Definitive endoderm derived from human embryonic stem cells highly express the integrin receptors αV and β5

Human embryonic stem cells (hESCs) can be directed to differentiate into a number of endoderm cell types, however mature functional cells have yet to be produced in vitro. This suggests that there may be important factors that have yet to be described, which may be essential for the proper derivation of these cells. One such factor is the integrin mediated interactions between a cell and the extracellular matrix (ECM). On this basis, the present study investigated the role of the ECM in the directed differentiation of hESCs to definitive endoderm via analysis of integrin gene expression. The results showed that definitive endoderm can be efficiently and effectively derived from hESCs in a feeder free, single defined ECM of laminin. Analysis of integrin expression also showed that definitive endoderm highly express the integrins αV and β5, which have the ability to bind to vitronectin, whilst expression of the pluripotency related laminin binding integrins α3, α6 and β4 were downregulated. This suggested a potential role of vitronectin binding integrins in the development of definitive endoderm. © 2010 Landes Bioscience

Health and social care service utilisation and associated expenditure among community-dwelling older adults with depressive symptoms

AIMS: Late-life depression has substantial impacts on individuals, families and society. Knowledge gaps remain in estimating the economic impacts associated with late-life depression by symptom severity, which has implications for resource prioritisation and research design (such as in modelling). This study examined the incremental health and social care expenditure of depressive symptoms by severity. METHODS: We analysed data collected from 2707 older adults aged 60 years and over in Hong Kong. The Patient Health Questionnaire-9 (PHQ-9) and the Client Service Receipt Inventory were used, respectively, to measure depressive symptoms and service utilisation as a basis for calculating care expenditure. Two-part models were used to estimate the incremental expenditure associated with symptom severity over 1 year. RESULTS: The average PHQ-9 score was 6.3 (standard deviation, s.d. = 4.0). The percentages of respondents with mild, moderate and moderately severe symptoms and non-depressed were 51.8%, 13.5%, 3.7% and 31.0%, respectively. Overall, the moderately severe group generated the largest average incremental expenditure (US$5886; 95$3849; 95% CI 2520-5177 or a 176% increase) and the moderate group (US$1843; 95$691; 95% CI 444-939), then gradually fell to negative between scores of 12 (US$- 35; 95$ -171; 95% CI - 417 to 76) and soared to positive and rebounded at the score of 23 (US$601; 95% CI -1652 to 2854). CONCLUSIONS: The association between depressive symptoms and care expenditure is stronger among older adults with mild and moderately severe symptoms. Older adults with the same symptom severity have different care utilisation and expenditure patterns. Non-psychiatric healthcare is the major cost element. These findings inform ways to optimise policy efforts to improve the financial sustainability of health and long-term care systems, including the involvement of primary care physicians and other geriatric healthcare providers in preventing and treating depression among older adults and related budgeting and accounting issues across services

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Definitive endoderm derived from human embryonic stem cells highly express the integrin receptors αV and β5

Human embryonic stem cells (hESCs) can be directed to differentiate into a number of endoderm cell types, however mature functional cells have yet to be produced in vitro. This suggests that there may be important factors that have yet to be described, which may be essential for the proper derivation of these cells. One such factor is the integrin mediated interactions between a cell and the extracellular matrix (ECM). On this basis, the present study investigated the role of the ECM in the directed differentiation of hESCs to definitive endoderm via analysis of integrin gene expression. The results showed that definitive endoderm can be efficiently and effectively derived from hESCs in a feeder free, single defined ECM of laminin. Analysis of integrin expression also showed that definitive endoderm highly express the integrins αV and β5, which have the ability to bind to vitronectin, whilst expression of the pluripotency related laminin binding integrins α3, α6 and β4 were downregulated. This suggested a potential role of vitronectin binding integrins in the development of definitive endoderm

Application of artificial intelligence in symptom monitoring in adult cancer survivorship: a systematic review

PURPOSE The adoption of artificial intelligence (AI) in health care may afford new avenues for personalized and patient-centered care. This systematic review explored the role of AI in symptom monitoring for adult cancer survivors. METHODS A comprehensive search was performed from inception to November 2023 in seven bibliographic databases and three clinical trial registries. This PROSPERO registered review (ID: CRD42023476027) assessed reports of empirical research studies of AI use in symptom monitoring (physical and psychological symptoms) across all cancer types in adults. RESULTS A total of 18,530 reports were identified, of which 41 met review criteria and were analyzed. Included studieswere predominantly published between 2021 and 2023, originated in the United States (39.0%) and Japan (14.6%), and primarily used cohort designs (80.5%), followed by cross-sectional designs (12.2%). The mean sample size was 617.14 (standard deviation 5 1,401.37), with most studies primarily including multiple tumor types (31.7%) or breast cancer survivors (26.8%). Machine learning algorithms (43.9%) was the most used AI method, followed by natural language processing (29.3%), AI-driven chatbots (17.1%), and decision support tools (9.8%). The most common inputs to the AI algorithms were textual data, patient-reported symptoms, and physiologic measurements. The most examined symptom was pain (34.2% of studies), followed by fatigue and nausea (17.1% of studies each). Overall, the review showed increasing AI technology use in the prediction and monitoring of cancer symptoms. CONCLUSION AI is being used to enhance symptom monitoring in various cancer settings. When considering integration into clinical practice, standardization of data capture, the use of analytics, investing in infrastructure, and the end-user experience should be considered for successful implementation and monitoring the improvement of patient outcomes

Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data

Background: Stroke thrombolysis with alteplase is currently recommended 0–4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. Methods: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. Findings: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15–2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23–76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81–2·96, p=0·66). Interpretation: Patients with ischaemic stroke 4·5–9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes

Search for intermediate-mass black hole binaries in the third observing run of Advanced LIGO and Advanced Virgo

International audienceIntermediate-mass black holes (IMBHs) span the approximate mass range 100−105 M⊙, between black holes (BHs) that formed by stellar collapse and the supermassive BHs at the centers of galaxies. Mergers of IMBH binaries are the most energetic gravitational-wave sources accessible by the terrestrial detector network. Searches of the first two observing runs of Advanced LIGO and Advanced Virgo did not yield any significant IMBH binary signals. In the third observing run (O3), the increased network sensitivity enabled the detection of GW190521, a signal consistent with a binary merger of mass ∼150 M⊙ providing direct evidence of IMBH formation. Here, we report on a dedicated search of O3 data for further IMBH binary mergers, combining both modeled (matched filter) and model-independent search methods. We find some marginal candidates, but none are sufficiently significant to indicate detection of further IMBH mergers. We quantify the sensitivity of the individual search methods and of the combined search using a suite of IMBH binary signals obtained via numerical relativity, including the effects of spins misaligned with the binary orbital axis, and present the resulting upper limits on astrophysical merger rates. Our most stringent limit is for equal mass and aligned spin BH binary of total mass 200 M⊙ and effective aligned spin 0.8 at 0.056 Gpc−3 yr−1 (90% confidence), a factor of 3.5 more constraining than previous LIGO-Virgo limits. We also update the estimated rate of mergers similar to GW190521 to 0.08 Gpc−3 yr−1.Key words: gravitational waves / stars: black holes / black hole physicsCorresponding author: W. Del Pozzo, e-mail: [email protected]† Deceased, August 2020