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Objective: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence. Method: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD (n = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: [greater than or equal to] 30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase. Results: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p = 0.65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = 0.27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < 0.0001). Conclusions: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time.

This study examined putative benefits of testing and production for learning new languages. Undergraduates (N = 156) were exposed to Turkish spoken dialogues under varying learning conditions (retrieval practice, comprehension, verbal repetition) in a computer-assisted language learning session. Participants completed pre- and posttests of number- and case-marking comprehension, a vocabulary test, and an explicit awareness questionnaire. Controlling for nonverbal ability and pretest scores, the retrieval-practice group performed highest overall. For number/case marking, the comprehension and retrieval-practice groups outperformed the verbal-repetition group, suggesting benefits of either recognition- or recall-based testing. For vocabulary, the verbal-repetition and retrieval-practice groups outperformed the comprehension group, indicating benefits of overt production. Case marking was easier to learn than number marking, suggesting advantages for learning word-final inflections. Explicit awareness correlated with comprehension accuracy, yet some participants demonstrated above-chance comprehension without showing awareness. Findings indicate the value of incorporating both practice tests and overt production in language pedagogy.

Canadian middle and high school students (N = 2,278) completed a "CTRL-F" curriculum teaching them how to evaluate online information by reading laterally to investigate sources, check claims, and trace information to original contexts. A subset of CTRL-F students (N = 316) were in classes with teacher-matched control groups (N = 287). Some CTRL-F students (N = 994) completed a delayed posttest. At pretest, students indicated preference for some lateral reading strategies, but preference rarely translated into use. Following instruction, CTRL-F students showed greater preference for and use of lateral reading than controls and greater alignment between preference and use. The curriculum's impact varied by demographic factors but not by differences in implementation. Gains were maintained from posttest to delayed posttest. Direct instruction and practice in lateral reading appear to strengthen connections between students' preferences and utilization of these strategies to evaluate online content relevant to academic and personal life.

Abstract Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer’s disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ 2 = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ 2 = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

Abstract Exposure to ionizing radiation for oncological therapy increases the risk for late-onset fractures in survivors. However, the effects of total body irradiation (TBI) on adult bone are not well-characterized. The primary aim of this study was to quantify the long-term effects of TBI on bone microstructure, material composition, and mechanical behavior in skeletally mature rhesus macaque (Macaca mulatta) non-human primates. Femora were obtained post-mortem from animals exposed to an acute dose of TBI (6.0–6.75 Gy) nearly a decade earlier, age-matched non-irradiated controls, and non-irradiated young animals. The microstructure of femoral trabecular and cortical bone was assessed via micro-computed tomography. Material composition was evaluated by measuring total fluorescent advanced glycation end products (fAGEs). Cortical bone mechanical behavior was quantified via four-point bending and cyclic reference point indentation (cRPI). Animals exposed to TBI had slightly worse cortical microstructure, including lower cortical thickness (-11%, p = 0.037) and cortical area (-24%, p = 0.049), but similar fAGE content and mechanical properties as age-matched controls. Aging did not influence cortical microstructure, fAGE content, or cRPI measures but diminished femoral cortical post-yield properties, including toughness to fracture (-32%, p = 0.032). Because TBI was administered after the acquisition of peak bone mass, these results suggest that the skeletons of long-term survivors of adulthood TBI may be resilient, retaining or recovering their mechanical integrity during the post-treatment period, despite radiation-induced architectural deficits. Further investigation is necessary to better understand radiation-induced skeletal fragility in mature and immature bone to improve care for radiation patients of all ages.

Abstract Recent advances in AI and intelligent vehicle technology hold the promise of revolutionizing mobility and transportation through advanced driver assistance systems (ADAS). Certain cognitive factors, such as impulsivity and inhibitory control have been shown to relate to risky driving behavior and on-road risk-taking. However, existing systems fail to leverage such factors in assistive driving technologies adequately. Varying the levels of these cognitive factors could influence the effectiveness and acceptance of ADAS interfaces. We demonstrate an approach for personalizing driver interaction via driver safety interfaces that are are triggered based on the inference of the driver’s latent cognitive states from their driving behavior. To accomplish this, we adopt a data-driven approach and train a recurrent neural network to infer impulsivity and inhibitory control from recent driving behavior. The network is trained on a population of human drivers to infer impulsivity and inhibitory control from recent driving behavior. Using data collected from a high-fidelity vehicle motion simulator experiment, we demonstrate the ability to deduce these factors from driver behavior. We then use these inferred factors to determine instantly whether or not to engage a driver safety interface. This approach was evaluated using leave-one-out cross validation using actual human data. Our evaluations reveal that our personalized driver safety interface that captures the cognitive profile of the driver is more effective in influencing driver behavior in yellow light zones by reducing their inclination to run through them.

