Distinct Inflammatory Phenotypes Are Associated With Subclinical and Clinical Cardiovascular Disease in People With Human Immunodeficiency Virus.

Despite inflammation being implicated in cardiovascular disease (CVD) in people with human immunodeficiency virus (PWH), considerable heterogeneity within populations of PWH exists. Stratifying CVD risk based on inflammatory phenotype could play an important role. Using principal component analyses and unsupervised hierarchical clustering, we examined 38 biomarkers to identify inflammatory phenotypes in 2 independent cohorts of PWH. We identified 3 distinct inflammatory clusters present in both cohorts that were associated with altered risk of both subclinical CVD (cohort 1) and prevalent clinical CVD (cohort 2) after adjusting for CVD risk factors. These data support precision medicine approaches to enhance CVD risk assessment in PWH.

Automatic Enrollment in Patient Portal Systems Mitigates the Digital Divide in Healthcare: An Interrupted Time Series Analysis of an Autoenrollment Workflow Intervention.

PURPOSE: Racial and ethnic healthcare disparities require innovative solutions. Patient portals enable online access to health records and clinician communication and are associated with improved health outcomes. Nevertheless, a digital divide in access to such portals persist, especially among people of minoritized race and non-English-speakers. This study assesses the impact of automatic enrollment (autoenrollment) on patient portal activation rates among adult patients at the University of California, San Francisco (UCSF), with a focus on disparities by race, ethnicity, and primary language. MATERIALS AND METHODS: Starting March 2020, autoenrollment offers for patient portals were sent to UCSF adult patients aged 18 or older via text message. Analysis considered patient portal activation before and after the intervention, examining variations by race, ethnicity, and primary language. Descriptive statistics and an interrupted time series analysis were used to assess the intervention's impact. RESULTS: Autoenrollment increased patient portal activation rates among all adult patients and patients of minoritized races saw greater increases in activation rates than White patients. While initially not statistically significant, by the end of the surveillance period, we observed statistically significant increases in activation rates in Latinx (3.5-fold, p = < 0.001), Black (3.2-fold, p = 0.003), and Asian (3.1-fold, p = 0.002) patient populations when compared with White patients. Increased activation rates over time in patients with a preferred language other than English (13-fold) were also statistically significant (p = < 0.001) when compared with the increase in English preferred language patients. CONCLUSION: An organization-based workflow intervention that provided autoenrollment in patient portals via text message was associated with statistically significant mitigation of racial, ethnic, and language-based disparities in patient portal activation rates. Although promising, the autoenrollment intervention did not eliminate disparities in portal enrollment. More work must be done to close the digital divide in access to healthcare technology.

External Validation of the Breast Cancer Surgery Risk Calculator (BCSRc): A Predictive Model for Postoperative Complications.

BACKGROUND: The breast cancer surgical risk calculator (BCSRc) is a prognostic tool that determines a breast cancer patient's unique risk of acute complications following each possible surgical intervention. When used in the preoperative setting, it can help to stratify patients with an increased complication risk and enhance the patient-physician informed decision-making process. The objective of this study was to externally validate the four models used in the BCSRc on a large cohort of patients who underwent breast cancer surgery. METHODS: The BCSRc was developed by using a retrospective cohort from the National Surgical Quality Improvement Program database from 2005 to 2018. Four models were built by using logistic regression methods to predict the following composite outcomes: overall, infectious, hematologic, and internal organ complications. This study obtained a new cohort of patients from the National Surgical Quality Improvement Program by utilizing participant user files from 2019 to 2020. The area under the curve, brier score, and Hosmer-Lemeshow goodness of fit test measured model performance, accuracy, and calibration, respectively. RESULTS: A total of 192,095 patients met inclusion criteria in the development of the BCSRc, and the validation cohort included 60,144 women. The area under the curve during external validation for each model was approximately 0.70. Accuracy, or Brier scores, were all between 0.04 and 0.003. Model calibration using the Hosmer-Lemeshow statistic found all p-values > 0.05. All of these model coefficients will be updated on the web-based BCSRc platform: www.breastcalc.org . CONCLUSIONS: The BCSRc continues to show excellent external-validation measures. Collectively, this prognostic tool can enhance the decision-making process, help stratify patients with an increased complication risk, and improve expectant management.

