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The dynamics of three-dimensional (3D) genome organization are essential to transcriptional regulation. While enhancers regulate spatiotemporal gene expression, chromatin looping is a means for enhancer-promoter interactions yielding cell-type-specific gene expression. Further, non-canonical DNA secondary structures, such as G-quadruplexes (G4s), are related to increased gene expression. However, the role of G4s in promoter-distal regulatory elements, such as super-enhancers (SE), and in chromatin looping has remained elusive. Here we show that mature microRNA 9 (miR-9) is enriched at promoters and SE of genes that are inducible by transforming growth factor beta 1 (TGFB1) signaling. Moreover, we find that miR-9 is required for formation of G4s, promoter-super-enhancer looping and broad domains of the euchromatin histone mark H3K4me3 at TGFB1-responsive genes. Our study places miR-9 in the same functional context with G4s and promoter-enhancer interactions during 3D genome organization and transcriptional activation induced by TGFB1 signaling, a critical signaling pathway in cancer and fibrosis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PG) consist of a core protein to which the glycosaminoglycan (GAG) chains, HS or CS, are attached through a common linker tetrasaccharide. In the extracellular space, they are involved in the regulation of cell communication, assuring development and homeostasis. The HSPG biosynthetic pathway has documented 51 genes, with many diseases associated to defects in some of them. The phenotypic consequences of this genetic variation in humans, and of genetic ablation in mice, and their expression patterns, led to a phenotypically centered HSPG biosynthetic pathway model. In this model, HS sequences produced by ubiquitous NDST1, HS2ST and HS6ST enzymes are essential for normal development and homeostasis, whereas tissue restricted HS sequences produced by the non-ubiquitous NDST2-4, HS6ST2-3, and HS3ST1-6 enzymes are involved in adaptative behaviors, cognition, tissue responsiveness to stimuli, and vulnerability to disease. The model indicates that the flux through the HSPG/CSPG pathways and its diverse branches is regulated by substrate preferences and protein-protein-interactions. This results in a privileged biosynthesis of HSPG over that of CSPGs, explaining the phenotypes of linkeropathies, disease caused by defects in genes involved in the biosynthesis of the common tetrasaccharide linker. Documented feedback loops whereby cells regulate HS sulfation, and hence the interactions of HS with protein partners, may be similarly implemented, e.g., protein tyrosine sulfation and other posttranslational modifications in enzymes of the HSPG pathway. Together, ubiquitous HS, specialized HS, and their biosynthesis model can facilitate research for a better understanding of HSPG roles in physiology and pathology., (© 2024 The Author(s).)

Objective: To test quantitative process measures characterizing the work of social needs case managers as they assisted patients with diverse health-related needs-spanning both medical and social domains., Study Setting and Design: The study analyzed secondary data on 7076 patients working with 147 case managers from the CommunityConnect social needs case management program in Contra Costa County, California from 2018 to 2021. The service-designed to be holistic with a focus on social determinants as root causes of health issues-helped patients navigate social services, health care, and mental health care., Data Sources and Analytic Sample: We used cross-sectional analyses to quantitatively characterize electronic health records (EHRs) derived measures of case management intensity (goal updates), duration (days goal was open), and outcomes for 19 different categories of health and social goals. Mixed-effects regression models were used to examine how work process measures varied according to goal categories. Models nested goals within patients within case managers and adjusted for patient-level covariates., Principal Findings: The most common goals were dental care (53%), food (40%), and housing (39%). In adjusted analyses, housing goals had significantly more case manager updates than any other type of goal with a marginal mean of 14.0 updates (95% CI: 13.4-14.7), were worked on for significantly longer (marginal mean of 417 days, 95% CI: 360-474) than any goal except dental care, and were least likely to be resolved. Utilities, insurance, and medication coordination goals were most likely to be resolved., Conclusions: Case managers and patients repeatedly worked on goals over many months. Meeting housing needs and accessing dental care were issues that were not easily resolved and required extensive follow-up. One-time referral interventions may need follow-up systems to meaningfully support social and health needs., (© 2024 Health Research and Educational Trust.)

