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How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a synergistic global workspace, comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brains default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.

Using pooled vaginal microbiota data from pregnancy cohorts (N = 683 participants) in the Environmental influences on Child Health Outcomes (ECHO) Program, we analyzed 16S rRNA gene amplicon sequences to identify clinical and demographic host factors that associate with vaginal microbiota structure in pregnancy both within and across diverse cohorts. Using PERMANOVA models, we assessed factors associated with vaginal community structure in pregnancy, examined whether host factors were conserved across populations, and tested the independent and combined effects of host factors on vaginal community state types (CSTs) using multinomial logistic regression models. Demographic and social factors explained a larger amount of variation in the vaginal microbiome in pregnancy than clinical factors. After adjustment, lower education, rather than self-identified race, remained a robust predictor of L. iners dominant (CST III) and diverse (CST IV) (OR = 8.44, 95% CI = 4.06-17.6 and OR = 4.18, 95% CI = 1.88-9.26, respectively). In random forest models, we identified specific taxonomic features of host factors, particularly urogenital pathogens associated with pregnancy complications (Aerococcus christensenii and Gardnerella spp.) among other facultative anaerobes and key markers of community instability (L. iners). Sociodemographic factors were robustly associated with vaginal microbiota structure in pregnancy and should be considered as sources of variation in human microbiome studies.

BACKGROUND: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

BACKGROUND: Reference to an intrinsic healing mechanism or an inner healer is commonplace amongst psychedelic drug-using cultures. The inner healer refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived inner healing effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or placebo (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of all pancreatic cancer cases. Five-year survival rates have remained below 12% since the 1970s, in part due to the difficulty in detection prior to metastasis (migration and invasion into neighboring organs and glands). Mechanical memory is a concept that has emerged over the past decade that may provide a path toward understanding how invading PDAC cells "remember" the mechanical properties of their diseased ("stiff", elastic modulus, E ≈ 10 kPa) microenvironment even while invading a healthy ("soft", E ≈ 1 kPa) microenvironment. Here, we investigated the role of mechanical priming by culturing a dilute suspension of PDAC (FG) cells within a 3D, rheologically tunable microgel platform from hydrogels with tunable mechanical properties. We conducted a suite of acute (short-term) priming studies where we cultured PDAC cells in either a soft (E ≈ 1 kPa) or stiff (E ≈ 10 kPa) environment for 6 h, then removed and placed them into a new soft or stiff 3D environment for another 18 h. Following these steps, we conducted RNA-seq analyses to quantify gene expression. Initial priming in the 3D culture showed persistent gene expression for the duration of the study, regardless of the subsequent environments (stiff or soft). Stiff 3D culture was associated with the downregulation of tumor suppressors (LATS1, BCAR3, CDKN2C), as well as the upregulation of cancer-associated genes (RAC3). Immunofluorescence staining (BCAR3, RAC3) further supported the persistence of this cellular response, with BCAR3 upregulated in soft culture and RAC3 upregulated in stiff-primed culture. Stiff-primed genes were stratified against patient data found in The Cancer Genome Atlas (TCGA). Upregulated genes in stiff-primed 3D culture were associated with decreased survival in patient data, suggesting a link between patient survival and mechanical priming.

Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development-before and after birth and through maturation to adulthood-and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain-favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video─potentially due to a competition between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidneys active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

AbstractLatinx populations face a higher burden of kidney failure and associated negative outcomes compared with non-Latinx White populations, despite sharing a similar prevalence of CKD. Community health worker (CHW) interventions have been shown to improve outcomes for Latinx individuals, but they are largely underutilized in kidney disease. We convened a workshop of four ongoing kidney disease CHW programs to identify successes, challenges, potential solutions, and needed research to promote CHW programs for Latinx individuals with kidney disease. Key points from the workshop and recommendations for intervention and research are highlighted. Facilitators of program success included prioritizing trust-building with participants, enabling participants to determine what aspects of the intervention were needed, providing participants with tools to help themselves and others after the intervention, and taking a trauma-informed approach to relationships. Challenges included persistent systemic barriers despite successful care navigation and low recruitment and retention. Research is needed to capture the effect of CHW interventions on outcomes and to determine how to implement CHW interventions for people with kidney disease nationwide.

