The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults.

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure wave fluctuations deeper into the cerebrovasculature, exacerbating neurodegeneration. This interactive effect was studied in older adults using multiple markers of neurodegeneration, including medial temporal lobe (MTL) volume, plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Older adults (N=105) without major neurological or systemic disease were recruited and underwent brain MRI and continuous BP monitoring to quantify inter-beat BPV through systolic average real variability (ARV) and intra-beat variability through arterial stiffness index (ASI). Plasma NfL and GFAP were assessed. The interactive effect of ARV and ASI on MTL atrophy, plasma NfL, and GFAP was studied using hierarchical linear regression. Voxel-based morphometry (VBM) was used to confirm region-of-interest analysis findings. The interaction between higher ARV and higher ASI was significantly associated with left-sided MTL atrophy in both the region-of-interest and false discovery rate-corrected VBM analysis. The interactive effect was also significantly associated with increased plasma NfL, but not GFAP. The interaction between higher ARV and higher ASI is independently associated with increased neurodegenerative markers, including MTL atrophy and plasma NfL, in independently living older adults. Findings could suggest the increased risk for neurodegeneration associated with higher inter-beat BPV may be compounded by increased intra-beat variability due to arterial stiffness.

Measuring algorithmic bias to analyze the reliability of AI tools that predict depression risk using smartphone sensed-behavioral data.

AI tools intend to transform mental healthcare by providing remote estimates of depression risk using behavioral data collected by sensors embedded in smartphones. While these tools accurately predict elevated symptoms in small, homogenous populations, recent studies show that these tools are less accurate in larger, more diverse populations. In this work, we show that accuracy is reduced because sensed-behaviors are unreliable predictors of depression across individuals; specifically the sensed-behaviors that predict depression risk are inconsistent across demographic and socioeconomic subgroups. We first identified subgroups where a developed AI tool underperformed by measuring algorithmic bias, where subgroups with depression were incorrectly predicted to be at lower risk than healthier subgroups. We then found inconsistencies between sensed-behaviors predictive of depression across these subgroups. Our findings suggest that researchers developing AI tools predicting mental health from behavior should think critically about the generalizability of these tools, and consider tailored solutions for targeted populations.

Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

Interface-modulated kinetic differentials in electron and hole transfer rates as a key design principle for redox photocatalysis by Sb2VO5/QD heterostructures.

The efficient conversion of solar energy to chemical energy represents a critical bottleneck to the energy transition. Photocatalytic splitting of water to generate solar fuels is a promising solution. Semiconductor quantum dots (QDs) are prime candidates for light-harvesting components of photocatalytic heterostructures, given their size-dependent photophysical properties and band-edge energies. A promising series of heterostructured photocatalysts interface QDs with transition-metal oxides which embed midgap electronic states derived from the stereochemically active electron lone pairs of p-block cations. Here, we examine the thermodynamic driving forces and dynamics of charge separation in Sb2VO5/CdSe QD heterostructures, wherein a high density of Sb 5s2-derived midgap states are prospective acceptors for photogenerated holes. Hard-x-ray valence band photoemission spectroscopy measurements of Sb2VO5/CdSe QD heterostructures were used to deduce thermodynamic driving forces for charge separation. Interfacial charge transfer dynamics in the heterostructures were examined as a function of the mode of interfacial connectivity, contrasting heterostructures with direct interfaces assembled by successive ion layer adsorption and reaction (SILAR) and interfaces comprising molecular bridges assembled by linker-assisted assembly (LAA). Transient absorption spectroscopy measurements indicate ultrafast (<2 ps) electron and hole transfer in SILAR-derived heterostructures, whereas LAA-derived heterostructures show orders of magnitude differentials in the kinetics of hole (<100 ps) and electron (∼1 ns) transfer. The interface-modulated kinetic differentials in electron and hole transfer rates underpin the more effective charge separation, reduced charge recombination, and greater photocatalytic efficiency observed for the LAA-derived Sb2VO5/CdSe QD heterostructures.