Abstract BackgroundStrong information systems are essential for safe and effective immunization programs. The COVID-19 vaccine rollout presented all immunization information systems (IIS) with challenging demands—requiring in-depth vaccine implementation data at all health system levels in real time. The system development approaches taken by countries were heterogeneous, with some countries opting to adapt existing systems and others implementing new ones. ObjectiveUsing data reported by Member States to the World Health Organization (WHO), we aim to develop a global understanding of (1) the types of IIS used to monitor COVID-19 vaccination implemented in 2021 and (2) the approaches taken by countries to develop these systems. MethodsWe conducted a descriptive analysis of data reported through a supplemental questionnaire of the WHO/United Nations Children's Emergency Fund (UNICEF) Joint Reporting Form on Immunization, collecting data for 2021 on (1) the use of and developmental approaches taken for 7 IIS functions (appointments, aggregate reporting, individual-level reporting, reminders, home-based records, safety surveillance, and stock management), and (2) modifications needed for digital health frameworks to permit COVID-19 vaccination monitoring. ResultsIn total, 188 of 194 WHO Member States responded to the supplemental questionnaire, with 155 reporting on the IIS-related questions. Among those reporting, for each of the 7 IIS functions explored, greater than 85% of responding countries reported that the system was in place for COVID-19 vaccines. Among responding countries, “aggregate reporting system” was the system most frequently reported as being in place (n=116, 98.3%), while “reminder system” was the least (n=77, 89%). Among the countries reporting using a system, whether an existing system was adapted for COVID-19 vaccines or a new one was developed varied by system. Additionally, two-thirds (n=127, 67.6%) of countries reported establishing at least one new system, ranging from 72% (n=42) in high-income countries (HICs) to 62% (n=16) in low-income countries. Concurrently, 55.3% (n=104) of countries reported adapting at least one system already in place for COVID-19 vaccines, with 62% (n=36) of HICs reporting this compared to about 53% for other income groups. Of those reporting developing new systems, for each of the systems explored, more than 85% of countries reported that they intended to keep new systems specific to COVID-19 vaccines. Further, 147 of the 188 (78.2%) Member States responding to the supplemental questionnaire responded to the digital health frameworks question. Lastly, 31% (n=46) of responding countries reported needing to adapt them for COVID-19 vaccination systems. HICs had a higher percentage. ConclusionsNearly all countries have adapted existing or developed new IIS to monitor COVID-19 vaccination. The approaches varied, notably by income group. Reflection is needed on how to sustain the investments made in IIS during the pandemic. Continued support for IIS is critical, given their essential role in program monitoring and performance.

Background and Objectives: ABO and Rh blood types are known to have associations with health and disease, but studies on their relationship to pregnancy outcomes have been largely inconclusive. We aimed to examine the associations between ABO and Rh blood groups in pregnant women with maternal–neonatal characteristics and outcomes including hypertensive disorders of pregnancy, gestational diabetes, cesarean section rate, preterm birth, postpartum quantitative blood loss, birth weight, and appearance, pulse, grimace, activity, and respiration scores. Methods: At the time of delivery, 2497 consecutive patients were tested for ABO and Rh blood groups. Only those who delivered singleton infants were included in the analysis (2392 patients, 95.8%). Demographic and clinical data were obtained from the electronic medical record. Associations between blood groups and maternal–neonatal characteristics and outcomes were assessed using logistic regression models. A significance threshold of 0.05 was used for all comparisons. Results: Of the 2392 delivering patients, 46.9% were blood group O, 37.5% were blood group A, 12.2% were blood group B, and 3.4% were blood group AB. In addition, 85.9% were Rh-positive and 14.1% Rh-negative. A total of 2127 (88.9%) women delivered at term. The cesarean section rate was 32.4%, 183 (7.7%) had chronic hypertension, 275 (11.5%) had gestational diabetes, and 396 (16.6%) had a postpartum hemorrhage. The median birth weight was 3330 g (interquartile range 2940–3640). No blood groups were significantly associated with these characteristic and outcome measures. Conclusion: At the time of delivery, no significant associations were identified between ABO and Rh blood groups and maternal–neonatal characteristics and outcomes in this delivery cohort of over 2000 women.

Background: Postpartum hemorrhage (PPH) remains a significant cause of maternal morbidity and mortality around the world, with rates increasing in the United States. The objective of this study was to determine predictors of, and outcomes associated with, PPH at a Midwest academic health center. Methods: Demographic and clinical data were obtained from the electronic medical record on all consecutive delivering patients between May 1, 2020, and April 30, 2021. Associations between PPH and perinatal characteristics and outcomes were assessed using logistic regression models. A significance threshold of 0.05 was used for all comparisons. Results: Of the 2497 delivering patients during the study period, 437 (18%) experienced PPH. Chronic hypertension, gestational hypertension, and preeclampsia with and without severe features were all associated with increased odds of PPH (odds rations [ORs], respectively, 1.61 (95% CI:1.13?2.24, p = 0.006), 1.62 (95% CI 1.18?2.21, p = 0.003), 1.81 (95% CI 1.14?2.80, p ? 0.001), and 1.92 (95% CI 1.29?2.82, p = 0.009). There were also increased odds of PPH with type I diabetes: 2.83 (95% CI 1.45?5.30, p = 0.001), type II diabetes: 2.14 (95% CI 1.15?3.82, p = 0.012), twin delivery: 3.20 (95% CI 2.11?4.81, p ? 0.001), cesarean delivery: 5.66 (95% CI 4.53?7.09, p ? 0.001), and assisted vaginal delivery: 3.12 (95% CI1.95?4.88, p ? 0.001). Infants of mothers with PPH had high odds of NICU admission (CI = 1.34?2.07, p < 0.001) and hypoxic ischemic encephalopathy (CI = 1.64?7.14, p < 0.001). Conclusion: Our findings confirm previous literature that preexisting and pregnancy-related hypertension, diabetes mellitus, multiple gestation, cesarean delivery, and assisted vaginal delivery are important predictors of PPH. In addition, we found that neonates of mothers with PPH had more adverse outcomes. These results may help to inform clinical care as rates of PPH continue to rise in the United States.

Abstract Warming can have profound impacts on ecological communities. However, explorations of how differences in biogeography and productivity might reshape the effect of warming have been limited to theoretical or proxy-based approaches: for instance, studies of latitudinal temperature gradients are often conflated with other drivers (e.g., species richness). Here, we overcome these limitations by using local geothermal temperature gradients across multiple high-latitude stream ecosystems. Each suite of streams (6-11 warmed by 1-15°C above ambient) is set within one of five regions (37 streams total); because the heating comes from the bedrock and is not confounded by changes in chemistry, we can isolate the effect of temperature. We found a negative overall relationship between diatom and invertebrate species richness and temperature, but the strength of the relationship varied regionally, declining more strongly in regions with low terrestrial productivity. Total invertebrate biomass increased with temperature in all regions. The latter pattern combined with the former suggests that the increased biomass of tolerant species might compensate for the loss of sensitive species. Our results show that the impact of warming can be dependent on regional conditions, demonstrating that local variation should be included in future climate projections rather than simply assuming universal relationships.

