tbuckley/cabot-search huggingface dataset:
The Urban Environment and Cardiometabolic Health
Authors: Sanjay Rajagopalan, Armando Vergara-Martel, Jeffrey Zhong, Haitham Khraishah, Mikhail Kosiborod, Ian J. Neeland, Jean-Eudes Dazard, Zhuo Chen, Thomas Munzel, Robert D. Brook, Mark Nieuwenhuijsen, Peter Hovmand, Sadeer Al-Kindi
Journal: Circulation (2024)

Urban environments contribute substantially to the rising burden of cardiometabolic diseases worldwide. Cities are complex adaptive systems that continually exchange resources, shaping exposures relevant to human health such as air pollution, noise, and chemical exposures. In addition, urban infrastructure and provisioning systems influence multiple domains of health risk, including behaviors, psychological stress, pollution, and nutrition through various pathways (eg, physical inactivity, air pollution, noise, heat stress, food systems, the availability of green space, and contaminant exposures). Beyond cardiometabolic health, city design may also affect climate change through energy and material consumption that share many of the same drivers with cardiometabolic diseases. Integrated spatial planning focusing on developing sustainable compact cities could simultaneously create heart-healthy and environmentally healthy city designs. This article reviews current evidence on the associations between the urban exposome (totality of exposures a person experiences, including environmental, occupational, lifestyle, social, and psychological factors) and cardiometabolic diseases within a systems science framework, and examines urban planning principles (eg, connectivity, density, diversity of land use, destination accessibility, and distance to transit). We highlight critical knowledge gaps regarding built-environment feature thresholds for optimizing cardiometabolic health outcomes. Last, we discuss emerging models and metrics to align urban development with the dual goals of mitigating cardiometabolic diseases while reducing climate change through cross-sector collaboration, governance, and community engagement. This review demonstrates that cities represent crucial settings for implementing policies and interventions to simultaneously tackle the global epidemics of cardiovascular disease and climate change.
Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis
Authors: Jinxia Liu, Jane MacNaughtan, Annarein J C Kerbert, Theo Portlock, Javier Martínez Gonzalez, Yi Jin, Frederick Clasen, Abeba Habtesion, Huoyan Ji, Qin Jin, Alexandra Phillips, Francesco De Chiara, Ganesh Ingavle, Cesar Jimenez, Giacomo Zaccherini, Katherine Husi, Miguel Angel Rodriguez Gandia, Paul Cordero, Junpei Soeda, Lynda McConaghy, Jude Oben, Karen Church, Jia V Li, Haifeng Wu, Aarti Jalan, Pere Gines, Elsa Solà, Simon Eaton, Carrie Morgan, Michal Kowalski, Daniel Green, Amir Gander, Lindsey A Edwards, I Jane Cox, Helena Cortez-Pinto, Thomas Avery, Reiner Wiest, Francois Durand, Paolo Caraceni, Roberto Elosua, Joan Vila, Marco Pavesi, Vicente Arroyo, Nathan Davies, Rajeshwar P Mookerjee, Victor Vargas, Susan Sandeman, Gautam Mehta, Saeed Shoaie, Julian Marchesi, Agustín Albillos, Fausto Andreola, Rajiv Jalan
Journal: Gut (2024)

Objective Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. Design Performance of Yaq-001 was evaluated in vitro . Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. Results Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo , Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. Conclusions This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. Trial registration number NCT03202498 .
Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer
Authors: Feifei Zhang, Varun Sahu, Ke Peng, Yichen Wang, Tianxia Li, Pratyusha Bala, Daulet Aitymbayev, Pranshu Sahgal, Antje Schaefer, Channing J Der, Sandra Ryeom, Sam Yoon, Nilay Sethi, Adam J Bass, Haisheng Zhang
Journal: Gut (2024)

Objective Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations. Design We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC. Results We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor gene Trp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth. Conclusion These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.
More research is needed on how to prevent vaping among young people
Authors: Coral Gartner, Wayne D. Hall
Journal: PLoS Medicine (2024)

