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Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ ; retrospective registration at ClinicalTrials.gov NCT06308744 ) multi-site study (nsites = 37, nparticipants = 2,239, 70.4% women, Mage = 22.4, s.d.age = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = -0.56; 95% confidence interval, -0.43 to -0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.

A combination of fifteen top quark mass measurements performed by the ATLAS and CMS experiments at the LHC is presented. The datasets used correspond to an integrated luminosity of up to 5 and 20  fb^{-1} of proton-proton collisions at center-of-mass energies of 7 and 8 TeV, respectively. The combination includes measurements in top quark pair events that exploit both the semileptonic and hadronic decays of the top quark, and a measurement using events enriched in single top quark production via the electroweak t channel. The combination accounts for the correlations between measurements and achieves an improvement in the total uncertainty of 31% relative to the most precise input measurement. The result is m_{t}=172.52±0.14(stat)±0.30(syst)  GeV, with a total uncertainty of 0.33 GeV.

ObjectivesThe cultural stress theory posits that immigrants experience a constellation of cultural stressors such as discrimination that could exacerbate alcohol- and other substance-related problems. Drawing on cultural stress theory, this study investigated the age-varying association between past-year discrimination and substance use disorders (SUDs) among Latin American immigrants aged 18-60 and whether childhood family support moderated the above association.MethodWe used data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) among adults aged 18-60 who identified as a Latin American immigrant (N = 3,049; 48% female).ResultsTime-varying effect models (TVEMs) revealed that experiencing past-year discrimination was associated with greater odds of having a SUD during young and middle adulthood for Latin American immigrants. Furthermore, for immigrants with lower childhood family support, discrimination was associated with SUD risk in young and middle adulthood.ConclusionThe present study documents that past-year discrimination was linked to greater SUD risk during young and middle adulthood. Childhood family support may serve as a protective factor in the association between discrimination and risk for SUD among Latin American immigrants. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

BACKGROUND: The efficacy and safety of opioid-free anaesthesia during bariatric surgery remain debated, particularly when administering multimodal analgesia. As multimodal analgesia has become the standard of care in many centres, we aimed to determine if such a strategy coupled with either dexmedetomidine (opioid-free anaesthesia) or remifentanil with a morphine transition (opioid-based anaesthesia), would reduce postoperative morphine requirements and opioid-related adverse events. METHODS: In this prospective double-blind study, 172 class III obese patients having laparoscopic gastric bypass surgery were randomly allocated to receive either sevoflurane-dexmedetomidine anaesthesia with a continuous infusion of lidocaine and ketamine (opioid-free group) or sevoflurane-remifentanil anaesthesia with a morphine transition (opioid-based group). Both groups received at anaesthesia induction a bolus of magnesium, lidocaine, ketamine, paracetamol, diclofenac, and dexamethasone. The primary outcome was 24-h postoperative morphine consumption. Secondary outcomes included postoperative quality of recovery (QoR40), incidence of hypoxaemia, bradycardia, and postoperative nausea and vomiting (PONV). RESULTS: Eighty-six patients were recruited in each group (predominantly women, 70% had obstructive sleep apnoea). There was no significant difference in postoperative morphine consumption (median [inter-quartile range]: 16 [13-26] vs 15 [10-24] mg, P=0.183). The QoR40 up to postoperative day 30 did not differ between groups, but PONV was less frequent in the opioid-free group (37% vs 59%, P=0.005). Hypoxaemia and bradycardia were not different between groups. CONCLUSIONS: During bariatric surgery, a multimodal opioid-free anaesthesia technique did not decrease postoperative morphine consumption when compared with a multimodal opioid-based strategy. Quality of recovery did not differ between groups although the incidence of PONV was less in the opioid-free group. CLINICAL TRIAL REGISTRATION: NCT05004519.

A search is presented for new Higgs bosons in proton-proton (pp) collision events in which a same-sign top quark pair is produced in association with a jet, via the pp→tH/A→ttc‾ and pp→tH/A→ttu‾ processes. Here, H and A represent the extra scalar and pseudoscalar boson, respectively, of the second Higgs doublet in the generalized two-Higgs-doublet model (g2HDM). The search is based on pp collision data collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 138 fb−1. Final states with a same-sign lepton pair in association with jets and missing transverse momentum are considered. New Higgs bosons in the 200–1000 GeV mass range and new Yukawa couplings between 0.1 and 1.0 are targeted in the search, for scenarios in which either H or A appear alone, or in which they coexist and interfere. No significant excess above the standard model prediction is observed. Exclusion limits are derived in the context of the g2HDM.

Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate intactness scores: the remaining proportion of an intact reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the regions major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems.