On the association between circulating biomarkers and atherosclerotic calcification in a cohort of arterial disease participants.

BACKGROUND AND AIMS: Atherosclerotic calcification is a powerful predictor of cardiovascular disease. This study aims to determine whether circulating levels of a local/systemic calcification inhibitor or a marker of bone formation correlate with measures of coronary or extracoronary calcification. METHODS AND RESULTS: Clinical computed tomography (CT) was performed on 64 arterial disease participants undergoing carotid and lower extremity endarterectomy. Coronary artery calcium (CAC) scores and volumes were acquired from the CT scans (n = 42). CAC scores and volumes were used to derive CAC density scores. Micro-CT was performed on excised carotid (n = 36) and lower extremity (n = 31) plaques to quantify the volume and volume fraction of extracoronary calcification. Circulating levels of dephospho-uncarboxylated Matrix Gla Protein (dp-ucMGP), fetuin-A, carboxylated and uncarboxylated osteocalcin (ucOC) were quantified using commercial immunoassays. Carotid participant CAC density scores were moderately negatively correlated with plasma dp-ucMGP (rs = -0.592, P = 0.008). A weak negative association was found between CAC scores and %ucOC for all participants (rs = -0.335, P = 0.040). Another weak negative correlation was observed between fetuin-A and the volume of calcification within excised carotid specimens (rs = -0.366, P = 0.031). Despite substantial differences in coronary and extracoronary calcium measurements, the levels of circulating biomarkers did not vary significantly between carotid and lower extremity subgroups. CONCLUSION: Correlations identified between circulating biomarkers and measures of coronary and extracoronary calcium were not consistent among participant subgroups. Further research is required to determine the association between circulating biomarkers, coronary and extracoronary calcium.

Correlating Ex Vivo Carotid Calcification Measurements With Cerebrovascular Symptoms: A Proof-of-Concept Study.

BACKGROUND AND PURPOSE: The purpose of this study is to examine the ability of ex vivo derived Agatston, Volume, and Density-Volume calcium scores or calcium density measurements to differentiate between carotid plaques based on preoperative cerebrovascular symptomatology. METHODS: Thirty-eight carotid plaques were acquired from standard endarterectomy. Micro-computed tomography was performed on the ex vivo samples. Image series were downsampled to represent the resolution of clinical multidetector computed tomography. Agatston, Volume, and Density-Volume carotid calcium scores were then calculated using coronary methodologies. The fractions of low- and high-density calcification were also determined. RESULTS: The coronary calcium scores could not differentiate between carotid plaques from asymptomatic versus symptomatic patients. However, plaques from asymptomatic patients contained significantly lower fractions of low-density calcification and higher fractions of high-density calcification. CONCLUSIONS: Screening for carotid calcium density in noncontrast computed tomography could reflect plaque stability.

Discovery of 4-arylquinoline-2-carboxamides, highly potent and selective class of mGluR2 negative allosteric modulators: From HTS to activity in animal models.

Antagonism of the mGluR2 receptor has the potential to provide therapeutic benefit to cognitive disorders by elevating synaptic glutamate, the primary excitatory neurotransmitter in the brain. Selective antagonism of the mGluR2 receptor, however, has so far been elusive, given the very high homology of this receptor with mGluR3, particularly at the orthosteric binding site. Given that inhibition of mGluR3 has been implicated in undesired effects, we sought to identify selective mGluR2 negative allosteric modulators. Herein we describe the discovery of the highly potent and selective class of mGluR2 negative allosteric modulators, 4-arylquinoline-2-carboxamides, following a successful HTS campaign and medicinal chemistry optimization, showing potent in vivo efficacy in rodent.

On the influence of wall calcification and intraluminal thrombus on prediction of abdominal aortic aneurysm rupture.

