ag and ZnO/Ag2O nanocomposites were produced using ZnO nanoparticles synthesized via a starch-mediated sol–gel method. XRD and Rietveld refinement confirmed the wurtzite-like structure of spherical 16-nm ZnO nanocrystals. These nanocrystals were further decorated with cubic nearly spherical ~ 7-nm Ag and irregular ~ 6-nm Ag2O nanocrystals, resulting in nanocomposites with distinct structural characteristics. The morphological analysis confirmed the distinct shapes and sizes of Ag, Ag2O, and ZnO nanoparticles. The nanocomposites exhibited a tuned optical bandgap and structural defects like V Zn , VO, and V O + . In vitro biological tests revealed that the Ag2O/ZnO nanocomposite displayed significantly enhanced antidiabetic, antimicrobial, and antioxidant activities. These enhanced biological properties were attributed in part to the unique morphology of Ag2O nanoparticles and the defective nature of ZnO/Ag2O nanocomposite. These results demonstrate that the green-synthesized ZnO nanoparticles decorated with Ag2O emerge as a promising material for biomedical applications. [ABSTRACT FROM AUTHOR]

Purpose: Acute heart failure (AHF) syndromes manifest increased inflammation and vascular dysfunction; however, mechanisms that integrate the two in AHF remain largely unknown. The glycocalyx (GAC) is a sugar-based shell that envelops all mammalian cells. Much GAC research has focused on its role in vascular responses, with comparatively little known about how the GAC regulates immune cell function. Methods: In this study, we sought to determine if GAC degradation products are elevated in AHF patients, how these degradation products relate to circulating inflammatory mediators, and whether the monocyte GAC (mGAC) itself modulates monocyte activation. Inflammatory markers and GAC degradation products were profiled using ELISAs. Flow cytometry was used to assess the mGAC and RNA-seq was employed to understand the role of the mGAC in regulating inflammatory activation programs. Results: In a cohort of hospitalized AHF patients (n = 17), we found that (1) the GAC degradation product heparan sulfate (HS) was elevated compared with age-matched controls (4396 and 2903 ng/mL; p = 0.01) and that (2) HS and soluble CD14 (a marker of monocyte activation) levels were closely related (Pearson's r = 0.65; p = 0.002). Mechanistically, Toll-like receptor (TLR) activation of human monocytes results in GAC remodeling and a decrease in the mGAC (71% compared with no treatment; p = 0.0007). Additionally, we found that ex vivo enzymatic removal of HS and disruption of the mGAC triggers human monocyte activation and amplifies monocyte inflammatory responses. Specifically, using RNA-seq, we found that enzymatic degradation of the mGAC increases transcription of inflammatory (IL6, CCL3) and vascular (tissue factor/F3) mediators. Conclusion: These studies indicate that the mGAC is dynamically remodeled during monocyte activation and that mGAC remodeling itself may contribute to the heightened inflammation associated with AHF. [ABSTRACT FROM AUTHOR]

Self-motion perception is a multi-sensory process that involves visual, vestibular, and other cues. When perception of self-motion is induced using only visual motion, vestibular cues indicate that the body remains stationary, which may bias an observer's perception. When lowering the precision of the vestibular cue by for example, lying down or by adapting to microgravity, these biases may decrease, accompanied by a decrease in precision. To test this hypothesis, we used a move-to-target task in virtual reality. Astronauts and Earth-based controls were shown a target at a range of simulated distances. After the target disappeared, forward self-motion was induced by optic flow. Participants indicated when they thought they had arrived at the target's previously seen location. Astronauts completed the task on Earth (supine and sitting upright) prior to space travel, early and late in space, and early and late after landing. Controls completed the experiment on Earth using a similar regime with a supine posture used to simulate being in space. While variability was similar across all conditions, the supine posture led to significantly higher gains (target distance/perceived travel distance) than the sitting posture for the astronauts pre-flight and early post-flight but not late post-flight. No difference was detected between the astronauts' performance on Earth and onboard the ISS, indicating that judgments of traveled distance were largely unaffected by long-term exposure to microgravity. Overall, this constitutes mixed evidence as to whether non-visual cues to travel distance are integrated with relevant visual cues when self-motion is simulated using optic flow alone. [ABSTRACT FROM AUTHOR]