Understanding the Importance of Drag Coefficient Assessment for a Deeper Insight into the Hydrodynamic Profile of Swimmers.

The main objective of this study was to confirm that the passive drag coefficient is less dependent on swimming speed than the passive drag, Froude, and Reynolds numbers, even as swimming speed increases. The sample consisted of 12 young proficient non-competitive swimmers (seven males and five females: 20.4 ± 1.9 years). Passive drag was measured with a low-voltage isokinetic engine at 1.2, 1.4, 1.6 and 1.8 m/s. The frontal surface area was measured using digital photogrammetry. Passive drag showed significant differences with a strong effect size over the four towing speeds measured (F = 116.84, p < 0.001, η2 = 0.91) with a quadratic relationship with speed. The Froude and Reynolds numbers had similar trends, but with linear relationships. Conversely, the passive drag coefficient showed non-significant differences across the four towing speeds (F = 3.50, p = 0.062, η2 = 0.33). This strongly suggests that the passive drag coefficient should be the variable of choice for monitoring the hydrodynamic profile of swimmers rather than the absolute value of passive drag.

Uncovering physical activity trade-offs in transportation policy: A spatial agent-based model of Bogotá, Colombia.

BACKGROUND: Transportation policies can impact health outcomes while simultaneously promoting social equity and environmental sustainability. We developed an agent-based model (ABM) to simulate the impacts of fare subsidies and congestion taxes on commuter decision-making and travel patterns. We report effects on mode share, travel time and transport-related physical activity (PA), including the variability of effects by socioeconomic strata (SES), and the trade-offs that may need to be considered in the implementation of these policies in a context with high levels of necessity-based physical activity. METHODS: The ABM design was informed by local stakeholder engagement. The demographic and spatial characteristics of the in-silico city, and its residents, were informed by local surveys and empirical studies. We used ridership and travel time data from the 2019 Bogotá Household Travel Survey to calibrate and validate the model by SES. We then explored the impacts of fare subsidy and congestion tax policy scenarios. RESULTS: Our model reproduced commuting patterns observed in Bogotá, including substantial necessity-based walking for transportation. At the city-level, congestion taxes fractionally reduced car use, including among mid-to-high SES groups but not among low SES commuters. Neither travel times nor physical activity levels were impacted at the city level or by SES. Comparatively, fare subsidies promoted city-level public transportation (PT) ridership, particularly under a 'free-fare' scenario, largely through reductions in walking trips. 'Free fare' policies also led to a large reduction in very long walking times and an overall reduction in the commuting-based attainment of physical activity guidelines. Differential effects were observed by SES, with free fares promoting PT ridership primarily among low-and-middle SES groups. These shifts to PT reduced median walking times among all SES groups, particularly low-SES groups. Moreover, the proportion of low-to-mid SES commuters meeting weekly physical activity recommendations decreased under the 'freefare' policy, with no change observed among high-SES groups. CONCLUSIONS: Transport policies can differentially impact SES-level disparities in necessity-based walking and travel times. Understanding these impacts is critical in shaping transportation policies that balance the dual aims of reducing SES-level disparities in travel time (and time poverty) and the promotion of choice-based physical activity.

Development of Allosteric Small Molecule APOBEC3B Inhibitors from In Silico Screening.

APOBEC3B cytosine deaminase contributes to the mutational burdens of tumors, resulting in tumor progression and therapy resistance. Small molecule APOBEC3B inhibitors have potential to slow or mitigate these detrimental outcomes. Through molecular dynamics (MD) simulations and computational solvent mapping analysis, we identified a novel putative allosteric pocket on the C-terminal domain of APOBEC3B (A3Bctd), and virtually screened the ChemBridge Diversity Set (N~110,000) against both the active and potential allosteric sites. Selected high-scoring compounds were subsequently purchased, characterized for purity and composition, and tested in biochemical assays, which yielded 13 hit compounds. Orthogonal NMR assays verified binding to the target protein. Initial selectivity studies suggest these compounds preferentially target A3Bctd over related deaminase APOBEC3A (A3A), and MD simulations indicate this selectivity may be due to the steric repulsion from H56 that is unique to A3A. Taken together, our studies represent the first virtual screening effort against A3Bctd that has yielded candidate inhibitors suitable for further development.

