Transient albuminuria in the setting of short-term severe hyperglycemia in type 1 diabetes.

In a cohort of 1817 children with type 1 diabetes (T1D), short-term hyperglycemia was associated with transient albuminuria (11 % during new-onset T1D without diabetic ketoacidosis (DKA), 12 % during/after DKA, 6 % during routine screening). Our findings have implications regarding future risk of diabetic kidney disease and further investigation is needed.

Pseudomonas aeruginosa Lipid A Structural Variants Induce Altered Immune Responses.

Pseudomonas aeruginosa causes chronic lung infection in cystic fibrosis (CF), resulting in structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous changes, adapting to host-specific airway pressures while establishing chronic infection. P. aeruginosa undergoes lipid A structural modification during CF chronic infection, not seen in any other disease state. Lipid A, the membrane anchor of lipopolysaccharide (i.e., endotoxin), comprises the majority of the outer membrane of Gram-negative bacteria and is a potent toll-like receptor (TLR)4 agonist. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4, and subsequent immune response. Prior work has identified P. aeruginosa strains with altered lipid A structures that arise during chronic CF lung infection; however, the impact of P. aeruginosa lipid A structure on airway disease has not been investigated. Here, we show that P. aeruginosa lipid A lacks PagL-mediated deacylation during human airway infection using a direct-from-sample mass spectrometry approach on human bronchoalveolar lavage fluid. This structure triggers increased pro-inflammatory cytokine production by primary human macrophages. Furthermore, alterations in lipid A 2-hydroxylation impact cytokine response in a site-specific manner, independent of CFTR function. Interestingly, there is a CF-specific reduction in IL-8 secretion within the epithelial-cell compartment that only occurs in CF bronchial epithelial cells when infected with CF-adapted P. aeruginosa that lack PagL-mediated lipid A deacylation. Taken together, we show that P. aeruginosa alters its lipid A structure during acute lung infection and that this lipid A structure induces stronger signaling through TLR4.

Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro.

BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.

Single-cell 'omic profiles of human aortic endothelial cells in vitro and human atherosclerotic lesions ex vivo reveal heterogeneity of endothelial subtype and response to activating perturbations.

Heterogeneity in endothelial cell (EC) sub-phenotypes is becoming increasingly appreciated in atherosclerosis progression. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs) exposed to activating environments characteristic of the atherosclerotic microenvironment in vitro. Meta-analysis of single-cell transcriptomes across 17 human ex vivo arterial specimens was performed and two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and ex vivo cell profiles. HAEC cultures were reproducibly populated by four major clusters with distinct pathway enrichment profiles and modest heterogeneous responses: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Quantitative comparisons between in vitro and ex vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated single-nucleotide polymorphisms from Genome Wide Association Studies (GWAS), suggesting that these cell phenotypes harbor CAD-modulating mechanisms. Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and ex vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.

Changes in partner seeking and sexual behavior among United States adults during the first two years of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic may have influenced partner-seeking and sexual behaviors of adults. METHODS: We examined cross-sectional survey data collected at the end of the first year (n = 1,161) and second year (n = 1,233) of the COVID-19 pandemic by the National Opinion Research Center's (NORC) nationally representative, probability-based AmeriSpeak panel. Data were analyzed to: 1) quantify behavioral changes across pandemic years, 2) examine changes of in-person dating prevalence during year 2, and 3) assess risk perception for acquiring COVID-19 or HIV/STIs through new partnerships during year 2. Weighted percentages were calculated for responses; univariate relationships between demographic characteristics and outcomes were assessed. RESULTS: Prevalence of new partners for dating remained stable across pandemic years (year 1: n = 1,157 [10%]; year 2: n = 1,225 [12%]). The prevalence of in-person sex with new partners was also stable (year 1: n = 1,157 [7%], year 2: n = 1,225 [6%]), marking a decline from a prepandemic estimate (2015-2016: 16%). Partner-seeking experiences varied by age and sexual identity in both years, and by race/ethnicity during year 2. Reports of in-person dating fluctuated throughout year 2, without clear relationship to viral variants. Respondents who met new partners in person during year 2 generally reported greater concern and preparedness for reducing risks associated with HIV/STIs than COVID-19. CONCLUSIONS: The prevalence of U.S. adults seeking new partners for dating or sex remained stable across pandemic years. During future public health emergencies, public health officials are encouraged to offer guidance for reducing disease risks in partnerships, while emphasizing sexual health and providing tailored messaging for persons more susceptible to infection.

