tbuckley/cabot-search huggingface dataset:
Ethical challenges in contemporary psychiatry: an overview and an appraisal of possible strategies and research needs
Authors: Silvana Galderisi, Paul S. Appelbaum, Neeraj Gill, Piers Gooding, Helen Herrman, Antonio Melillo, Keris Myrick, Soumitra Pathare, Martha Savage, George Szmukler, John Torous
Journal: World Psychiatry (2024)

Psychiatry shares most ethical issues with other branches of medicine, but also faces special challenges. The Code of Ethics of the World Psychiatric Association offers guidance, but many mental health care professionals are unaware of it and the principles it supports. Furthermore, following codes of ethics is not always sufficient to address ethical dilemmas arising from possible clashes among their principles, and from continuing changes in knowledge, culture, attitudes, and socio‐economic context. In this paper, we identify topics that pose difficult ethical challenges in contemporary psychiatry; that may have a significant impact on clinical practice, education and research activities; and that may require revision of the profession's codes of ethics. These include: the relationships between human rights and mental health care, research and training; human rights and mental health legislation; digital psychiatry; early intervention in psychiatry; end‐of‐life decisions by people with mental health conditions; conflicts of interests in clinical practice, training and research; and the role of people with lived experience and family/informal supporters in shaping the agenda of mental health care, policy, research and training. For each topic, we highlight the ethical concerns, suggest strategies to address them, call attention to the risks that these strategies entail, and highlight the gaps to be narrowed by further research. We conclude that, in order to effectively address current ethical challenges in psychiatry, we need to rethink policies, services, training, attitudes, research methods and codes of ethics, with the concurrent input of a range of stakeholders, open minded discussions, new models of care, and an adequate organizational capacity to roll‐out the implementation across routine clinical care contexts, training and research.
Endoplasmic reticulum-targeted biomimetic nanoparticles induce apoptosis and ferroptosis by regulating endoplasmic reticulum function in colon cancer
Authors: Hongxin Tan, Ziqi Shen, Xiaohua Wang, Sicheng Shu, Jie Deng, Li Lu, Ziyan Fan, Danni Hu, Pu Cheng, Xi Cao, Qi Huang
Journal: Journal of Controlled Release (2024)
The Pivotal Role of Germline <i>BRCA2</i> Pathogenic Variants in “Apparently Sporadic” Pancreatic Cancer
Authors: Jonathan R. Brody, Alison P. Klein
Journal: Cancer Research (2024)

Abstract In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360–4
<scp>IĸBζ</scp> is a central modulator of inflammatory arthritis pathogenesis
Authors: Gaurav Swarnkar, Musarrat Naaz, Dorothy Mims, Prashant Gupta, Timothy Peterson, Matthew J. Christopher, Srikanth Singamaneni, Gabriel Mbalaviele, Yousef Abu‐Amer
Journal: Arthritis & Rheumatology (2024)

Objective Current therapies targeting individual factors in inflammatory arthritis show variable efficacy, often requiring treatment with combinations of drugs, and are associated with undesirable side effects. NF‐ĸB is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF‐ĸB is precarious. Hence, identifying pathways downstream of NF‐ĸB that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified IĸBζ as a unique inflammatory signature of NF‐ĸB that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF‐ĸB signals. Methods We generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding IĸBζ). These models were subjected to serum transfer‐induced arthritis. Additionally, pharmacologic inhibitors of IĸBζ were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples. Results Global deletion of Nfkbiz or depletion of neutrophils (vastly IĸBζ + cells) reduced inflammatory synovial cells and increased anti‐inflammatory and regenerative synovial cells, plummeted expression of inflammatory factors and ameliorated experimental mouse inflammatory arthritis. Further, expression of immune responsive gene‐1, the enzyme responsible for itaconate production, was increased in synovial cells. Accordingly, the itaconate derivative dimethyl itaconate (DI) inhibited IĸBζ‐mediated inflammatory factors. Further, in silico screen identified 8‐hydroxyquinoline (HQ) as a putative inhibitor of IĸBζ not affecting physiologic NF‐ĸB activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage. Conclusion Our study positions IĸBζ as an inflammation‐specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF‐ĸB. image
Keep It Moving: Physical Activity in the Prevention of Obesity-Driven Pancreatic Cancer
Authors: Akin Sogunro, Mandar D. Muzumdar
Journal: Cancer Research (2024)

