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Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through calcium (Ca2+) signalling1-7. Astrocyte Ca2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales-from fast, subcellular activity3,4 to slow, synchronized activity across connected astrocyte networks8-10-to influence many processes5,7,11. However, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon astrocyte imaging while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca2+ responses beyond an individual stimulated cell. Further, we find that a key subset of Ca2+ activity-propagative activity-differentiates astrocyte network responses to these two main neurotransmitters, and may influence responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over a minutes-long time course, contributing to accumulating evidence that substantial astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales12-14. These findings will enable future studies to investigate the link between specific astrocyte Ca2+ activity and specific functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.

Intertemporal choices - decisions that play out over time - pervade our life. Thus, how people make intertemporal choices is a fundamental question. Here, we investigate the role of attribute latency (the time between when people start to process different attributes) in shaping intertemporal preferences using five experiments with choices between smaller-sooner and larger-later rewards. In the first experiment, we identify attribute latencies using mouse-trajectories and find that they predict individual differences in choices, response times, and changes across time constraints. In the other four experiments we test the causal link from attribute latencies to choice, staggering the display of the attributes. This changes attribute latencies and intertemporal preferences. Displaying the amount information first makes people more patient, while displaying time information first does the opposite. These findings highlight the importance of intra-choice dynamics in shaping intertemporal choices and suggest that manipulating attribute latency may be a useful technique for nudging.

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.

During the COVID-19 pandemic, wastewater surveillance of the SARS CoV-2 virus has been demonstrated to be effective for population surveillance at the county level down to the building level. At the University of California, San Diego, daily high-resolution wastewater surveillance conducted at the building level is being used to identify potential undiagnosed infections and trigger notification of residents and responsive testing, but the optimal determinants for notifications are unknown. To fill this gap, we propose a pipeline for data processing and identifying features of a series of wastewater test results that can predict the presence of COVID-19 in residences associated with the test sites. Using time series of wastewater results and individual testing results during periods of routine asymptomatic testing among UCSD students from 11/2020 to 11/2021, we develop hierarchical classification/decision tree models to select the most informative wastewater features (patterns of results) which predict individual infections. We find that the best predictor of positive individual level tests in residence buildings is whether or not the wastewater samples were positive in at least 3 of the past 7 days. We also demonstrate that the tree models outperform a wide range of other statistical and machine models in predicting the individual COVID-19 infections while preserving interpretability. Results of this study have been used to refine campus-wide guidelines and email notification systems to alert residents of potential infections.

Molecular clock models undergird modern methods of divergence-time estimation. Local clock models propose that the rate of molecular evolution is constant within phylogenetic subtrees. Current local clock inference procedures exhibit one or more weaknesses, namely they achieve limited scalability to trees with large numbers of taxa, impose model misspecification, or require a priori knowledge of the existence and location of clocks. To overcome these challenges, we present an autocorrelated, Bayesian model of heritable clock rate evolution that leverages heavy-tailed priors with mean zero to shrink increments of change between branch-specific clocks. We further develop an efficient Hamiltonian Monte Carlo sampler that exploits closed form gradient computations to scale our model to large trees. Inference under our shrinkage clock exhibits a speed-up compared to the popular random local clock when estimating branch-specific clock rates on a variety of simulated datasets. This speed-up increases with the size of the problem. We further show our shrinkage clock recovers known local clocks within a rodent and mammalian phylogeny. Finally, in a problem that once appeared computationally impractical, we investigate the heritable clock structure of various surface glycoproteins of influenza A virus in the absence of prior knowledge about clock placement. We implement our shrinkage clock and make it publicly available in the BEAST software package.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

The majority of people with HIV live in sub-Saharan Africa, where epidemics are generalized. For these epidemics to develop, populations need to be mobile. However, the role of population-level mobility in the development of generalized HIV epidemics has not been studied. Here we do so by studying historical migration data from Botswana, which has one of the most severe generalized HIV epidemics worldwide; HIV prevalence was 21% in 2021. The country reported its first AIDS case in 1985 when it began to rapidly urbanize. We hypothesize that, during the development of Botswanas epidemic, the population was extremely mobile and the country was highly connected by substantial migratory flows. We test this mobility hypothesis by conducting a network analysis using a historical time series (1981-2011) of micro-census data from Botswana. Our results support our hypothesis. We found complex migration networks with very high rates of rural-to-urban, and urban-to-rural, migration: 10% of the population moved annually. Mining towns (where AIDS cases were first reported, and risk behavior was high) were important in-flow and out-flow migration hubs, suggesting that they functioned as core groups for HIV transmission and dissemination. Migration networks could have dispersed HIV throughout Botswana and generated the current hyperendemic epidemic.

Carotid endarterectomy (CEA) is the gold-standard method of carotid revascularization in symptomatic patients with ≥50% and in asymptomatic patients with ≥70% stenosis. Transfemoral carotid artery stenting (TFCAS) has been associated with higher perioperative stroke rates compared to CEA in several studies. On the other hand, transcarotid artery revascularization (TCAR) has outperformed TFCAS in patients who are considered high risk for surgery. There is increasing data that supports TCAR as a safe and efficient technique with outcomes similar to those of CEA, but additional level-one studies are necessary to evaluate the long-term outcomes of TCAR in high- and standard-risk patients.

Protracted global conflicts during the past decade have led to repeated major humanitarian protection crises in Europe. During the height of the Syrian refugee crisis at the end of 2015, Europe hosted around 2.3 million people requesting asylum1. Today, the ongoing war in Ukraine has resulted in one of the largest humanitarian emergencies in Europe since World War II, with more than eight million Ukrainians seeking refuge across Europe2. Here we explore whether repeated humanitarian crises threaten to exhaust solidarity and whether Europeans welcome Ukrainian asylum seekers over other asylum seekers3,4. We conducted repeat conjoint experiments during the 2015-2016 and 2022 refugee crises, asking 33,000 citizens in 15 European countries to evaluate randomly varied profiles of asylum seekers. We find that public preferences for asylum seekers with specific attributes have remained remarkably stable and general support has, if anything, increased slightly over time. Ukrainian asylum seekers were welcomed in 2022, with their demographic, religious and displacement profile having a larger role than their nationality. Yet, this welcome did not come at the expense of support for other marginalized refugee groups, such as Muslim refugees. These findings have implications for our theoretical understanding of the drivers and resilience of public attitudes towards refugees and for policymakers tasked to find effective responses to the enduring stress on the asylum system5-8.

