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Abstract Background Food insecurity (FI) is a significant public health problem. Possible sequelae of prolonged food insecurity include kidney disease, obesity, and diabetes. Our objective was to assess the feasibility of a partnership between Henry Ford Health System (HFHS) and Gleaners Community Foodbank of Southeastern Michigan to implement and evaluate a food supplementation intervention initiated in a hospital outpatient clinic setting. Methods We established a protocol for using the Hunger Vital Signs to screen HFHS internal medicine patients for food insecurity and established the data sharing infrastructure and agreements necessary for an HFHS-Gleaners partnership that would allow home delivery of food to consenting patients. We evaluated the food supplementation program using a quasi-experimental design and constructing a historical comparison group using the electronic medical record. Patients identified as food insecure through screening were enrolled in the program and received food supplementation twice per month for a total of 12 months, mostly by home delivery. The feasibility outcomes included successful clinic-based screening and enrollment and successful food delivery to consenting patients. Our evaluation compared healthcare utilization between the intervention and historical comparison group during a 12-month observation period using a difference-in-differences (DID) analysis. Results Of 1691 patients screened, 353 patients (20.9%) met the criteria for FI, of which 340/353 (96.3%) consented, and 256/340 (75.3%) were matched and had data sufficient for analysis. Food deliveries were successfully made to 89.9% of participant households. At follow-up, the intervention group showed greater reductions in emergency department visits than the comparison group, −41.5% and −25.3% reduction, respectively. Similar results were observed for hospitalizations, −55.9% and −17.6% reduction for intervention and control groups, respectively. DID regression analysis also showed lower trends in ED visits and hospitalizations for the intervention group compared to the comparison group. Conclusions Results suggest that community-health system partnerships to address patient-reported food insecurity are feasible and potentially could reduce healthcare utilization in these patients. A larger, randomized trial may be the next step in fully evaluating this intervention, perhaps with more outcomes (e.g., medication adherence), and additional covariates (e.g., housing insecurity and financial strain).

OBJECTIVES: This study evaluates the variation in practice patterns associated with contrast-induced acute kidney injury (CI-AKI) and identifies clinical practices that have been associated with a reduction in CI-AKI. Background CI-AKI is recognised as a complication of invasive cardiovascular procedures and is associated with cardiovascular events, prolonged hospitalisation, end-stage renal disease, and all-cause mortality. Reducing the risk of CI-AKI is a patient safety objective set by the National Quality Forum. METHODS: This study prospectively collected quantitative and qualitative data from 10 centres, which participate in the Northern New England Cardiovascular Disease Study Group PCI Registry. Quantitative data were collected from the PCI Registry. Qualitative data were obtained through clinical team meetings to map care processes related to CI-AKI and focus groups to understand attitudes towards CI-AKI prophylaxis. Fixed and random effects modelling were conducted to test the differences across centres. RESULTS: Significant variation in rates of CI-AKI were found across 10 medical centres. Both fixed effects and mixed effects logistic regression demonstrated significant variability across centres, even after adjustment for baseline covariates (p<0.001 for both modelling approaches). Patterns were found in reported processes and clinical leadership that were attributable to centres with lower rates of CI-AKI. These included reducing nil by mouth (NPO) time to 4 h prior to case, and standardising volume administration protocols in combination with administering three to four high doses of N-acetylcysteine (1200 mg) for each patient. CONCLUSIONS: These data suggest that clinical leadership and institution-focused efforts to standardise preventive practices can help reduce the incidence of CI-AKI. [ABSTRACT FROM AUTHOR]