Bone Density Screening Rates Among Medicare Beneficiaries: An Analysis with a focus on Asian Americans.

PURPOSE: To report osteoporosis screening utilization rates among Asian American (AsA) populations in the USA. METHODS: We retrospectively assessed the use of dual-energy X-ray absorptiometry (DXA) screening using the Medicare 5% Research Identifiable Files. Using Current Procedural Terminology (CPT) codes indicative of a DXA scan, we identified patients recommended for DXA screening according to the ACR-SPR-SSR Practice Parameters (females ≥ 65 years, males ≥ 70 years). Sociodemographic factors and their association with screening were evaluated using chi-square tests. RESULTS: There were 80,439 eligible AsA beneficiaries, and 12,102 (15.1%) received osteoporosis screening. DXA rate for women was approximately four times greater than the rate for men (19.8% vs. 5.0%; p < 0.001). AsA beneficiaries in zip codes with higher mean household income (MHI) were more likely to have DXA than those in lower MHI areas (17.6% vs. 14.3%, p < 0.001). AsA beneficiaries aged < 80 were more likely to receive DXA (15.5%) than those aged ≥ 80 (14.1%, p < 0.001). There were 2,979,801 eligible non-AsA beneficiaries, and 496,957 (16.7%) received osteoporosis screening during the study period. Non-Hispanic white beneficiaries had the highest overall screening rate (17.5%), followed by North American Native (13.0%), Black (11.8%), and Hispanic (11.1%) beneficiaries. Comparing AsA to non-AsA populations, there were significantly lower DXA rates among AsA beneficiaries when controlling for years of Medicare eligibility, patient age, sex, location, and mean income (p < 0.001). CONCLUSION: We found lower than expected DXA screening rates for AsA patients. A better understanding of the barriers and facilitators to AsA osteoporosis screening is needed to improve patient care.

Noninferiority of Hypofractionated vs Conventional Postprostatectomy Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3 Randomized Clinical Trial.

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy. Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years. Design, Setting, and Participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed. Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT). Main Outcomes and Measures: The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events. Results: Of the 296 patients randomized (median [range] age, 65 [44-81] years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 [18.43] and -7.06 [12.78], respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean [SD] GU score: HYPORT, -5.01 [15.10] and COPORT, -4.07 [14.67]; P = .005; mean [SD] GI score: HYPORT, -4.17 [10.97] and COPORT, -1.41 [8.32]; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28). Conclusions and Relevance: In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03274687.

Neutrophil peptidylarginine deiminase 4 plays a systemic role in obesity-induced chronic inflammation in mice.

BACKGROUND: Obesity is an increasing problem in our current society and is expected to keep rising in incidence. With its multiorigin, complex pathophysiology, it is difficult to treat and easy to acquire unnoticeably. During obesity, it has been established that the body is in a constant state of low-grade inflammation, thereby causing changes in immune cell physiology. OBJECTIVES: Here, we investigated the influence of neutrophils, more specifically as a result of peptidylarginine deiminase 4 (PAD4) activity and the release of neutrophil extracellular traps (NETs), during obesity-induced chronic inflammation. METHODS: Wild-type mice were placed on a high-fat diet (HFD) and investigated over a period of 10 weeks for NET formation and its impact on the heart. Neutrophil-selective PAD4 knockout (Ne-PAD4-/-) mice were studied in parallel. RESULTS: As a result of high fat intake, we observed clear alteration in the priming status of isolated neutrophils toward NET release, including early stages of speck formation and histone citrullination of apoptosis-associated speck-like protein containing a CARD. Ne-PAD4-/- mice deficient in NET formation did not increase bodyweight to the same extent as their littermate controls, with Ne-PAD4-/- mice being leaner after 10 weeks of HFD feeding. Interestingly, obesity progression led to cardiac remodeling and diastolic dysfunction in wild-type mice after 10 weeks, while this remodeling and subsequent decrease in function were absent in Ne-PAD4-/- mice. Surprisingly, HFD did not alter NET content or thrombus formation in the inferior vena cava stenosis model. CONCLUSION: Detrimental physiological effects, the result of obesity progression, can in part be attributed to neutrophil PAD4 and NETs in response to chronic inflammation.

Metabolomic Signatures Differentiate Immune Responses in Avian Influenza Vaccine Recipients.

