Transient Generalized Osteosclerosis in a Newborn Mimicking Congenital Osteopetrosis with Negative Comprehensive Genetic Workup: A Case Report.

We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs with severe forms of osteopetrosis, familiarity with this condition is crucial for correct diagnosis and management.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer.

OBJECTIVES: External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. METHODS: We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. RESULTS: Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). CONCLUSIONS: Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Exploring Integrin α5ß1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies.

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5ß1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5ß1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5ß1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5ß1 integrin inhibition as a promising therapy for pulmonary hypertension. One sentence summary: The α5ß1 integrin plays a crucial role in pulmonary vascular remodeling.

Bioproducts of Pseudomonas chlororaphis suppress DMI fungicide-induced CsCYP51A and CsCYP51B gene expression in Colletotrichum siamense and generate synergistic effects with metconazole and propiconazole.

Mixtures of fungicides with different modes of action are commonly used as disease and resistance management tools, but little is known of mixtures of natural and synthetic products. In this study, mixtures of metabolites from the rhizobacterium Pseudomonas chlororaphis strain ASF009 formulated as Howler EVO with below label rates (50 µg/ml) of conventional sterol demethylation inhibitor (DMI) fungicides were investigated for control of anthracnose of cherry (Prunus avium) caused by Colletotrichum siamense. Howler mixed with metconazole or propiconazole synergistically reduced disease severity through lesion growth. Realtime PCR showed that difenoconazole, flutriafol, metconazole, and propiconazole induced the expression of DMI target genes CsCYP51A and CsCYP51B in C. siamense. The addition of Howler completely suppressed the DMI fungicide-induced expression of both CYP51 genes. We hypothesize that the downregulation of DMI fungicide-induced expression of the DMI target genes may, at least in part, explain the synergism observed in detached fruit assays.

Nicotine or marijuana vaping exposure during pregnancy and altered immune responses in offspring.

Electronic nicotine delivery systems (ENDS) - which include electronic cigarettes or e-cigarettes, or simply e-cigs, and marijuana vaping have become increasingly popular. ENDS devices have been established as one of the tobacco quit methods and promoted to be safer compared to traditional tobacco cigarettes. Emerging evidence demonstrates that e-cigarette and marijuana vape use can be harmful, with potential associations with cancer. Herein, we summarize the level of evidence to date for altered immune response, with a focus on cancer risks in the offspring after maternal use of, or aerosol exposures from, ENDS or marijuana vape during pregnancy. From 27 published articles retrieved from PubMed, we sought to find out identified carcinogens in ENDS aerosols and marijuana vapor, which cross the placental barrier and can increase cancer risk in the offspring. Carcinogens in vaping aerosols include aldehydes, metals, tobacco-specific nitrosamines, tobacco alkaloids, polycyclic aromatic hydrocarbons, and volatile organic compounds. Additionally, there was only one passive vaping exposure case study on a human fetus, which noted that glycerol, aluminum, chromium, nickel, copper, zinc, selenium, and lead crossed from the mother to the offspring's cord blood. The carcinogens (metals) in that study were at lower concentrations compared to the mother's biological matrices. Lastly, we observed that in utero exposures to ENDS-associated chemicals can occur in vital organs such as the lungs, kidneys, brain, bladder, and heart. Any resulting DNA damage increases the risk of tumorigenesis. Future epidemiological studies are needed to examine the effects of passive aerosol exposures from existing and emerging electronic nicotine and marijuana products on developing offspring to cancer.

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency. Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria. Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria. Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Complete genome sequences of six S19 poliovirus reference strains.

We report the complete genome sequences of six S19 poliovirus reference strains for all three poliovirus serotypes, including three Sabin vaccine-derived and three wild-type-derived strains. The S19 strains are extensively attenuated and genetically stable when compared to the reference poliovirus strains, while maintaining the same antigenicity and immunogenicity.

Investigating the Relationship between Bleeding, Clotting, and Coagulopathy During Automated Partial REBOA Strategies in a Highly Lethal Porcine Hemorrhage Model.