Objective: In vitro evidence suggests insulin glargine promotes tumors; observational human studies are conflicting. We aimed to expand understanding of this potential treatment risk.Research Design and Methods: This retrospective cohort study of type 2 diabetic patients >68 years old used Medicare inpatient, outpatient (2003-2008), and prescription data (2006-2008). Adjusting for patient characteristics, dose, and metformin use, Cox models yielded hazard ratios (HRs) for incident cancer (breast, prostate, pancreas, colon, any site) associated with three forms of insulin: nonglargine, glargine, or glargine plus nonglargine (combination).Results: Overall, 81,681 patients were followed for a mean of 23.1 months. Mean age was 77.4 years. Treatment group distribution was 20.7% glargine, 60.5% nonglargine, 18.7% combination insulin. We observed 5,466 incident cancers; crude rates did not vary by treatment group. In fully adjusted models, nonglargine use was the referent; glargine was not associated with significant increased risk of any cancer measure. In secondary analyses including only the top quartile of daily insulin dose patients, glargine was not associated with any cancer risk difference; combination insulin was associated with higher breast cancer risk (HR 1.75 [95% CI 1.10-2.78]) and lower colon cancer risk (0.33 [0.13-0.80]). In age-stratified analyses of highest-dose users, combination insulin conferred a higher risk of breast cancer in those ≤75 years old (2.87 [1.45-1.59]).Conclusions: The general lack of association between glargine-only use and cancer is reassuring. Breast cancer risk associated with high-dose combination insulin in secondary analyses could result from multiple comparisons, residual confounding, or true association; further research is warranted. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to identify and determine the influence of perceived intrinsic barriers to physical activity among mothers living in rural areas. Methods: Mothers were identified through a study of child-parent dyads in the predominantly rural states of New Hampshire and Vermont. Using a telephone interview, we asked mothers ( n = 1691) about their level of physical activity and assessed eight potential barriers to physical activity. Data were analyzed using chi-square tests, t tests, and analysis of variance (ANOVA) comparisons for groups within each variable. We used multiple regression analysis to assess associations between perceived barriers to physical activity and self-reported levels of physical activity. Results: Each barrier was inversely associated with physical activity. Multivariate models that included terms for all potential barriers and covariates identified three barriers associated with lower levels of physical activity: lack of self-discipline, lack of time, and lack of interest. Conclusions: Rural mothers are less likely to be physically active if they identify lack of self-discipline, time, or interest as barriers, suggesting that they have difficulty prioritizing exercise for themselves. Interventions aimed at increasing physical activity for mothers should specifically consider these barriers. One possible solution may be to support infrastructure that facilitates active living as the default option, to remove the issue of having to purposefully engage in physical activity as a separate aspect of a mother's life. [ABSTRACT FROM AUTHOR]

We compared demographic profiles across two rural-urban classification schemes to determine whether rural-urban disparities in health status persisted among Veterans Administration (VA) users over time. Using demographic and SF-12 survey data collected from 2002 to 2006, we conducted serial cross-sectional analyses of demographic variables and health status for veterans residing in VA- and rural-urban commuting area (RUCA)-defined rural-urban groups. VA and RUCA definitions yielded similar results for the "urban" population; however, VA- and RUCA-defined "rural" categories represent dissimilar populations. Compared to earlier years, the VA user population in 2006 was younger, more educated, wealthier, and more likely to be employed and privately insured. For all years and using both VA and RUCA rural-urban definitions, physical component summary (PCS) scores were lower but mental component summary (MCS) scores were slightly higher for more rural compared to urban veterans. Anticipating and meeting the needs of rural VA users will require accurate identification of those who lack access to services and therefore defining "rural" appropriately. [ABSTRACT FROM AUTHOR]

PURPOSE: To redefine the clinical remission period for different aged children receiving the current standard of diabetes care. METHODS: An electronic patient records system was used to identify 552 children newly diagnosed with type 1 diabetes (T1D) from 1997 to 2001 who had an initial hemoglobin A1c (HbA1c) value at the time of diagnosis and at least one other value measured in the ensuing year. The insulin dosage previously used to define the remission period [<0.5 units per kg body weight per day (U/kg/d)] was evaluated for the different aged children. RESULTS: The mean insulin dosages for all age groups were >0.5 U/kg/d by 9 months after diagnosis. The mean HbA1c values were above 8% by 6 months after diagnosis for the 6-9 and the 10-12 yr age groups and by 9 months after diagnosis for the >or=13 yr age group. The percentage of children