We model and constrain the unique indirect detection signature produced bydark matter particles that annihilate through a $U(1)$ gauge symmetry into darkphotons that subsequently decay into three-photon final states. We focus onscenarios where the dark photon is long-lived, and show that $\gamma$-rayprobes of celestial objects can set strong constraints on the darkmatter/baryon scattering cross section that in many cases surpass the power ofcurrent direct detection constraints, and in some cases even peer into theneutrino fog.

Intensive care unit (ICU) nurses frequently manually titrate norepinephrine to maintain a predefined mean arterial pressure (MAP) target after high-risk surgery. However, achieving this task is often suboptimal. We have developed a closed-loop vasopressor (CLV) controller to better maintain MAP within a narrow range. After ethical committee approval, fifty-three patients admitted to the ICU following high-risk abdominal surgery were randomized to CLV or manual norepinephrine titration. In both groups, the aim was to maintain MAP in the predefined target of 80-90 mmHg. Fluid administration was standardized in the two groups using an advanced hemodynamic monitoring device. The primary outcome of our study was the percentage of time patients were in the MAP target. Over the 2-hour study period, the percentage of time with MAP in target was greater in the CLV group than in the control group (median: IQR25-75: 80 [68-88]% vs. 42 [22-65]%), difference 37.2, 95% CI (23.0-49.2); p  90 mmHg was not statistically different between groups. In patients admitted to the ICU after high-risk abdominal surgery, closed-loop control of norepinephrine infusion better maintained a MAP target of 80 to 90 mmHg and significantly decreased postoperative hypotensive when compared to manual norepinephrine titration.

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Computing demands for large scientific experiments, such as the CMS experiment at the CERN LHC, will increase dramatically in the next decades. To complement the future performance increases of software running on central processing units (CPUs), explorations of coprocessor usage in data processing hold great potential and interest. Coprocessors are a class of computer processors that supplement CPUs, often improving the execution of certain functions due to architectural design choices. We explore the approach of Services for Optimized Network Inference on Coprocessors (SONIC) and study the deployment of this as-a-service approach in large-scale data processing. In the studies, we take a data processing workflow of the CMS experiment and run the main workflow on CPUs, while offloading several machine learning (ML) inference tasks onto either remote or local coprocessors, specifically graphics processing units (GPUs). With experiments performed at Google Cloud, the Purdue Tier-2 computing center, and combinations of the two, we demonstrate the acceleration of these ML algorithms individually on coprocessors and the corresponding throughput improvement for the entire workflow. This approach can be easily generalized to different types of coprocessors and deployed on local CPUs without decreasing the throughput performance. We emphasize that the SONIC approach enables high coprocessor usage and enables the portability to run workflows on different types of coprocessors.

Scientific evidence regularly guides policy decisions1, with behavioural science increasingly part of this process2. In April 2020, an influential paper3 proposed 19 policy recommendations (claims) detailing how evidence from behavioural science could contribute to efforts to reduce impacts and end the COVID-19 pandemic. Here we assess 747 pandemic-related research articles that empirically investigated those claims. We report the scale of evidence and whether evidence supports them to indicate applicability for policymaking. Two independent teams, involving 72 reviewers, found evidence for 18 of 19 claims, with both teams finding evidence supporting 16 (89%) of those 18 claims. The strongest evidence supported claims that anticipated culture, polarization and misinformation would be associated with policy effectiveness. Claims suggesting trusted leaders and positive social norms increased adherence to behavioural interventions also had strong empirical support, as did appealing to social consensus or bipartisan agreement. Targeted language in messaging yielded mixed effects and there were no effects for highlighting individual benefits or protecting others. No available evidence existed to assess any distinct differences in effects between using the terms physical distancing and social distancing. Analysis of 463 papers containing data showed generally large samples; 418 involved human participants with a mean of 16,848 (median of 1,699). That statistical power underscored improved suitability of behavioural science research for informing policy decisions. Furthermore, by implementing a standardized approach to evidence selection and synthesis, we amplify broader implications for advancing scientific evidence in policy formulation and prioritization.

Tubular adenomas are rare, benign breast tumors primarily found in postmenarchal, premenopausal women. We report a case of tubular adenoma in a 56-year-old man with a history of alcoholic cirrhosis. The breast mass was incidentally discovered on computed tomography imaging performed as part of a patient liver transplant evaluation. Dedicated breast imaging and ultrasound-guided biopsy confirmed the diagnosis of tubular adenoma.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