BACKGROUND: Death due to hemorrhagic shock, particularly, non-compressible truncal hemorrhage (NCTH), remains one of the leading causes of potentially preventable deaths. Automated partial and intermittent resuscitative endovascular balloon occlusion of the aorta (i.e., pREBOA and iREBOA, respectively) are lifesaving endovascular strategies aimed to achieve quick hemostatic control while mitigating distal ischemia. In iREBOA, the balloon is titrated from full occlusion to no occlusion intermittently whereas in pREBOA, a partial occlusion is maintained. Therefore, these two interventions impose different hemodynamic conditions, which may impact coagulation and the endothelial glycocalyx layer (EGL). In this study, we aimed to characterize the clotting kinetics and coagulopathy associated with iREBOA and pREBOA, using thromboelastography (TEG). We hypothesized that iREBOA would be associated with a more hypercoagulopathic response compared to pREBOA due to more oscillatory flow. METHODS: Yorkshire swine (n = 8/group) were subjected to an uncontrolled hemorrhage by liver transection, followed by 90 minutes of automated partial REBOA (pREBOA), intermittent REBOA (iREBOA), or no balloon support (Control). Hemodynamic parameters were continuously recorded, and blood samples were serially collected during the experiment (i.e., 8 key time points: baseline (BL), T0, T10, T30, T60, T90, T120, T210 minutes). Citrated kaolin heparinase (CKH) assays were run on a TEG 5000 (Haemonetics, Niles, IL). General linear mixed models were employed to compare differences in TEG parameters between groups and over time using STATA (v17; College Station, TX), while adjusting for sex and weight. RESULTS: As expected, iREBOA was associated with more oscillations in proximal pressure (and greater magnitudes of peak pressure) because of the intermittent periods of full aortic occlusion and complete balloon deflation, compared to pREBOA. Despite these differences in acute hemodynamics, there were no significant differences in any of the TEG parameters between iREBOA and pREBOA groups. However, animals in both groups experienced a significant reduction in clotting times (R-time: p < 0.001; K-time: p < 0.001) and clot strength (MA: p = 0.01; G: p = 0.02) over the duration of the experiment. CONCLUSIONS: Despite observing acute differences in peak proximal pressures between iREBOA and pREBOA groups, we did not observe any significant differences in TEG parameters between iREBOA and pREBOA. The changes in TEG profiles were significant over time, indicating that a severe hemorrhage followed by both pREBOA and iREBOA can result in faster clotting reaction times (i.e., R-times). Nevertheless, when considering the significant reduction in transfusion requirements and more stable hemodynamic response in the pREBOA group, there may be some evidence favoring pREBOA usage over iREBOA.

Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) secreted by triple-negative breast cancer promotes peri-tumoral fibrosis.

Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells. The screen identified an adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) that is secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG is linked to poor prognosis in TNBC patients, but not in patients with other clinical subtypes of breast cancer. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of adipocyte stem and progenitor cells into cancer-associated fibroblasts to support tumorigenesis.

Holmium Laser Enucleation Of The Prostate (HOLEP) Learning Curve - Resident Perspective: Survey Of Senior Residents From High-Volume Tertiary Center.

OBJECTIVE: We aim to report the learning curve and experience performing holmium laser enucleation of the prostate (HOLEP) from a resident standpoint trained at a tertiary high-volume center. METHODS: An electronic survey was distributed to ten surveyees that included recently graduated chief residents trained at Indiana University in the last 3 years i.e. between 2020-2022 with a 100% response rate. The questionnaire focused on HOLEP training experience based on a recently established mentorship curriculum in training the residents through each individual step of the surgery. RESULTS: The average learning curve for performing HOLEP was reported to be greater than 25 cases with 50% of the residents reporting >50 cases to master the technique. The surgical difficulty of steps of the HOLEP were rated on a subjective scale of 1-5: 1 = very easy, 2 = easy, 3= neutral, 4 = hard, and 5 = very hard. The common challenging steps in decreasing the order of difficulty as reported are performing apical enucleation, joining anterior and posterior planes, and dividing anterior commissure with a mean rating of 3.5, 3.1, and 3.1 respectively. The most difficult aspect of the surgery to master was performing apical dissection (60%). Comparing operative parameters for HOLEP to transurethral resection of the prostate (TURP) in aspects of resection volume and times, 70 % of candidates reported it better for HOLEP whereas 20% had similar times for both procedures. 90 % of the residents felt confident to offer HOLEP as part of their practice without the need for any further training. CONCLUSION: We believe HOLEP can be performed immediately after residency training and incorporated into practice with high volume, repeated exposure to HoLEP surgery throughout residency based on study results. The average learning curve reported for performing HOLEP was greater than 25 case.