Introduction: We aimed to determine the effect of years of schooling (YoS) and age on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) scores in preclinical carriers group (PCG) and non-carriers group (NCG) of the APP V717I mutation., Methods: We included 39 first-degree Mexican relatives of APP V717I carriers (PCG = 15; NCG = 24). We report eight CERAD-MX tasks: Mini-Mental State Examination (MMSE), Word List Learning (WLL), Delayed Recall (WLD) and Recognition (WLR), Constructional Praxis Copy (CPC) and Recall (CPR), Semantic Verbal Fluency (SVF), and Verbal Boston Naming (VBN), comparing both groups' performance and simulating new samples' random vectors by inverse transform sampling., Results: PCG and NCG performed similarly on CERAD-MX. In both groups, YoS and age influence all z scores. A positive age effect resulted for PCG on CPC and SVF; for the NCG on MMSE, SVF, and VBN., Discussion: All tasks are influenced by YoS. Higher YoS/younger age or YoS/older age interactions affected different tasks, suggesting that YoS confounds outcomes., Highlights: Years of schooling (YoS) and age affect the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease scores of APP V717I preclinical carriers.Preclinical carriers underperformed non-carriers on Constructional Praxis Recall.Fewer YoS emerges as a confounding variable when detecting cognitive failures.Younger participants in both groups overperformed the older ones in the Memory tasks.Randomized data simulation increases statistical power when analyzing rare diseases., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The article describes a successful clinical outcome in the case of a 24-year-old male with a diagnosis of an ostium secundum atrial defect secondary to a perforated aneurysm associated with vena cava agenesis. During hospitalization, an echocardiogram revealed the presence of ostium secundum inter-atrial communication with a left to right shunt, a left ventricular ejection fraction (LVEF) of 60%, and mild pulmonary hypertension, measured at 40 mmHg. CT imaging showed anomalous dilation of the azygos vein (16.8 mm), associated with interruption of the vena cava in the intrahepatic and adrenal portion, continuing through the azygos system and draining into the superior vena cava. Open-heart surgery was performed with pericardium patch placement on the defect. Postoperative transthoracic echocardiography revealed a tracking of the interatrial septum, with adequate placement of the surgical patch and no evidence of residual short circuits. The postoperative recovery was favorable, and the patient was discharged five days after surgery. Outpatient monitoring at the first and third months showed no complications during physical examination and echocardiogram imaging., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Arias Rivera et al.)

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity., Competing Interests: Declaration of interests D.E.F. has a financial interest in Soltego. S.M. and D.A.H. are cofounders of TellBio. G.M.B. has sponsored research agreements with Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals; served on advisory boards for Iovance, Merck, Nektar Therapeutics, Novartis, and Ankyra Therapeutics; consults for Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics; and holds equity in Ankyra Therapeutics. M.S.-F. received funding from Calico Life Sciences, Bristol-Myers Squibb, Istari Oncology, and consultants for Galvanize Therapeutics. R.W.J. is a member of the advisory board for/has a financial interest in Xsphera Biosciences Inc. R.W.J. has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), and Bioxcel Therapeutics (invited speaker). R.W.J. has ownership interest in U.S. patents US20200399573A9 and US20210363595A1. A.N.H. has received grants/research support from Amgen, Blueprint Medicines, BridgeBio, Bristol-Myers Squibb, C4 Therapeutics, Eli Lilly, Novartis, Nuvalent, Pfizer, Roche/Genentech, and Scorpion Therapeutics. A.N.H. has served as a compensated consultant for Amgen, Engine Biosciences, Nuvalent, Oncovalent, Pfizer, TigaTx, and Tolremo Therapeutics. M.L.S. is an equity holder and scientific co-founder/advisory board member of Immunitas Therapeutics. C.J.O. received funding from Scorpion Therapeutics, Gilead Sciences, and eFFECTOR Therapeutics. L.B.-P. is a founder/consultant/holds privately held equity in Scorpion Therapeutics. All relationships for investigators have been reviewed/managed by their respective institutions in accordance with their conflict-of-interest policies. M.M., B.H., R.D.W., H.E.M., C.-C.T., G.K., N.B., J.R.N., and B.R.M. are employees of Scorpion Therapeutics and some hold equity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Malnutrition in adult intensive care unit patients is associated with poor clinical outcomes. Providing adequate nutritional support to the critically ill adult should be an important goal for the intensivist. This narrative review aims to delineate the role of parenteral nutrition (PN) in meeting nutritional goals. We examined the data regarding the safety and efficacy of PN compared to enteral nutrition. In addition, we describe practical considerations for the use of PN in the ICU including patient nutritional risk stratification, nutrient composition selection for PN, route of PN administration, and biochemical monitoring., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet as measured by conditioned place preference but do not have a greater motivation to obtain food reward using a progressive ratio task, relative to wildtype littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone levels compared to wildtype mice. Taken together, these results are the first to show that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress., Competing Interests: Declaration of Competing Interest The authors do not report any conflicts of interest., (Published by Elsevier B.V.)