OBJECTIVE: To use more precise measures of which hospitals are electronically connected to determine whether health information exchange (HIE) is associated with lower emergency department (ED)-related utilization. MATERIALS AND METHODS: We combined 2018 Medicare fee-for-service claims to identify beneficiaries with 2 ED encounters within 30 days, and Definitive Healthcare and AHA IT Supplement data to identify hospital participation in HIE networks (HIOs and EHR vendor networks). We determined whether the 2 encounters for the same beneficiary occurred at: the same organization, different organizations connected by HIE, or different organizations not connected by HIE. Outcomes were: (1) whether any repeat imaging occurred during the second ED visit; (2) for beneficiaries with a treat-and-release ED visit followed by a second ED visit, whether they were admitted to the hospital after the second visit; (3) for beneficiaries discharged from the hospital followed by an ED visit, whether they were admitted to the hospital. RESULTS: In adjusted mixed effects models, for all outcomes, beneficiaries returning to the same organization had significantly lower utilization compared to those going to different organizations. Comparing only those going to different organizations, HIE was not associated with lower levels of repeat imaging. HIE was associated with lower likelihood of hospital admission following a treat-and-release ED visit (1.83 percentage points [-3.44 to -0.21]) but higher likelihood of admission following hospital discharge (2.78 percentage points [0.48-5.08]). DISCUSSION: Lower utilization for beneficiaries returning to the same organization could reflect better access to information or other factors such as aligned incentives. CONCLUSION: HIE is not consistently associated with utilization outcomes reflecting more coordinated care in the ED setting.

Despite gradual progress over the past decades, the simulation of progressive damage in composite laminates remains a challenging task, in part due to inherent uncertainties of material properties. This paper combines three computational methods - finite element analysis (FEA), machine learning and Markov Chain Monte Carlo - to estimate the probability density of FEA input parameters while accounting for the variation of mechanical properties. First, 15,000 FEA simulations of open-hole tension tests are carried out with randomly varying input parameters by applying continuum damage mechanics material models. This synthetically-generated data is then used to train and validate a neural network consisting of five hidden layers and 32 nodes per layer to develop a highly efficient surrogate model. With this surrogate model and the incorporation of statistical test data from experiments, the application of Markov Chain Monte Carlo algorithms enables Bayesian parameter estimation to learn the probability density of input parameters for the simulation of progressive damage evolution in fibre reinforced composites. This methodology is validated against various open-hole tension test geometries enabling the determination of virtual design allowables.

OBJECTIVE: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. METHODS: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. RESULTS: All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. CONCLUSIONS: The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.

Schizophrenia is marked by deficits in facial affect processing associated with abnormalities in GABAergic circuitry, deficits also found in first-degree relatives. Facial affect processing involves a distributed network of brain regions including limbic regions like amygdala and visual processing areas like fusiform cortex. Pharmacological modulation of GABAergic circuitry using benzodiazepines like alprazolam can be useful for studying this facial affect processing network and associated GABAergic abnormalities in schizophrenia. Here, we use pharmacological modulation and computational modeling to study the contribution of GABAergic abnormalities toward emotion processing deficits in schizophrenia. Specifically, we apply principles from network control theory to model persistence energy - the control energy required to maintain brain activation states - during emotion identification and recall tasks, with and without administration of alprazolam, in a sample of first-degree relatives and healthy controls. Here, persistence energy quantifies the magnitude of theoretical external inputs during the task. We find that alprazolam increases persistence energy in relatives but not in controls during threatening face processing, suggesting a compensatory mechanism given the relative absence of behavioral abnormalities in this sample of unaffected relatives. Further, we demonstrate that regions in the fusiform and occipital cortices are important for facilitating state transitions during facial affect processing. Finally, we uncover spatial relationships (i) between regional variation in differential control energy (alprazolam versus placebo) and (ii) both serotonin and dopamine neurotransmitter systems, indicating that alprazolam may exert its effects by altering neuromodulatory systems. Together, these findings provide a new perspective on the distributed emotion processing network and the effect of GABAergic modulation on this network, in addition to identifying an association between schizophrenia risk and abnormal GABAergic effects on persistence energy during threat processing.

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleiotropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic-rFunctional connectivity = 0.71 [0.40-0.87] and rTranscriptomic-rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms-amenable to intervention-across psychiatric conditions and genetic risks.

Drinking water and sanitation services in high-income countries typically bring widespread health and other benefits to their populations. Yet gaps in this essential public health infrastructure persist, driven by structural inequalities, racism, poverty, housing instability, migration, climate change, insufficient continued investment, and poor planning. Although the burden of disease attributable to these gaps is mostly uncharacterised in high-income settings, case studies from marginalised communities and data from targeted studies of microbial and chemical contaminants underscore the need for continued investment to realise the human rights to water and sanitation. Delivering on these rights requires: applying a systems approach to the problems; accessible, disaggregated data; new approaches to service provision that centre communities and groups without consistent access; and actionable policies that recognise safe water and sanitation provision as an obligation of government, regardless of factors such as race, ethnicity, gender, ability to pay, citizenship status, disability, land tenure, or property rights.