The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events.Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p

Aim: Young adults with serious mental illness (SMI) have poor physical health and high Emergency Department (ED) and hospital utilization. Integrating primary care into community mental health care may be an important form of early intervention., Methods: Adjusted multivariable regressions assessed changes in self-reported annual primary care, ED and hospital utilization for 83 young adults with SMI enrolled in integrated care., Results: Participants' mean annual per person utilization changed significantly as follows: primary care visits, from 1.8 to 3.6, p < .001; medical ED visits, from 1.0 to 0.6, p < .01; psychiatric ED visits from 0.6 to 0.2, p < .001; medical inpatient days, from 1.2 to 0.1, p < .001 and psychiatric inpatient days, from 6.3 to 2.6, p < .001., Conclusions: Young adults with SMI receiving integrated care increased primary care and reduced ED and inpatient utilization. Future controlled research is warranted to further assess integrated care for young adults with SMI., (© 2024 John Wiley & Sons Australia, Ltd.)

The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl - and HCO 3 - secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl - secretion, and defensin gene expression ( DEFB1 ) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase ( HMOX1 ). qPCR analysis confirmed DEFB1 , HMOX1 , MMP10 and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases in DEFB1 , and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI induced reduction in inflammation observed in pwCF.

When low muscle mass and impaired strength and physical function coexist with excess adiposity, it is termed sarcopenic obesity (SO). Handgrip strength (HGS) is a predictor of disability and mortality. Asymmetry in HGS, particularly ≥ 10% strength differences between hands, may indicate neuromuscular dysfunction observable prior to declines in maximal strength are detectedand therefore could be incorporated to identify those at risk of physical limitations and SO. This study compares HGS values and asymmetry in older adults with excess adiposity and evaluates their relationships with physical function. Baseline data from two previous pilot weight loss studies in 85 older adults with body mass index values ≥ 30 kg m -2 are included with measures of body composition, walking speed, and chair stand ability. Sixty-three participants met the criteria for SO. HGS correlated to gait speed (r = 0.22), distance walked (r = 0.40), chair stand time for 5 repetitions (r = 0.42) and during 30 s (r = 0.31). HGS asymmetry is only correlated to gait speed (r = 0.31) and there are no differences in physical function between those with and without asymmetry. Maximal HGS tests should continue to be used to screen for functional decline and disability., (© 2024 Wiley‐VCH GmbH.)

Background: Congenital heart defects (CHD) are the most common birth defects and previous estimates report the disease affects 1% of births annually in the United States. To date, CHD prevalence estimates are inconsistent due to varied definitions, data reliant on birth registries, and are geographically limited. These data sources may not be representative of the total prevalence of the CHD population. It is therefore important to derive high-quality, population-based estimates of the prevalence of CHD to help care for this vulnerable population., Methods: We performed a descriptive, retrospective 8-year analysis using all-payer claims data from Colorado from 2012 to 2019. Children with CHD were identified by applying International Classification of Diseases-Ninth Revision (ICD-9 ) and International Classification of Diseases-Tenth Revision ( ICD-10 ) diagnosis codes from the American Heart Association-American College of Cardiology harmonized cardiac codes. We included children with CHD <18 years of age who resided in Colorado, had a documented zip code, and had at least 1 health care claim. CHD type was categorized as simple, moderate, and severe disease. Association with comorbid conditions and genetic diagnoses were analyzed using χ 2 test. We used direct standardization to calculate adjusted prevalence rates, controlling for age, sex, primary insurance provider, and urban-rural residence., Results: We identified 1 566 328 children receiving care in Colorado from 2012 to 2019. Of those, 30 512 children had at least 1 CHD diagnosis, comprising 1.95% (95% CI, 1.93-1.97) of the pediatric population. Over half of the children with CHD also had at least 1 complex chronic condition. After direct standardization, the adjusted prevalence rates show a small increase in simple severity diagnoses across the study period (adjusted rate of 11.5 [2012]-14.4 [2019]; P <0.001)., Conclusions: The current study is the first population-level analysis of pediatric CHD in the United States. Using administrative claims data, our study found a higher CHD prevalence and comorbidity burden compared with previous estimates., Competing Interests: None.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Castillo, Ramírez, Ramos, Martinez-Arribas, Domingo-Contreras, Mackenzie, Peña-Varas, Lindemann, Montero, Annang, Vicente, Genilloud, González-Pacanowska and Fernandez-Godino.)