Despite the already dire impact of pancreatic cancer, a growing subset of patients with obesity exhibits an amplified risk of disease and worse outcomes. Mouse models have revealed that obesity is distinctly pathogenic, accelerating pancreatic ductal adenocarcinoma (PDAC) progression and inducing increased desmoplasia and myeloid cell infiltration in the tumor microenvironment. However, whether and how obesity-countering interventions, such as exercise, reverse the protumorigenic effects of obesity is incompletely understood. In this issue of Cancer Research, Pita-Grisanti and colleagues investigate the impact of physical activity (PA) in disrupting obesity-driven PDAC. Employing a variety of sophisticated models, including autochthonous genetically engineered mice, orthotopic syngeneic allografts, high-fat diet–induced obesity, and PA interventions in mice and humans, the authors found that PA impedes PDAC development in obese mice but does not impact the growth of advanced tumors. These antitumor effects correlated with reduced inflammation and fibrosis in the tumor microenvironment, a decline in high-fat diet–induced circulating inflammatory cytokines, and an increase in the IL15 signaling axis in white adipose tissue. Although adipose-targeted IL15 therapy was effective in suppressing advanced tumor growth in lean mice, obese mice were resistant to its therapeutic benefits. Together, the findings argue that PA delays obesity-driven early PDAC progression, implicating the preferential benefit of exercise as a preventative strategy. They further identify changes in obesity-associated local and systemic cytokine production as a possible mechanism for the antitumor effects of PA and help define context-specific determinants of response for emerging IL15-based immunotherapies. See related article by Pita-Grisanti et al., p. 3058
Short‐term risk of cardiovascular events in people newly diagnosed with gout
Authors: Edoardo Cipolletta, Georgina Nakafero, Pascal Richette, Anthony J. Avery, Mamas A. Mamas, Laila J. Tata, Abhishek Abhishek
Journal: Arthritis & Rheumatology (2024)

Objective To investigate the temporal association between the first diagnosis of gout and cardiovascular events in the short term. Methods We performed a self‐controlled case series analysis and a cohort study using data from linked primary care, hospitalization, and mortality records from the United Kingdom's Clinical Practice Research Database‐GOLD. We included individuals with a new diagnosis of gout either in the primary care or secondary care between January 1, 1997 and December 31, 2020. The first consultation at which gout was diagnosed was the exposure of interest. The main outcome consisted of cardiovascular events (ie, a composite of fatal and nonfatal myocardial infarction, ischemic or hemorrhagic stroke, and transient ischemic attack). Results The 4,398 patients (66.9% male, mean age 74.6 years) had a cardiovascular event within at least two years of their first recorded diagnosis of gout. The incidence of cardiovascular events was significantly higher in the 30 days after the first diagnosis of gout compared to baseline (adjusted incidence rate ratio 1.55, 95% confidence interval [CI] 1.33–1.83). Among 76,440 patients (72.9% male, mean age 63.2 years) included in the cohort study, the incidence of cardiovascular events in the 30 days after the first gout diagnosis (31.2 events per 1,000 person‐years, 95% CI 27.1–35.9) was significantly higher than in days 31 to 730 after gout diagnosis (21.6 events per 1,000 person‐years, 95% CI 20.8–22.4) with a rate difference of −9.6 events per 1,000 person‐years (95% CI −14.0 to −5.1). Conclusion Individuals had a short‐term increased risk of cardiovascular events in the 30 days following the first consultation at which gout was diagnosed.
Social Determinants of Cardiovascular Health in Asian Americans: A Scientific Statement From the American Heart Association
Authors: Nilay S. Shah, Namratha R. Kandula, Yvonne Commodore-Mensah, Brittany N. Morey, Shivani A. Patel, Sally Wong, Eugene Yang, Stella Yi
Journal: Circulation (2024)