BackgroundTwo antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.Research questionWhat are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF?Study design and methodsThis study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, 2019, were identified. Hierarchical logistic regression models were used to examine factors associated with antifibrotic uptake, accounting for comorbidities, facility clustering, and follow-up time. Fine-Gray models were used to evaluate antifibrotic use by demographic factors, accounting for the competing risk of death.ResultsAmong 14,792 veterans with IPF, 17% received antifibrotics. There were significant disparities in adoption, with lower uptake associated with female sex (adjusted OR, 0.41; 95% CI, 0.27-0.63; P < .001), Black race (adjusted OR, 0.60; 95% CI, 0.49-0.73; P < .001), and rural residence (adjusted OR, 0.88; 95% CI, 0.80-0.97; P = .012). Veterans who received their index diagnosis of IPF outside the VA were less likely to receive antifibrotic therapy (adjusted OR, 0.15; 95% CI, 0.10-0.22; P < .001).InterpretationThis study is the first to evaluate the real-world adoption of antifibrotic medications among veterans with IPF. Overall uptake was low, and there were significant disparities in use. Interventions to address these issues deserve further investigation.

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Lesbian, gay, bisexual, transgender, and queer (LGBTQ) youth of color experience high rates of mental health disorders, yet they experience challenges to accessing mental health services. Community health worker (CHW) models of care have potential to promote equitable mental health services among LGBTQ youth. Our aim was to understand how CHW models could be adapted to better support LGBTQ youth of color in accessing mental health services. Semi-structured qualitative interviews were conducted with LGBTQ youth of color (n = 16), caregivers of LGBTQ youth (n = 11), and CHWs (n = 15) in Massachusetts and California. Interviews were coded by 8 members of the research team. A Rapid Qualitative Analysis was conducted to identify themes. Caregivers, youth, and CHWs all endorsed the value of CHW models for this population. They also almost universally suggested multiple adaptations are needed for the model to be effective. Four main categories of themes emerged related to intervention adaptations: (1) Why adaptations are needed for LGBTQ youth, (2) Who should serve as CHWs providing care, (3) How CHWs should be trained, and (4) What content needs to be included in the intervention. Broadly, findings suggest the relevance of having CHW models for LGBTQ youth of color to address stigma and discrimination experienced, access to culturally and linguistically relevant services, and the need for caregiver support of LGBTQ youth. CHWs need increased training in these areas.

BackgroundDifficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation.MethodsWe queried a multicentre registry for children who experienced "difficult" or "impossible" facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed.ResultsThe incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with "difficult" mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening.ConclusionsCertain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

IntroductionChronic conditions, such as diabetes, obesity, heart disease and depression, are highly prevalent and frequently co-occur with food insecurity in communities served by community health centres in the USA. Community health centres are increasingly implementing 'Food as Medicine' programmes to address the dual challenge of chronic conditions and food insecurity, yet they have been infrequently evaluated.Methods and analysisThe goal of this quasi-experimental study was to evaluate the effectiveness of Recipe4Health, a 'Food as Medicine' programme. Recipe4Health includes two components: (1) a 'Food Farmacy' that includes 16 weekly deliveries of produce and (2) a 'Behavioural Pharmacy' which is a group medical visit. We will use mixed models to compare pre/post changes among participants who receive the Food Farmacy alone (n=250) and those who receive the Food Farmacy and Behavioural Pharmacy (n=140). The primary outcome, fruit and vegetable consumption, and secondary outcomes (eg, food security status, physical activity, depressive symptoms) will be collected via survey. We will also use electronic health record (EHR) data on laboratory values, prescriptions and healthcare usage. Propensity score matching will be used to compare Recipe4Health participants to a control group of patients in clinics where Recipe4Health has not been implemented for EHR-derived outcomes. Data from surveys, EHR, group visit attendance and produce delivery is linked with a common identifier (medical record number) and then deidentified for analysis with use of an assigned unique study ID. This study will provide important preliminary evidence on the effectiveness of primary care-based strategies to address food insecurity and chronic conditions.Ethics and disseminationThis study was approved by the Stanford University Institutional Review Board (reference protocol ID 57239). Appropriate study result dissemination will be determined in partnership with the Community Advisory Board.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