Background: The incidence of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer (UBC) has continued to increase, despite an absent survival benefit except in populations at highest risk for developing contralateral breast cancer (CBC). CPM rates may be higher in rural populations but causes remain unclear. A study performed at our institution previously found that 21.8 % of patients with UBC underwent CPM from 2000 to 2009. This study aimed to evaluate the CPM trend at a single institution serving a rural population and identify the CPM rate in average-risk patients. Methods: Retrospective review of patients who underwent mastectomies for UBC at our institution from 2017 to 2021 was performed. Analysis utilized frequencies and percentages, descriptive statistics, chi-square, and independent sample t-tests. Results: A total of 438 patients were included, of whom 64.4 % underwent bilateral mastectomy for UBC (CPM). Patients who underwent CPM were significantly younger, underwent genetic testing, had germline pathogenic variants, had a family history of breast cancer, had smaller tumors, underwent reconstruction, and had more wound infections. Of CPM patients, 50.4 % had no identifiable factors for increased risk of developing CBC. Conclusions: The rate of CPM in a rural population at a single institution increased from 21.8 % to 64.4 % over two decades, with an average-risk CPM rate of 50.4 %. Those that undergo CPM are more likely to undergo reconstruction and have more wound infections. Identifying characteristics of patients undergoing CPM in a rural population and the increased associated risks allows for a better understanding of this trend to guide conversations with patients. Key message: This study demonstrates that the rate of contralateral prophylactic mastectomy for unilateral breast cancers performed at a single institution serving a largely rural population has nearly tripled over the last two decades, with half of these patients having no factors that increase the risk for developing contralateral breast cancers. Contralateral prophylactic mastectomy was significantly associated with smaller tumors, younger age, genetic testing, germline pathogenic variants, family history of breast cancer, breast reconstruction, and increased wound infections.

ObjectiveTo analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication.DesignRetrospective case-control study.SubjectsPatients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea.MethodsTargeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features.Main outcome measuresPresence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence.ResultsHotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized.ConclusionsIn this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.

Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-β accumulation causing full-blown AD phenotype by the age of 8 months. Micro-computed tomography indicated significantly lower trabecular and cortical bone parameters in 8-month-old male, but not female, 5xFAD mice than sex-matched wild-type littermates. Dynamic histomorphometry revealed reduced bone formation and increased bone resorption, and quantitative RT-PCR showed elevated skeletal RANKL gene expression in 5xFAD males. These mice also had diminished body fat percentage with unaltered lean mass, as determined by dual-energy X-ray absorptiometry (DXA), and elevated Ucp1 mRNA levels in brown adipose tissue, consistent with increased sympathetic tone, which may contribute to the osteopenia observed in 5xFAD males. Nevertheless, no significant changes could be detected between male 5xFAD and wild-type littermates regarding the serum and skeletal concentrations of norepinephrine. Thus, brain-specific amyloid-β pathology is associated with osteopenia and appears to affect both bone formation and bone resorption. Our findings shed new light on the pathophysiologic link between Alzheimer's disease and osteoporosis.

Abstract The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.

Abstract Anomalous peak abundances of platinum and Fe-rich microspherules with high-temperature minerals have previously been demonstrated to be a chronostratigraphic marker for the lower Younger Dryas Boundary (YDB) dating to 12.8 ka. This study used Bayesian analyses to test this hypothesis in multiple sequences (units) of sandy, weakly stratified sediments at Wakulla Springs, Florida. Our investigations included platinum geochemistry, granulometry, optically stimulated luminescence (OSL) dating, and culturally dated lithics. In addition, sediments were analyzed using scanning electron microscopy and energy dispersive x-ray spectroscopy to investigate dendritic, iron-rich microspherules previously identified elsewhere in peak abundances at the onset of the Younger Dryas (YD) cool climatic episode. Our work has revealed this abundance peak in platinum and dendritic spherules in five sediment sequences at Wakulla Springs. A YDB age of ~ 12.8 ka for the platinum and spherule chronostratigraphic datum in these Wakulla Springs sequences is consistent with the archaeological data and OSL dating. This study confirms the utility of this YDB datum layer for intersequence correlation and for assessing relative ages of Paleoamerican artifacts, including those of likely Clovis, pre-Clovis, and post-Clovis age and their possible responses to environmental changes known to have occurred during the Younger Dryas cool climatic episode.

IntroductionLiquid-solvent direct air capture (DAC) is a prominent approach for carbon dioxide removal but knowing where to site these systems is challenging because it requires considering a multitude of interrelated geospatial factors. Two of the most pressing factors are: (1) how should DAC be powered to provide the greatest net removal of CO2 and (2) how does weather impact its performance?.MethodsTo investigate these questions, this study develops a process-level model of a liquid-solvent DAC system and couples it to a 20-year dataset of temperature and humidity conditions at a ~9km resolution across the contiguous US.Results and discussionWe find that the amount of CO2 sequestered could be 30% to 50% greater than the amount of CO2 removed from the atmosphere if natural gas is burned on site to power DAC, but that the optimal way to power DAC is independent of capture rate (i.e., weather), depending solely on the upstream GHG intensity of electricity and natural gas. Regardless of how it is powered, air temperature and humidity conditions can change the performance of DAC by up to ~3x and can also vary substantially across weather years. Across the continuous US, we find that southern states (e.g., Gulf Coast) are preferrable locations for a variety of reasons, including higher and less variable air temperature and relative humidity. Lastly, we also find the performance of liquid-solvent DAC calculated with monthly means is within 2% of the estimated performance calculated with hourly data for more than a third of the country, including in the states with weather most favorable for liquid-solvent DAC.