N,N'-Dimethylsquaramide as a central scaffold for anionophore design.

The N,N'-dimethylation of a diphenylsquaramide induces a conformational change in the orientation of the phenyl rings. This has been exploited to create a series of bis-urea, -thiourea and -squaramide anionophores. The compounds were shown to bind to Cl- using proton NMR titration techniques and to transport H+/Cl- through the lipid bilayers, whereas a non-methylated analogue displayed limited transport activity. Despite their potency in transport studies, the series had a negligible impact on cancer cell viability.

Associations Between Prenatal Vitamin D and Placental Gene Expression.

Background: Vitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D. Objective: We investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort. Methods: Participants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks' gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA). Results: The median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy ( N =774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery ( N =753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors including ARNT2 , BHLHE40 , FOSL2 , JUND , and NFKB1 . Conclusions: Our results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.

Shadows over Caribbean reefs: Identification of a new invasive soft coral species, Xenia umbellata , in southwest Puerto Rico.

In October 2023, several colonies of an alien soft coral species were reported on shallow reefs in southwest Puerto Rico. The soft coral was identified as a xeniid octocoral (species undetermined), resembling the octocoral Unomia stolonifera , which has invaded and overgrown reefs in Venezuela in recent years. To conclusively characterize the species of the invading xeniid, we employed multilocus barcoding targeting four genes (ND2, mtMutS, COI, and 28S) of three separate colonies across three locations in southwest Puerto Rico. Sequence comparisons with xeniid sequences from GenBank, including those from the genera Xenia and Unomia , indicated a 100% sequence identity (>3,000 bp combined) with the species Xenia umbellata (Octocorallia : Malacalcyonacea : Xeniidae). Xenia umbellata is native to the Red Sea and to our knowledge, this represents the first confirmed case of this species as an invader on Caribbean reefs. Similar to U. stolonifera, X. umbellata is well known for its ability to rapidly overgrow substrate as well as tolerate environmental extremes. In addition, X. umbellata has recently been proposed as a model system for tissue regeneration having the ability to regenerate completely from a single tentacle. These characteristics greatly amplify X. umbellata' s potential to adversely affect any reef it invades. Our findings necessitate continued collaborative action between local management agencies and stakeholders in Puerto Rico, as well as neighboring islands, to monitor and control this invasion prior to significant ecological perturbation.

Neural correlates of rapid familiarization to novel taste.

The gustatory cortex (GC) plays a pivotal role in taste perception, with neural ensemble responses reflecting taste quality and influencing behavior. Recent work, however, has shown that GC taste responses change across sessions of novel taste exposure in taste-naïve rats. Here, we use single-trial analyses to explore changes in the cortical taste-code on the scale of individual trials. Contrary to the traditional view of taste perception as innate, our findings suggest rapid, experience-dependent changes in GC responses during initial taste exposure trials. Specifically, we find that early responses to novel taste are less "stereotyped" and encode taste identity less reliably compared to later responses. These changes underscore the dynamic nature of sensory processing and provides novel insights into the real-time dynamics of sensory processing across novel-taste familiarization.

Effect of acute exposure to settleable atmospheric particulate matter emitted by the steel industry on hematology and innate immunity of fat snook (Centropomus parallelus).