We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness ( KLF4 and FGFR2 ) and epithelial-mesenchymal transition ( ZEB2 , TWIST2 , SNAI2 , CDH2 , and VIM ) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.

Environmental pollution nowadays has not only a direct correlation with human health changes but a direct social impact. Epidemiological studies have evidenced the increased damage to human health on a daily basis because of damage to the ecological niche. Rapid urban growth and industrialized societies importantly compromise air quality, which can be assessed by a notable accumulation of air pollutants in both the gas and the particle phases. Of them, particulate matter (PM) represents a highly complex mixture of organic and inorganic compounds of the most variable size, composition, and origin. PM being one of the most complex environmental pollutants, its accumulation also varies in a temporal and spatial manner, which challenges current analytical techniques used to investigate PM interactions. Nevertheless, the characterization of the chemical composition of PM is a reliable indicator of the composition of the atmosphere, the quality of breathed air in urbanized societies, industrial zones and consequently gives support for pertinent measures to avoid serious health damage. Epigenomic damage is one of the most promising biological mechanisms of air pollution-derived carcinogenesis. Therefore, this review aims to highlight the implication of PM exposure in diverse molecular mechanisms driving human diseases by altered epigenetic regulation. The presented findings in the context of pan-organic cancer, fibrosis, neurodegeneration and metabolic diseases may provide valuable insights into the toxicity effects of PM components at the epigenomic level and may serve as biomarkers of early detection for novel targeted therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gavito-Covarrubias, Ramírez-Díaz, Guzmán-Linares, Limón, Manuel-Sánchez, Molina-Herrera, Coral-García, Anastasio, Anaya-Hernández, López-Salazar, Juárez-Díaz, Martínez-Juárez, Torres-Jácome, Albarado-Ibáñez, Martínez-Laguna, Morán and Rubio.)

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

Background: Lung cancer (LC) causes more deaths worldwide than any other cancer type. Despite advances in therapeutic strategies, the fatality rate of LC cases remains high (95%) since the majority of patients are diagnosed at late stages when patient prognosis is poor. Analysis of the International Association for the Study of Lung Cancer (IASLC) database indicates that early diagnosis is significantly associated with favorable outcome. However, since symptoms of LC at early stages are unspecific and resemble those of benign pathologies, current diagnostic approaches are mostly initiated at advanced LC stages., Methods: We developed a LC diagnosis test based on the analysis of distinct RNA isoforms expressed from the GATA6 and NKX2-1 gene loci, which are detected in exhaled breath condensates (EBCs). Levels of these transcript isoforms in EBCs were combined to calculate a diagnostic score (the LC score). In the present study, we aimed to confirm the applicability of the LC score for the diagnosis of early stage LC under clinical settings. Thus, we evaluated EBCs from patients with early stage, resectable non-small cell lung cancer (NSCLC), who were prospectively enrolled in the EMoLung study at three sites in Germany., Results: LC score-based classification of EBCs confirmed its performance under clinical conditions, achieving a sensitivity of 95.7%, 91.3% and 84.6% for LC detection at stages I, II and III, respectively., Conclusions: The LC score is an accurate and non-invasive option for early LC diagnosis and a valuable complement to LC screening procedures based on computed tomography., (© 2023. Springer Science+Business Media, LLC.)