BackgroundHostile proximal aortic neck anatomy has been associated with an increased risk of perioperative mortality after endovascular aneurysm repair (EVAR). However, all available mortality risk prediction models after EVAR lack neck anatomic associations. The aim of this study is to develop a preoperative prediction model for perioperative mortality after EVAR incorporating important anatomic factors.MethodsData were obtained from the Vascular Quality Initiative database on all patients who underwent elective EVAR between January 2015 and December 2018. A stepwise multivariable logistic regression analysis was implemented to identify independent predictors and develop a risk calculator for perioperative mortality after EVAR. Internal validation was done using bootstrap of 1,000 reps.ResultsA total of 25,133 patients were included, of whom 1.1% (N = 271) died within 30 days or before discharge. Significant preoperative predictors of perioperative mortality were age (odds ratio [OR], 1.053; 95% confidence interval [CI], 1.050-1.056; P < 0.001), female sex (OR, 1.46; 95% CI, 1.38-1.54; P < 0.001), chronic kidney disease (OR, 1.65; 95% CI, 1.57-1.73; P < 0.001), chronic obstructive pulmonary disease (OR, 1.86; 95% CI, 1.77-1.94; P < 0.001), congestive heart failure (OR, 2.02; 95% CI, 1.91-2.13, P < 0.001), aneurysm diameter ≥ 6.5 cm (OR, 2.35; 95% CI, 2.24-2.47, P < 0.001), proximal neck length < 10 mm (OR, 1.96; 95% CI, 1.81-2.12; P < 0.001), proximal neck diameter ≥ 30 mm (OR, 1.41; 95% CI, 1.32-1.5; P < 0.001), infrarenal neck angulation ≥ 60° (OR, 1.27; 95% CI, 1.18-1.26; P < 0.001), and suprarenal neck angulation ≥ 60° (OR, 1.26; 95% CI, 1.16-1.37; P < 0.001). Significant protective factors included aspirin use (OR, 0.89; 95% CI, 0.85-0.93; P < 0.001) and statin intake (OR, 0.77; 95% CI, 0.73-0.81; P < 0.001). These predictors were incorporated to build an interactive risk calculator of perioperative mortality after EVAR (C-statistic = 0.749).ConclusionsThis study provides a prediction model for mortality following EVAR that incorporates aortic neck features. The risk calculator can be used to weigh risk/benefit ratio when counseling patients preoperatively. Prospective use of this risk calculator may show its benefit in long-term prediction of adverse outcomes.

BackgroundStudies generally show that higher acculturation is associated with greater cardiovascular disease (CVD) risk among immigrants in the United States (US). However, few studies have compared how proxies of acculturation are differentially associated with metabolic abnormalities measured using objective biomarkers, self-reported diagnosis, and medication use, particularly among East Asian Americans.MethodsSurvey data and biomarker measurements collected from random (non-fasting) blood samples of Chinese and Korean immigrants in the US (n = 328) were used to examine the associations between two proxies for acculturation (years living in the US and English speaking proficiency) with three cardiometabolic abnormalities (high triglyceride levels, diabetes, and hypercholesterolemia). Poisson regression models estimated prevalence ratios adjusted for demographic characteristics, socioeconomic factors, and body mass index. Gender, Asian subgroup, and household income were tested as potential effect modifiers.ResultsLiving longer in the US was associated with greater likelihood of having high triglycerides. In addition, living longer in the US was associated with greater likelihood of diabetes for people with lower household income and greater likelihood of hypercholesterolemia for people with higher household income. Higher level of English proficiency was less consistently associated with higher cardiometabolic risk, although there was a significant association with greater likelihood of hypercholesterolemia.ConclusionsLonger time lived in the US is associated with higher risk of cardiometabolic abnormalities among Chinese and Korean Americans. Future studies of acculturation and cardiometabolic risk should carefully consider potential mechanisms and what proxy measures of acculturation capture.Trial registration numberNCT03481296, date of registration: 3/29/2018.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

BackgroundWhile Transfemoral Carotid Artery Stenting (TFCAS) is a valid minimally invasive option for patients who also might be suitable for carotid endarterectomy (CEA) or transcarotid artery revascularization (TCAR), alternative access sites such as transbrachial (TB) or transradial (TR) are only utilized when anatomic factors preclude direct carotid or transfemoral access. In this study, we aimed to evaluate the outcomes of TR/TB access in comparison to TF for percutaneous carotid artery revascularization.MethodsAll patients undergoing non-TCAR carotid artery stenting (CAS) from January 2012 to June 2021 in the Vascular Quality Initiative (VQI) Database were included. Patients were divided into 2 groups based on the access site for CAS: TF or TR/TB. Primary outcomes included stroke/death, technical failure and access site complications (hematoma, stenosis, infection, pseudoaneurysm and AV fistula). Secondary outcomes included stroke, TIA, MI, death, non-home discharge, extended length of postoperative stay (LOS) (>1 day), and composite endpoints of stroke/MI and stroke/death/MI. Univariable and multivariable logistic regression models were used to assess postoperative outcomes, and results were adjusted for relevant potential confounders including age, gender, race, degree of stenosis, symptomatic status, anesthesia, comorbidities, and preoperative medications.ResultsOut of the 23,965 patients, TR/TB approach was employed in 819 (3.4%) while TF was used in 23,146 (96.6%). Baseline characteristics found men were more likely to undergo revascularization using TR/TB approach (69.4% vs. 64.9%, P = 0.009). Patients undergoing TR/TB approach were also more likely to be symptomatic (49.9% vs. 28.6%, P

BackgroundType II endoleaks (ELII) are the most common complication following endovascular aneurysm repair (EVAR). Persistent ELII require continual surveillance and have been shown to increase the risk of Type I and III endoleaks, sac growth, need for intervention, conversion to open or even rupture, directly or indirectly. These are often difficult to treat following EVAR, and there are limited data regarding the effectiveness of prophylactic treatment of ELII. The aim of this study is to report the midterm outcomes of prophylactic perigraft arterial sac embolization (pPASE) performed in patients undergoing EVAR.MethodsThis is a comparison of 2 elective cohorts of those undergoing EVAR using the Ovation stent graft with and without prophylactic branch vessel and sac embolization. Patients who underwent pPASE at our institution had their data collected in a prospective, institutional review board-approved database. These were compared against the core lab-adjudicated data from the Ovation Investigational Device Exemption trial. Prophylactic PASE was performed at the time of EVAR with thrombin, contrast, and Gelfoam if the lumbar or mesenteric arteries were patent. Endpoints included freedom from ELII, reintervention, sac growth, all-cause mortality, and aneurysm-related mortality.ResultsThirty-six patients (13.1%) underwent pPASE, while 238 patients (86.9%) had standard EVAR. Median follow-up was 56 months (33-60 months). The 4-year freedom from ELII estimates were 84% for the pPASE versus 50.7% for the standard EVAR group (P = 0.0002). All aneurysms in the pPASE group remained stable in size or demonstrated regression, whereas aneurysm sac expansion was seen in 10.9% of the standard EVAR group, P = 0.03. At 4 years, mean AAA diameter decreased by 11 mm (95% CI 8-15) in the pPASE group versus 5 mm (95% CI 4-6) for the standard EVAR group, P = 0.0005. There were no differences in the 4-year freedom from all-cause mortality and aneurysm-related mortality. However, the difference in reintervention for ELII trended toward significance (0.0% vs. 10.7%, P = 0.1). On multivariable analysis, pPASE was associated with a 76% reduction in ELII [(95% CI): 0.24 (0.08-0.65), P = 0.005].ConclusionsThese results suggest that pPASE in those undergoing EVAR is safe and effective in the prevention of ELII and significantly improves sac regression over standard EVAR while minimizing the need for reintervention.