A risk assessment on the aquatic toxicity of the plant biostimulant strigolactone mimic (2-(4-methyl-5-oxo-2,5-dihydro-furan-2-yloxy)-benzo[de]isoquinoline-1,3-dione (SL-6) was performed using a suite of standardised bioassays representing different trophic groups and acute and chronic endpoints. In freshwater, three trophic groups of algae, crustacea and fish were used. Whilst in seawater, algae (unicellular and macroalgae), Crustacea and Mollusca were employed. In addition, the genotoxicity of SL-6 was determined with the comet assessment performed on unicellular marine algae, oysters, and fish embryos. This was the first time ecotoxicity tests have been performed on SL-6. In freshwater, the lowest LOEC was measured in the unicellular algae at 0.31 mg/L SL-6. Although, similar LOEC values were found for embryo malformations and impacts on hatching rate in zebrafish (LOEC 0.31–0.33 mg/L). Consistent malformations of pericardial and yolk sac oedemas were identified in the zebrafish embryos at 0.31 mg/L. In marine species, the lowest LOEC was found for both Tisbe battagliai mortality and microalgae growth at an SL-6 concentration of 1.0 mg/L. Significant genotoxicity was observed above control levels at 0.0031 mg/L SL-6 in the unicellular algae and 0.001 mg/L SL-6 in the oyster and zebrafish larvae. When applying the simple risk assessment, based on the lowest NOECs and appropriate assessment factors, the calculated predicted no effect concentration (PNEC), for the ecotoxicity and the genotoxicity tests were 1.0 µg/L and 0.01 µg/L respectively.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Abstract Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to lack research and monitoring capacity, preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for >2000 coral reefs, we estimate site-specific sustainable reference points for coral reef fisheries and use these and available catch estimates to assess the status of global coral reef fish stocks. We reveal that >50% of sites and jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world’s coral reef fisheries.

Females historically experience sleep disturbances and overall poor sleep compared to males. Creatine has been proposed to impact sleep; however, the effects are not well known. The purpose of this study was to examine the effects of creatine supplementation on sleep among naturally menstruating females. Twenty-one participants completed a double-blind, randomized controlled trial in which they consumed 5 g creatine + 5 g maltodextrin or placebo, 10 g maltodextrin, daily for 6 weeks. Participants completed resistance training 2x/week using the TONAL® (Tonal Systems Inc., San Francisco, CA, USA) at-home gym. Pre- and post-testing assessed body composition, Pittsburgh Sleep Quality Index (PSQI), dietary intake, and muscular strength. Sleep was assessed nightly using an ŌURA® (Oulu, Finland) ring. Compared to the placebo group, those consuming creatine experienced significant increases in total sleep on training days (p = 0.013). No significant changes in chronic sleep and PSQI (pre–post) were observed. There was a significant increase in TONAL® strength score over time (p < 0.001), with no between-group differences. Participants reduced their total calorie (kcal) (p = 0.039), protein (g/kg) (p = 0.009), carbohydrate (g/kg) (p = 0.023), and fat (g) (p = 0.036) intake over time. Creatine supplementation increases sleep duration on resistance training days in naturally menstruating females.

Aims: The aims of the study were to report for a cohort aged younger than 40 years: 1) indications for HRA; 2) patient-reported outcomes in terms of the modified Harris Hip Score (HHS); 3) dislocation rate; and 4) revision rate. Methods: This retrospective analysis identified 267 hips from 224 patients who underwent an hip resurfacing arthroplasty (HRA) from a single fellowship-trained surgeon using the direct lateral approach between 2007 and 2019. Inclusion criteria was minimum two-year follow-up, and age younger than 40 years. Patients were followed using a prospectively maintained institutional database. Results: A total of 217 hips (81%) were included for follow-up analysis at a mean of 3.8 years. Of the 23 females who underwent HRA, none were revised, and the median head size was 46 mm (compared to 50 mm for males). The most common indication for HRA was femoroacetabular impingement syndrome (n = 133), and avascular necrosis ( (n = 53). Mean postoperative HHS was 100 at two and five years. No dislocations occurred. A total of four hips (1.8%) required reoperation for resection of heterotopic ossification, removal of components for infection, and subsidence with loosening. The overall revision rate was 0.9%. Conclusion: For younger patients with higher functional expectations and increased lifetime risk for revision, HRA is an excellent bone preserving intervention carrying low complication rates, revision rates, and excellent patient outcomes without lifetime restrictions allowing these patients to return to activity and sport. Thus, in younger male patients with end-stage hip disease and higher demands, referral to a high-volume HRA surgeon should be considered. Cite this article: Bone Jt Open 2023;4(6):408–415.

Abstract Previous immunological studies in the eastern USA have failed to establish a direct connection between Paleoamericans and extinct megafauna species. The lack of physical evidence for the presence of extinct megafauna begs the question, did early Paleoamericans regularly hunt or scavenge these animals, or were some megafauna already extinct? In this study of 120 Paleoamerican stone tools from across North and South Carolina, we investigate this question using crossover immunoelectrophoresis (CIEP). We find immunological support for the exploitation of extant and extinct megafauna, including Proboscidea, Equidae, and Bovidae (possibly Bison antiquus), on Clovis points and scrapers, as well as possible early Paleoamerican Haw River points. Post-Clovis points tested positive for Equidae and Bovidae but not Proboscidea. Microwear results are consistent with projectile usage, butchery, fresh- and dry hide scraping, the use of ochre-coated dry hides for hafting, and dry hide sheath wear. This study represents the first direct evidence of the exploitation of extinct megafauna by Clovis and other Paleoamerican cultures in the Carolinas and more broadly, across the eastern United States, where there is generally poor to non-existent faunal preservation. Future CIEP analysis of stone tools may provide evidence on the timing and demography of megafaunal collapse leading to eventual extinction.