Utilization of supportive care medications and opportunities for pre-emptive pharmacogenomic testing in pediatric and young adults with leukemia.

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009-2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters.

Detection of periodic peaks in Karenia brevis concentration consistent with the time-delay logistic equation.

The logistic equation models single-species population growth with a sigmoid curve that begins as exponential and ends with an asymptotic approach to a final population determined by natural system carrying capacity. But the population of a natural system often does not stabilize as it approaches carrying capacity. Instead, it exhibits periodic change, sometimes with very large amplitudes. The time-delay modification of the logistic equation accounts for this behavior by connecting the present rate of population growth to conditions at an earlier time. The periodic change in population with time can progress from a monotonic approach to the carrying capacity; to oscillation around the carrying capacity; to limit-cycle periodic change; and, finally, to chaotic change. The presence of multiple species and inadequate sampling frequency and spatial coverage hinder the application of the time-delay logistic equation to real-world populations. Blooms of Karenia brevis along the southwest Florida Gulf Coast, however, provide a unique opportunity in that blooms are nearly monospecific and are sampled frequently over a wide geographic region, they are good candidates for testing the time-delay logistic equation. We show that these blooms exhibit peaks in concentration with periods in the range of 40-100 days, consistent with that predicted by the time-delay logistic equation. Cell concentrations in the valleys between the peaks are at least 2-3 orders of magnitude lower than peak values, offering predictable windows of opportunity for potential mitigation efforts.

COVID-19 Vaccine Side Effects and Long-Term Neutralizing Antibody Response : A Prospective Cohort Study.

BACKGROUND: Concern about side effects is a common reason for SARS-CoV-2 vaccine hesitancy. OBJECTIVE: To determine whether short-term side effects of SARS-CoV-2 messenger RNA (mRNA) vaccination are associated with subsequent neutralizing antibody (nAB) response. DESIGN: Prospective cohort study. SETTING: San Francisco Bay Area. PARTICIPANTS: Adults who had not been vaccinated against or exposed to SARS-CoV-2, who then received 2 doses of either BNT162b2 or mRNA-1273. MEASUREMENTS: Serum nAB titer at 1 month and 6 months after the second vaccine dose. Daily symptom surveys and objective biometric measurements at each dose. RESULTS: 363 participants were included in symptom-related analyses (65.6% female; mean age, 52.4 years [SD, 11.9]), and 147 were included in biometric-related analyses (66.0% female; mean age, 58.8 years [SD, 5.3]). Chills, tiredness, feeling unwell, and headache after the second dose were each associated with 1.4 to 1.6 fold higher nAB at 1 and 6 months after vaccination. Symptom count and vaccination-induced change in skin temperature and heart rate were all positively associated with nAB across both follow-up time points. Each 1 °C increase in skin temperature after dose 2 was associated with 1.8 fold higher nAB 1 month later and 3.1 fold higher nAB 6 months later. LIMITATIONS: The study was conducted in 2021 in people receiving the primary vaccine series, making generalizability to people with prior SARS-CoV-2 vaccination or exposure unclear. Whether the observed associations would also apply for neutralizing activity against non-ancestral SARS-CoV-2 strains is also unknown. CONCLUSION: Convergent self-report and objective biometric findings indicate that short-term systemic side effects of SARS-CoV-2 mRNA vaccination are associated with greater long-lasting nAB responses. This may be relevant in addressing negative attitudes toward vaccine side effects, which are a barrier to vaccine uptake. PRIMARY FUNDING SOURCE: National Institute on Aging.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.

Higher blood glucose is associated with the severity of hemorrhagic transformation after endovascular therapy for stroke.