Background: It remains unclear whether the racial-ethnic composition or the socioeconomic profiles of eligible primary care practices better explain practice participation in the Centers for Medicare and Medicaid Services' (CMS) Comprehensive Primary Care Plus (CPC+) program., Objective: To examine whether practices serving high proportions of Black or Latino Medicare fee-for-service (FFS) beneficiaries were less likely to participate in CPC+ in 2021 compared to practices serving lower proportions of these populations., Design: 2019 IQVIA OneKey data on practice characteristics was linked with 2018 CMS claims data and 2021 CMS CPC+ participation data. Medicare FFS beneficiaries were attributed to practices using CMS's primary care attribution method., Participants: 11,718 primary care practices and 7,264,812 attributed Medicare FFS beneficiaries across 18 eligible regions., Methods: Multivariable logistic regression models examined whether eligible practices with relatively high shares of Black or Latino Medicare FFS beneficiaries were less likely to participate in CPC+ in 2021, controlling for the clinical and socioeconomic profiles of practices., Main Measures: Proportion of Medicare FFS beneficiaries attributed to each practice that are (1) Latino and (2) Black., Key Results: Of the eligible practices, 26.9% were CPC+ participants. In adjusted analyses, practices with relatively high shares of Black (adjusted odds ratio, aOR = 0.62, p < 0.05) and Latino (aOR = 0.32, p < 0.01) beneficiaries were less likely to participate in CPC+ compared to practices with lower shares of these beneficiary groups. State differences in CPC+ participation rates partially explained participation disparities for practices with relatively high shares of Black beneficiaries, but did not explain participation disparities for practices with relatively high shares of Latino beneficiaries., Conclusions: The racial-ethnic composition of eligible primary care practices is more strongly associated with CPC+ participation than census tract-level poverty. Practice eligibility requirements for CMS-sponsored initiatives should be reconsidered so that Black and Latino beneficiaries are not left out of the benefits of practice transformation., (© 2023. The Author(s).)

Limonium sinuatum (Plumbaginaceae) is the most commonly cultivated recognizable cut flower crop in the genus Limonium. It is known by several common names including statice and sea lavender, due to its lilac-colored flowers and the fact that it naturally inhabits mainly coastal areas (Mellesse et al, 2013). Limonium sinuatum is native to the Mediterranean, although as a popular garden plant, has been naturalized in other parts of the world including coastal areas of California (USDA NRCS 2020). Cultivated L. sinuatum is used in fresh and dry flower arrangements in the Americas, comprising approximately 20% of the floriculture cultivated area in Ecuador (Vega and Morales 2011; Abascal Cañas 2017). In December 2014, L. sinuatum plants in the public park "Baños del Inca" in Cajamarca, Peru (S 7 9'46"; W 78 27'53"), were found infected with a rust disease. The plants were scattered in the park but infection incidence was 100% as individual plants were all found to be infected (Fig 1). Based on the percentage of symptomatic areas, including the yellow halos around pustules, calculated with ImageJ (Collins, 2007) from field photographs, the disease severity was estimated to be 58.9% in average, ranging from 19.8% up to 90.0%. Uredinia were present on both sides of the leaves as well as on stems and were roundish, oblong, pulverulent, and cinnamon brown in color; urediniospores 25.5 to 35.0 × 22.5 to 31.0 µm, were globoid to ellipsoid; urediniospore walls were cinnamon-brown, 2.5 to 3.0 µm thick, densely verrucose, with 2 to 3 equatorial germ pores. Few telia were present on leaves; these were scattered roundish or oblong, and greyish in color; teliospores 26.5 to 41.0 × 16.0 to 25.0 µm, were ellipsoid to obovoid, mostly attenuated at the apex; teliospore walls were colorless, 2-3 µm thick at sides, and up to 10 µm thick at apex. Teliospores readily germinated in sori producing basidia and basidiospores (Fig. 2). The rust features and dimensions of rust spores are consistent with available descriptions of Uromyces savulescui Rayss (Guyot 1951; Vakalounakis and Malathrakis 1987). To confirm identity, a 576 bp region of the 28S subunit of the ribosomal DNA repeat was sequenced following previously published protocols and primers (Aime 2006, Aime et al. 2018). The resulting sequence (GenBank Accession No. OR291160) shared 99.83% (573/574 bp) identity with a sequence deposited as Uromyces limonii (DC.) Lev. (accession KY764194, BPI910295, Demers et al. unpublished) from L. sinuatum in Ethiopia. However, U. limonii produces orange uredinia, thin-walled yellow-orange urediniospores, teliospores with mostly light chestnut brown wall and infects different hosts (Savile and Conners 1951). It is likely that KY764194 represents a misannotated record of U. savulescui. While Koch's postulates can be a useful tool for establishing causality in certain infectious diseases, their use may be limited when it comes to rust diseases based on old herbarium specimens. In our case, due to the age of the specimen, which is almost nine years old, various other methods were employed to identify the pathogen. These methods included microscopic examination for morphological criteria of the urediniospores and teliospores, as well as molecular techniques like 28S rDNA sequencing. Rust disease on L. sinuatum has been previously reported in Ecuador but the causal agent was identified as a Puccinia sp. and reported that the rust was able to destroy entire plots in humid conditions (Vega and Morales 2011). Whether this report also represent U. savulescui is not certain, but given that the urediniospores of Puccinia species are generally 2-celled, it is unlikely. García-Hernández et al. (2008) reported U. limonii on Limonium spp. from Chile, and Coca (2020) also reported U. limonii on Limonium sp., from Bolivia. However, judging from the photomicrographs (Coca 2020), the rust in the latter report is definitely U. savulescui and not U. limonii. Uromyces savulescui has been previously reported from the Mediterranean region and the Canary Islands (Vakalounakis and Malathrakis 1987). To our knowledge there is no report of this rust in the Americas, excepting the probable misidentifications already listed herein. The specimen has been deposited in the Arthur Fungarium at Purdue University as PURN15037.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