Protein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most cellular physiological processes and their regulations. As for all intracellular proteins, PKs are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PK localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein–protein and protein–lipid interactions, as well as liquid–liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular quantal unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the composition and mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.

Collegiate dance is unique because it requires athletic and academic performance; therefore, optimizing physical and mental function is crucial. Research among athletic populations demonstrate improvements in body composition, performance, and cognition following creatine monohydrate (CR) supplementation, yet dancers have not been investigated. The purpose of this study was to determine the effects of CR supplementation on body composition, performance, and cognitive function in female collegiate dancers. Participants were randomized to CR (CR; n = 7; 0.1 g·kg −1·day −1 CM +0.1 g·kg −1·day −1 corn-starch maltodextrin) or placebo (PL; n = 6; 0.2 g·kg −1·day −1 corn-starch maltodextrin) for 42 days. Pre- and post-testing included body composition, total body water (TBW), Depression, Anxiety and Stress Scale, Diet History Questionnaire, the National Institute of Health Toolbox fluid cognition battery and isokinetic strength, vertical jump, medicine ball throw, and Wingate anaerobic power test. CR demonstrated a significant increase in TBW (pre, 32.2 ± 3.5 kg; post, 32.7 ± 3.6 kg; p = 0.024) and lean mass (LM; pre, 39.8 ± 3.6 kg; post, 41.5 ± 4.5 kg; p = 0.020). CR supplementation may be an effective strategy to increase TBW and estimates of LM in female collegiate dancers. Although this may optimize aesthetics, larger samples sizes with resistance training are needed to determine if CR supplementation increases muscle mass and translates to improved performance.

Objective: Epstein-Barr virus (EBV) is the cause of infectious mononucleosis, which disproportionately affects university students. This population has the potential to benefit from a prophylactic EBV vaccine trial. Our objectives were to determine EBV infection status and associated demographic/lifestyle factors among first year undergraduate university students at the beginning and end of first year. Methods EBV infection status was assessed by testing for circulating IgG class antibodies against EBV viral capsid antigen. Results Of 198 starting students; 56.1% were positive for EBV antibodies with a higher rate in women (64.8%) than male (41.1%); p = 0.002. A history of deep kissing was associated with a higher rate of EBV antibody positivity. On follow-up 8 months later at the end of freshman year, 22.4% had acquired EBV antibodies for a primary infection incidence of 33.6/100 person years. Conclusion These findings indicate that our first year undergraduate population contains sufficient EBV-naïve subjects for a prophylactic vaccine trial.

The human papillomavirus is the most common sexually transmitted infection in the world. Most HPV infections clear spontaneously within 2 years of infection; however, persistent infection can result in a wide array of diseases, ranging from genital warts to cancer. Most cases of cervical, anal, and oropharyngeal cancers are due to HPV infection, with cervical cancer being one of the leading causes of cancer death in women worldwide. Screening is available for HPV and cervical cancer, but is not available everywhere, particularly in lower-resource settings. HPV infection disproportionally affects individuals living with HIV, resulting in decreased clearance, increased development of cancer, and increased mortality. The development of the HPV vaccine has shown a drastic decrease in HPV-related diseases. The vaccine prevents cervical cancer with near 100% efficacy, if given prior to first sexual activity. Vaccination uptake remains low worldwide due to a lack of access and limited knowledge of HPV. Increasing awareness of HPV and access to vaccination are necessary to decrease cancer and HPV-related morbidity and mortality worldwide.

Traumatic brain injury (TBI) is one of the leading causes of death and disability. TBI is associated with neuroinflammation, but temporal changes in immune and inflammatory signaling following TBI have not been fully elucidated. Furthermore, there have been no previous studies on changes in immune cell populations following TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). The current study aimed to determine the time course changes to inflammatory marker mRNA expression in the acute period following TBI in juvenile rats and to determine acute changes to brain and circulating immune cell populations. For this study, post-natal day (PND)-30 male Long Evans rats sustained a TBI or Sham TBI and were euthanized at 0, 3, 6, 12, 24, or 96 h post-injury. Prefrontal cortex and hippocampus samples were used to determine mRNA expression changes of inflammatory factors. The mRNA expression of the pro-inflammatory cytokine TNF-α was significantly elevated at 6 h post-injury in both regions evaluated. To evaluate immune cell populations, male Long Evans rats were euthanized at 48 h post-injury, and brain and blood samples were used for cell sorting by marker-specific antibodies. In the peripheral blood, there was an elevation in CD3+ total T cells, CD45R+ total B cells, and CD3+CD4+ helper T cells in the TBI subjects. However, there were no changes to natural killer cells or CD3+CD8+ cytotoxic T cell populations. In the brain, there was a reduction in CD11b/c+ monocytes/macrophages, but no changes in other immune cell populations. At 48 h post-injury, the TBI subjects also demonstrated expansion of the thymic medulla. These changes in the cerebral and blood immune cell populations and thymic medulla expansion may implicate the subacute recovery timeframe as a vulnerable window for the immune system in the pediatric population.

Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may differ. Little is known about their differential effects on osteocytes. We compared cortical osteocyte and skeletal responses to ABL and TPTD in sham-operated and ovariectomized mice. Administered 7 weeks after ovariectomy for 4 weeks at a dose of 40 μg/kg/d, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. In cortical osteocytes, both treatments decreased lacunar area, reflecting altered peri-lacunar remodeling favoring matrix accumulation. Osteocyte RNA-Seq revealed that several genes and pathways were altered by ovariectomy and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were uniquely regulated by ABL. Thus, in mice, TPTD and ABL induced a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected the osteocyte transcriptome differently. We concluded that ABL affected the cortical osteocyte transcriptome in a manner subtly different from TPTD, resulting in more beneficial remodeling/modeling changes and homeostasis of the cortex.

Abstract Natural history collections are invaluable resources for understanding biotic response to global change. Museums around the world are currently imaging specimens, capturing specimen data and making them freely available online. In parallel to the digitisation effort, there have been great advancements in computer vision: the computer trained automated recognition/detection, and measurement of features in digital images. Applying computer vision to digitised natural history collections has the potential to greatly accelerate the use of these collections for biotic response to global change research. In this paper, we apply computer vision to a very large, digitised collection to test hypotheses in an established area of biotic response to climate change research: temperature‐size responses. We develop a computer vision pipeline (Mothra) and apply it to the NHM collection of British butterflies (>180,000 imaged specimens). Mothra automatically detects the specimen and other objects in the image, sets the scale, measures wing features (e.g. forewing length), determines the orientation of the specimen (pinned ventrally or dorsally) and identifies the sex. We pair these measurements and specimen collection data with temperature records for 17,726 specimens across a subset of 24 species to test how adult size varies with temperature during the immature stages of species. We also assess patterns of sexual size dimorphism across species and families for 32 species trained for automated sex ID. Mothra accurately measures the forewing lengths of butterfly specimens compared to manual measurements and accurately determines the sex of specimens, with females as the larger sex in most species. An increase in adult body size with warmer monthly temperatures during the late larval stages is the most common temperature‐size response. These results confirm suspected patterns and support hypotheses based on recent studies using a smaller dataset of manually measured specimens. We show that computer vision can be a powerful tool to efficiently and accurately extract phenotypic data from a very large collection of digital natural history collections. In the future, computer vision will become widely applied to digital collections to advance ecological and evolutionary research and to accelerate their use to investigate biotic response to global change.

Abstract Human‐mediated salinity increases are occurring in freshwaters globally, with consequent negative effects on freshwater biodiversity. Salinity comprises multiple anions and cations. While total concentrations are typically used to infer effects, individual ion concentrations and ion ratios are critical in determining effects. Moreover, estimates of toxicity from single‐species laboratory tests, may not accurately predict relative effects on populations and communities. Here, we compared salinity increases from synthetic marine salts and sodium bicarbonate in an outdoor mesocosm experiment in southeastern Australia. We found different effects of salt types on stream macroinvertebrates at the population and community levels, where similar effects were predicted from single‐species laboratory tests. Our results caution against the use of single‐species laboratory‐derived toxicological data to predict both environmentally safe salinity levels and the relative effects of different salt sources on freshwater biodiversity.

Lipid peroxidation plays an important role in cell signaling and disease as well as therapy, however, the effect on the membrane structure and mechanical behavior remains poorly understood. Here, the authors report the direct and quantitative measurement of the bilayer’s structure and viscoelastic properties upon peroxidation of lipid membranes.

Abstract Background Subconcussive blast exposure during military training has been the subject of both anecdotal concerns and reports in the medical literature, but prior studies have often been small and have used inconsistent methods. Methods This paper presents the methodology employed in INVestigating traIning assoCiated blasT pAthology (INVICTA) to assess a wide range of aspects of brain function, including immediate and delayed recall, gait and balance, audiologic and oculomotor function, cerebral blood flow, brain electrical activity and neuroimaging and blood biomarkers. Results A number of the methods employed in INVICTA are relatively easy to reproducibly utilize, and can be completed efficiently, while other measures require greater technical expertise, take longer to complete, or may have logistical challenges. Conclusions This presentation of methods used to assess the impact of blast exposure on the brain is intended to facilitate greater uniformity of data collection in this setting, which would enable comparison between different types of blast exposure and environmental circumstances, as well as to facilitate meta-analyses and syntheses across studies.

Natural resource management agencies in the United States have a legal responsibility to represent Indigenous Peoples and federally recognized Tribes in environmental stewardship. This comment article is a call to action that argues for genuine representation of Tribes and other Indigenous Peoples through adherence to existing, formal consultation policies and coproduction of knowledge. Agencies must recognize and respect the differences between public involvement and government-to-government consultation with federally-recognized Tribes. Sovereign tribal nations are not the public and have a unique relationship with federal agencies based in the federal trust responsibility. Coproduction of knowledge is an emerging enterprise that has potential for meaningfully engaging and genuinely and equitably representing Indigenous Peoples and Tribes and should be codeveloped and implemented as policy. Agencies should build capacity to properly represent tribal nations in decisions. Agency employees and Indigenous Peoples must spend more time together to increase cultural awareness and build meaningful relationships to facilitate genuine consultation and coproduction of knowledge.