Traits that mediate reproductive isolation between species, such as those involved in mate choice and/or recognition, are predicted to experience stabilizing selection towards the species mean. Male orchid bees collect chemical compounds from many sources, such as plants and fungi, which they use as a perfume signal (pheromone) during courtship display, and are suggested to contribute to reproductive isolation between species. Environmentally acquired signals are more prone to variation as source availability can vary through space and time. If orchid bee perfumes are important for reproductive isolation between species, we expect them to exhibit stable species-specific differences in time and space. Here, we describe phenotypic patterns of inter- and intraspecific variation in the male perfumes of three sympatric species of Euglossa orchid bees across an entire year, investigating both their seasonality and species specificity. Our analysis revealed considerable within-species variation in perfumes. However, species specificity was maintained consistently throughout the year, supporting the idea that these perfumes could play an important role in reproductive isolation and are experiencing stabilizing selection towards a species mean. Our analysis also identified strong correlations in the abundance of some compounds, possibly due to shared collection sources between species. Our study suggests that orchid bee perfumes are robust in the face of environmental changes in resource availability and thus can maintain reproductive isolation between species.

Mindful attention is characterized by acknowledging the present experience as a transient mental event. Early stages of mindfulness practice may require greater neural effort for later efficiency. Early effort may self-regulate behavior and focalize the present, but this understanding lacks a computational explanation. Here we used network control theory as a model of how external control inputs-operationalizing effort-distribute changes in neural activity evoked during mindful attention across the white matter network. We hypothesized that individuals with greater network controllability, thereby efficiently distributing control inputs, effectively self-regulate behavior. We further hypothesized that brain regions that utilize greater control input exhibit shorter intrinsic timescales of neural activity. Shorter timescales characterize quickly discontinuing past processing to focalize the present. We tested these hypotheses in a randomized controlled study that primed participants to either mindfully respond or naturally react to alcohol cues during fMRI and administered text reminders and measurements of alcohol consumption during 4 wk postscan. We found that participants with greater network controllability moderated alcohol consumption. Mindful regulation of alcohol cues, compared to ones own natural reactions, reduced craving, but craving did not differ from the baseline group. Mindful regulation of alcohol cues, compared to the natural reactions of the baseline group, involved more-effortful control of neural dynamics across cognitive control and attention subnetworks. This effort persisted in the natural reactions of the mindful group compared to the baseline group. More-effortful neural states had shorter timescales than less effortful states, offering an explanation for how mindful attention promotes being present.

BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits. METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects). RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease. CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.

ObjectivesTo evaluate the association between plasma metabolites, biochemical analytes, diagnostic imaging findings, and the histologic diagnosis of hepatic lipidosis in bearded dragons. To assess the effects of gemfibrozil therapy on hepatic lipid accumulation and associated diagnostic tests.AnimalsFourteen bearded dragons (Pogona vitticeps) with varying severity of hepatic lipid accumulation (with and without hepatic lipidosis) were included.ProceduresAnimals underwent coelomic ultrasound, computed tomography (CT) scans, and coelioscopic hepatic biopsies. Clinical pathology tests included lipidologic tests, hepatic biomarkers, and mass spectrometry-based metabolomics. Animals were medicated with gemfibrozil 6mg/kg orally once a day for 2 months in a randomized blinded clinical trial prior to repeating previous diagnostic testing.ResultsHounsfield units on CT were negatively associated with increased hepatic vacuolation, while ultrasound and gross evaluation of the liver were not reliable. Beta-hydroxybutyric-acid (BHBA) concentrations were significantly associated with hepatic lipidosis. Metabolomics and lipidomics data found BHBA and succinic acid to be potential biomarkers for diagnosing hepatic lipidosis in bearded dragons. Succinic acid concentrations were significantly lower in the gemfibrozil treatment group. There was a tendency for improvement in the biomarkers and reduced hepatic fat in bearded dragons with hepatic lipidosis when treated with gemfibrozil, though the improvement was not statistically significant.ConclusionsThese findings provide information on the antemortem assessment of hepatic lipidosis in bearded dragons and paves the way for further research in diagnosis and treatment of this disease.

[This corrects the article DOI: 10.1371/journal.pcbi.1010651.].