Our study focused on deciphering the role of F-actin and related regulatory factors during SARS-CoV-2 particle production and transmission in human pulmonary cells. Quantitative high-resolution microscopies revealed that the late phases of SARS-CoV-2 infection induce a strong rearrangement of F-actin nanostructures dependent on the viral M, E, and N structural proteins. Intracellular vesicles containing viral components are labeled with Rab7 and Lamp1 and are surrounded by F-actin ring-shaped structures, suggesting their role in viral trafficking toward the cell membrane for virus release. Furthermore, filopodia-like nanostructures were loaded with viruses, potentially facilitating their egress and transmission between lung cells. Gene expression analysis revealed the involvement of alpha-actinins under the regulation of the protein kinase N (PKN). The use of a PKN inhibitor efficiently reduces virus particle production, restoring endoplasmic reticulum and F-actin cellular shape. Our results highlight an important role of F-actin rearrangements during the productive phases of SARS-CoV-2 particles., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Patient-engagement strategies are being encouraged by payers and governments, but with limited evidence about whether practice adoption of these strategies impacts utilization and spending. We examine the association of physician practice adoption of patient-engagement strategies (low vs moderate vs high) with potentially preventable utilization and total spending for patients with type 2 diabetes and/or cardiovascular disease using US physician practice survey (n = 2086) and Medicare fee-for-service (n = 736 269) data. In adjusted analyses, there were no differences in potentially preventable utilization associated with practice adoption of patient-engagement strategies. Compared with patients attributed to practices with moderate adoption, patients attributed to practices with high adoption had higher total spending ($26 364 vs $25 991; P < .05) driven by spending for long-term services and supports, including home health agency, long-term care, skilled nursing facilities, and hospice payments. In contrast, patients attributed to practices with low adoption had higher total spending ($26 481 vs $25 991; P < .01) driven by spending for tests and acute care and clinical access spending. The results highlight that stakeholders that encourage the use of patient-engagement strategies should not necessarily expect reduced spending., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2023. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: Small cell lung cancer (SCLC) is an extremely aggressive cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC remains elusive. Methods: We analyzed human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines by classical methods of molecular biology and biochemistry. In addition, we performed RNA-sequencing-based transcriptomic analysis in human lung cancer cells and human lung tissue samples, as well as high-resolution mass spectrometric analysis of the protein cargo from extracellular vesicles (EVs) that were isolated from human lung cancer cells. Results: Our results demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which may be used for stratification of SCLC patients and prognosis prediction of LC patients. We also found a cell-cell communication mechanism based on EVs containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers. Conclusions: We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Complex molecular mechanisms define our responses to environmental stimuli. Beyond the DNA sequence itself, epigenetic machinery orchestrates changes in gene expression induced by diet, physical activity, stress and pollution, among others. Importantly, nutrition has a strong impact on epigenetic players and, consequently, sustains a promising role in the regulation of cellular responses such as oxidative stress. As oxidative stress is a natural physiological process where the presence of reactive oxygen-derived species and nitrogen-derived species overcomes the uptake strategy of antioxidant defenses, it plays an essential role in epigenetic changes induced by environmental pollutants and culminates in signaling the disruption of redox control. In this review, we present an update on epigenetic mechanisms induced by environmental factors that lead to oxidative stress and potentially to pathogenesis and disease progression in humans. In addition, we introduce the microenvironment factors (physical contacts, nutrients, extracellular vesicle-mediated communication) that influence the epigenetic regulation of cellular responses. Understanding the mechanisms by which nutrients influence the epigenome, and thus global transcription, is crucial for future early diagnostic and therapeutic efforts in the field of environmental medicine.