Abstract Parental religious beliefs and practices (religiosity) may have profound effects on youth, especially in neurodevelopmentally complex periods such as adolescence. In n = 5566 children (median age = 120.0 months; 52.1% females; 71.2% with religious affiliation) from the Adolescent Brain Cognitive Development study, relationships between parental religiosity and non-religious beliefs on family values (data on youth beliefs were not available), topological properties of youth resting-state brain networks, and executive function, inhibitory control, and cognitive flexibility were investigated. Lower caregiver education and family income were associated with stronger parental beliefs (p

BackgroundIt has been reported that hepatitis B virus (HBV) double mutations (A1762T, G1764A) are an aetiological factor of hepatocellular carcinoma (HCC). However, it is unclear who is prone to develop HCC, among those infected with the mutant. Exploring HBV quasispecies, which are strongly influenced by host immune pressure, may provide more information about the association of viral factors and HCC.Materials and methodsNine HCC cases and 10 controls were selected from the Long An cohort. Serum samples were collected in 2004 and 2019 from subjects with HBV double mutations and the complete genome of HBV was amplified and sequenced using next-generation sequencing (NGS).ResultsThe Shannon entropy values increased from 2004 to 2019 in most cases and controls. There was no significant difference in mean intrahost quasispecies genetic distances between cases and controls. The change in the values of mean intrahost quasispecies genetic distances of the controls between 2004 and 2019 was significantly higher than that of the cases (P

Summary: In daylight, demand for visual chromophore (11-cis-retinal) exceeds supply by the classical visual cycle. This shortfall is compensated, in part, by the retinal G-protein-coupled receptor (RGR) photoisomerase, which is expressed in both the retinal pigment epithelium (RPE) and in Müller cells. The relative contributions of these two cellular pools of RGR to the maintenance of photoreceptor light responses are not known. Here, we use a cell-specific gene reactivation approach to elucidate the kinetics of RGR-mediated recovery of photoreceptor responses following light exposure. Electroretinographic measurements in mice with RGR expression limited to either cell type reveal that the RPE and a specialized subset of Müller glia contribute both to scotopic and photopic function. We demonstrate that 11-cis-retinal formed through photoisomerization is rapidly hydrolyzed, consistent with its role in a rapid visual pigment regeneration process. Our study shows that RGR provides a pan-retinal sink for all-trans-retinal released under sustained light conditions and supports rapid chromophore regeneration through the photic visual cycle.

Objective: A novel transdermal arterial gasotransmitter sensor (TAGS) has been tested as a diagnostic tool for lower limb microvascular disease in individuals with and without diabetes mellitus (DM). Methods: The TAGS system noninvasively measures hydrogen sulfide (H2S) emitted from the skin. Measurements were made on the forearm and lower limbs of individuals from three cohorts, including subjects with DM and chronic limb-threatening ischemia, to evaluate skin microvascular integrity. These measurements were compared with diagnosis of peripheral artery disease (PAD) using the standard approach of the toe brachial index. Other measures of vascular health were made in some subjects including fasting blood glucose, hemoglobin A1c, plasma lipids, blood pressure, estimated glomerular filtration, and body mass index. Results: The leg:arm ratio of H2S emissions correlated with risk factors for microvascular disease (ie, high-density lipoprotein levels, estimated glomerular filtration rate, systolic blood pressure, and hemoglobin A1c). The ratios were significantly lower in symptomatic DM subjects being treated for chronic limb-threatening ischemia (n = 8, 0.48 ± 0.21) compared with healthy controls (n = 5, 1.08 ± 0.30; P = .0001) and with asymptomatic DM subjects (n = 4, 0.79 ± 0.08; P = .0086). The asymptomatic DM group ratios were also significantly lower than the healthy controls (P = .0194). Using ratios of leg:arm transdermal H2S measurement (17 subjects, 34 ratios), the overall accuracy to identify limbs with severe PAD had an area under the curve of the receiver operating curve of 0.93. Conclusions: Ratios of transdermal H2S measurements are lower in legs with impaired microvascular function, and the decrease in ratio precedes clinically apparent severe microvascular disease and diabetic ulcers. The TAGS instrument is a novel, sensitive tool that may aid in the early detection and monitoring of PAD complications and efforts for limb salvage.

The DIII-D tokamak has elucidated crucial physics and developed projectable solutions for ITER and fusion power plants in the key areas of core performance, boundary heat and particle transport, and integrated scenario operation, with closing the core-edge integration knowledge gap being the overarching mission. New experimental validation of high-fidelity, multi-channel, non-linear gyrokinetic turbulent transport models for ITER provides strong confidence it will achieve Q ⩾ 10 operation. Experiments identify options for easing H-mode access in hydrogen, and give new insight into the isotopic dependence of transport and confinement. Analysis of 2,1 islands in unoptimized low-torque IBS demonstration discharges suggests their onset time occurs randomly in the constant β phase, most often triggered by non-linear 3-wave coupling, thus identifying an NTM seeding mechanism to avoid. Pure deuterium SPI for disruption mitigation is shown to provide favorable slow cooling, but poor core assimilation, suggesting paths for improved SPI on ITER. At the boundary, measured neutral density and ionization source fluxes are strongly poloidally asymmetric, implying a 2D treatment is needed to model pedestal fuelling. Detailed measurements of pedestal and SOL quantities and impurity charge state radiation in detached divertors has validated edge fluid modelling and new self-consistent ‘pedestal-to-divertor’ integrated modeling that can be used to optimize reactors. New feedback adaptive ELM control minimizes confinement reduction, and RMP ELM suppression with sustained high core performance was obtained for the first time with the outer strike point in a W-coated, compact and unpumped small-angle slot divertor. Advances have been made in integrated operational scenarios for ITER and power plants. Wide pedestal intrinsically ELM-free QH-modes are produced with more reactor-relevant conditions, Low torque IBS with W-equivalent radiators can exhibit predator-prey oscillations in T _e and radiation which need control. High- β _P scenarios with q _min > 2, q _95 –7.9, β _N > 4, β _T –3.3% and H _98y2 > 1.5 are sustained with high density ( $\bar n$ = 7E19 m ^−3 , f _G –1) for 6 τ _E , improving confidence in steady-state tokamak reactors. Diverted NT plasmas achieve high core performance with a non-ELMing edge, offering a possible highly attractive core-edge integration solution for reactors.