To achieve cardiovascular health (CVH) equity in the United States, an understanding of the social and structural factors that contribute to differences and disparities in health is necessary. The Asian American population is the fastest-growing racial group in the United States but remains persistently underrepresented in health research. There is heterogeneity in how individual Asian American ethnic groups experience CVH and cardiovascular disease outcomes, with certain ethnic groups experiencing a higher burden of adverse social conditions, disproportionately high burden of suboptimal CVH, or excess adverse cardiovascular disease outcomes. In this scientific statement, upstream structural and social determinants that influence CVH in the Asian American population are highlighted, with particular emphasis on the role of social determinants of health across disaggregated Asian American ethnic groups. Key social determinants that operate in Asian American communities include socioeconomic position, immigration and nativity, social and physical environments, food and nutrition access, and health system–level factors. The role of underlying structural factors such as health, social, and economic policies and structural racism is also discussed in the context of CVH in Asian Americans. To improve individual-, community-, and population-level CVH and to reduce CVH disparities in Asian American ethnic subgroups, multilevel interventions that address adverse structural and social determinants are critical to achieve CVH equity for the Asian American population. Critical research gaps for the Asian American population are given, along with recommendations for strategic approaches to investigate social determinants of health and intervene to reduce health disparities in these communities.
Cancer-Associated Fibroblasts: From Spectators to Protagonists in Pancreatic Cancer Progression
Authors: Gianluca Mucciolo, Wenlong Li, Giulia Biffi
Journal: Cancer Research (2024)

Abstract Our knowledge of the origins, heterogeneity, and functions of cancer-associated fibroblasts (CAF) in pancreatic ductal adenocarcinoma (PDAC) has exponentially increased over the last two decades. This has been facilitated by the implementation of new models and single-cell technologies. However, a few key studies preceded the current exciting times in CAF research and were fundamental in initiating the investigation of CAFs and of their roles in PDAC. With their study published in Cancer Research in 2008, Hwang and colleagues have been first to successfully isolate and immortalize human pancreatic stellate cells (HPSC) from PDAC tissues. This new tool allowed them to probe the roles of CAFs in PDAC as never done before. By performing complementary in vitro and in vivo analyses, the authors demonstrated the involvement of HPSCs in PDAC malignant cell proliferation, invasion, and therapy resistance. Here, we leverage that seminal study as a framework to discuss the advances made over the last 16 years in understanding the complexity and central roles of CAFs in PDAC progression. See related article by Hwang and colleagues, Cancer Res 2008;68:918–26
Electronic Health Record Nudges and Health Care Quality and Outcomes in Primary Care
Authors: Oliver T. Nguyen, Avaneesh R. Kunta, SriVarsha Katoju, Sara Gheytasvand, Niloofar Masoumi, Ronia Tavasolian, Amir Alishahi Tabriz, Young-Rock Hong, Karim Hanna, Randa Perkins, Arpan Parekh, Kea Turner
Journal: JAMA Network Open (2024)