OBJECTIVE: Parameters other than maximum diameter that predict rupture of abdominal aortic aneurysms (AAAs) may be helpful for risk-benefit analysis in individual patients. The aim of this study was to characterize the biomechanical-structural characteristics associated with AAA walls to better identify the related mechanistic variables required for an accurate prediction of rupture risk. METHODS: Anterior AAA wall (n = 40) and intraluminal thrombus (ILT; n = 114) samples were acquired from 18 patients undergoing open surgical repair. Biomechanical characterization was performed using controlled circumferential stretching tests combined with a speckle-strain tracking technique to quantify the spatial heterogeneity in deformation and localized strains in the AAA walls containing calcification. After mechanical testing, the accompanying microstructural characteristics of the AAA wall and ILT types were examined using electron microscopy. RESULTS: No significant correlation was found between the AAA diameter and the wall mechanical properties in terms of Cauchy stress (rs = -0.139; P = .596) or stiffness (rs = -0.451; P = .069). Quantification of significant localized peak strains, which were concentrated in the tissue regions surrounding calcification, reveals that peak strains increased by a mean of 174% as a result of calcification and corresponding peak stresses by 18.2%. Four ILT types characteristic of diverse stages in the evolving tissue microstructure were directly associated with distinct mechanical stiffness properties of the ILT and underlying AAA wall. ILT types were independent of geometric factors, including ILT volume and AAA diameter measures (ILT stiffness and AAA diameter [rs = -0.511; P = .074]; ILT stiffness and ILT volume [rs = -0.245; P = .467]). CONCLUSIONS: AAA wall stiffness properties are controlled by the load-bearing capacity of the noncalcified tissue portion, and low stiffness properties represent a highly degraded vulnerable wall. The presence of calcification that is contiguous with the inner wall causes severe tissue overstretching in surrounding tissue areas. The results highlight the use of additional biomechanical measures, detailing the biomechanical-structural characteristics of AAA tissue, that may be a helpful adjunct to improve the accuracy of rupture prediction.

Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

In vitro toxicoproteomic analysis of A549 human lung epithelial cells exposed to urban air particulate matter and its water-soluble and insoluble fractions.

BACKGROUND: Toxicity of airborne particulate matter (PM) is difficult to assess because PM composition is complex and variable due to source contribution and atmospheric transformation. In this study, we used an in vitro toxicoproteomic approach to identify the toxicity mechanisms associated with different subfractions of Ottawa urban dust (EHC-93). METHODS: A549 human lung epithelial cells were exposed to 0, 60, 140 and 200 µg/cm2 doses of EHC-93 (total), its insoluble and soluble fractions for 24 h. Multiple cytotoxicity assays and proteomic analyses were used to assess particle toxicity in the exposed cells. RESULTS: The cytotoxicity data based on cellular ATP, BrdU incorporation and LDH leakage indicated that the insoluble, but not the soluble, fraction is responsible for the toxicity of EHC-93 in A549 cells. Two-dimensional gel electrophoresis results revealed that the expressions of 206 protein spots were significantly altered after particle exposures, where 154 were identified by MALDI-TOF-TOF-MS/MS. The results from cytotoxicity assays and proteomic analyses converged to a similar finding that the effects of the total and insoluble fraction may be alike, but their effects were distinguishable, and their effects were significantly different from the soluble fraction. Furthermore, the toxic potency of EHC-93 total is not equal to the sum of its insoluble and soluble fractions, implying inter-component interactions between insoluble and soluble materials resulting in synergistic or antagonistic cytotoxic effects. Pathway analysis based on the low toxicity dose (60 µg/cm2) indicated that the two subfractions can alter the expression of those proteins involved in pathways including cell death, cell proliferation and inflammatory response in a distinguishable manner. For example, the insoluble and soluble fractions differentially affected the secretion of pro-inflammatory cytokines such as MCP-1 and IL-8 and distinctly altered the expression of those proteins (e.g., TREM1, PDIA3 and ENO1) involved in an inflammatory response pathway in A549 cells. CONCLUSIONS: This study demonstrated the impact of different fractions of urban air particles constituted of various chemical species on different mechanistic pathways and thus on cytotoxicity effects. In vitro toxicoproteomics can be a valuable tool in mapping these differences in air pollutant exposure-related toxicity mechanisms.