We need effective policies to reduce youth use of ENDS globally.Countries have implemented a variety of regulations to reduce ENDS use by youth, including comprehensive sales bans, but more research is needed on the effectiveness of these policies.Tobacco use continues to be the leading preventable cause of global disease burden [1].However, concern is increasing about the growing use of other nicotine-containing products among youth, especially Electronic Nicotine Delivery Systems (ENDS), due to uncertainty about their long-term health risks [2] and whether they provide a "gateway" to tobacco smoking [3].The World Health Organization (WHO) recommends that member states either ban or strictly regulate the sale of ENDS to prevent youth uptake [2].Thirty-four countries have banned their sale [2].A complete ban on sales may seem the most straightforward way to prevent young people from using ENDS (also known as vaping), but there is little evidence to support its effectiveness, in comparison to other policies in the MPOWER policy package that WHO recommends WHO to reduce the global burden of tobacco smoking [2].Only 8 (24%) out of the 34 countries that have banned the sale of ENDS have monitored the impact of the bans on ENDS use by youth and adults [2].Recent analyses of survey data suggest that these bans have had little effect.A systematic review of survey data from 2014 to 2021 reported that 7.7% of young people aged under 26 years currently use ENDS [2], and rates in countries with a sales ban are no lower than in those without bans (e.g., 9.0% in Mexico and 6.7% in Thailand) [4].Countries that have not banned ENDS have adopted a variety of approaches to regulate them.For example, England and New Zealand (also known as Aotearoa) allow ENDS to be sold as consumer products and encourage adults to use them for smoking cessation and as a lower risk alternative to cigarettes.The USA allows ENDS to be sold to consumers as a substitute for cigarettes, but US health authorities generally discourage their use [5].Australia regulates ENDS as a prescription medicine, but no ENDS have been approved as cessation products, and leading medical organisations discourage doctors from prescribing them as unapproved medicines [5].ENDS use among youth has increased in Australia and New Zealand despite their very different policy approaches.In New Zealand, daily ENDS use has increased among adolescents aged 14 to 15 years from around 1% in 2015 to 10.6% in 2022 [6].In Australia, a recent survey suggests that ENDS use in the past year among 14-to 17-year-olds may be even higher than in countries with fewer restrictions on ENDS sales [7].ENDS use is likely to be less harmful than continuing to smoke cigarettes [8], but there are compelling reasons to minimise uptake among youth who have not smoked tobacco.These include the risks of nicotine addiction and uncertainty about the health risks of long-term ENDS use [8].In designing policies to minimise ENDS use among youth, however, regulators
18F-FDG PET/CT of Intracholecystic Papillary Neoplasm in Cystic Neck and Duct
Authors: Jun-Yu Xu, Yong-Kang Shuai, Yan-Ping Xie, Su-E Cao, Qiong Zou
Journal: Clinical Nuclear Medicine (2024)

We report 18 F-FDG PET/CT appearances of intracholecystic papillary neoplasm (ICPN) in the gallbladder neck and duct of a 74-year-old woman with a history of hepatitis B cirrhosis. The lesion presented with a large and sessile soft mass in the neck and duct of gallbladder with obvious glucose metabolism on PET/CT images, which was confirmed pathologically as ICPN (gastric foveolar type) with high-grade intraepithelial neoplasia. ICPN localized in the gallbladder neck and duct is extremely rare, and is easily misdiagnosed as gallbladder carcinoma. Our report aids in the application of PET/CT in the differential diagnosis of ICPN and guiding early surgery.
Journal club
Authors: Beenish Iqbal
Journal: Thorax (2024)

EFFUSIONMalignant pleural effusion (MPE) is a common problem in advanced malignancies and causes debilitating breathlessness leading to poor quality of life.There are two treatment options available to 'definitively' manage MPE which include chest drain with talc pleurodesis and indwelling pleural catheters (IPCs).Although both treatments have been in use for a long time, there has been limited research on the impact of these treatments on patient quality of life.Sivakumar and colleagues (Eur Respir J 2023, DOI: 10
Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy
Authors: Jie Wang, Zilong Zhang, Yan Zhuo, Zhuan Zhang, Rongrong Chen, Li Liang, Xiaohe Jiang, Di Nie, Chang Liu, Zhiwen Zou, Xiang Li, Jiaxin Li, Bingqi Wang, Rui Wang, Yong Gan, Miaorong Yu
Journal: Acta Pharmaceutica Sinica B (2024)

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.
Burden of Childhood Cancer and the Social and Economic Challenges in Adulthood
Authors: Márk Viktor Hernádfői, Dóra Kornélia Koch, Tamás Kói, Marcell Imrei, Rita Nagy, Vanda Máté, Réka Garai, Jessica Donnet, József Balogh, Gábor T. Kovács, Andrea Párniczky, Péter Hegyi, Miklós Garami
Journal: JAMA Pediatrics (2024)

Importance Significant advancements in pediatric oncology have led to a continuously growing population of survivors. Although extensive research is being conducted on the short-, medium-, and long-term somatic effects, reports on psychosocial reintegration are often conflicting; therefore, there is an urgent need to synthesize the evidence to obtain the clearest understanding and the most comprehensive answer. Objective To provide a comprehensive review and analysis of the socioeconomic attainment of childhood cancer survivors (CCSs) compared with their unaffected peers. Data Sources A systematic review and meta-analysis was conducted using data obtained from a comprehensive search of MEDLINE (via PubMed), Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) databases on October 23, 2021; the search was updated until July 31, 2023. Study Selection Eligible articles reported on educational attainment, employment, family formation, quality of life (QoL), or health-risk behavior-related outcomes of CCSs, and compared them with their unaffected peers. Study selection was performed in duplicate by 4 blinded independent coauthors. Data Extraction and Synthesis Data extraction was performed in duplicate by 4 independent authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Outcome measures were odds ratios (ORs) and mean differences with 95% CIs; data were pooled using a random-effects model. Results The search identified 43 913 articles, 280 of which were eligible for analysis, reporting data on a total of 389 502 survivors. CCSs were less likely to complete higher levels of education (OR, 0.69; 95% CI, 0.40-1.18), had higher odds of health-related unemployment (OR, 2.94; 95% CI, 1.90-4.57), and showed lower rates of marriage (OR, 0.72; 95% CI, 0.63-0.84) and parenthood (OR, 0.60; 95% CI, 0.49-0.74) compared with population-based controls. Conclusion and Relevance Study findings suggest that CCSs face several socioeconomic difficulties; as a result, the next goal of pediatric oncology should be to minimize adverse effects, as well as to provide lifelong survivorship support aimed at maximizing social reintegration.
AI-Generated Draft Replies Integrated Into Health Records and Physicians’ Electronic Communication
Authors: Ming Tai-Seale, Sally L. Baxter, Florin Vaida, Amanda Walker, Amy M. Sitapati, Chad Osborne, Joseph Diaz, Nimit Desai, Sophie Webb, Gregory Polston, Teresa Helsten, Erin Gross, Jessica Thackaberry, Ammar Mandvi, Dustin Lillie, Steve Li, Geneen Gin, Suraj Achar, Heather Hofflich, Christopher Sharp, Marlene Millen, Christopher A. Longhurst
Journal: JAMA Network Open (2024)