The nearby, luminous infrared galaxy NGC 7469 hosts a Seyfert nucleus with a circumnuclear star-forming ring and is thus the ideal local laboratory for investigating the starburst-AGN (active galactic nucleus) connection in detail. We present integral-field observations of the central 1.3 kpc region in NGC 7469 obtained with the JWST Mid-InfraRed Instrument. Molecular and ionized gas distributions and kinematics at a resolution of ∼100 pc over the 4.9-7.6 μm region are examined to study the gas dynamics influenced by the central AGN. The low-ionization [Fe ii] λ5.34 μm and [Ar ii] λ6.99 μm lines are bright on the nucleus and in the starburst ring, as opposed to H2 S(5) λ6.91 μm, which is strongly peaked at the center and surrounding ISM. The high-ionization [Mg v] line is resolved and shows a broad, blueshifted component associated with the outflow. It has a nearly face-on geometry that is strongly peaked on the nucleus, where it reaches a maximum velocity of −650 km s−1, and extends about 400 pc to the east. Regions of enhanced velocity dispersion in H2 and [Fe ii] ∼ 180 pc from the AGN that also show high L(H2)/L(PAH) and L([Fe ii])/L(Pfα) ratios to the W and N of the nucleus pinpoint regions where the ionized outflow is depositing energy, via shocks, into the dense interstellar medium between the nucleus and the starburst ring. These resolved mid-infrared observations of the nuclear gas dynamics demonstrate the power of JWST and its high-sensitivity integral-field spectroscopic capability to resolve feedback processes around supermassive black holes in the dusty cores of nearby luminous infrared galaxies.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

Unless a toxicant builds up in a deep compartment, intake by the human body must on average balance the amount that is lost. We apply this idea to assess arsenic (As) exposure misclassification in three previously studied populations in rural Bangladesh (n = 11,224), Navajo Nation in the Southwestern United States (n = 619), and northern Chile (n = 630), under varying assumptions about As sources. Relationships between As intake and excretion were simulated by taking into account additional sources, as well as variability in urine dilution inferred from urinary creatinine. The simulations bring As intake closer to As excretion but also indicate that some exposure misclassification remains. In rural Bangladesh, accounting for intake from more than one well and rice improved the alignment of intake and excretion, especially at low exposure. In Navajo Nation, comparing intake and excretion revealed home dust as an important source. Finally, in northern Chile, while food-frequency questionnaires and urinary As speciation indicate fish and shellfish sources, persistent imbalance of intake and excretion suggests imprecise measures of drinking water arsenic as a major cause of exposure misclassification. The mass-balance approach could prove to be useful for evaluating sources of exposure to toxicants in other settings.

BackgroundMetaphyseal sclerosis secondary to canine distemper virus has been described histopathologically, but its radiographic appearance has not been described.ObjectivesDescribe the radiographic appearance of metaphyseal sclerosis secondary to canine distemper virus in juvenile dogs as distinct from metaphyseal osteopathy (formerly called hypertrophic osteodystrophy).AnimalsFour dogs (2 intact females and 2 intact males) between 2.5 and 4 months of age presented to 2 different veterinary teaching hospitals.MethodsRetrospective case series in which definitive diagnosis of canine distemper virus based on antemortem positive reverse transcription-polymerase chain reaction (RT-PCR) result or necropsy was required.ResultsAll 4 dogs were presented for evaluation of neurologic abnormalities, respiratory signs, and lethargy; 2 dogs had gastrointestinal signs and ocular abnormalities. Radiographs on all patients featured multifocal, symmetric, metaphyseal sclerosis, with no evidence of lysis or changes to the adjacent growth plate. The metaphyseal sclerosis was most apparent at the proximal humeral diaphyses and other included long bones. Diagnosis of distemper was confirmed by necropsy (2 of 4 dogs) or positive RT-PCR results (2 of 4 dogs). Three dogs were euthanized because of progressive illness, and 1 dog was lost to follow-up.Conclusion and clinical importanceIdentification of metaphyseal sclerosis on radiographs during diagnostic evaluation of young dogs should lead to a clinical suspicion of canine distemper virus infection. Sclerosis identified secondary to canine distemper virus is distinct from the necrosis and inflammation of metaphyseal osteopathy.

Promotion and tenure (P&T) letters are a key component of the academic advancement portfolio. Despite their importance, many faculty are not trained to write these letters and there is limited literature describing the approach and key components. This paper reviews the role of P&T letters and provides general guidelines for writers. We present a step-by-step guide, which includes how to respond to requests, the role of institutional guidelines, providing context to the letter, evaluating candidates, and delivering an overall recommendation. Finally, we discuss current controversies in P&T letters. This paper is intended to help novice and more experienced writers to enhance their P&T letters, while also helping applicants for promotion understand what is being asked of their letter writers.