The scientific community improvised to respond quickly to the SARS-CoV-2 pandemic without a template on how to work together on a global scale to understand and combat the virus. Here, we describe how we tackled impediments to success and the valuable lessons learned that prepare us for a future pandemic.

Under certain conditions, the retrieval of some information can increase the recall of other information, a phenomenon known as retrieval-induced facilitation. Chan (Journal of Memory and Language 61:153-170, 2009) proposed two moderating factors to account for why retrieval causes facilitation in some situations and forgetting in others: (1) integration at the time of encoding and (2) the delay between retrieval practice and final test. Chan found a 9-11% facilitation effect when the materials were well integrated and the final test occurred after a 24-h delay. Two sets of experiments sought to replicate and extend Chan's study by examining retrieval-induced facilitation not only following a 24-h delay but after longer delays (i.e., 1 or 2 weeks). A meta-analysis including these replications and the original experiments was also conducted. The results provide additional evidence of retrieval-induced facilitation, with no evidence that the effect varies as a function of the final delay. However, the size of the effect was found to be somewhat smaller than previously observed.

Background and Aim: This study investigates temporal trends in gastrointestinal cancer‐related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race. Methods: We investigated the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999–2020) for gastrointestinal cancer‐related mortality with a focus on the underlying cause of death. Results: A total of 3 115 243 gastrointestinal cancer‐related deaths occurred from 1999 to 2020. The overall age‐adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was −0.9% (95% CI: −1.0%, −0.9%, P < 0.001), with no significant difference in AAPC between the sexes but some difference between races and related to individual cancers. African Americans and Asian Americans, and Pacific Islanders experienced a greater decrease in mortality compared with Whites. Mortality rates for American Indian and Alaskan Native populations also decreased significantly from 1999 to 2020 (P < 0.001). There were significant declines in esophageal, stomach, colon, rectal, and gallbladder cancer‐related mortality but increases in the small bowel, anal, pancreatic, and hepatic cancer‐related mortality (P < 0.001), with variation across different sexes and racial groups. Conclusion: While overall gastrointestinal cancer‐related mortality declined significantly in the United States from 1999 to 2020, mortality from some cancers increased. Furthermore, differences between sexes and racial groups underscore crucial differences in gastrointestinal cancer mortality, highlighting areas for future research. [ABSTRACT FROM AUTHOR]

Background Transfusion services aim to maintain sufficient blood inventory to support patients, even with challenges introduced by COVID-19. Objectives To review blood usage and wastage before, during, and after COVID-19 surges, and to evaluate effects on inventory. Methods In a retrospective review, we evaluated the association between time periods corresponding to the initial wave of COVID-19 (pre–COVID-19, quarantine, and postquarantine) and blood usage/wastage. Data were stratified by period, and χ 2 testing was used to examine the association between these time periods and blood usage/wastage. Results In the period before COVID-19, the transfusion service used more units, and in the period after quarantine, more units went to waste. Across all time periods, the most-used product was RBCs, and the most wasted product was plasma. A statistically significant association existed between usage (χ 2 [6/3209 (0.2%)]) = 24.534; P ≤.001; Cramer V = 0.62), wastage (χ 2 [6/775 (0.8%)]) = 21.673; P =.001; Cramer V = 0.118), and time period. The postquarantine period displayed the highest wastage costs ($51,032.35), compared with the pre–COVID-19 period ($29,734.45). Conclusion Changes in blood inventory use and waste are significantly associated with the onset and continuation of COVID-19. [ABSTRACT FROM AUTHOR]

Objectives: Aim of this study was to assess the influence of restorative treatment timing on the periodontal, patient and operator-reported outcomes following crown lengthening surgery (CLS). Materials and methods: Eighteen study participants requiring CLS were divided into two groups based on prosthetic rehabilitation timing (6 or 14 weeks postoperatively). Clinical parameters were recorded around treated and neighboring teeth before and after surgery, 6 and 14 weeks postoperatively, at prosthesis delivery, and three and six months after. Soft tissue and radiographic bone changes were evaluated. Patients assessed their perception of the procedure by means of a questionnaire. The final treatment outcome was rated by both patients and prosthodontists. Results: CLS resulted in statistically significant and stable apical displacement of the gingival margin, at both treated and adjacent sites. Plaque and bleeding scores remained low throughout. No statistically significant differences were observed between groups for any clinical or radiographic parameter examined. Healing was uneventful and treatment outcome was satisfying for both patients and prosthodontists, without statistically significant differences between groups. Conclusions: The present study has been characterized as pilot, because it was not possible to reach the sample size indicated by the a priori power analysis. CLS is an effective pre-prosthetic procedure as long as it is performed under a certain surgical protocol which predicts for at least a 3 mm distance between bone crest and the flap margin at suturing. Within the limitations of this study, six weeks after surgery may be an adequate healing time for the onset of prosthetic restoration. Clinical relevance: Crown lengthening surgery is commonly performed in daily clinical practice with the aim to restore teeth with short clinical crowns. Based on periodontal, patient and operator-reported criteria, 6 weeks after CLS may be adequate healing time before the onset of prosthetic restoration. Trial registration: ClinicalTrials.gov Identifier: NCT03947658, 13/05/2019, retrospectively registered. [ABSTRACT FROM AUTHOR]

Objective: To analyze the temporal trend of tuberculosis cure indicators in Brazil. Methods: An ecological time-series study using administrative data of reported cases of the disease nationwide between 2001 and 2022. We estimated cure indicators for each federative unit (FU) considering individuals with pulmonary tuberculosis, tuberculosis-HIV coinfection, and those in tuberculosis retreatment. We used regression models using joinpoint regression for trend analysis, reporting the annual percentage change and the average annual percentage change. Results: For the three groups analyzed, we observed heterogeneity in the annual percentage change in the Brazilian FUs, with a predominance of significantly decreasing trends in the cure indicator in most FUs, especially at the end of the time series. When considering national indicators, an average annual percentage change of -0.97% (95% CI: -1.23 to -0.74) was identified for the cure of people with pulmonary tuberculosis, of -1.11% (95% CI: -1.42 to -0.85) for the cure of people with tuberculosis-HIV coinfection, and of -1.44% (95% CI: -1.62 to -1.31) for the cure of people in tuberculosis retreatment. Conclusions: The decreasing trends of cure indicators in Brazil are concerning and underscore a warning to public authorities, as it points to the possible occurrence of other treatment outcomes, such as treatment discontinuity and death. This finding contradicts current public health care policies and requires urgent strategies aiming to promote follow-up of patients during tuberculosis treatment in Brazil. [ABSTRACT FROM AUTHOR]

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated African population history in which present-day population structure dates back to Marine Isotope Stage 5. The earliest population divergence among contemporary populations occurred 120,000 to 135,000 years ago and was preceded by links between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years. Such weakly structured stem models explain patterns of polymorphism that had previously been attributed to contributions from archaic hominins in Africa2-7. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be genetically and morphologically similar, and that only an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains the variation in previous estimates of divergence times, and argue that studying a range of models is key to making robust inferences about deep history.