Importance Timely tests are warranted to assess the association between generative artificial intelligence (GenAI) use and physicians’ work efforts. Objective To investigate the association between GenAI-drafted replies for patient messages and physician time spent on answering messages and the length of replies. Design, Setting, and Participants Randomized waiting list quality improvement (QI) study from June to August 2023 in an academic health system. Primary care physicians were randomized to an immediate activation group and a delayed activation group. Data were analyzed from August to November 2023. Exposure Access to GenAI-drafted replies for patient messages. Main Outcomes and Measures Time spent (1) reading messages, (2) replying to messages, (3) length of replies, and (4) physician likelihood to recommend GenAI drafts. The a priori hypothesis was that GenAI drafts would be associated with less physician time spent reading and replying to messages. A mixed-effects model was used. Results Fifty-two physicians participated in this QI study, with 25 randomized to the immediate activation group and 27 randomized to the delayed activation group. A contemporary control group included 70 physicians. There were 18 female participants (72.0%) in the immediate group and 17 female participants (63.0%) in the delayed group; the median age range was 35-44 years in the immediate group and 45-54 years in the delayed group. The median (IQR) time spent reading messages in the immediate group was 26 (11-69) seconds at baseline, 31 (15-70) seconds 3 weeks after entry to the intervention, and 31 (14-70) seconds 6 weeks after entry. The delayed group’s median (IQR) read time was 25 (10-67) seconds at baseline, 29 (11-77) seconds during the 3-week waiting period, and 32 (15-72) seconds 3 weeks after entry to the intervention. The contemporary control group’s median (IQR) read times were 21 (9-54), 22 (9-63), and 23 (9-60) seconds in corresponding periods. The estimated association of GenAI was a 21.8% increase in read time (95% CI, 5.2% to 41.0%; P = .008), a −5.9% change in reply time (95% CI, −16.6% to 6.2%; P = .33), and a 17.9% increase in reply length (95% CI, 10.1% to 26.2%; P &amp;amp;lt; .001). Participants recognized GenAI’s value and suggested areas for improvement. Conclusions and Relevance In this QI study, GenAI-drafted replies were associated with significantly increased read time, no change in reply time, significantly increased reply length, and some perceived benefits. Rigorous empirical tests are necessary to further examine GenAI’s performance. Future studies should examine patient experience and compare multiple GenAIs, including those with medical training.
Adverse Pregnancy Outcomes and Long-Term Mortality in Women
Authors: Casey Crump, Jan Sundquist, Kristina Sundquist
Journal: JAMA Internal Medicine (2024)

Women with adverse pregnancy outcomes, such as preterm delivery or preeclampsia, have higher future risks of cardiometabolic disorders; however, little is known about their long-term mortality risks. A better understanding of such risks is needed to facilitate early identification of high-risk women and preventive actions.
High glutamine increases stroke risk by inducing the endothelial‐to‐mesenchymal transition in moyamoya disease
Authors: Qiheng He, Junsheng Li, Chuming Tao, Chaofan Zeng, Chenglong Liu, Zhiyao Zheng, Siqi Mou, Wei Liu, Bojian Zhang, Xiaofan Yu, Yuanren Zhai, Jia Wang, Qian Zhang, Yan Zhang, Dong Zhang, Jizong Zhao, Peicong Ge
Journal: MedComm (2024)

Abstract At present, there is limited research on the mechanisms underlying moyamoya disease (MMD). Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial‐to‐mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients. We found glutamine levels were positively associated with a greater risk of stroke (OR = 1.599, p = 0.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4‐transfected HBMECs, the MAPK–ERK–TGF–β/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4‐transfected HBMECs. We also found the protein level of ITGB4 was upregulated in the superficial temporal arteries of patients with MMD. In conclusion, our study suggests that glutamine may be an independent risk factor for hemorrhage or infarction in patients with MMD and targeting ITGB4 could potentially be therapeutic approaches for MMD.