Objectives: The COVID-19 pandemic accelerated telemedicine use nationally, but differences across health systems are understudied. We examine telemedicine use for adults with diabetes and/or hypertension across 10 health systems and analyze practice and patient characteristics associated with greater use., Study Design: Encounter-level data from the AMGA Optum Data Warehouse for March 13, 2020, to December 31, 2020, were analyzed, which included 3,016,761 clinical encounters from 764,521 adults with diabetes and/or hypertension attributed to 1 of 1207 practice sites with at least 50 system-attributed patients., Methods: Linear spline regression estimated whether practice size and ownership were associated with telemedicine during the adoption (weeks 0-4), de-adoption (weeks 5-12), and maintenance (weeks 13-42) periods, controlling for patient socioeconomic and clinical characteristics., Results: Telemedicine use peaked at 11% to 42% of weekly encounters after 4 weeks. In adjusted analyses, small practices had lower telemedicine use for adults with diabetes during the maintenance period compared with larger practices. Practice ownership was not associated with telemedicine use. Practices with higher proportions of Black patients continued to expand telemedicine use during the de-adoption and maintenance periods., Conclusions: Practice ownership was not associated with telemedicine use during first months of the pandemic. Small practices de-adopted telemedicine to a greater degree than medium and large practices. Technical support for small practices, irrespective of their ownership, could enable telemedicine use for adults with diabetes and/or hypertension.

Background: Patient-reported outcome measures (PROs) can help clinicians adjust treatments and deliver patient-centered care, but organizational adoption of PROs remains low., Objective: This study examines the extent of PRO adoption among health systems and physician practices nationally and examines the organizational capabilities associated with more extensive PRO adoption., Design: Two nationally representative surveys were analyzed in parallel to assess health system and physician practice capabilities associated with adoption of PROs of disability, pain, and depression., Participants: A total of 323 US health system and 2,190 physician practice respondents METHODS: Multivariable regression models separately estimated the association of health system and physician practice capabilities associated with system-level and practice-level adoption of PROs., Main Measures: Health system and physician practice adoption of PROs for depression, pain, and disability., Key Results: Pain (50.6%) and depression (43.8%) PROs were more commonly adopted by all hospitals and medical groups within health systems compared to disability PROs (26.5%). In adjusted analyses, systems with more advanced health IT functions were more likely to use disability (p<0.05) and depression (p<0.01) PROs than systems with less advanced health IT. Practice-level advanced health IT was positively associated with use of depression PRO (p<0.05), but not disability or pain PRO use. Practices with more chronic care management processes, broader medical and social risk screening, and more processes to support patient responsiveness were more likely to adopt each of the three PROs. Compared to independent physician practices, system-owned practices and community health centers were less likely to adopt PROs., Conclusions: Chronic care management programs, routine screening, and patient-centered care initiatives can enable PRO adoption at the practice level. Developing these practice-level capabilities may improve PRO adoption more than solely expanding health IT functions., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Objective: The Centers for Medicare and Medicaid Services State Innovation Models (SIM) initiative has invested more than $1 billion to test state-led delivery system and payment reforms that can affect diabetes care management. We examined whether SIM implementation between 2013 and 2017 was associated with diagnosed diabetes prevalence or with hospitalization or 30-day readmission rate among diagnosed adults., Research Design and Methods: The quasiexperimental design compared study outcomes before and after the SIM initiative in 12 SIM states versus five comparison states using difference-in-differences (DiD) regression models of 21,055,714 hospitalizations for adults age ≥18 years diagnosed with diabetes in 889 counties from 2010 to 2017 across the 17 states. For readmission analyses, comparative interrupted time series (CITS) models included 11,812,993 hospitalizations from a subset of nine states., Results: Diagnosed diabetes prevalence changes were not significantly different between SIM states and comparison states. Hospitalization rates were inconsistent across models, with DiD estimates ranging from -5.34 to -0.37 and from -13.16 to 0.92, respectively. CITS results indicate that SIM states had greater increases in odds of 30-day readmission during SIM implementation compared with comparison states (round 1: adjusted odds ratio [AOR] 1.07; 95% CI 1.04, 1.11; P < 0.001; round 2: AOR 1.06; 95% CI 1.03, 1.10; P = 0.001)., Conclusions: The SIM initiative was not sufficiently focused to have a population-level effect on diabetes detection or management. SIM states had greater increases in 30-day readmission for adults with diabetes than comparison states, highlighting potential unintended effects of engaging in the multipayer alignment efforts required of state-led delivery system and payment reforms., (© 2022 by the American Diabetes Association.)