In May 2022, individuals infected with the monkeypox virus were detected in the UK without clear travel links to endemic areas. Understanding the clinical characteristics and infection severity of mpox is necessary for effective public health policy. The study period of this paper, from the 1st June 2022 to 30th September 2022, included 3,375 individuals that tested positive for the monkeypox virus. The posterior mean times from infection to hospital admission and length of hospital stay were 14.89 days (95% Credible Intervals (CrI): 13.60, 16.32) and 7.07 days (95% CrI: 6.07, 8.23), respectively. We estimated the modelled Infection Hospitalisation Risk to be 4.13% (95% CrI: 3.04, 5.02), compared to the overall sample Case Hospitalisation Risk (CHR) of 5.10% (95% CrI: 4.38, 5.86). The overall sample CHR was estimated to be 17.86% (95% CrI: 6.06, 33.11) for females and 4.99% (95% CrI: 4.27, 5.75) for males. A notable difference was observed between the CHRs that were estimated for each sex, which may be indicative of increased infection severity in females or a considerably lower infection ascertainment rate. It was estimated that 74.65% (95% CrI: 55.78, 86.85) of infections with the monkeypox virus in the UK were captured over the outbreak.Mpox cases without known travel links to endemic countries began to be detected in the UK in mid-2022. In this study, the authors characterise the severity of mpox cases in the UK and estimate the overall infection hospitalisation risk at ~4%. [ABSTRACT FROM AUTHOR]

Radiative gravitational collapse is an important and much studied phenomenon in astrophysics. Einstein's theory of general relativity (GR) is well suited to describing such processes provided closure of the system of nonlinear differential equations is achieved. Within a perturbative scheme, the property of vanishing complexity factor is used in order to complete the description of the radiative, self-gravitating system. We show that a physically viable model may be obtained which reflects the absence of energy inhomogeneities for lower density systems, in contrast to what might be expected for more aggressive collapse processes. [ABSTRACT FROM AUTHOR]

When we move our head while in virtual reality, display lag will generate differences in our virtual and physical head pose (known as DVP). While DVP are a major trigger for cybersickness, theories differ as to exactly how they constitute a provocative sensory conflict. Here, we test two competing theories: the subjective vertical conflict theory and the DVP hypothesis. Thirty-two HMD users made continuous, oscillatory head rotations in either pitch or yaw while viewing a large virtual room. Additional display lag was applied selectively to the simulation about the same, or an orthogonal, axis to the instructed head rotation (generating Yaw-Lag + Yaw-Move, Yaw-Lag + Pitch-Move, Pitch-Lag + Yaw-Move, and Pitch-Lag + Pitch-Move conditions). At the end of each trial: (1) participants rated their sickness severity and scene instability; and (2) their head tracking data were used to estimate DVP throughout the trial. Consistent with our DVP hypothesis, but contrary to subjective vertical conflict theory, Yaw-Lag + Yaw-Move conditions induced significant cybersickness, which was similar in magnitude to that in the Pitch-Lag + Pitch-Move conditions. When extra lag was added along the same axis as the instructed head movement, DVP was found to predict 73–76% of the variance in sickness severity (with measures of the spatial magnitude and the temporal dynamics of the DVP both contributing significantly). Ratings of scene instability were also found to predict sickness severity. Taken together, these findings suggest that: (1) cybersickness can be predicted from objective estimates of the DVP; and (2) provocative stimuli for this sickness can be identified from subjective reports of scene instability. [ABSTRACT FROM AUTHOR]

We investigated the multifaceted gas sensing properties of porous silicon thin films electrodeposited onto (100) oriented P-type silicon wafers substrates. Our investigation delves into morphological, optical properties, and sensing capabilities, aiming to optimize their use as efficient gas sensors. Morphological analysis revealed the development of unique surfaces with distinct characteristics compared to untreated sample, yielding substantially rougher yet flat surfaces, corroborated by Minkowski Functionals analysis. Fractal mathematics exploration emphasized that despite increased roughness, HF/ethanol-treated surfaces exhibit flatter attributes compared to untreated Si sample. Optical approaches established a correlation between increased porosity and elevated localized states and defects, influencing the Urbach energy value. This contributed to a reduction in steepness values, attributed to heightened dislocations and structural disturbances, while the transconductance parameter decreases. Simultaneously, porosity enhances the strength of electron‒phonon interaction. The porous silicon thin films were further tested as effective gas sensors for CO2 and O2 vapors at room temperature, displaying notable changes in electrical resistance with varying concentrations. These findings bring a comprehensive exploration of some important characteristics of porous silicon surfaces and established their potential for advanced industrial applications. [ABSTRACT FROM AUTHOR]