BACKGROUND: Avian influenza viruses pose significant risk to human health. Vaccines targeting the hemagglutinin of these viruses are poorly immunogenic without the use of adjuvants. METHODS: Twenty healthy men and women (18-49 years of age) were randomized to receive two doses of inactivated influenza A/H5N1 vaccine alone (IIV) or with AS03 adjuvant (IIV-AS03) one month apart. Urine and serum samples were collected on day 0 and on days 1, 3, and 7 following first vaccination and subjected to metabolomics analyses to identify metabolites, metabolic pathways, and metabolite clusters associated with immunization. RESULTS: Seventy-three differentially abundant (DA) serum and 88 urine metabolites were identified for any post-vaccination day comparison. Pathway analysis revealed enrichment of tryptophan, tyrosine and nicotinate metabolism in urine and serum among IIV-AS03 recipients. Increased urine abundance of 4-vinylphenol sulfate on Day 1 was associated with serologic response based on hemagglutination inhibition responses. In addition, 9 DA urine metabolites were identified in participants with malaise compared to those without. CONCLUSIONS: Our findings suggest that tryptophan, tyrosine, and nicotinate metabolism are upregulated among IIV-AS03 recipients compared with IIV alone. Metabolites within these pathways may serve as measures of immunogenicity and may provide mechanistic insights for adjuvanted vaccines.

The Neiman Imaging Comorbidity Index: Development and Validation in a National Commercial Claims Database.

OBJECTIVE: To build the Neiman Imaging Comorbidity Index (NICI), based on variables available in claims datasets, which provides good discrimination of an individual's chance of receiving advanced imaging (CT, MR, PET), and thus, utility as a control variable in research. METHODS: This retrospective study used national commercial claims data from Optum's deidentified Clinformatics Data Mart database from the period January 1, 2018 to December 31, 2019. Individuals with continuous enrollment during this 2-year study period were included. Lasso (least absolute shrinkage and selection operator) regression was used to predict the chance of receiving advanced imaging in 2019 based on the presence of comorbidities in 2018. A numerical index was created in a development cohort (70% of the total dataset) using weights assigned to each comorbidity, based on regression ß coefficients. Internal validation of assigned scores was performed in the remaining 30% of claims, with comparison to the commonly used Charlson Comorbidity Index. RESULTS: The final sample (development and validation cohorts) included 10,532,734 beneficiaries, of whom 2,116,348 (20.1%) received advanced imaging. After model development, the NICI included nine comorbidities. In the internal validation set, the NICI achieved good discrimination of receipt of advanced imaging with a C statistic of 0.709 (95% confidence interval [CI] 0.708-0.709), which predicted advanced imaging better than the CCI (C 0.692, 95% CI 0.691-0.692). Controlling for age and sex yielded better discrimination (C 0.748, 95% CI 0.748-0.749). DISCUSSION: The NICI is an easily calculated measure of comorbidity burden that can be used to adjust for patients' chances of receiving advanced imaging. Future work should explore external validation of the NICI.

Hearing ability of prairie voles (Microtus ochrogaster).

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.

Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.

Vascular homeostasis and pathophysiology are tightly regulated by mechanical forces generated by hemodynamics. Vascular disorders such as atherosclerotic diseases largely occur at curvatures and bifurcations where disturbed blood flow activates endothelial cells while unidirectional flow at the straight part of vessels promotes endothelial health. Integrated analysis of the endothelial transcriptome, the 3D epigenome, and human genetics systematically identified the SNP-enriched cistrome in vascular endothelium subjected to well-defined atherosclerosis-prone disturbed flow or atherosclerosis-protective unidirectional flow. Our results characterized the endothelial typical- and super-enhancers and underscored the critical regulatory role of flow-sensitive endothelial super-enhancers. CRISPR interference and activation validated the function of a previously unrecognized unidirectional flow-induced super-enhancer that upregulates antioxidant genes NQO1, CYB5B, and WWP2, and a disturbed flow-induced super-enhancer in endothelium which drives prothrombotic genes EDN1 and HIVEP in vascular endothelium. Our results employing multiomics identify the cis-regulatory architecture of the flow-sensitive endothelial epigenome related to atherosclerosis and highlight the regulatory role of super-enhancers in mechanotransduction mechanisms.

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.

Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both by inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.

Single cell 'omic profiles of human aortic endothelial cells in vitro and human atherosclerotic lesions ex vivo reveals heterogeneity of endothelial subtype and response to activating perturbations.