The hippocampus is a mammalian brain structure that expresses spatial representations1 and is crucial for navigation2,3. Navigation, in turn, intricately depends on locomotion; however, current accounts suggest a dissociation between hippocampal spatial representations and the details of locomotor processes. Specifically, the hippocampus is thought to represent mainly higher-order cognitive and locomotor variables such as position, speed and direction of movement4-7, whereas the limb movements that propel the animal can be computed and represented primarily in subcortical circuits, including the spinal cord, brainstem and cerebellum8-11. Whether hippocampal representations are actually decoupled from the detailed structure of locomotor processes remains unknown. To address this question, here we simultaneously monitored hippocampal spatial representations and ongoing limb movements underlying locomotion at fast timescales. We found that the forelimb stepping cycle in freely behaving rats is rhythmic and peaks at around 8 Hz during movement, matching the approximately 8 Hz modulation of hippocampal activity and spatial representations during locomotion12. We also discovered precisely timed coordination between the time at which the forelimbs touch the ground ('plant' times of the stepping cycle) and the hippocampal representation of space. Notably, plant times coincide with hippocampal representations that are closest to the actual position of the nose of the rat, whereas between these plant times, the hippocampal representation progresses towards possible future locations. This synchronization was specifically detectable when rats approached spatial decisions. Together, our results reveal a profound and dynamic coordination on a timescale of tens of milliseconds between central cognitive representations and peripheral motor processes. This coordination engages and disengages rapidly in association with cognitive demands and is well suited to support rapid information exchange between cognitive and sensory-motor circuits.

The Hawaiian Islands have been identified as a global biodiversity hotspot. We examine the Normalized Difference Vegetation Index (NDVI) using Climate Data Records products (0.05 × 0.05°) to identify significant differences in NDVI between neutral El Niño-Southern Oscillation years (1984, 2019) and significant long-term changes over the entire time series (1982-2019) for the Hawaiian Islands and six land cover classes. Overall, there has been a significant decline in NDVI (i.e., browning) across the Hawaiian Islands from 1982 to 2019 with the islands of Lānai and Hawaii experiencing the greatest decreases in NDVI (≥44%). All land cover classes significantly decreased in NDVI for most months, especially during the wet season month of March. Native vegetation cover across all islands also experienced significant declines in NDVI, with the leeward, southwestern side of the island of Hawaii experiencing the greatest declines. The long-term trends in the annual total precipitation and annual mean Palmer Drought Severity Index (PDSI) for 1982-2019 on the Hawaiian Islands show significant concurrent declines. Primarily positive correlations between the native ecosystem NDVI and precipitation imply that significant decreases in precipitation may exacerbate the decrease in NDVI of native ecosystems. NDVI-PDSI correlations were primarily negative on the windward side of the islands and positive on the leeward sides, suggesting a higher sensitivity to drought for leeward native ecosystems. Multi-decadal time series and spatially explicit data for native landscapes provide natural resource managers with long-term trends and monthly changes associated with vegetation health and stability.

PurposeBrace treatment is the most common nonoperative treatment to prevent curve progression in adolescent idiopathic scoliosis (AIS). The goal of this review and analysis is to characterize curve behavior after completion of brace treatment and to identify factors that may facilitate the estimation of long-term curve progression.MethodA review of the English language literature was completed using the MEDLINE (PUBMED) database of publications after 1990 until September 2020. Studies were included if they detailed a minimum of 1 year post-brace removal follow-up of AIS patients. Data retrieved from the articles included Cobb angle measurements of the major curves at "in-brace," weaning, and follow-up visit(s) for all patients described and for subset populations.ResultsFrom 75 articles, 18 relevant studies describing a follow-up period of 1-25 years following brace removal were included in the analyses. The reviewed literature demonstrates that curves continue to progress after brace treatment is completed with three main phases of progression: (i) immediate (upon brace removal) where a mean curve progression of 7° occurs; (ii) short term (within five years of brace removal) where a relatively high progression rate is evident (0.8°/year); and (iii) long term (more than five years after brace removal) where the progression rate slows (0.2°/year). The magnitude and rate of curve progression is mainly dependent on the degree of curve at weaning as curves weaned at

We assessed the effects of removing some constraints that characterise traditional experiments on the effects of spaced, rather than massed, study opportunities. In five experiments-using lists of to-be-remembered words-we examined the effects of how total study time was distributed across multiple repetitions of a given to-be-remembered word. Overall, within a given list, recall profited from study time being distributed (e.g., four 1-s presentations or two 2-s presentations vs one 4-s presentation). Among the implications of these findings is that if students choose to engage in massed studying (by virtue of constraints on their study time or a failure to appreciate the benefits of spaced study sessions), then studying the information twice but for half the time may produce memory benefits in a single study session.

Funding sourceMedicines360. The Sponsor, Medicines360, designed the study and oversaw its conduct, including funding the trial and providing all study product free of charge to participants.Clinical trial registrationClinicalTrials.gov, NCT00995150.

The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral genome-wide phylogenomic signals using concatenation and coalescent-based approaches, interrogated phylogenetic variation across chromosomes, and analyzed extensive catalogs of structural variants. Interordinal relationships exhibit relatively low rates of phylogenomic conflict across diverse datasets and analytical methods. Conversely, X-chromosome versus autosome conflicts characterize multiple independent clades that radiated during the Cenozoic. Genomic time trees reveal an accumulation of cladogenic events before and immediately after the Cretaceous-Paleogene (K-Pg) boundary, implying important roles for Cretaceous continental vicariance and the K-Pg extinction in the placental radiation.

Sleep is a crucial part of the daily activity patterns of mammals. However, in marine species that spend months or entire lifetimes at sea, the location, timing, and duration of sleep may be constrained. To understand how marine mammals satisfy their daily sleep requirements while at sea, we monitored electroencephalographic activity in wild northern elephant seals (Mirounga angustirostris) diving in Monterey Bay, California. Brain-wave patterns showed that seals took short (less than 20 minutes) naps while diving (maximum depth 377 meters; 104 sleeping dives). Linking these patterns to accelerometry and the time-depth profiles of 334 free-ranging seals (514,406 sleeping dives) revealed a North Pacific sleepscape in which seals averaged only 2 hours of sleep per day for 7 months, rivaling the record for the least sleep among all mammals, which is currently held by the African elephant (about 2 hours per day).