Responses of A549 human lung epithelial cells to cristobalite and α-quartz exposures assessed by toxicoproteomics and gene expression analysis.

In this study, we used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite (CR) and α-quartz (Min-U-Sil 5, MI). Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2'-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. While cytotoxicity assays revealed little difference between CR and MI exposures, proteomic and gene expression analyses unveiled both similar and unique molecular changes in A549 cells. For instance, two-dimensional gel electrophoresis data indicated that the expression of proteins in the cell death (e.g., ALDH1A1, HTRA2 and PRDX6) and cell proliferation (e.g., FSCN1, HNRNPAB and PGK1) pathways were significantly different between the two silica particles. Reverse transcription-polymerase chain reaction data provided additional evidence supporting the proteomic findings. Preliminary assessment of the physical differences between CR and MI suggested that the extent of surface interaction between particles and cells could explain some of the observed biological effects. However, the differential dose-response curves for some other genes and proteins suggest that other physical attributes of particulate matter can also contribute to particulate matter-related cellular toxicity. Our results demonstrated that toxicoproteomic and gene expression analyses are sensitive in distinguishing subtle toxicity differences associated with silica particles of varying physical properties compared to traditional cytotoxicity endpoints. Copyright © 2016 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.

An appraisal of the computed axial tomographic appearance of the human mesentery based on mesenteric contiguity from the duodenojejunal flexure to the mesorectal level.

OBJECTIVE: The human mesentery is now regarded as contiguous from the duodenojejunal (DJ) to anorectal level. This interpretation prompts re-appraisal of computed tomography (CT) images of the mesentery. METHODS: A digital model and reference atlas of the mesentery were generated using the full-colour data set of the Visible Human Project (VHP). Seventy one normal abdominal CT images were examined to identify mesenteric regions. CT appearances were correlated with cadaveric and histological appearances at corresponding levels. RESULTS: Ascending, descending and sigmoid mesocolons were identifiable in 75%, 86% and 88% of the CTs, respectively. Flexural contiguity was evident in 66%, 68%, 71% and 80% for the ileocaecal, hepatic, splenic and rectosigmoid flexures, respectively. A posterior mesocolic boundary corresponding to the anterior renal fascia was evident in 40% and 54% of cases on the right and left, respectively. The anterior pararenal space (in front of the boundary) corresponded to the mesocolon. CONCLUSIONS: Using the VHP, a mesenteric digital model and reference atlas were developed. This enabled re-appraisal of CT images of the mesentery, in which contiguous flexural and non-flexural mesenteric regions were repeatedly identifiable. The anterior pararenal space corresponded to the mesocolon. KEY POINTS: The Visible Human Project (VHP) allows direct identification of mesenteric structures. Correlating CT and VHP allows identification of flexural and non-flexural mesenteric components. Radiologic appearance of intraperitoneal structures is assessed, starting from a mesenteric platform.

Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology.

While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.

Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis.

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.

Comparison of Oleo- vs Petro-Sourcing of Fatty Alcohols via Cradle-to-Gate Life Cycle Assessment.