Purpose: Cholesterol in lipoprotein(a) [Lp(a)-C] is commonly estimated as 30% of the measured Lp(a) mass. However, difficulties in the accurate measurement of Lp(a) mass, along with the inaccuracy of the 30% assumption, produce erroneous values when LDL-C is corrected for Lp(a) [LDL-CLp(a)corr]. Our aim was to develop a new formula for LDL-CLp(a)corr to reduce this error. Methods: We developed a new formula to calculate Lp(a)-C from the molar measurement of Lp(a), which is Lp(a) nmol/L × 0.077 = Lp(a)-C mg/dL. The calculated Lp(a)-C is subtracted from LDL-C to obtain LDL-CLp(a)corr. The results obtained with our novel formula versus the conventional formula were compared in 440 samples from 239 participants enrolled in the BANTING study. Results: With the conventional formula, approximately 7% of samples with low LDL-C resulted in negative LDL-CLp(a)corr values. With the new formula, no negative LDL-CLp(a)corr values occurred. Among groups with the highest Lp(a)/apoB ratio (p < 0.001) and smaller apolipoprotein(a) isoform size (p < 0.006), LDL-CLp(a)corr was significantly underestimated by the conventional formula, which may result in the undertreatment of some patients. Conclusion: The new formula provides more reliable estimates of LDL-CLp(a)corr than the conventional formula. Trial registration: ClinicalTrials.gov NCT02739984. [ABSTRACT FROM AUTHOR]

Limited competency in genetics among primary care providers (PCPs) is a barrier to use of genetic information in healthcare. Formal genetics lessons require time and interest, and knowledge wanes. We hypothesized another path to competency: participation in our PCP-centered adult clinical genomic population health screening program. We asked participating Family Medicine PCPs about their perceptions of growth in their genetics competency. An anonymous, voluntary, cross-sectional survey was developed and distributed to PCPs offering the screening. Results were compiled after 3 weeks. PCPs rated several program resources for value and provided open-ended feedback. Seventy-five percent of respondents agreed that genetics is important to their practice. Eighty-seven percent felt that their knowledge of clinical genetics topics had grown. Eighty-seven percent perceived increased confidence in offering genetic testing and in discussing common genetic results with patients. Respondents gained appreciation for the scope of clinical utility that genetic information offers patients. Each education resource rated at least 3.75 out of 5 for contributing to genetics knowledge. The case-specific Genomic Medicine Action Plan rated highest in educational value, 4.5 out of 5. Most responding PCPs offering genomic population health screening perceived growth in their genetic competency and found hands-on, case-based resources most useful. [ABSTRACT FROM AUTHOR]

This article, titled "A New Measure of Monetary Accommodation," discusses the development of a quantitative measure of central bank monetary accommodation. The authors argue that monetary accommodation is increasingly linked to financial stability and propose a Central Bank Accommodation Index that combines the growth rates of the money supply and GDP, as well as the difference between inflation and the Fed Funds rate. The index is used to analyze historical trends and the impact of the COVID-19 pandemic on monetary policy. The authors also raise questions about the future trajectory of the index and its predictive power. [Extracted from the article]

Abstract Conventional maximum‐tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment‐free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia‐inducible factor (HIF)‐1α and (HIF)‐2α (hereafter referred to as HIFα). Instead, frequent low‐dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre‐clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog‐specific, MTD‐dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11‐gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα‐targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra‐metastatic tumor microenvironment.

Targeting the metastatic process is a critical pursuit in the treatment of malignant disease. There are currently no specific anti‐metastatic drugs approved for clinical use, despite metastasis being the leading cause of death for cancer patients. Targeting the Tie1 receptor was shown as a possible strategy for selective anti‐metastasis therapies based on previous gene deletion studies. This current study is the first description of a human antibody against Tie1 with the potential for clinical use in targeting extravasation of tumor cells into organs such as the lung, without having a detrimental effect on immune cell infiltration.

The article explores the impact of social determinants of health (SDOH) on neurosurgical outcomes and the potential for enhanced recovery after surgery (ERAS) programs to address health disparities. It highlights racial and socioeconomic disparities in neurosurgical outcomes and the limited consideration of SDOH in ERAS studies. The article emphasizes the need for further research and interdisciplinary collaboration to integrate SDOH into ERAS protocols and reduce health disparities. [Extracted from the article]