Introduction: Decision aids for breast cancer screening are increasingly being used by physicians, but the association between physician practice decision-aid use and mammography rates remains uncertain. Using national data, this study examines the association between practice-level decision-aid use and mammography use among older women., Methods: Physician practice responses to the 2017/2018 National Survey of Healthcare Organizations and Systems (n=1,236) were linked to 2016 and 2017 Medicare fee-for-service beneficiary data from eligible beneficiaries (n=439,684) aged 65-74 years. In 2021, multivariable generalized linear models estimated the association of practice decision-aid use for breast cancer screening and advanced health information technology functions with mammography use, controlling for practice and beneficiary characteristics., Results: Overall, 60.1% of eligible beneficiaries had a screening mammogram, and 37.3% of physician practices routinely used decision aids for breast cancer screening. In adjusted analyses, advanced health information technology functions (OR=1.19, p=0.04) were associated with mammography use, but practice use of decision aids was not (OR=0.95, p=0.21). Beneficiary clinical and socioeconomic characteristics, including race, comorbidities, Medicare and Medicaid eligibility, and median household income were more strongly associated with mammography use than practice-level decision-aid use or advanced health information technology functions., Conclusions: Health information technology‒enabled automation of mammography reminders and other advanced health information technology functions may support mammography, whereas breast cancer decision aids may reduce patients' propensities to be screened through the alignment of their preferences and screening decision. More resources may be needed for decision aids to be routinely implemented to improve solicitation of patient preferences and targeting of mammography services., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylation, histone modifications, and ncRNAs with their impact on breast cancer, as well as to discuss studies highlighting the central role of epigenetic mechanisms in breast cancer pathogenesis. We propose new research areas that may facilitate locus-specific epigenome editing as breast cancer therapeutics.

Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21 , PELI1 , and SPRY2 . There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2 , proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d . Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2 . Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF.

Environmental factors, including pollutants and lifestyle, constitute a significant role in severe, chronic pathologies with an essential societal, economic burden. The measurement of all environmental exposures and assessing their correlation with effects on individual health is defined as the exposome, which interacts with our unique characteristics such as genetics, physiology, and epigenetics. Epigenetics investigates modifications in the expression of genes that do not depend on the underlying DNA sequence. Some studies have confirmed that environmental factors may promote disease in individuals or subsequent progeny through epigenetic alterations. Variations in the epigenetic machinery cause a spectrum of different disorders since these mechanisms are more sensitive to the environment than the genome, due to the inherent reversible nature of the epigenetic landscape. Several epigenetic mechanisms, including modifications in DNA (e.g., methylation), histones, and noncoding RNAs can change genome expression under the exogenous influence. Notably, the role of long noncoding RNAs in epigenetic processes has not been well explored in the context of exposome-induced tumorigenesis. In the present review, our scope is to provide relevant evidence indicating that epigenetic alterations mediate those detrimental effects caused by exposure to environmental toxicants, focusing mainly on a multi-step regulation by diverse noncoding RNAs subtypes.