The soluble epoxide hydrolase (sEH) is possibly both a marker for and target of numerous diseases. Herein, we describe a homogeneous mix-and-read assay for the detection of human sEH based on using split-luciferase detection coupled with anti-sEH nanobodies. Selective anti-sEH nanobodies were individually fused with NanoLuc Binary Technology (NanoBiT), which consists of a large and small portion of NanoLuc (LgBiT and SmBiT, respectively). Different orientations of the LgBiT and SmBiT-nanobody fusions were expressed and investigated for their ability to reform the active NanoLuc in the presence of the sEH. After optimization, the linear range of the assay could reach 3 orders of magnitude with a limit of detection (LOD) of 1.4 ng/mL. The assay has a high sensitivity to human sEH and reached a similar detection limit to our previously reported conventional nanobody-based ELISA. The procedure of the assay was faster (30 min total) and easy to operate, providing a more flexible and simple way to monitor human sEH levels in biological samples. In general, the immunoassay proposed here offers a more efficient detection and quantification approach that can be easily adapted to numerous macromolecules.

IntroductionPhysical activity before COVID-19 infection is associated with less severe outcomes. The study determined whether a dose‒response association was observed and whether the associations were consistent across demographic subgroups and chronic conditions.MethodsA retrospective cohort study of Kaiser Permanente Southern California adult patients who had a positive COVID-19 diagnosis between January 1, 2020 and May 31, 2021 was created. The exposure was the median of at least 3 physical activity self-reports before diagnosis. Patients were categorized as follows: always inactive, all assessments at 10 minutes/week or less; mostly inactive, median of 0-60 minutes per week; some activity, median of 60-150 minutes per week; consistently active, median>150 minutes per week; and always active, all assessments>150 minutes per week. Outcomes were hospitalization, deterioration event, or death 90 days after a COVID-19 diagnosis. Data were analyzed in 2022.ResultsOf 194,191 adults with COVID-19 infection, 6.3% were hospitalized, 3.1% experienced a deterioration event, and 2.8% died within 90 days. Dose‒response effects were strong; for example, patients in the some activity category had higher odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), deterioration (OR=1.83; 95% CI=1.49, 2.25), and death (OR=1.92; 95% CI=1.48, 2.49) than those in the always active category. Results were generally consistent across sex, race and ethnicity, age, and BMI categories and for patients with cardiovascular disease or hypertension.ConclusionsThere were protective associations of physical activity for adverse COVID-19 outcomes across demographic and clinical characteristics. Public health leaders should add physical activity to pandemic control strategies.

Background and objectivesTelemedicine bridges the gap between care needs and provider availability. The value of telemedicine can be eclipsed by long wait times, especially if patients are stuck in virtual waiting rooms. UCSD Tele-Untethered allows patients to join visits without waiting in virtual waiting rooms. Tele-Untethered uses a text-to-video link to improve clinic flow, decrease virtual waiting room reliance, improve throughput, and potentially improve satisfaction.MethodsThis institutional review board (IRB)-approved quality improvement pilot (IRB #210364QI) included patients seen in a single vascular neurology clinic, within the pilot period, if they had a smartphone/cell phone, and agreed to participate in a flexible approach to telehealth visits. Standard work was disseminated (patient instructions, scripting, and workflows). Patients provided a cell phone number to receive a text link when the provider was ready to see them. Metrics included demographics, volumes, visit rates, percentage seen early/late, time savings, and satisfaction surveys.ResultsOver 2.5 months, 22 patients were scheduled. Of those arriving, 76% were "Tele-Untethered" and 24% were "Standard Telemedicine." Text-for-video link was used for 94% of Tele-Untethered. Fifty-five percent were seen early. There was a 55-minute-per-session time savings.ConclusionThis UCSD Tele-Untethered pilot benefitted patients by allowing scheduling flexibility while not being tied to a "virtual waiting room." It benefited providers as it allowed them to see patients in order/not tied to exact times, improved throughput, and saved time. Even modest time savings for busy providers, coupled with Lean workflows, can provide critical value. High Tele-Untethered uptake and use of verbal check-in highlight that patients expect flexibility and ease of use. As our initial UCSD Tele-Untethered successes included patient flexibility and time savings for patients and providers, it can serve as a model as enterprises strive for optimal care and improved satisfaction. Expansion to other clinic settings is underway with a mantra of "UCSD Tele-Untethered: Your provider can see you now."

Calcium imaging with protein-based indicators1,2 is widely used to follow neural activity in intact nervous systems, but current protein sensors report neural activity at timescales much slower than electrical signalling and are limited by trade-offs between sensitivity and kinetics. Here we used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators3-8. The resulting 'jGCaMP8' sensors, based on the calcium-binding protein calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (half-rise times of 2 ms) and the highest sensitivity for neural activity reported for a protein-based calcium sensor. jGCaMP8 sensors will allow tracking of large populations of neurons on timescales relevant to neural computation.

Forecasting the response of ecological systems to environmental change is a critical challenge for sustainable management. The metabolic theory of ecology (MTE) posits scaling of biological rates with temperature, but it has had limited application to population dynamic forecasting. Here we use the temperature dependence of the MTE to constrain empirical dynamic modeling (EDM), an equation-free nonlinear machine learning approach for forecasting. By rescaling time with temperature and modeling dynamics on a metabolic time step, our method (MTE-EDM) improved forecast accuracy in 18 of 19 empirical ectotherm time series (by 19% on average), with the largest gains in more seasonal environments. MTE-EDM assumes that temperature affects only the rate, rather than the form, of population dynamics, and that interacting species have approximately similar temperature dependence. A review of laboratory studies suggests these assumptions are reasonable, at least approximately, though not for all ecological systems. Our approach highlights how to combine modern data-driven forecasting techniques with ecological theory and mechanistic understanding to predict the response of complex ecosystems to temperature variability and trends.