BACKGROUND: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. METHODS: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  - 2.5 or ≥  + 2.5 with a standard deviation not crossing zero. RESULTS: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. CONCLUSIONS: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

BACKGROUND: Virtually all adults with Down syndrome (DS) develop Alzheimers disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. OBJECTIVE: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (-versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression. METHODS: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77). RESULTS: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16-20 months. CONCLUSION: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.

BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimers disease (AD). OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. METHODS: Analyses involved adults with DS from the Alzheimers Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau. RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be modeled by pairwise maximum entropy Ising models at various distances from a phase transition, i.e., from criticality. Here we aim to characterize two brain states (psychedelics-induced and placebo) as captured by functional magnetic resonance imaging (fMRI), with features derived from the Ising spin model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. We hypothesized, along the lines of the entropic brain hypothesis, that psychedelics drive brain dynamics into a more disordered state at a higher Ising temperature and increased complexity. We analyze resting state blood-oxygen-level-dependent (BOLD) fMRI data collected in an earlier study from fifteen subjects in a control condition (placebo) and during ingestion of lysergic acid diethylamide (LSD). Working with the automated anatomical labeling (AAL) brain parcellation, we first create "archetype" Ising models representative of the entire dataset (global) and of the data in each condition. Remarkably, we find that such archetypes exhibit a strong correlation with an average structural connectome template obtained from dMRI (r = 0.6). We compare the archetypes from the two conditions and find that the Ising connectivity in the LSD condition is lower than in the placebo one, especially in homotopic links (interhemispheric connectivity), reflecting a significant decrease of homotopic functional connectivity in the LSD condition. The global archetype is then personalized for each individual and condition by adjusting the system temperature. The resulting temperatures are all near but above the critical point of the model in the paramagnetic (disordered) phase. The individualized Ising temperatures are higher in the LSD condition than in the placebo condition (p = 9 × 10-5). Next, we estimate the Lempel-Ziv-Welch (LZW) complexity of the binarized BOLD data and the synthetic data generated with the individualized model using the Metropolis algorithm for each participant and condition. The LZW complexity computed from experimental data reveals a weak statistical relationship with condition (p = 0.04 one-tailed Wilcoxon test) and none with Ising temperature (r(13) = 0.13, p = 0.65), presumably because of the limited length of the BOLD time series. Similarly, we explore complexity using the block decomposition method (BDM), a more advanced method for estimating algorithmic complexity. The BDM complexity of the experimental data displays a significant correlation with Ising temperature (r(13) = 0.56, p = 0.03) and a weak but significant correlation with condition (p = 0.04, one-tailed Wilcoxon test). This study suggests that the effects of LSD increase the complexity of brain dynamics by loosening interhemispheric connectivity-especially homotopic links. In agreement with earlier work using the Ising formalism with BOLD data, we find the brain state in the placebo condition is already above the critical point, with LSD resulting in a shift further away from criticality into a more disordered state.