No research has considered a range of physician practice capabilities for managing patient care when examining practice-level influences on quality of care, utilization, and spending. Using data from the 2017 National Survey of Healthcare Organizations and Systems linked to 2017 Medicare fee-for-service claims data from attributed beneficiaries, we examined the association of practice-level capabilities with process measures of quality, utilization, and spending. In propensity score-weighted mixed-effects regression analyses, physician practice locations with "robust" capabilities had lower total spending compared to locations with "mixed" or "limited" capabilities. Quality and utilization, however, did not differ by practice-level capabilities. Physician practice locations with robust capabilities spend less on Medicare fee-for-service beneficiaries but deliver quality of care that is comparable to the quality delivered in locations with low or mixed capabilities. Reforms beyond those targeting practice capabilities, including multipayer alignment and payment reform, may be needed to support larger performance advantages for practices with robust capabilities.

Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Despite the growing interest in transformational performance improvement among nearly all countries, international benchmarking has rarely been used. Cross-comparative research could allow an appreciation of the extent of Lean's use in healthcare and a better evaluation of possible cultural influences on Lean implementation. This study provides a comparative international benchmarking of Lean adoption, implementation, and outcomes of hospitals in the US and Italy., Methods: The National Survey of Lean, developed in 2017 in the US and adapted in Italy in 2019 was used to compare the two healthcare systems along three dimensions: the maturity of adoption, the implementation approach, identifying both strategic and operational activities and tools, and the Lean performance, investigated through patients, employed, and affiliated staff, costs, and service provision areas. Descriptive statistics including T-tests were used to examine differences between the two countries on the study variables., Results: Lean has been adopted less by Italian public hospitals (36%) than US public hospitals (53%). Each country averages 4 years of experience with Lean. Italian hospitals reported being at a higher maturity stage while the US implemented a more system-wide approach, developing Lean in more operational units. The daily management system, leadership commitment, education and training indexes were higher or the same in the US while in Italy, hospitals had a higher self-reported performance index., Conclusion: This exploratory work is one of the first international benchmarking studies on Lean implementation in healthcare systems using a standardized survey with a common set of definitions and questions. The study identifies different forms of Lean implementation that can be adopted, both at strategic and operational levels, with related perceived outcomes. Despite the US public hospitals being more likely to report a higher number of units using Lean, a higher daily management system index and use of Lean tools, Italian hospitals report more achievements primarily due to Lean. Further research can build on these findings by examining the relationship between Lean adoption/implementation and independent, objective performance measures., (© 2022. The Author(s).)

Obesity is a complex disease that is the result of a number of different factors including genetic, environmental, and endocrine abnormalities. Given that monogenic forms of obesity are rare, it is important to identify other mechanisms that contribute to its etiology. Methyl-Cp-G binding protein 2 (MeCP2) is a neuroepigenetic factor that binds to methylated regions of DNA to influence transcription. Past studies demonstrate that disruption in MeCP2 function produces obesity in mice. Using a diet-induced obesity mouse model, we show that perinatal exposure to high fat diet significantly decreases MeCP2 protein expression in the hypothalamus of female mice, effects not seen when high fat diet is given to mice during adulthood. Moreover, these effects are seen specifically in a subregion of the hypothalamus known as the arcuate nucleus with females having decreased MeCP2 expression in rostral areas and males having decreased MeCP2 expression in intermediate regions of the arcuate nucleus. Interestingly, mice gain more weight when exposed to high fat diet during adulthood relative to mice exposed to high fat diet perinatally, suggesting that perhaps high fat diet exposure during adulthood may be affecting mechanisms independent of MeCP2 function. Collectively, our data demonstrate that there are developmentally sensitive periods in which MeCP2 expression is influenced by high fat diet exposure and this occurs in a sexually dimorphic manner., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.