BackgroundVasopressors are a cornerstone for the management of vasodilatory hypotension. Vasopressor infusions are currently adjusted manually to achieve a predefined arterial pressure target. We have developed a closed-loop vasopressor (CLV) controller to help correct hypotension more efficiently during the perioperative period. We tested the hypothesis that patients managed using such a system postcardiac surgery would present less hypotension compared to patients receiving standard management.MethodsA total of 40 patients admitted to the intensive care unit (ICU) after cardiac surgery were randomized into 2 groups for a 2-hour study period. In all patients, the objective was to maintain mean arterial pressure (MAP) between 65 and 75 mm Hg using norepinephrine. In the CLV group, the norepinephrine infusion was controlled via the CLV system; in the control group, it was adjusted manually by the ICU nurse. Fluid administration was standardized in both groups using an assisted fluid management system linked to an advanced hemodynamic monitoring system. The primary outcome was the percentage of time patients were hypotensive, defined as MAP 75 mm Hg (and norepinephrine still being infused) was also significantly lower in patients in the CLV group than that in the control group (3.2% [1.9-5.4] vs 20.6% [8.9-32.5]; location difference, -17% [95% CI, -10 to -24]; P < .001).The number of norepinephrine infusion rate modifications over the study period was greater in the CLV group than that in the control group (581 [548-597] vs 13 [11-14]; location difference, 568 [578-538]; P < .001). No adverse event occurred during the study period in both groups.ConclusionsClosed-loop control of norepinephrine infusion significantly decreases postoperative hypotension compared to manual control in patients admitted to the ICU after cardiac surgery.

BackgroundThe optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database.Materials and methodsIntensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity.ResultsOut of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p

Time perspective is conceptualized as a multidimensional construct that assesses individuals' feelings and thoughts about the past, present, and future. The current study examined relationships between feelings (time attitudes) and thoughts (time orientation) about time and substance use behaviors across three adolescent samples. Participants included a high-risk sample of adjudicated youth (N=124; M age =15.54, SD=1.69; 51.61% female) and two general population school samples (N=777; M age =15.82, SD=1.23; 53.41% female; N=1873; M age =15.87, SD=1.28; 52.22% female). Cross-sectional survey data were collected from samples in schools during 2010, 2016, and 2011, respectively. Poisson and negative binomial regression analyses indicated that overall, more positive feelings about time were associated with fewer substances used and, conversely, more negative feelings about time were associated with more substances used. These findings were particularly salient for participants with stronger positive and negative feelings toward the past and present time periods. Further, across the three samples, adolescents with a balanced time orientation (i.e., equal emphasis on all three time periods) generally reported less substance use than individuals who emphasized only one or two time periods. Findings highlight relationships between time perspective dimensions and substance use across diverse samples and illustrate opportunities for adapting time perspective-based substance use interventions for adolescents.

ObjectiveTo assess longitudinal primary care organization participation patterns in large-scale reform programs and identify organizational characteristics associated with multiprogram participation.Data sourcesSecondary data analysis of national program participation data over an eight-year period (2009-2016).Study designWe conducted a retrospective, observational study by creating a unique set of data linkages (including Medicare and Medicaid Meaningful Use and Medicare Shared Savings Program Accountable Care Organization (MSSP ACO) participation from CMS, Patient-Centered Medical Home (PCMH) participation from the National Committee for Quality Assurance, and organizational characteristics) to measure longitudinal participation and identify what types of organizations participate in one or more of these reform programs. We used multivariate models to identify organizational characteristics that differentiate those that participate in none, one, or two-to-three programs.Data extraction methodsWe used Medicare claims to identify organizations that delivered primary care services (n = 56 ,287) and then linked organizations to program participation data and characteristics.Principal findingsNo program achieved more than 50% participation across the 56,287 organizations in a given year, and participation levels flattened or decreased in later years. 36% of organizations did not participate in any program over the eight-year study period; 50% participated in one; 13% in two; and 1% in all three. 14.31% of organizations participated in five or more years of Meaningful Use while 3.84% of organizations participated in five years of the MSSP ACO Program and 0.64% participated in at least five years of PCMH. Larger organizations, those with younger providers, those with more primary care providers, and those with larger Medicare patient panels were more likely to participate in more programs.Conclusions and relevancePrimary care transformation via use of voluntary programs, each with their own participation requirements and approach to incentives, has failed to broadly engage primary care organizations. Those that have chosen to participate in multiple programs are likely those already providing high-quality care.