BackgroundPsilocybin is a serotonin type 2A (5-HT2A) receptor agonist and naturally occurring psychedelic. 5-HT2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes.MethodData were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis.ResultsResults support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater 'dread of ego dissolution' in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not.ConclusionsThese findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

The COVID-19 pandemic revealed weaknesses in the public health infrastructure of the United States, including persistent barriers to engaging marginalized communities toward inclusion in clinical research, including trials. Inclusive participation in clinical trials is crucial for promoting vaccine confidence, public trust, and addressing disparate health outcomes. A long-standing body of literature describes the value of community-based participatory research in increasing marginalized community participation in research. Community-based participatory research emphasizes shared leadership with community members in all phases of the research process, including in the planning and implementation, interpretation, and dissemination. Shared leadership between academic and industry with marginalized communities can assist with inclusive participation in vaccine trials and increase public trust in the development of the vaccines and other therapies used during public emergencies. Nevertheless, epidemiologic and clinical research do not yet have a strong culture of community partnership in the scientific process, which takes time to build and therefore may be difficult to develop and rapidly scale to respond to the pandemic. We outline practices that contribute to a lack of inclusive participation and suggest steps that trialists and other researchers can take to increase marginalized communities' participation in research. Practices include planning for community engagement during the planning and recruitment phases, having regular dialogues with communities about their priorities, supporting them throughout a study, and navigating complex structural determinants of health. Additionally, we discuss how research institutions can support inclusive practices by reexamining their policies to increase participation in clinical trials and instilling institutional trustworthiness.

People with diabetes and chronic kidney disease (CKD) are at high risk for kidney failure, atherosclerotic cardiovascular disease, heart failure, and premature mortality. Recent clinical trials support new approaches to treat diabetes and CKD. The 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease each provide evidence-based recommendations for management. A joint group of ADA and KDIGO representatives reviewed and developed a series of consensus statements to guide clinical care from the ADA and KDIGO guidelines. The published guidelines are aligned in the areas of CKD screening and diagnosis, glycemia monitoring, lifestyle therapies, treatment goals, and pharmacologic management. Recommendations include comprehensive care in which pharmacotherapy that is proven to improve kidney and cardiovascular outcomes is layered on a foundation of healthy lifestyle. Consensus statements provide specific guidance on use of renin-angiotensin system inhibitors, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist. These areas of consensus provide clear direction for implementation of care to improve clinical outcomes of people with diabetes and CKD.

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards a deeper understanding of these different alterations of normal consciousness, here we compare the changes in neural dynamics induced by LSD and ketamine (in healthy volunteers) against those associated with schizophrenia, as observed in resting-state M/EEG recordings. While both conditions exhibit increased neural signal diversity, our findings reveal that this is accompanied by an increased transfer entropy from the front to the back of the brain in schizophrenia, versus an overall reduction under the two drugs. Furthermore, we show that these effects can be reproduced via different alterations of standard Bayesian inference applied on a computational model based on the predictive processing framework. In particular, the effects observed under the drugs are modelled as a reduction of the precision of the priors, while the effects of schizophrenia correspond to an increased precision of sensory information. These findings shed new light on the similarities and differences between schizophrenia and two psychotomimetic drug states, and have potential implications for the study of consciousness and future mental health treatments.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Background: Social disadvantage is associated with childrens risk of being overweight or obese, but little is known about how it impacts weight trajectory. This longitudinal analysis examines food insecurity and weight change over time among low-income children in a multidisciplinary weight management clinic. Methods: Food insecurity was assessed between 2008 and 2016 among 794 low-income patients (household income

ObjectivesHIV outcomes centre primarily around clinical markers with limited focus on patient-reported outcomes. With a global trend towards capturing the outcomes that matter most to patients, there is agreement that standardizing the definition of value in HIV care is key to their incorporation. This study aims to address the lack of routine, standardized data in HIV care.MethodsAn international working group (WG) of 37 experts and patients, and a steering group (SG) of 18 experts were convened from 14 countries. The project team (PT) identified outcomes by conducting a literature review, screening 1979 articles and reviewing the full texts of 547 of these articles. Semi-structured interviews and advisory groups were performed with the WG, SG and people living with HIV to add to the list of potentially relevant outcomes. The WG voted via a modified Delphi process - informed by six Zoom calls - to establish a core set of outcomes for use in clinical practice.ResultsFrom 156 identified outcomes, consensus was reached to include three patient-reported outcomes, four clinician-reported measures and one administratively reported outcome; standardized measures were included. The WG also reached agreement to measure 22 risk-adjustment variables. This outcome set can be applied to any person living with HIV aged > 18 years.ConclusionsAdoption of the HIV360 outcome set will enable healthcare providers to record, compare and integrate standardized metrics across treatment sites to drive quality improvement in HIV care.