BackgroundCerebrospinal fluid (CSF) is highly labile and delayed processing might alter results of analysis.Hypothesis/objectivesTo determine the effects of time and addition of autologous serum on cytological evaluation of CSF.AnimalsTen client-owned adult horses requiring euthanasia.MethodsProspective study. Serum and CSF were collected from each horse before and within 10 minutes after euthanasia. CSF samples were divided into 15 aliquots (2 mL each); 1 aliquot was submitted for routine CSF analysis within 60 minutes of collection. Four drops of autologous serum were added to 7 of the aliquots, and stored at 4°C (serum group); the remaining 7 samples were stored unaltered at 4°C (control group). Total nucleated cell count (TNCC) and cell morphology score were done at T4, T8, T12, T24, T48, T72, and T96 hours after collection. Protein concentration was measured in the control group at T0 and T96 hours.ResultsThe cell morphology scores were significantly different in the control group at T48 (median 2, range 0-4), T72 (2, 0-4), and T96 (3, 0-4) in comparison to T0 (1). No change was observed in the serum group. TNCC remained stable over time in both groups. No statistically significant difference in CSF protein concentration was found between T0 and T96.Conclusions and clinical importanceThe addition of autologous serum to an aliquot of CSF sample before shipping improves the preservation of cell morphology up to 96 hours after collection.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Osteoarthritis is a common chronic degenerative disease that causes pain and disability with increasing incidence worldwide. The osteochondral junction is a dynamic region of the joint that is associated with the early development and progression of osteoarthritis. Despite the substantial advances achieved in the imaging of cartilage and application to osteoarthritis in recent years, the osteochondral junction has received limited attention. This is primarily related to technical limitations encountered with conventional MR sequences that are relatively insensitive to short T2 tissues and the rapid signal decay that characterizes these tissues. MR sequences with ultrashort echo time (UTE) are of great interest because they can provide images of high resolution and contrast in this region. Here, we briefly review the anatomy and function of cartilage, focusing on the osteochondral junction. We also review basic concepts and recent applications of UTE MR sequences focusing on the osteochondral junction.

ObjectivesLow-income, first-time mothers generally breastfeed exclusively and, overall, for a shorter average duration than high-income, multiparous mothers. A potential barrier to breastfeeding success is access to a breast pump for home use. In this pilot study, we estimated the effect of providing a manual breast pump during birth hospitalization for home use on any/exclusive breastfeeding and investigated participant attitudes about manual pumps and their breastfeeding experiences.MethodsSixty low-income, first-time mothers were enrolled in a pilot randomized controlled trial. One-half received a manual breast pump and the other half received an attention control. Breastfeeding exclusivity, duration, and use of the manual pump were assessed at 6 and 12 weeks. Qualitative interviews regarding the breastfeeding experience were completed. Thirty-one women answered 13 questions that were then transcribed, coded, and grouped into themes.ResultsParticipants who were randomized to manual breast pump receipt during birth hospitalization had increased manual pump use at 6 weeks (13/19 [68%] versus controls 5/17 [29%]), there was no effect of pump receipt on any nor exclusive breastfeeding at 12 weeks. In qualitative analysis of the overall breastfeeding experience, participants expressed a need for additional support and had conflicting attitudes regarding breastfeeding and the pumping experience.ConclusionsManual breast pump receipt in hospital among low-income, first-time mothers did not affect breastfeeding exclusivity or duration. Participants reported that early and ongoing lactation support is essential. Strategies to improve breastfeeding outcomes low-income, first-time mothers are needed.

Although learning is often viewed as a unique feature of organisms with complex nervous systems, single-celled organisms also demonstrate basic forms of learning. The giant ciliate Stentor coeruleus responds to mechanical stimuli by contracting into a compact shape, presumably as a defense mechanism. When a Stentor cell is repeatedly stimulated at a constant level of force, it will learn to ignore that stimulus but will still respond to stronger stimuli. Prior studies of habituation in Stentor reported a graded response, suggesting that cells transition through a continuous range of response probabilities. By analyzing single cells using an automated apparatus to deliver calibrated stimuli, we find that habituation occurs via a single step-like switch in contraction probability within each cell, with the graded response in a population arising from the random distribution of switching times in individual cells. This step-like response allows Stentor behavior to be represented by a simple two-state model whose parameters can be estimated from experimental measurements. We find that transition rates depend on stimulus force and also on the time between stimuli. The ability to measure the behavior of the same cell to the same stimulus allowed us to quantify the functional heterogeneity among single cells. Together, our results suggest that the behavior of Stentor is governed by a two-state stochastic machine whose transition rates are sensitive to the time series properties of the input stimuli.

Evolutionary innovations, defined as character states that transcend clade norms, are often studied in an exclusively phylogenetic context, but their distribution in time and space indicates that geography also influences the evolution of new ecological, morphological, and physiological traits. In an analysis of 99 fossillzable, norm-breaking innovations in tropical marine Neogene molluscan clades that arose uniquely in either (but not in both) the Indo-West Pacific (IWP) or Atlantic-East Pacific (AEP) realms, I show that there are far more innovations in the IWP (79%) than those in the AEP (21%). Most of the innovations are interpretable as defensive or competitive adaptations or as indicators of extreme habitat specialization. Although the innovations arose in taxonomically rich biotas, only 9% are associated with subclades comprising 10 or more species each, indicating that they contributed little to overall taxonomic richness. Compilations of extant species in 30 pantropical molluscan clades show that the IWP accounts for 71% of tropical shallow-water species, implying that the per-species incidence of norm-breaking innovations is higher there than in the AEP. Only 5% of innovations became extinct in the IWP as compared with 38% in the AEP, mirroring a similar difference in the magnitudes of Late Miocene and later taxonomic extinction in the two realms. These data imply that large-scale disruption strongly limits norm-breaking innovation. Opportunities for adaptive innovation are therefore likely to be few in today's heavily overexploited and disturbed biosphere.

BackgroundBivariate alternating recurrent event data can arise in longitudinal studies where patients with chronic diseases go through two states that occur repeatedly, e.g., care periods and break periods. However, there was no statistical software that provided tools for the analysis of such data. To meet this software need, we developed BivRec, a package for R that contains a set of tools for exploratory, nonparametric and semiparametric regression analysis of bivariate alternating recurrent events.ResultsThe BivRec package provides functions for nonparametric estimations for the joint distribution of bivariate gap times (bivrecNP) and semiparametric regression methods for evaluating covariate effects on the two types of gap times under the accelerated failure time model framework (bivrecReg). The package also provides exploratory data analysis tools such as a visualization of the gap times by groups. We utilize a subset of the South Verona Psychiatric Case Register (PCR) data to illustrate the use of the BivRec package for the reviewed methods.ConclusionsWe demonstrate BivRec's capability for data visualization, nonparametric and regression based analysis, as well as data simulation. The package has default methods with satisfactory performance despite the complexity of calculations and fills a gap in software for statistical analysis of bivariate alternating recurrent events. BivRec is accessible under the GPL-3 General Public License through CRAN, facilitating its installation.