A study targeting novel antifungal metabolites identified potent in vitro antifungal activity against key plant pathogens in acetone extracts of Streptomyces sp. strain CA-296093. Feature-based molecular networking revealed the presence in this extract of antimycin-related compounds, leading to the isolation of four new compounds: escuzarmycins A-D ( 1 - 4 ). Extensive structural elucidation, employing 1D and 2D NMR, high-resolution mass spectrometry, Marfey's analysis, and NOESY correlations, confirmed their structures. The bioactivity of these compounds was tested against six fungal phytopathogens, and compounds 3 and 4 demonstrated strong efficacy, particularly against Zymoseptoria tritici , with compound 3 exhibiting the highest potency (EC 50 : 11 nM). Both compounds also displayed significant antifungal activity against Botrytis cinerea and Colletotrichum acutatum , with compound 4 proving to be the most potent. Despite moderate cytotoxicity against the human cancer cell line HepG2, compounds 3 and 4 emerge as promising fungicides for combating Septoria tritici blotch, anthracnose, and gray mold.

Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Colorectal cancer is a leading cause of cancer-related death. Adenomas and serrated polyps are precursors of colorectal cancer, with serrated polyps being more difficult to detect during colonoscopy. The relationship between propofol use and polyp detection remains unclear. The authors investigated the association of propofol-based versus mild-moderate sedation on adenoma and serrated polyp detection during colonoscopy., Methods: This retrospective cohort study used observational data from the New Hampshire Colonoscopy Registry. Patients aged greater than 50 yr with screening or surveillance colonoscopies between January 1, 2015, and February 28, 2020, were included. Exclusions were diagnostic examinations, no sedation, missing pathology data, and poor bowel preparation. Multivariate logistic regression was used to evaluate differences in polyp detection between propofol and moderate sedation in the full sample while adjusting for covariates. Propensity score adjustment and clustering at the endoscopist level were used in a restricted sample analysis that included endoscopists and facilities with between 5% and 95% propofol sedation use., Results: A total of 54,063 colonoscopies were analyzed in the full sample and 18,998 in the restricted sample. Serrated polyp prevalence was significantly higher using propofol (9,957 of 29,312; 34.0% [95% CI, 33.4 to 34.5%]) versus moderate sedation (6,066 of 24,751; 24.5% [95% CI, 24.0 to 25.1%]) in the full sample and restricted samples (1,410 of 4,661; 30.3% [95% CI, 28.9 to 31.6%] vs. 3,690 of 14,337; 25.7% [95% CI, 25.0 to 26.5%]). In the full sample multivariate logistic regression, propofol was associated with higher neoplasm (adjusted odds ratio, 1.25 [95% CI, 1.21 to 1.29]), adenoma (odds ratio, 1.07 [95% CI, 1.03 to 1.11]), and serrated polyp detection (odds ratio, 1.51 [95% CI, 1.46 to 1.57]). In the restricted sample using inverse probability of treatment weighted propensity score adjustment and clustering at the endoscopist level, an attenuated but statistically significant effect size was observed for serrated polyps (odds ratio, 1.13 [95% CI, 1.07 to 1.19]), but not for adenomas (odds ratio, 1.00 [95% CI, 0.95 to 1.05]) or any neoplastic lesion (odds ratio, 1.03 [95% CI, 0.98 to 1.08])., Conclusions: Propofol sedation during colonoscopy may be associated with improved detection of serrated polyps, but not adenomas., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background and Aims: Adenomas per colonoscopy (APC) may be a better