The third Gravitational-Wave Transient Catalog (GWTC-3) describes signals detected with Advanced LIGO and Advanced Virgo up to the end of their third observing run. Updating the previous GWTC-2.1, we present candidate gravitational waves from compact binary coalescences during the second half of the third observing run (O3b) between 1 November 2019, 15∶00 Coordinated Universal Time (UTC) and 27 March 2020, 17∶00 UTC. There are 35 compact binary coalescence candidates identified by at least one of our search algorithms with a probability of astrophysical origin p_{astro}>0.5. Of these, 18 were previously reported as low-latency public alerts, and 17 are reported here for the first time. Based upon estimates for the component masses, our O3b candidates with p_{astro}>0.5 are consistent with gravitational-wave signals from binary black holes or neutron-star–black-hole binaries, and we identify none from binary neutron stars. However, from the gravitational-wave data alone, we are not able to measure matter effects that distinguish whether the binary components are neutron stars or black holes. The range of inferred component masses is similar to that found with previous catalogs, but the O3b candidates include the first confident observations of neutron-star–black-hole binaries. Including the 35 candidates from O3b in addition to those from GWTC-2.1, GWTC-3 contains 90 candidates found by our analysis with p_{astro}>0.5 across the first three observing runs. These observations of compact binary coalescences present an unprecedented view of the properties of black holes and neutron stars.

Abstract Atherosclerotic plaque rupture is the etiology of ischemic stroke and myocardial infarction. The molecular mechanisms responsible for rupture remain unclear, in part, due to the lack of data from plaques at the time of rupture. Ribosome-depleted total RNA was sequenced from carotid plaques obtained from patients undergoing carotid endarterectomy with high-grade stenosis and either (1) a carotid-related ischemic cerebrovascular event within the previous 5 days ('recently ruptured,' n = 6) or (2) an absence of a cerebrovascular event ('asymptomatic,' n = 5). Principal component analysis confirmed plaque rupture was responsible for the greatest percentage of the variability between samples (23.2%), and recently ruptured plaques were enriched for transcripts associated with inflammation and extracellular matrix degradation. Hierarchical clustering achieved differentiation of the asymptomatic from the recently ruptured plaques. This analysis also found co-expression of transcripts for immunoglobulins and B lymphocyte function, matrix metalloproteinases, and interferon response genes. Examination of the differentially expressed genes supported the importance of inflammation and inhibition of proliferation and migration coupled with an increase in apoptosis. Thus, the transcriptome of recently ruptured plaques is enriched with transcripts associated with inflammation and fibrous cap thinning and support further examination of the role of B lymphocytes and interferons in atherosclerotic plaque rupture.

Abstract We conducted a pilot trial of an intervention targeting intersectional stigma related to being pregnant and living with HIV while promoting capabilities for achieving ‘respected motherhood’ (‘what matters most’) in Botswana. A pragmatic design allocated participants to the intervention (N = 44) group and the treatment-as-usual (N = 15) group. An intent-to-treat, difference-in-difference analysis found the intervention group had significant decreases in HIV stigma (d = − 1.20; 95% CI − 1.99, − 0.39) and depressive symptoms (d = − 1.96; 95% CI − 2.89, − 1.02) from baseline to 4-months postpartum. Some, albeit less pronounced, changes in intersectional stigma were observed, suggesting the importance of structural-level intervention components to reduce intersectional stigma.

Abstract Determine the prevalence of pelvic floor disorders (PFD) stratified by age, race, body mass index (BMI), and parity in adult women attending family medicine and general internal medicine clinics at an academic health system. The medical records of 25,425 adult women attending primary care clinics were queried using International Classification of Diseases-10th Revision codes (ICD-10 codes) for PFD [urinary incontinence (UI), pelvic organ prolapse (POP), and bowel dysfunction (anal incontinence (AI) and difficult defecation)]. Prevalence and odds ratios were calculated using univariate and multivariate analysis for age, race, BMI, and parity when available. Multivariate logistic regression models were used to assess the impact of age, race, BMI, and parity on the likelihood of being diagnosed with a PFD. A separate model was constructed for each of the three PFD categories (UI, POP, and bowel dysfunction) as well as a model assessing the likelihood of occurrence for any type of PFD. The percentage of women with at least one PFD was 32.0% with bowel dysfunction the most common (24.6%), followed by UI (11.1%) and POP (4.4%). 5.5% had exactly two PFD and 1.1% had all 3 categories of PFD. Older age and higher BMI were strongly and significantly associated with each of the three PFD categories, except for BMI and prolapse. Relative to White patients, Asian patients were at significantly lower risk for each category of PFD, while Black patients were at significantly lower risk for UI and POP, but at significantly greater risk for bowel dysfunction and the presence of any PFD. Higher parity was also significantly associated with pelvic organ prolapse. Using multivariate analyses, age, race, and BMI were all independently associated with PFD. PFD are highly prevalent in the primary care setting and should be screened for, especially in older and obese women. BMI may represent a modifiable risk factor.

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor–inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease–mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

Summary: Growth hormone (GH) acts via JAK2 and LYN to regulate growth, metabolism, and neural function. However, the relationship between these tyrosine kinases remains enigmatic. Through an interdisciplinary approach combining cell biology, structural biology, computation, and single-particle tracking on live cells, we find overlapping LYN and JAK2 Box1-Box2-binding regions in GH receptor (GHR). Our data implicate direct competition between JAK2 and LYN for GHR binding and imply divergent signaling profiles. We show that GHR exhibits distinct mobility states within the cell membrane and that activation of LYN by GH mediates GHR immobilization, thereby initiating its nanoclustering in the membrane. Importantly, we observe that LYN mediates cytokine receptor degradation, thereby controlling receptor turnover and activity, and this applies to related cytokine receptors. Our study offers insight into the molecular interactions of LYN with GHR and highlights important functions for LYN in regulating GHR nanoclustering, signaling, and degradation, traits broadly relevant to many cytokine receptors.