PurposeOptimal cognitive performance might prevent vehicle accidents. Identifying time-related circadian and homeostatic parameters having an impact on cognitive performance of drivers may be crucial to optimize drivers' performance.MethodsIn this prospective study conducted on bus drivers, two drivers alternated driving during a 24-h round trip and were accompanied by an interviewer. Each driver was tested using Karolinska Sleepiness Scale (KSS) and the reversed digit span Wechsler Working Memory test before the start of his shift and then every 6 h during a "work/driving" day. Psychomotor Vigilance Task (PVT) was assessed before and after the journey. Linear mixed model was used to explore the factors affecting cognitive performance and sleepiness in univariate and multivariate analysis.ResultsAmong 35 bus drivers, the effect of time of day on working memories was statistically significant (p = 0.001), with the lowest working memory scores at 04:00 am (± 1). The highest score of subjective sleepiness was also at 04:00 am (± 1). The time on task parameter affected sleepiness significantly (p = 0.024) and sleepiness was significantly associated with decreased working memory. Psychomotor Vigilance Task reaction time mean and the number of minor lapses were significantly increased after the journey, which suggested decreased vigilance. In multivariable analysis, a longer interval between the beginning of working hours and testing time (B (95% CI) = 15.25 (0.49 to 30), p = 0.043) was associated with higher (i.e., slower) PVT reaction time mean.ConclusionsThese results suggest that optimizing bus drivers' working schedules may improve drivers' sleepiness and cognitive performance and thus increase road safety.

Physiological response to physical exercise through analysis of cardiopulmonary measurements has been shown to be predictive of a variety of diseases. Nonetheless, the clinical use of exercise testing remains limited because interpretation of test results requires experience and specialized training. Additionally, until this work no methods have identified which dynamic gas exchange or heart rate responses influence an individual's decision to start or stop physical activity. This research examines the use of advanced machine learning methods to predict completion of a test consisting of multiple exercise bouts by a group of healthy children and adolescents. All participants could complete the ten bouts at low or moderate-intensity work rates, however, when the bout work rates were high-intensity, 50% refused to begin the subsequent exercise bout before all ten bouts had been completed (task failure). We explored machine learning strategies to model the relationship between the physiological time series, the participant's anthropometric variables, and the binary outcome variable indicating whether the participant completed the test. The best performing model, a generalized spectral additive model with functional and scalar covariates, achieved 93.6% classification accuracy and an F1 score of 93.5%. Additionally, functional analysis of variance testing showed that participants in the 'failed' and 'success' groups have significantly different functional means in three signals: heart rate, oxygen uptake rate, and carbon dioxide uptake rate. Overall, these results show the capability of functional data analysis with generalized spectral additive models to identify key differences in the exercise-induced responses of participants in multiple bout exercise testing.

BackgroundIt remains unclear how the variability of adiposity indices relates to incident HF. This study evaluated the associations of the variability in several adiposity indices with incident heart failure (HF) in individuals with type 2 diabetes (T2DM).MethodsWe included 4073 participants from the Look AHEAD (Action for Health in Diabetes) study. We assessed variability of body mass index (BMI), waist circumference (WC), and body weight across four annual visits using three variability metrics, the variability independent of the mean (VIM), coefficient of variation (CV), and intraindividual standard deviation (SD). Multivariable Cox regression models were used to generate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for incident HF.ResultsOver a median of 6.7 years, 120 participants developed incident HF. After adjusting for relevant confounders including baseline adiposity levels, the aHR for the highest (Q4) versus lowest quartile (Q1) of VIM of BMI was 3.61 (95% CI 1.91-6.80). The corresponding aHRs for CV and SD of BMI were 2.48 (95% CI 1.36-4.53) and 2.88 (1.52-5.46), respectively. Regarding WC variability, the equivalent aHRs were 1.90 (95% CI 1.11-3.26), 1.79 (95% CI 1.07-3.01), and 1.73 (1.01-2.95) for Q4 versus Q1 of VIM, CV and SD of WC, respectively.ConclusionsIn a large sample of adults with T2DM, a greater variability of adiposity indices was associated with higher risks of incident HF, independently of traditional risk factors and baseline adiposity levels. Registration-URL: https://clinicaltrials.gov/ct2/show/NCT00000620 .

Abstract Background Current studies have shown that longer observation time can improve neoplastic detection rate. This study aimed to clarify whether endoscopists with longer observation times can detect more focal lesions. Methods Based on the mean examination time for Esophagogastroduodenoscopy (EGD) without biopsy, endoscopists were divided into fast and slow groups, and the detection rate of focal lesions was compared between the two groups. Univariate analysis, multivariate analysis and restricted cubic spline were used to explore the factors of focal lesion detection rate. Results Mean examination time of EGD without biopsy was 4.5 min. The cut-off times used were 5 min. 17 endoscopists were classified into the fast (4.7 ± 3.6 min), and 16 into the slow (7.11 ± 4.6 min) groups. Compared with fast endoscopists, slow endoscopists had a higher detection rate of focal lesions (47.2% vs. 51.4%, P

Abstract Background Medical humanities education is an important part of medical education. The purpose of this study was to determine the effectiveness of medical humanities in improving empathy among medical students and healthcare professionals. Methods PubMed, Embase, EBSCO-ERIC, Web of Science were searched systematically for studies in the English language. The last retrieval date is May 1, 2023. Best Evidence Medical Education (BEME) Global Rating Scale and Kirkpatrick-based results were used to evaluate the quality of literature. In this study, a meta-analysis of continuous data was conducted. Results The pooled results by single-arm test meta-analysis showed a benefit with medical humanities programs in empathy (SMD 1.33; 95% CI 0.69–1.96). For single-arm trials of medical humanities program interventions of less than 4 months, 4 months to 12 months, and more than one year, the standardized mean differences(SMD) between post-test and pre-test were 1.74 (P

Real-time chemical sensing is crucial for applications in environmental and health monitoring1. Biosensors can detect a variety of molecules through genetic circuits that use these chemicals to trigger the synthesis of a coloured protein, thereby producing an optical signal2-4. However, the process of protein expression limits the speed of this sensing to approximately half an hour, and optical signals are often difficult to detect in situ5-8. Here we combine synthetic biology and materials engineering to develop biosensors that produce electrical readouts and have detection times of minutes. We programmed Escherichia coli to produce an electrical current in response to specific chemicals using a modular, eight-component, synthetic electron transport chain. As designed, this strain produced current following exposure to thiosulfate, an anion that causes microbial blooms, within 2 min. This amperometric sensor was then modified to detect an endocrine disruptor. The incorporation of a protein switch into the synthetic pathway and encapsulation of the bacteria with conductive nanomaterials enabled the detection of the endocrine disruptor in urban waterway samples within 3 min. Our results provide design rules to sense various chemicals with mass-transport-limited detection times and a new platform for miniature, low-power bioelectronic sensors that safeguard ecological and human health.