measure of colonoscopy quality than adenoma detection rate (ADR) because it credits endoscopists for each detected adenoma. There are few data examining the association between APC and postcolonoscopy colorectal cancer (PCCRC) incidence. We used data from the New Hampshire Colonoscopy Registry to examine APC and PCCRC risk., Methods: We included New Hampshire Colonoscopy Registry patients with an index examination and at least 1 follow-up event, either a colonoscopy or a colorectal cancer (CRC) diagnosis. Our outcome was PCCRC defined as any CRC diagnosed ≥6 months after an index examination. The exposure variable was endoscopist-specific APC quintiles of .25, .40, .50, and .70. Cox regression was used to model the hazard of PCCRC on APC, controlled for age, sex, year of index examination, index findings, bowel preparation, and having more than 1 surveillance examination., Results: In 32,535 patients, a lower hazard for PCCRC (n = 178) was observed for higher APCs as compared to APCs of <.25 (reference): .25 to <.40: hazard ratio (HR), .35; 95% confidence interval (CI), .22-.56; .40 to <.50: HR, .31; 95% CI, .20-.49; .50 to <.70: HR, .20; 95% CI, .11-.36; and ≥.70: HR, .19; 95% CI, .09-.37. When examining endoscopists with an ADR of at least 25%, an APC of <.50 was associated with a significantly higher hazard than an APC of ≥.50 (HR, 1.65; 95% CI, 1.06-2.56). A large proportion of endoscopists-one-fifth (32 of 152; 21.1%)-had an ADR of ≥25% but an APC of <.50., Conclusions: Our novel data demonstrating lower PCCRC risk in examinations performed by endoscopists with higher APCs suggest that APC could be a useful quality measure. Quality improvement programs may identify important deficiencies in endoscopist detection performance by measuring APC for endoscopists with an ADR of ≥25%., Competing Interests: Disclosure The following authors disclosed financial relationships: L. Butterly: Grants from Exact Sciences during the conduct of the study. C. Robinson: Grants from Exact Sciences during the conduct of the study. W. Hisey: Grants from Exact Sciences during the conduct of the study. D. Rex: Consultant for Olympus Corporation, Boston Scientific, Braintree Laboratories, Norgine, Medtronic, and Acacia Pharmaceuticals; research support from Olympus Corporation, Medivators, Erbe USA Inc, and Braintree Laboratories; and shareholder for Satisfai Health. All other authors disclosed no financial relationships. Funding for this study was received from the Division of Cancer Prevention, National Cancer Institute (5R01CA243449; grant recipient: L. Butterly)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging. Microbial natural products (NPs) are a source of small molecules with vast chemical diversity that have proved anti-tumoral activities, but which immunotherapeutic properties as PD-1/PD-L1 inhibitors had remained uncharacterized so far. Here, we have developed the first cell-based PD-1/PD-L1 blockade reporter assay to screen NPs libraries. In this study, 6000 microbial extracts of maximum biosynthetic diversity were screened. A secondary metabolite called alpha-cyclopiazonic acid (α-CPA) of a bioactive fungal extract was confirmed as a new PD-1/PD-L1 inhibitor with low micromolar range in the cellular assay and in an additional cell-free competitive assay. Thermal denaturation experiments with PD-1 confirmed that the mechanism of inhibition is based on its stabilization upon binding to α-CPA. The identification of α-CPA as a novel PD-1 stabilizer proves the unprecedented resolution of this methodology at capturing specific PD-1/PD-L1 PPI inhibitors from chemically diverse NP libraries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