Dynamical systems modeling, particularly via systems of ordinary differential equations, has been used to effectively capture the temporal behavior of different biochemical components in signal transduction networks. Despite the recent advances in experimental measurements, including sensor development and '-omics' studies that have helped populate protein-protein interaction networks in great detail, modeling in systems biology lacks systematic methods to estimate kinetic parameters and quantify associated uncertainties. This is because of multiple reasons, including sparse and noisy experimental measurements, lack of detailed molecular mechanisms underlying the reactions, and missing biochemical interactions. Additionally, the inherent nonlinearities with respect to the states and parameters associated with the system of differential equations further compound the challenges of parameter estimation. In this study, we propose a comprehensive framework for Bayesian parameter estimation and complete quantification of the effects of uncertainties in the data and models. We apply these methods to a series of signaling models of increasing mathematical complexity. Systematic analysis of these dynamical systems showed that parameter estimation depends on data sparsity, noise level, and model structure, including the existence of multiple steady states. These results highlight how focused uncertainty quantification can enrich systems biology modeling and enable additional quantitative analyses for parameter estimation.

BackgroundThe inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known.ObjectiveTo evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI.Design setting and participantsA retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10−8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP. Calculated structure accuracy improved dramatically in this round, implying that models should now be much more useful for resolving many sorts of experimental difficulties. To test this, selected models for seven unsolved targets were provided to the experimental groups. These models were from the AlphaFold2 group, who overall submitted the most accurate predictions in CASP14. Four targets were solved with the aid of the models, and, additionally, the structure of an already solved target was improved. An a posteriori analysis showed that, in some cases, models from other groups would also be effective. This paper provides accounts of the successful application of models to structure determination, including molecular replacement for X-ray crystallography, backbone tracing and sequence positioning in a cryo-electron microscopy structure, and correction of local features. The results suggest that, in future, there will be greatly increased synergy between computational and experimental approaches to structure determination.

BackgroundToll-like receptor 4 (TLR4) has been suggested as one of the forefront cross-communicators between the intestinal bacteria and the host to regulate inflammatory signals and energy homeostasis. High-fat diet-induced inflammation is mediated by changes in gut microbiota and requires a functional TLR-4, the deficiency of which renders mice resistant to diet-induced obesity and its associated metabolic dysfunction. Furthermore, gut microbiota was suggested to play a key role in the beneficial effects of Roux-en-Y gastric bypass (RYGB), a commonly performed bariatric procedure.ObjectivesTo explore whether TLR4, myeloid differentiation factor 8 (MyD88; 1 of its key downstream signaling regulators) and gut microbiota play an integrative role in RYGB-induced metabolic outcomes.SettingAnimal- based study.MethodWe performed RYGB in TLR4 and MyD88 knock-out (KO) mice and used fecal microbiota transplant (FMT) from RYGB-operated animals to these genetic mouse models to address our questions.ResultsWe demonstrate that RYGB reduces TLR4 expression explicitly in the small and large intestine of C57Blc/6J mice. We also show that TLR4 KO mice have an attenuated glucoregulatory response to RYGB. In addition, we reveal that MyD88 KO mice fail to respond to all RYGB-induced metabolic effects. Finally, fecal microbiota transplant from RYGB-operated mice into TLR4 KO and MyD88 KO naïve recipients fails to induce a metabolic phenotype similar to that of the donors, as it does in wild-type recipients.ConclusionTLR4 and MyD88 are required for RYGB-induced metabolic response that is likely mediated by gut microbiome.

BackgroundAcute kidney injury (AKI) occurs frequently after liver transplant surgery and is associated with significant morbidity and mortality. While the impact of intraoperative hypotension (IOH) on postoperative AKI has been well demonstrated in patients undergoing a wide variety of non-cardiac surgeries, it remains poorly studied in liver transplant surgery. We tested the hypothesis that IOH is associated with AKI following liver transplant surgery.MethodsThis historical cohort study included all patients who underwent liver transplant surgery between 2014 and 2019 except those with a preoperative creatinine > 1.5 mg/dl and/or who had combined transplantation surgery. IOH was defined as any mean arterial pressure (MAP)  39.5%) duration. AKI stages were classified according to a "modified" "Kidney Disease: Improving Global Outcomes" (KDIGO) criteria. Logistic regression modelling was conducted to assess the association between IOH and postoperative AKI. The model was run both as a univariate and with multiple perioperative covariates to test for robustness to confounders.ResultsOf the 205 patients who met our inclusion criteria, 117 (57.1%) developed AKI. Fifty-two (25%), 102 (50%) and 51 (25%) patients had short, intermediate and long duration of IOH respectively. In multivariate analysis, IOH was independently associated with an increased risk of AKI (adjusted odds ratio [OR] 1.05; 95%CI 1.02-1.09; P