RationaleClassic psychedelics are currently being studied as novel treatments for a range of psychiatric disorders. However, research on how psychedelics interact with other psychoactive substances remains scarce.ObjectivesThe current study aimed to explore the subjective effects of psychedelics when used alongside cannabis.MethodsParticipants (n = 321) completed a set of online surveys at 2 time points: 7 days before, and 1 day after a planned experience with a serotonergic psychedelic. The collected data included demographics, environmental factors (so-called setting) and five validated questionnaires: Mystical Experience Questionnaire (MEQ), visual subscales of Altered States of Consciousness Questionnaire (ASC-Vis), Challenging Experience Questionnaire (CEQ), Ego Dissolution Inventory (EDI) and Emotional Breakthrough Inventory (EBI). Participants were grouped according to whether they had reported using no cannabis (n = 195) or low (n = 53), medium (n = 45) or high (n = 28) dose, directly concomitant with the psychedelic. Multivariate analysis of covariance (MANCOVA) and contrasts was used to analyse differences in subjective effects between groups while controlling for potential confounding contextual 'setting' variables.ResultsThe simultaneous use of cannabis together with classic serotonergic psychedelics was associated with more intense psychedelic experience across a range of measures: a linear relationship was found between dose and MEQ, ASC-Vis and EDI scores, while a quadratic relationship was found for CEQ scores. No relationship was found between the dose of cannabis and the EBI.ConclusionsResults imply a possible interaction between the cannabis and psychedelic on acute subjective experiences; however, design limitations hamper our ability to draw firm inferences on directions of causality and the clinical implications of any such interactions.

The course-based research experience (CRE) with its documented educational benefits is increasingly being implemented in science, technology, engineering, and mathematics education. This article reports on a study that was done over a period of 3 years to explicate the instructional processes involved in teaching an undergraduate CRE. One hundred and two instructors from the established and large multi-institutional SEA-PHAGES program were surveyed for their understanding of the aims and practices of CRE teaching. This was followed by large-scale feedback sessions with the cohort of instructors at the annual SEA Faculty Meeting and subsequently with a small focus group of expert CRE instructors. Using a qualitative content analysis approach, the survey data were analyzed for the aims of inquiry instruction and pedagogical practices used to achieve these goals. The results characterize CRE inquiry teaching as involving three instructional models: 1) being a scientist and generating data; 2) teaching procedural knowledge; and 3) fostering project ownership. Each of these models is explicated and visualized in terms of the specific pedagogical practices and their relationships. The models present a complex picture of the ways in which CRE instruction is conducted on a daily basis and can inform instructors and institutions new to CRE teaching.

BackgroundInterstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral.Research questionCan consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs?Study design and methodsPulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement.ResultsFifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System "S-modifier" [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD.InterpretationGuidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA.

IntroductionAs their name suggests, 'psychedelic' (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS).MethodsThe PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific 'global psychedelic survey' study.ResultsPrincipal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach's α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being.ConclusionThe PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight - as measured by the PIS - was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Parent-child interaction therapy (PCIT) is a best-practice treatment for behavior problems in young children. In PCIT, therapists coach parents during in-vivo interactions to strengthen the parent-child relationship and teach parents effective ways of managing difficult child behaviors. Past research has found that different therapist coaching styles may be associated with faster skill acquisition and improved parent engagement. However, most research examining therapist behaviors has been conducted with English-speaking families, and there is limited research examining therapist behaviors when working with Spanish-speaking clients. In this study, English- and Spanish-speaking therapists' coaching behaviors (e.g., directive versus responsive) were examined, as well as their association with client outcomes, including speed of parental skill acquisition and treatment completion. Results suggested that coaching styles varied significantly between sessions conducted in Spanish versus English. In Spanish sessions, therapists had more total verbalizations than in English sessions and demonstrated higher rates of both total directive and responsive coaching. Responsive coaching was found to predict treatment completion across groups, while directive coaching was not. Directive and responsive coaching were not found to predict the rate of parental skill acquisition. Implications regarding the training of therapists and emphasizing cultural considerations are discussed.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