Alcohol ethoxylates surfactants are produced via ethoxylation of fatty alcohol (FA) with ethylene oxide. The source of FA could be either palm kernel oil (PKO) or petrochemicals. The study aimed to compare the potential environmental impacts for PKO-derived FA (PKO-FA) and petrochemicals-derived FA (petro-FA). Cradle-to-gate life cycle assessment has been performed for this purpose because it enables understanding of the impacts across the life cycle and impact categories. The results show that petro-FA has overall lower average greenhouse gas (GHG) emissions (~2.97 kg CO2e) compared to PKO-FA (~5.27 kg CO2e). (1) The practices in land use change for palm plantations, (2) end-of-life treatment for palm oil mill wastewater effluent and (3) end-of-life treatment for empty fruit bunches are the three determining factors for the environmental impacts of PKO-FA. For petro-FA, n-olefin production, ethylene production and thermal energy production are the main factors. We found the judicious decisions on land use change, effluent treatment and solid waste treatment are key to making PKO-FA environmentally sustainable. The sensitivity results show the broad distribution for PKO-FA due to varying practices in palm cultivation. PKO-FA has higher impacts on average for 12 out of 18 impact categories evaluated. For the base case, when accounted for uncertainty and sensitivity analyses results, the study finds that marine eutrophication, agricultural land occupation, natural land occupation, fossil depletion, particulate matter formation, and water depletion are affected by the sourcing decision. The sourcing of FA involves trade-offs and depends on the specific practices through the PKO life cycle from an environmental impact perspective.

Exploring the prevalence and management of wounds in an urban area in Ireland.

AIM: This study explores the prevalence and management of wounds within an urban setting in Ireland. METHOD: It employs a cross-sectional survey design, using a predesigned, validated data-collection instrument. FINDINGS: The point prevalence of wounds was 3.7% (n=445), with surgical wounds being the most prevalent (43%; n=189). Wound care was provided across a wide variety of clinical settings, with the majority of patients (60%; n=271) managed in the acute care setting. Most dressings were changed 2-3 times a week (60%; n=271). The mean dressing time was 15 minutes (SD: 12.4 minutes), varying from 2 minutes to 90 minutes. The mean nurse travel time was 3 minutes (SD: 6.5 minutes), varying from 0-60 minutes. Among participants managed using silver and iodine dressings, 53% (n=10, silver) and 78% (n=50, iodine) were prescribed for wounds described as being not infected. Alginate dressings were used incorrectly in 75% of cases, foam dressings in 63% of cases and Hydrofiber dressings in 63% of cases. CONCLUSION: Wound management within the explored geographical area is an important clinical intervention. This study identified areas of practice that need to be addressed, primarily those related to the topical management of the wound and use of offloading. The data has been used to inform practice, education, and further research in this important clinical specialty.

Breast-Conserving Surgery in Bilateral Breast Cancer.

BACKGROUND: Bilateral breast cancer (BBC) may present as synchronous (SBC) or metachronous breast cancer (MBC). Optimal surgical management of BBC patients is not well-defined. In this study, we report on histopathology, treatment, and outcomes in BBC patients. METHODS: Upon Institutional Review Board approval, we identified BBC patients diagnosed and treated for invasive breast cancer between 1999 and 2007. Retrospective chart review for demographics, histopathology, treatment, and outcomes was performed, and factors associated with BCS choice were collected. Contraindication to BCS was defined as any of the following one-breast findings: multicentric disease, tumor considered too large for BCS, and a patient without a nominal breast size for acceptable cosmetic results. McNemar's test for matched pairs (binary variables) or the paired t test (continuous variables) were used to examine if a pathologic characteristic differed within a cancer pair. Kaplan-Meier methods estimated overall survival (OS). RESULTS: A total of 203 BBC patients (119 SBC, 84 MBC) comprised our study group. Histopathologic characteristics of the first and second cancers diagnosed in both the SBC and MBC patients were very similar in histologic type and molecular profiles. Overall, 57% of MBC patients underwent breast-conserving surgery (BCS) at initial diagnosis versus 34% of patients with SBC. BCS contraindications were similar in both groups: 16 (34%) MBC patients and 28 (36%) SBC patients. Kaplan-Meier OS estimates at 5 and 10 years were 86 and 78% for MBC, and 87 and 77% for SBC patients, respectively. CONCLUSIONS: OS was excellent for both the MBC and SBC groups. Contraindications to BCS did not differ between groups. However, patients with SBC were less likely to undergo BCS compared with patients with MBC at the time of initial diagnosis.

Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties.

Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

Synthesis and evaluation of carbon-linked analogs of dual orexin receptor antagonist filorexant.

Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.