Assessment of integrated personal exposure (PE) to airborne particulate matter (PM) across diverse microenvironments (MEs) over 24 hours under different exposure scenarios is necessary to identify appropriate strategies to improve urban air quality and mitigate the health effects of PM. We carried out a collaborative study in a densely populated city-state (Singapore) to assess the integrated PE to fine particles (PM2.5), ultrafine particles (UFPs) and black carbon (BC) across diverse indoor and outdoor urban MEs, estimate related health risks and make suitable recommendations for healthy living in cities. Two volunteers with different lifestyles participated in the study by tracking their PE to particulate air pollution and the time-activity patterns over 24 hours using portable PM monitoring devices and recording their whereabouts using GPS coordinates. Home, transport and recreation (i.e., food court) MEs represented pollution hotspots of PM2.5 (21.0 μg/m3), BC (3.4 μg/m3) and UFP (33.0 × 103 #/cm3), respectively. Among the different modes of transport used by the participants (walking, cycling, e-scooter, mass rapid transport (MRT), bus, car and taxi), the air pollutants had elevated concentrations while commuting by public transport (bus and MRT) as well as during active modes of transport (walking and cycling). Air-conditioned cars and taxis, equipped with air filtration systems, represented the lowest PE. The health risk assessment revealed that there are potential carcinogenic risks associated with the long-term exposure to elevated levels of PM2.5-bound toxic trace elements. These risks can be mitigated with the introduction of low-carbon and active modes of transport in place of internal combustion engines and the use of indoor air pollution exposure mitigation devices.

Assessment of integrated personal exposure (PE) to airborne particulate matter (PM) across diverse microenvironments (MEs) over 24 hours under different exposure scenarios is necessary to identify appropriate strategies to improve urban air quality and mitigate the health effects of PM. We carried out a collaborative study in a densely populated city-state (Singapore) to assess the integrated PE to fine particles (PM2.5), ultrafine particles (UFPs) and black carbon (BC) across diverse indoor and outdoor urban MEs, estimate related health risks and make suitable recommendations for healthy living in cities. Two volunteers with different lifestyles participated in the study by tracking their PE to particulate air pollution and the time-activity patterns over 24 hours using portable PM monitoring devices and recording their whereabouts using GPS coordinates. Home, transport and recreation (i.e., food court) MEs represented pollution hotspots of PM2.5 (21.0 μg/m3), BC (3.4 μg/m3) and UFP (33.0 × 103 #/cm3), respectively. Among the different modes of transport used by the participants (walking, cycling, e-scooter, mass rapid transport (MRT), bus, car and taxi), the air pollutants had elevated concentrations while commuting by public transport (bus and MRT) as well as during active modes of transport (walking and cycling). Air-conditioned cars and taxis, equipped with air filtration systems, represented the lowest PE. The health risk assessment revealed that there are potential carcinogenic risks associated with the long-term exposure to elevated levels of PM2.5-bound toxic trace elements. These risks can be mitigated with the introduction of low-carbon and active modes of transport in place of internal combustion engines and the use of indoor air pollution exposure mitigation devices.

BackgroundIndividualized hemodynamic management during surgery relies on accurate titration of vasopressors and fluids. In this context, computer systems have been developed to assist anesthesia providers in delivering these interventions. This study tested the hypothesis that computer-assisted individualized hemodynamic management could reduce intraoperative hypotension in patients undergoing intermediate- to high-risk surgery.MethodsThis single-center, parallel, two-arm, prospective randomized controlled single blinded superiority study included 38 patients undergoing abdominal or orthopedic surgery. All included patients had a radial arterial catheter inserted after anesthesia induction and connected to an uncalibrated pulse contour monitoring device. In the manually adjusted goal-directed therapy group (N = 19), the individualized hemodynamic management consisted of manual titration of norepinephrine infusion to maintain mean arterial pressure within 10% of the patient's baseline value, and mini-fluid challenges to maximize the stroke volume index. In the computer-assisted group (N = 19), the same approach was applied using a closed-loop system for norepinephrine adjustments and a decision-support system for the infusion of mini-fluid challenges (100 ml). The primary outcome was intraoperative hypotension defined as the percentage of intraoperative case time patients spent with a mean arterial pressure of less than 90% of the patient's baseline value, measured during the preoperative screening. Secondary outcome was the incidence of minor postoperative complications.ResultsAll patients were included in the analysis. Intraoperative hypotension was 1.2% [0.4 to 2.0%] (median [25th to 75th] percentiles) in the computer-assisted group compared to 21.5% [14.5 to 31.8%] in the manually adjusted goal-directed therapy group (difference, -21.1 [95% CI, -15.9 to -27.6%]; P < 0.001). The incidence of minor postoperative complications was not different between groups (42 vs. 58%; P = 0.330). Mean stroke volume index and cardiac index were both significantly higher in the computer-assisted group than in the manually adjusted goal-directed therapy group (P < 0.001).ConclusionsIn patients having intermediate- to high-risk surgery, computer-assisted individualized hemodynamic management significantly reduces intraoperative hypotension compared to a manually controlled goal-directed approach.Editor’s perspective