BackgroundHumanwide was precision health embedded in primary care aiming to leverage high-tech and high-touch medicine to promote wellness, predict and prevent illness, and tailor treatment to individual medical and psychosocial needs.MethodsWe conducted a study assessing implementation outcomes to inform spread and scale, using mixed methods of semi-structured interviews with diverse stakeholders and chart reviews. Humanwide included: 1) health coaching; 2) four digital health tools for blood-pressure, weight, glucose, and activity; 3) pharmacogenomic testing; and 4) genetic screening/testing. We examined implementation science constructs: reach/penetration, acceptability, feasibility, and sustainability. Chart reviews captured preliminary clinical outcomes.ResultsFifty of 69 patients (72%) invited by primary care providers participated in the Humanwide pilot. We performed chart reviews for the 50 participating patients. Participants were diverse overall (50% non-white, 66% female). Over half of the participants were obese and 58% had one or more major cardiovascular risk factor: dyslipidemia, hypertension, diabetes. Reach/penetration of Humanwide components varied: pharmacogenomics testing 94%, health coaching 80%, genetic testing 72%, and digital health 64%. Interview participants (n=27) included patients (n=16), providers (n=9), and the 2 staff who were allocated dedicated time for Humanwide patient intake and orientation. Patients and providers reported Humanwide was acceptable; it engaged patients holistically, supported faster medication titration, and strengthened patient-provider relationships. All patients benefited clinically from at least one Humanwide component. Feasibility challenges included: low provider self-efficacy for interpreting genetics and pharmacogenomics; difficulties with data integration; patient technology challenges; and additional staffing needs. Patient financial burden concerns surfaced with respect to sustainability.ConclusionThis is the first report of implementation of a multi-component precision health model embedded in team-based primary care. We found acceptance from both patients and providers; however, feasibility barriers must be overcome to enable broad spread and sustainability. We found that barriers to implementation of precision health in a team-based primary care clinic are mundane and straightforward, though not necessarily easy to overcome. Future implementation endeavors should invest in basics: education, workflow, and reflection/evaluation. Strengthening fundamentals will enable healthcare systems to more nimbly accept the responsibility of meeting patients at the crossroads of innovative science and routinized clinical systems.

Precision mental health holds great potential for revolutionizing care and reducing the burden of mental illness. All races and ethnicities such as Asian Americans, the fastest growing racial group in the United States (U.S.), need to be engaged in precision mental health research. Owing to its global popularity, Korean drama ('K-drama') television shows may be an effective educational tool to increase precision mental health knowledge, attitudes and behaviors among Asian Americans. This qualitative study examined the participants' perspectives about and acceptance of using K-dramas to educate and engage Asian Americans about precision mental health. Twelve workshops were conducted in English, Vietnamese and Korean with a convenience sample in the San Francisco Bay Area in the U.S. (n = 122). Discussions were coded for themes. Findings revealed that all language groups reported positive reactions to using K-dramas to learn about precision health, genetics and mental health. Overall, participants shared that they learned about topics that are not generally talked about (e.g. precision health; genetic testing; mental health), from other people's perspectives, and the importance of mental health. Participants expressed how much they enjoyed the workshop, how they felt relieved due to the workshop, thought the workshop was interesting, and had an opportunity for self-reflection/healing. This pilot test demonstrated that K-dramas has promise to be used as a health educational tool in a workshop format focused on mental health among a diverse group of Asian Americans. Given the widespread access to K-dramas, they present a scalable opportunity for increasing awareness about specific health topics.