Objective: Endothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs) are major cell types in atherosclerosis progression, and heterogeneity in EC sub-phenotypes are becoming increasingly appreciated. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Approach and Results: To create an in vitro dataset to study human EC heterogeneity, multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs). To model pro-inflammatory and activating environments characteristic of the atherosclerotic microenvironment in vitro, HAECs from at least three donors were exposed to three distinct perturbations with their respective controls: transforming growth factor beta-2 (TGFB2), interleukin-1 beta (IL1B), and siRNA-mediated knock-down of the endothelial transcription factor ERG (siERG). To form a comprehensive in vivo/ex vivo dataset of human atherosclerotic cell types, meta-analysis of single cell transcriptomes across 17 human arterial specimens was performed. Two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and in vivo cell profiles. HAEC cultures were reproducibly populated by 4 major clusters with distinct pathway enrichment profiles: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Exposure to siERG, IL1B or TGFB2 elicited mostly distinct transcriptional and accessible chromatin responses. EC1 and EC2, the most canonically 'healthy' EC populations, were affected predominantly by siERG; the activated cluster EC3 was most responsive to IL1B; and the mesenchymal population EC4 was most affected by TGFB2. Quantitative comparisons between in vitro and in vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated SNPs from GWAS, suggesting these cell phenotypes harbor CAD-modulating mechanisms. Conclusion: Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here, which have been reported by others to be involved in the pathogenesis of atherosclerosis as well as induce endothelial-to-mesenchymal transition (EndMT), only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and in vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.

Ultrasound Utilization Among Medicare Beneficiaries From 2009 to 2021 by Billing Specialty and Place of Service.

Patterns of ultrasound utilization in the national Medicare population shifted from 2009 to 2021. Office ultrasound services were increasingly performed by radiologists, whereas hospital outpatient and inpatient services were increasingly performed by cardiologists/cardiac surgeons; ultrasound services in other places of service were increasingly performed by nonphysician practitioners.

Complementary cognitive roles for D2-MSNs and D1-MSNs in interval timing.

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds, which involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited opposing dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model. This model predicted that disrupting either D2-MSN or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also increased response times, shifted MSN dynamics, and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs make complementary contributions to interval timing despite opposing dynamics, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for a broad range of human striatal diseases and for therapies targeting striatal pathways.

Modifications to Sexual Behaviors Associated With Mpox (Monkeypox) Virus Transmission Among Persons Presenting for mpox Vaccination, Washington, DC, August-October, 2022.

BACKGROUND: Over 30,000 mpox cases were reported during the 2022 mpox outbreak with many cases occurring among gay, bisexual and other men who have sex with men (MSM). Decreases in U.S. mpox cases were likely accelerated by a combination of vaccination and modifications to sexual behaviors associated with mpox virus transmission. We assessed reports of sexual behavior change among participants receiving mpox vaccination in Washington, DC. METHODS: During August to October 2022, 711 adults aged ≥18 years receiving mpox vaccination at two public health clinics in Washington, DC completed a self-administered questionnaire that asked whether sexual behaviors changed since learning about mpox. We calculated the frequency and percentages of participants reporting an increase, decrease, or no change in 4 of these behaviors by demographic, clinical, and behavioral characteristics with 95% confidence intervals. RESULTS: Overall, between 46% and 61% of participants reported a decrease in sexual behaviors associated with mpox virus transmission, 39% to 54% reported no change in these behaviors, and <1% reported an increase. Approximately 61% reported decreases in one-time sexual encounters (95% confidence interval [CI], 56.8%-64.7%), 54.3% reduced numbers of sex partners (95% CI, 50.4%-58.0%), 53.4% decreased sex via a dating app or sex venue (95% CI, 49.7%-58.0%), and 45.6% reported less group sex (95% CI, 40.4%-50.9%). Reported decreases in these behaviors were higher for MSM than women; in non-Hispanic Black than non-Hispanic White participants; and in participants with human immunodeficiency virus than participants without human immunodeficiency virus. CONCLUSIONS: Most participants receiving mpox vaccination reported decreasing sexual behaviors associated with mpox virus transmission, including groups disproportionately affected by the outbreak.

Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells.