"Replace Cysto" is a multisite randomized phase 2 trial including 240 participants with low-grade intermediate-risk non-muscle-invasive bladder cancer, in which participants will be randomized 1:1:1 to one of two urine marker-based approaches alternating a urine marker test (Xpert Bladder Cancer Monitor or Bladder EpiCheck) with cystoscopy or to frequent scheduled cystoscopy. The primary objective is to determine whether urinary quality of life after surveillance is significantly improved in the urine marker arms. The primary outcome will be the patient-reported urinary quality of life domain score of the validated QLQ-NMIBC24 instrument, measured 1-3 d after surveillance. Exploratory outcomes include discomfort after surveillance, the number of invasive procedures that participants undergo per 1000 person years, complications from these procedures per 1000 person years, nonurinary quality of life, acceptability of surveillance, and bladder cancer recurrence and progression. Comparators include surveillance using (1) the Xpert Bladder Cancer Monitor test, (2) the Bladder EpiCheck urinary marker, or (3) frequent cystoscopy alone. After a negative cystoscopy ≤4 mo following bladder tumor resection, all the participants will undergo surveillance at 6, 12, 18, and 24 mo (with time zero defined as the date of the most recent bladder tumor resection). In the urine marker arms, surveillance at 6 and 18 mo will be performed with the marker. Regardless of the arm, participants will undergo cystoscopy at 12 and 24 mo. End of study for each participant will be their 24-mo cystoscopy. Overall trial duration is estimated at 5 yr from when the study opens to enrollment until completion of data analyses. The trial is registered at clinicaltrials.gov (NCT05796375).

An appealing strategy for finding novel bioactive molecules in Nature consists in exploring underrepresented and -studied microorganisms. Here, we investigated the antimicrobial and tumoral anti-proliferative bioactivities of twenty-three marine and estuarine bacteria of the fascinating phylum Planctomycetota. This was achieved through extraction of compounds produced by the Planctomycetota cultured in oligotrophic medium followed by an antimicrobial screening against ten relevant human pathogens including Gram-positive and Gram-negative bacteria, and fungi. Cytotoxic effects of the extracts were also evaluated against five tumoral cell lines. Moderate to potent activities were obtained against Enterococcus faecalis, methicillin-sensitive and methicillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus faecium. Anti-fungal effects were observed against Trichophyton rubrum, Candida albicans and Aspergillus fumigatus. The highest cytotoxic effects were observed against human breast, pancreas and melanoma tumoral cell lines. Novipirellula caenicola and Rhodopirellula spp. strains displayed the widest spectrum of bioactivities while Rubinisphaera margarita ICM&#95;H10 T  affected all Gram-positive bacteria tested. LC-HRMS analysis of the extracts did not reveal the presence of any known bioactive natural product, suggesting that the observed activities are most likely caused by novel molecules, that need identification. In summary, we expanded the scope of planctomycetal species investigated for bioactivities and demonstrated that various strains are promising sources of novel bioactive compounds, which reenforces the potential biotechnological prospects offered by Planctomycetota., (© 2024. The Author(s).)

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus Angustimassarina populi CF-097565. Bioassay-guided fractionation of this extract led to the identification and isolation of herbarin ( 1 ), 1-hydroxydehydroherbarin ( 4 ) plus other three naphthoquinone derivatives of which 3 and 5 are new natural products and 2 is herein described from a natural source for the first time. Four of these compounds ( 1 , 3 , 4 and 5 ) confirmed a specific cytotoxic effect against the human breast cancer cell line MCF-7. To evaluate the therapeutic potential of the compounds isolated, their efficacy was validated in 3D cultures, a cancer model of higher functionality. Additionally, an in-depth study was carried out to test the effect of the compounds in terms of cell mortality, sphere disaggregation, shrinkage, and morphology. The cell profile of the compounds was also compared to that of known cytotoxic compounds with the aim to distinguish the drug mode of action (MoA). The profiles of 1 , 3 and 4 showed more biosimilarity between them, different to 5 , and even more different to other known cytotoxic agents, suggesting an alternative MoA responsible for their cytotoxicity in 3D cultures.

Importance: The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1,280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity., Competing Interests: The authors declare no conflict of interest.