BackgroundPatients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome.MethodsAmong 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage.ResultsThe mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death.ConclusionsMore advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time.

Emerging evidence links genes within human-specific segmental duplications (HSDs) to traits and diseases unique to our species. Strikingly, despite being nearly identical by sequence (>98.5%), paralogous HSD genes are differentially expressed across human cell and tissue types, though the underlying mechanisms have not been examined. We compared cross-tissue mRNA levels of 75 HSD genes from 30 families between humans and chimpanzees and found expression patterns consistent with relaxed selection on or neofunctionalization of derived paralogs. In general, ancestral paralogs exhibited greatest expression conservation with chimpanzee orthologs, though exceptions suggest certain derived paralogs may retain or supplant ancestral functions. Concordantly, analysis of long-read isoform sequencing data sets from diverse human tissues and cell lines found that about half of derived paralogs exhibited globally lower expression. To understand mechanisms underlying these differences, we leveraged data from human lymphoblastoid cell lines (LCLs) and found no relationship between paralogous expression divergence and post-transcriptional regulation, sequence divergence, or copy-number variation. Considering cis-regulation, we reanalyzed ENCODE data and recovered hundreds of previously unidentified candidate CREs in HSDs. We also generated large-insert ChIP-sequencing data for active chromatin features in an LCL to better distinguish paralogous regions. Some duplicated CREs were sufficient to drive differential reporter activity, suggesting they may contribute to divergent cis-regulation of paralogous genes. This work provides evidence that cis-regulatory divergence contributes to novel expression patterns of recent gene duplicates in humans.

BackgroundThe accuracy of the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing 'mild cognitive impairment (MCI-DS)'.MethodKnowledgeable informants were interviewed with the NTG-EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination).ResultsResults indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the 'Memory' or 'Language and Communication' domains being most informative.ConclusionsThe NTG-EDSD is a useful tool for evaluating dementia status, including MCI-DS. However, estimates of sensitivity and specificity, even for detecting frank dementia, indicated that NTG-EDSD findings need to be supplemented by additional sources of relevant information to achieve an acceptable level of diagnostic/screening accuracy.

BackgroundCoronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.MethodsIn this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo.ResultsOf the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94).ConclusionsIn this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a 'self-blinding' citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

BackgroundThe need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.ObjectiveThis study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.MethodsPlasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.ResultsIn distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.ConclusionAdvanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

The broad concept of emergence is instrumental in various of the most challenging open scientific questions-yet, few quantitative theories of what constitutes emergent phenomena have been proposed. This article introduces a formal theory of causal emergence in multivariate systems, which studies the relationship between the dynamics of parts of a system and macroscopic features of interest. Our theory provides a quantitative definition of downward causation, and introduces a complementary modality of emergent behaviour-which we refer to as causal decoupling. Moreover, the theory allows practical criteria that can be efficiently calculated in large systems, making our framework applicable in a range of scenarios of practical interest. We illustrate our findings in a number of case studies, including Conway's Game of Life, Reynolds' flocking model, and neural activity as measured by electrocorticography.

ObjectiveAdults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.MethodsParticipants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status.ResultsThere were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.InterpretationThe findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Purpose of reviewThis review examines the current evidence about the ways in which food insecurity relates to obesity in children and adolescents, examining diet and diet-related behaviors, and taking into consideration the role of stress.Recent findingsWhile living with food insecurity impacts stress and diet-related behaviors in children and adolescents, it is not clear whether food insecurity is associated with obesity above and beyond the influence of poverty. However, strategies to mitigate food insecurity and obesity are inherently connected, and recent examples from clinical practice (e.g., screening for food insecurity among patients) and advocacy (e.g., policy considerations regarding federal food programs such as the Supplemental Nutrition Assistance Program, or SNAP) are discussed. Food insecurity and obesity coexist in low-income children and adolescents in the USA. The COVID-19 pandemic exerts disproportionate burden on low-income children and families, magnifying their vulnerability to both food insecurity and pediatric obesity.