BACKGROUND: Biological sex differences play a vital role in cardiovascular diseases, including atherosclerosis. The endothelium is a critical contributor to cardiovascular pathologies since endothelial cells (ECs) regulate vascular tone, redox balance, and inflammatory reactions. Although EC activation and dysfunction play an essential role in the early and late stages of atherosclerosis development, little is known about sex-dependent differences in EC. METHODS: We used human and mouse aortic EC as well as EC-lineage tracing (Cdh5-CreERT2 Rosa-YFP [yellow fluorescence protein]) atherosclerotic Apoe-/- mice to investigate the biological sexual dimorphism of the EC functions in vitro and in vivo. Bioinformatics analyses were performed on male and female mouse aortic EC and human lung and aortic EC. RESULTS: In vitro, female human and mouse aortic ECs showed more apoptosis and higher cellular reactive oxygen species levels than male EC. In addition, female mouse aortic EC had lower mitochondrial membrane potential (ΔΨm), lower TFAM (mitochondrial transcription factor A) levels, and decreased angiogenic potential (tube formation, cell viability, and proliferation) compared with male mouse aortic EC. In vivo, female mice had significantly higher lipid accumulation within the aortas, impaired glucose tolerance, and lower endothelial-mediated vasorelaxation than males. Using the EC-lineage tracing approach, we found that female lesions had significantly lower rates of intraplaque neovascularization and endothelial-to-mesenchymal transition within advanced atherosclerotic lesions but higher incidents of missing EC lumen coverage and higher levels of oxidative products and apoptosis. RNA-seq analyses revealed that both mouse and human female EC had higher expression of genes associated with inflammation and apoptosis and lower expression of genes related to angiogenesis and oxidative phosphorylation than male EC. CONCLUSIONS: Our study delineates critical sex-specific differences in EC relevant to proinflammatory, pro-oxidant, and angiogenic characteristics, which are entirely consistent with a vulnerable phenotype in females. Our results provide a biological basis for sex-specific proatherosclerotic mechanisms.

Modelling the impact of vaccination and sexual behaviour adaptations on mpox cases in the USA during the 2022 outbreak.

BACKGROUND: The 2022 mpox outbreak has infected over 30 000 people in the USA, with cases declining since mid-August. Infections were commonly associated with sexual contact between men. Interventions to mitigate the outbreak included vaccination and a reduction in sexual partnerships. Understanding the contributions of these interventions to decreasing cases can inform future public health efforts. METHODS: We fit a dynamic network transmission model to mpox cases reported by Washington DC through 10 January 2023. This model incorporated both vaccine administration data and reported reductions in sexual partner acquisition by gay, bisexual or other men who have sex with men (MSM). The model output consisted of daily cases over time with or without vaccination and/or behavioural adaptation. RESULTS: We found that initial declines in cases were likely caused by behavioural adaptations. One year into the outbreak, vaccination and behavioural adaptation together prevented an estimated 84% (IQR 67% to 91%) of cases. Vaccination alone averted 79% (IQR 64% to 88%) of cases and behavioural adaptation alone averted 25% (IQR 10% to 42%) of cases. We further found that in the absence of vaccination, behavioural adaptation would have reduced the number of cases, but would have prolonged the outbreak. CONCLUSIONS: We found that initial declines in cases were likely caused by behavioural adaptation, but vaccination averted more cases overall and was key to hastening outbreak conclusion. Overall, this indicates that outreach to encourage individuals to protect themselves from infection was vital in the early stages of the mpox outbreak, but that combination with a robust vaccination programme hastened outbreak conclusion.

Prevalence of "One-Off Events" in Radiology: Implications for Radiology in Episode-Based Alternative Payment Models.

OBJECTIVE: As reimbursement mechanisms become more value-based, there are questions about the applicability of these mechanisms for nonepisodic care, particularly care provided by nonpatient-facing specialists, for example, radiologists. Accordingly, this study examined the prevalence of nonepisodic care-one-off events-in diagnostic radiology. METHODS: We conducted a multiyear (2015-2019) retrospective study of diagnostic imaging using a large commercial payer database including commercial insurance and Medicare Advantage. Using a 12-month evaluation period starting with the day of the initial imaging study/studies, we categorized imaging studies as one-off events if there were no additional studies (beyond the first day of the evaluation period) for the next 12 months in the same body region. We also evaluated an alternative, more stringent definition of a one-off event: the only imaging study during the 12-month evaluation period. We computed the percentage of one-off events overall and by body region. RESULTS: We found that one-off events comprised 33.2%-45.8% of imaging studies depending on whether one-off events are defined as the only study in the evaluation period or imaging only on the first day of the evaluation period, respectively. This share varied widely by body region: highest for cardiac (80.9%-87.7%) and lower for chest (26.8%-35.2%). By place-of-service, the proportion was lowest for the inpatient (12.9%-29.1%) and long-term care settings (18.6%-30%). DISCUSSION: Given the sizeable share of imaging studies categorized as one-off events, much of radiologists' workload falls outside of the framework of episodic measurement tools and value-based payment models.