The steel industry is a significant worldwide source of atmospheric particulate matter (PM). Part of PM may settle (SePM) and deposit metal/metalloid and metallic nanoparticles in aquatic ecosystems. However, such an air-to-water cross-contamination is not observed by most monitoring agencies. The region of Vitoria City is the main location of iron processing for exports in Brazil, and it has rivers, estuaries, and coastal areas affected by SePM. We have evaluated the effects of SePM on a local representative fish species, the fat snook, Centropomus parallelus. After acclimation, 48 fishes (61.67 ± 27.83 g) were individually exposed for 96 h to diverse levels of SePM (0.0, 0.01, 0.1 and 1 g/L-1). The presence of metals in the blood and several blood biomarkers were analyzed to evaluate the impact of SePM on stress signaling, blood oxygen transport capacity, and innate immune activity. Metal bioaccumulation was measured from blood in two separately analyzed compartments: intracellular (erythrocytes plus white blood cells) and extracellular (plasma). The major metals present at all contamination levels in both compartments were Fe and Zn, followed by Al and Cu, plus traces of 'Emerging metals': Ba, Ce, La, Rb, Se, Sr, and Ti. Emerging metals refer to those that have recently been identified in water as contaminants, encompassing rare earth elements and critical technology elements, as documented in previous studies (See REEs and TCEs in Cobelo-García et al., 2015; Batley et al., 2022). Multivariate analysis revealed that SePM had strong, dose-dependent correlations with all biomarker groups and indicated that blood oxygen-carrying capacity had the highest contamination responsiveness. Metal contamination also increased cortisol and blood glucose levels, attesting to increased stress signaling, and had a negative effect on innate immune activity. Knowledge of the risks related to SePM contamination remains rudimentary. However, the fact that there was metal bioaccumulation, causing impairment of fundamental physiological and cellular processes in this ecologically relevant fish species, consumed by the local human population, highlights the pressing need for further monitoring and eventual control of SePM contamination.

Faculty as Teachers: Career Development for the Clinician-Educator.

Clinician-Educators are the primary faculty in academic anesthesiology departments. These individuals assist with the departmental mission of clinical care and of education. Despite the critical role of the clinician-educator, academic advancement for these individuals has been difficult with the criteria for promotion continuing to evolve. The problem lies in the documentation of clinical and educational excellence in a means that a promotion committee may understand. Faculty development and advanced degrees in education have been helpful with the success of programs remaining unclear.

Phytochemical Modulation of Ion Channels in Oncologic Symptomatology and Treatment.

Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset of patients with an actionable mutation. They too come with side effects and, ultimately, 'self-resistance' to the treatment. There is recent interest in the modulation of ion channels, transmembrane proteins that regulate the flow of electrically charged molecules in and out of cells, as an approach to aid treatment of cancer. Phytochemicals have been shown to act on ion channels with high specificity regardless of the tumor's genetic profile. This paper explores the use of phytochemicals in cancer symptom management and treatment.

Reliability of beat-to-beat blood pressure variability in older adults.

Blood pressure variability (BPV) is emerging as an important risk factor across numerous disease states, including cerebrovascular and neurodegenerative disease in older adults. However, there is no current consensus regarding specific use cases for the numerous available BPV metrics. There is also little published data supporting the ability to reliably measure BPV across metrics in older adults. BPV metrics were derived from continuous beat-to-beat blood pressure monitoring data. Two sequential 7-minute waveforms were analyzed. Absolute and relative reliability testing was performed. Differences between antihypertensive medication users and non-users on BPV metric reliability was also assessed. All sequence and dispersion based BPV metrics displayed good test-retest reliability. A measure of BP instability displayed only moderate reliability. Systolic and diastolic average real variability displayed the highest levels of reliability at ICC= .87 and .82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. Beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained from older adults using noninvasive continuous blood pressure monitoring. Average real variability may be the most reliable and specific beat-to-beat blood pressure variability metric due to its decreased susceptibility to outliers and low frequency blood pressure oscillations.

COVID-19 Vaccines: Moderna And Pfizer-BioNTech Use Varied By Urban, Rural Counties.

We investigated county-level variation in mRNA COVID-19 vaccine use among Medicare beneficiaries throughout the United States. There was greater use of Pfizer-BioNTech vaccines than Moderna vaccines in urban areas for first and booster doses.