BACKGROUND: Frailty assessment adds important prognostic information during preoperative decision-making but can be cumbersome to implement into routine clinical care. We developed and tested an abbreviated method of frailty assessment using variables routinely collected by the Vascular Quality Initiative (VQI) registry. METHODS: An abbreviated frailty score (the simple Vascular Quality Initiative-Frailty Score [VQI-FS]) was developed using 11 or fewer VQI variables (hypertension, congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes, chronic obstructive pulmonary disease, renal impairment, anemia, underweight, nonhome residence, and nonambulatory status) that map to recognized frailty domains in the Comprehensive Geriatric Assessment and the literature. Nonemergent cases registered in the VQI from 2010 to 2017 (n = 265,632) in seven registries (carotid endarterectomy, n = 77,111; carotid artery stenting, n = 13,215; endovascular abdominal aortic aneurysm repair, n = 29,607; open abdominal aortic aneurysm repair, n = 7442; infrainguinal bypass, n = 33,128; suprainguinal bypass, n = 10,661; and peripheral vascular intervention, n = 94,468) were analyzed using logistic regression models to determine the predictive power of the VQI-FS for perioperative and longer term (9-month) mortality. Nomograms were created using weighted regression coefficients to assist in individualized frailty assessment and estimation of 9-month mortality. RESULTS: The VQI-FS, using equal weighting of these 11 VQI variables, effectively predicted 9-month mortality with an area under the curve of 0.724 by receiver operating characteristic curve analysis. However, differential weighting of the variables allowed simplification of the model to only seven variables (congestive heart failure, renal impairment, chronic obstructive pulmonary disease, not living at home, not ambulatory, anemia, and underweight status); hypertension, coronary artery disease, peripheral vascular disease, and diabetes had relatively low predictive power. Adding procedure-specific risk further improved performance of the model with a final area under the curve on receiver operating characteristic curve analysis of 0.758. Model calibration was excellent with predicted/observed regression line slope of 0.991 and intercept of 5.449e-04. CONCLUSIONS: A differentially weighted abbreviated VQI-FS using seven variables in addition to procedure-specific risk has strong correlation with 9-month mortality. Nomograms incorporating patient- and procedure-adjusted risk can effectively predict 9-month mortality. Reliable estimates of longer term mortality should assist in preoperative decision-making for vascular procedures that often carry substantial risk of mortality.

OBJECTIVE: Previous studies on carotid endarterectomy and transfemoral carotid artery stenting demonstrated that perioperative outcomes differed according to preoperative neurologic injury severity, but this has not been assessed in transcarotid artery revascularization (TCAR). In this study, we examined contemporary perioperative outcomes in patients who underwent TCAR stratified by specific preprocedural symptom status. METHODS: Patients who underwent TCAR between 2016 and 2021 in the Vascular Quality Initiative were included. We stratified patients into the following groups based on preprocedural symptoms: asymptomatic, recent (symptoms occurring 180 days before TCAR). First, we used trend tests to assess outcomes in asymptomatic patients versus those with an increasing severity of recent neurologic injury (recent ocular TIA vs recent hemispheric TIA vs recent stroke). Then, we compared outcomes between asymptomatic and formerly symptomatic patients. Our primary outcome was in-hospital stroke/death rates. Multivariable logistic regression was used to adjust for demographics and comorbidities across groups. RESULTS: We identified 18,477 patients undergoing TCAR, of whom 62.0% were asymptomatic, 3.2% had a recent ocular TIA, 7.6a % had recent hemispheric TIA, 18.0% had a recent stroke, and 9.2% were formerly symptomatic. In patients with recent symptoms, we observed higher rates of stroke/death with increasing neurologic injury severity: asymptomatic 1.1% versus recent ocular TIA 0.8% versus recent hemispheric TIA 2.1% versus recent stroke 3.1% (Ptrend < .01). In formerly symptomatic patients, the rate of stroke/death was higher compared with asymptomatic patients, but this difference was not statistically significant (1.7% vs 1.1%; P = .06). After risk adjustment, compared with asymptomatic patients, there was a higher odds of stroke/death in patients with a recent stroke (odds ratio [OR], 2.8; 95% confidence interval [CI], 2.1-3.7; P < .01), a recent hemispheric TIA (OR, 2.0; 95% CI, 1.3-3.0; P < .01), and former symptoms (OR, 1.6; 95% CI, 1.1-2.5; P = .02), but there was no difference in stroke/death rates in patients with a recent ocular TIA (OR, 0.9; 95% CI, 0.4-2.2; P = .78). CONCLUSIONS: After TCAR, compared with asymptomatic status, a recent stroke and a recent hemispheric TIA were associated with higher stroke/death rates, whereas a recent ocular TIA was associated with similar stroke/death rates. In addition, a formerly symptomatic status was associated with higher stroke/death rates compared with an asymptomatic status. Overall, our findings suggest that classifying patients undergoing TCAR as symptomatic versus asymptomatic may be an oversimplification and that patients specific preoperative neurologic symptoms should instead be used in risk assessment and outcome reporting for TCAR.

ObjectiveManagement of Paget-Schroetter syndrome (PSS) with first rib resection (FRR) and venoplasty is successful in re-establishing subclavian vein (SCV) patency in most cases. However, in cases with subacute or chronic venous occlusion, SCV patency may not be achieved. Thus, the role for FRR remains controversial in cases of subacute or chronic SCV occlusion. Our goal is to determine whether FRR is beneficial in PSS patients with subacute or chronic SCV occlusion.MethodsA prospectively maintained thoracic outlet syndrome (TOS) database was searched for patients undergoing FRR who were identified as having SCV occlusion on preoperative venography between 2012 and 2021. Preoperative and postoperative venous patency were determined by venography. Standardized functional outcomes were assessed using the Quick Disability Arm, Shoulder, Hand (QuickDASH-QDS) and Somatic Pain Scale (SPS) before and after FRR. The Derkash outcome score was recorded after FRR.ResultsOver the study period, 966 TOS operations were performed; of these, 401 were for venous TOS, and 33 patients were identified with subacute or chronic preoperative SCV occlusion verified by venography. The median age was 29 years, with 73% men. Eighteen patients had attempted thrombolysis; eight were performed at our institution, and ten performed at a referring facility. The median time from the symptom onset of SCV occlusion to FRR was 78 days for all patients. For the group that achieved venous patency after FRR, the time from SCV occlusion to FRR was 71 days, and it was 106 days for the group that remained occluded after FRR. All underwent postoperative venography and percutaneous attempt at SCV recanalization. Recanalization was successful in 64% (21) and unsuccessful in 36% (12). All patients experienced improvement in SPS and QDS. For all patients, the average SPS improved from 1.69 preoperatively to 0.25 postoperatively and the average QDS improved from 27.63 preoperatively to 10.19 postoperatively (P > .05). For patients who were successfully recanalized, the final SPS was 0.18 and the final QDS was 11.22 (P > .05). In patients who failed to achieve recanalization, the final SPS was 0.40 and the final QDS was 9.06 (P > .05). All postoperative Derkash outcome scores were excellent and good, with none fair or poor.ConclusionsIn patients with subacute or chronic preoperative SCV occlusion, surgical decompression and postoperative angioplasty resulted in re-establishing SCV patency in 64% of patients. Symptomatic patients clinically improve after surgical decompression regardless of whether venous patency is successfully re-established. These results indicate that symptomatic patients with PSS should be considered for TOS decompression even if their SCV is occluded in the subacute or chronic presentation.