Importance Nudges have been increasingly studied as a tool for facilitating behavior change and may represent a novel way to modify the electronic health record (EHR) to encourage evidence-based care. Objective To evaluate the association between EHR nudges and health care outcomes in primary care settings and describe implementation facilitators and barriers. Evidence Review On June 9, 2023, an electronic search was performed in PubMed, Embase, PsycINFO, CINAHL, and Web of Science for all articles about clinician-facing EHR nudges. After reviewing titles, abstracts, and full texts, the present review was restricted to articles that used a randomized clinical trial (RCT) design, focused on primary care settings, and evaluated the association between EHR nudges and health care quality and patient outcome measures. Two reviewers abstracted the following elements: country, targeted clinician types, medical conditions studied, length of evaluation period, study design, sample size, intervention conditions, nudge mechanisms, implementation facilitators and barriers encountered, and major findings. The findings were qualitatively reported by type of health care quality and patient outcome and type of primary care condition targeted. The Risk of Bias 2.0 tool was adapted to evaluate the studies based on RCT design (cluster, parallel, crossover). Studies were scored from 0 to 5 points, with higher scores indicating lower risk of bias. Findings Fifty-four studies met the inclusion criteria. Overall, most studies (79.6%) were assessed to have a moderate risk of bias. Most or all descriptive (eg, documentation patterns) (30 of 38) or patient-centeredness measures (4 of 4) had positive associations with EHR nudges. As for other measures of health care quality and patient outcomes, few had positive associations between EHR nudges and patient safety (4 of 12), effectiveness (19 of 48), efficiency (0 of 4), patient-reported outcomes (0 of 3), patient adherence (1 of 2), or clinical outcome measures (1 of 7). Conclusions and Relevance This systematic review found low- and moderate-quality evidence that suggested that EHR nudges were associated with improved descriptive measures (eg, documentation patterns). Meanwhile, it was unclear whether EHR nudges were associated with improvements in other areas of health care quality, such as effectiveness and patient safety outcomes. Future research is needed using longer evaluation periods, a broader range of primary care conditions, and in deimplementation contexts.
Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF
Authors: Alwin Tubben, George Markousis-Mavrogenis, Laura M G Meems, Bart J van Essen, Lukas Baumhove, Milou Berends, Hendrea S A Tingen, Johan Bijzet, Bouke P C Hazenberg, Adriaan A Voors, Dirk J van Veldhuisen, Riemer H J A Slart, Hans L A Nienhuis, Peter van der Meer
Journal: Cardiovascular Research (2024)

Abstract Aims Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. Methods and results In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61–0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65–0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. Conclusion ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.
Chronic Illness and Quality of Life 5 Years After Displacement Among Rohingya Refugees in Bangladesh
Authors: Ahmed Hossain, Redwan Bin Abdul Baten, Altaf Saadi, Juwel Rana, Taifur Rahman, Hasan Mahmud Reza, Mohamad Alameddine
Journal: JAMA Network Open (2024)

Importance Rohingya refugees, forcibly displaced from Myanmar, face challenges adapting to Bangladesh. Examining their quality of life (QOL) is vital to identifying nuanced factors associated with their well-being, informing targeted interventions for an improved QOL. Objectives To identify the QOL among Rohingya refugees 5 years after migration to Bangladesh, with a particular emphasis on understanding the complex interplay between sociodemographic factors and chronic illnesses. Design, Setting, and Participants A cross-sectional study involving resettled Rohingya adults was conducted between May 18 and July 7, 2021, approximately 5 years after their resettlement in Bangladesh. Of the participants, 500 individuals were healthy, whereas 558 individuals were undergoing treatment for at least 1 chronic disease. Data were analyzed from January to February 2024. Main Outcomes and Measures The study assessed QOL using the short version of the World Health Organization’s QOL Questionnaire, covering 4 domains: physical, psychological, social, and environmental. Scores were transformed to a maximum of 100. Tobit linear regression, adjusted for potential confounders, was employed for analysis. Results The study included a total of 1058 respondents, who were predominantly female (630 participants [59.5%]) and had a mean (SD) age of 42.5 (16.1) years. Despite being healthy, individuals without chronic illnesses had median QOL scores ranging from 44 to 56 out of 100, indicating a relatively poor QOL. A total of 260 participants (46.6%) with chronic diseases reported very poor or poor QOL, in contrast to 58 healthy individuals (11.6%) in the fifth year after displacement. Specifically, patients with cancer and those who had multimorbidity exhibited the lowest QOL scores across all domains, with significant reductions in the physical health (10.57 decrease; 95% CI, −12.97 to −8.17) and psychological domain scores (7.20 decrease; 95% CI, −9.71 to −5.93) according to Tobit regression analysis. Conclusions and Relevance This study found that chronic illnesses were associated with all domains of QOL among Rohingya refugees, particularly those with musculoskeletal disorders, cancer, and multimorbid conditions. This heightened vulnerability may contribute to poor QOL in this population. By uncovering these disparities, the study lays the groundwork for targeted interventions and policies aligned with the United Nations’ goal of leaving no one behind in sustainable development efforts.