OBJECTIVES: Hyperglycemia is associated with poor outcome in large vessel occlusion (LVO) stroke, with mechanism for this effect unknown. MATERIALS AND METHODS: We used our prospective, multicenter, observational study, Blood Pressure After Endovascular Stroke Therapy (BEST), of anterior circulation LVO stroke undergoing endovascular therapy (EVT) from 11/2017-7/2018 to determine association between increasing blood glucose (BG) and intracerebral hemorrhage (ICH). Our primary outcome was degree of ICH, classified as none, asymptomatic ICH, or symptomatic ICH (≥4-point increase in National Institutes of Health Stroke Scale [NIHSS] at 24 h with any hemorrhage on imaging). Secondary outcomes included 24 h NIHSS, early neurologic recovery (ENR, NIHSS 0-1 or NIHSS reduction by ≥8 within 24 h), and 90-day modified Rankin Scale (mRS) using univariate and multivariable regression. RESULTS: Of 485 enrolled patients, increasing BG was associated with increasing severity of ICH (adjusted OR, aOR 1.06, 95 % CI 1.02-1.1, p < 0.001), higher 24 h NIHSS (aOR 1.22, 95 % CI 1.11-1.34, p < 0.001), ENR (aOR 0.90, 95 % CI 0.82-1.00, p < 0.002), and 90-day mRS (aOR 1.06, 95 % CI 1.03-1.09, p < 0.001) when adjusted for age, presenting NIHSS, ASPECTS, 24-hour peak systolic blood pressure, time from last known well, and successful recanalization. CONCLUSIONS: In the BEST study, increasing BG was associated with greater odds of increasing ICH severity. Further study is warranted to determine whether treatment of will decrease ICH severity following EVT.

A historical perspective and recent advances on the evolution of the relationship between acute and chronic pain and cardiovascular disease.

The relationship between acute pain and the cardiovascular system was recognized approximately 50 years ago following the initial observation, along with several subsequent experimental studies, that hypertension can result in decreases in the perception of pain. These studies provided a strong impetus to study potential mechanisms to clarify commonalities between the regulatory pathways associated with pain and the cardiovascular system. Attention subsequently shifted to an emphasis on the impact of chronic pain on cardiovascular diseases and mortality with several large meta-analyses of longitudinal studies providing clear evidence that chronic widespread pain increases the risk for developing cardiovascular disease and is associated with excess morbidity and mortality. Cardiovascular associated mortality from myocardial infarction and stroke appears to be directly related to the duration and severity of chronic pain, a result often characterized as a 'dose-response' relationship. The availability and reproducibility of extensive large-scale observational and retrospective studies have emphasized the critical need for more research, including prospective studies, along with the need for the development of preclinical animal models, to better understand the relationship(s) and underlying mechanisms between chronic pain, associated comorbidities, and cardiovascular disease. Elucidation and a deeper understanding of these relationships, including a focus on the link between chronic pain, cardiovascular disease, and depression, could provide valuable information to guide the development of potential treatment interventions to aid in attenuating pain while preventing pain-associated cardiovascular disease, comorbidities, and mortality.

Cognitive Assessment with Cognivue Clarity®: Psychometric Properties and Normative Ranges in a Diverse Population.

Background: Detecting cognitive impairment in clinical practice is challenging as most instruments do not perform well in diverse samples of older adults. These same instruments are often used for eligibility into clinical trials making it difficult to recruit minoritized adults into Alzheimer's disease (AD) studies. Cognivue Clarity® is an FDA-cleared computerized 10-minute cognitive screening platform using adaptive psychophysics to detect cognitive impairment. Objective: Test the ability of Cognivue Clarity to measure cognitive performance in a diverse community sample compared with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Methods: This study enrolled 452 participants across 6 US study sites and completed both Cognivue Clarity device and RBANS. Psychometric properties and exploratory factor analysis of Cognivue Clarity were explored and comparisons against RBANS across different age, sex, education, and ethnoracial groups were conducted. Results: Participants had a mean age of 47.9±16.1 years (range: 18-85), 63.6% were female, 45.9% had ≤12 years of education, 31.2% were African American and 9.2% were Hispanic. Cognivue Clarity had strong internal consistency, test-retest reliability and minimal practice effects. A 4-factor structure (Memory, Attention, Visuomotor, and Discrimination) had excellent goodness-of-fit. Normalizing age effects improved performance. Race and education effects were similar to those seen with RBANS. Cognivue Clarity had strong correlations with RBANS. Conclusions: Our study supports the use of Cognivue Clarity as an easy-to-use, brief, and valid cognitive assessment that measures cognitive performance. In the correct clinical setting, Cognivue Clarity may identify individuals with likely cognitive impairment who could be candidates for AD research studies.