Plant macrofossils from packrat (Neotoma spp.) middens provide direct evidence of past vegetation changes in arid regions of North America. Here we describe the newest version (version 5.0) of the U.S. Geological Survey (USGS) North American Packrat Midden Database. The database contains published and contributed data from 3,331 midden samples collected in southwest Canada, the western United States, and northern Mexico, with samples ranging in age from 48 ka to the present. The database includes original midden-sample macrofossil counts and relative-abundance data along with a standardized relative-abundance scheme that makes it easier to compare macrofossil data across midden-sample sites. In addition to the midden-sample data, this version of the midden database includes calibrated radiocarbon (14C) ages for the midden samples and plant functional type (PFT) assignments for the midden taxa. We also provide World Wildlife Fund ecoregion assignments and climate and bioclimate data for each midden-sample site location. The data are provided in tabular (.xlsx), comma-separated values (.csv), and relational database (.mdb) files. [ABSTRACT FROM AUTHOR]

The US fee-for-service payment system under-reimburses clinics offering access to comprehensive treatments for opioid use disorder (OUD). The funding shortfall limits a clinic's ability to expand and improve access, especially for socially marginalized patients with OUD. New payment models, however, should reflect the high variation in cost for using a clinic's clinical and voluntary psychosocial and recovery support services. The authors applied time-driven activity-based costing, a patient-level, micro-costing approach, to estimate the cost at an outpatient clinic that delivers medication for opiate used disorder (MOUD) and voluntary psychosocial and recovery support services. Much of the cost variation could be explained by classifying patients into three archetypes: (1) light touch (1–3 visits): no significant co-occurring psychiatric illness, stable housing, and easy to connect for ongoing OUD treatment in a traditional outpatient setting; (2) standard (average of 8 visits): initially requires an integrated team-based care model but soon stabilizes for transition to community-based outpatient care; (3) quad morbidity (> 20 visits): multiple co-occurring substance use disorders, unhoused, co-occurring medical and psychiatric complexity, and limited social supports. With the cost of the initial visit set at an indexed value of 100, an average light touch patient had a cost of 352, a standard patient was 718, and a quad morbidity patient was 1701. The cost structure revealed by this analysis provides the foundation for alternative payment models that would enable new MOUD clinics, staffed with multi-disciplinary care teams, and located for convenient access by high-risk patients, to be established and sustained. [ABSTRACT FROM AUTHOR]

We make use of the condition of vanishing complexity, based on the current definition proposed by Herrera (Phys Rev D 97:044010, 2018), to find exact interior solutions to the Einstein equations for describing compact stellar objects. In the framework of general relativity, the complexity factor is an outcome of the orthogonal splitting of the Riemann tensor from which structure scalars are obtained. By using the Vaidya–Tikekar (V–T) metric ansatz (J Astrophys Astron 3:325, 1982) for the spacetime of a static spherically symmetric matter distribution, we model superdense, relativistic stars. The interior spacetime is matched to the exterior Schwarzschild solution across the boundary of the star where the radial pressure vanishes. The physical viability of the model has been tested following the current data corresponding to the pulsar 4 U 1820 - 30 . The stability of the model fulfilled the given criteria, namely the Tolman–Oppenheimer–Volkoff equation, the adiabatic index and the causality conditions. [ABSTRACT FROM AUTHOR]

Isolated indigenous societies who actively avoid sustained peaceful contact with the outside world are critically endangered. Last year, "Tanaru", the lone surviving man of his tribe for at least 35 years, died in Southwest Amazonia, marking the latest cultural extinction event in a long history of massacres, enslavement, and epidemics. Yet in the upper reaches of the Amazon Basin, dozens of resilient isolated tribes still manage to survive. Remote sensing is a reliable method of monitoring the population dynamics of uncontacted populations by quantifying the area cleared for gardens and villages, along with the fire detections associated with the burning of those clearings. Remote sensing also provides a method to document the number of residential structures and village fissioning. Only with these longitudinal assessments can we better evaluate the current no-contact policies by the United Nations and governments, along with the prospects for the long-term survival of isolated tribes. While the world's largest isolated indigenous metapopulation, Pano speakers in Acre, Brazil, appears to be thriving, other smaller isolated populations disconnected from metapopulations continue to be extremely vulnerable to external threats. Our applied anthropological conservation approach is to provide analyses of publicly available remote sensing datasets to help inform policies that enhance the survival and well-being of isolated cultural groups. [ABSTRACT FROM AUTHOR]

We study the differential uniformity of the Wan-Lidl polynomials over finite fields. A general upper bound, independent of the order of the field, is established. Additional bounds are established in settings where one of the parameters is restricted. In particular, we establish a class of permutation polynomials which have differential uniformity at most 5 over fields of order 3 mod 4, irrespective of the field size. Computational results are also given. [ABSTRACT FROM AUTHOR]