The availability of multiple publicly-available datasets studying the same phenomenon has the promise of accelerating scientific discovery. Meta-analysis can address issues of reproducibility and often increase power. The promise of meta-analysis is especially germane to rarer diseases like cystic fibrosis (CF), which affects roughly 100,000 people worldwide. A recent search of the National Institute of Health's Gene Expression Omnibus revealed 1.3 million data sets related to cancer compared to about 2,000 related to CF. These studies are highly diverse, involving different tissues, animal models, treatments, and clinical covariates. In our search for gene expression studies of primary human airway epithelial cells, we identified three studies with compatible methodologies and sufficient metadata: GSE139078, Sala Study, and PRJEB9292. Even so, experimental designs were not identical, and we identified significant batch effects that would have complicated functional analysis. Here we present quantile discretization and Bayesian network construction using the Hill climb method as a powerful tool to overcome experimental differences and reveal biologically relevant responses to the CF genotype itself, exposure to virus, bacteria, and drugs used to treat CF. Functional patterns revealed by cluster Profiler included interferon signaling, interferon gamma signaling, interleukins 4 and 13 signaling, interleukin 6 signaling, interleukin 21 signaling, and inactivation of CSF3/G-CSF signaling pathways showing significant alterations. These pathways were consistently associated with higher gene expression in CF epithelial cells compared to non-CF cells, suggesting that targeting these pathways could improve clinical outcomes. The success of quantile discretization and Bayesian network analysis in the context of CF suggests that these approaches might be applicable to other contexts where exactly comparable data sets are hard to find.

Background: Propensity score methods are used in observational studies to compensate for the lack of random allocation by balancing measured baseline characteristics between treated and untreated patients. We sought to explain the treatment effect estimates derived from different propensity score methods., Methods: We performed a retrospective analysis of long-term mortality after single internal mammary artery versus bilateral internal mammary artery (BIMA) conduit in 47 984 index isolated coronary artery bypass grafting procedures from 1992 to 2014 in the Northern New England Cardiovascular Disease Study Group registry using multivariable Cox regression, 1:1 propensity score matching, inverse probability weighting (IPW) among the treated, and IPW among the overall population treatment estimates., Results: The mean duration of follow-up was 13.2 (interquartile range, 7.4-17.7) years. In multivariable Cox regression, the adjusted hazard ratio for mortality was 0.83 (95% CI, 0.75-0.92) in patients receiving BIMA compared with a single internal mammary artery. The 1:1 propensity matched (hazard ratio, 0.79 [95% CI, 0.69-0.91]) and IPW among the treated (hazard ratio, 0.83 [95% CI, 0.75-0.92]) estimates showed a protective treatment effect of BIMA use on mortality. However, the IPW estimate of treatment effect for the overall population showed an increased risk of mortality after BIMA that was not statistically significant (hazard ratio, 1.08 [95% CI, 0.94-1.24])., Conclusions: While the multivariable Cox regression, 1:1 propensity matching, and IPW treatment effect in the treated estimates demonstrate that BIMA was associated with a statistically significantly decreased risk of mortality, the IPW treatment effect in the average study population showed an increased risk of mortality associated with BIMA that was not statistically significant. This is attributed to the different populations (weighted to look like the overall study population versus treated group) represented by the 2 IPW approaches. Determining how the study population is balanced is a large driver of the treatment effect. Ultimately, the treatment effect estimate desired should drive the choice of the propensity score method., Competing Interests: Disclosures None.

The fungal strain BC17 was isolated from sediments collected in the intertidal zone of the inner Bay of Cadiz and characterized as Emericellopsis maritima . On the basis of the one strain-many compounds (OSMAC) approach, four new eremophilane-type sesquiterpenes ( 1 - 4 ), together with thirteen known derivatives ( 5 - 17 ) and two reported diketopiperazines ( 18 , 19 ), were isolated from this strain. The chemical structures and absolute configurations of the new compounds were determined through extensive NMR and HRESIMS spectroscopic studies and ECD calculation. Thirteen of the isolated eremophilanes were examined for cytotoxic and antimicrobial activities. PR toxin ( 16 ) exhibited cytotoxic activity against HepG2, MCF-7, A549, A2058, and Mia PaCa-2 human cancer cell lines with IC 50 values ranging from 3.75 to 33.44 µM. (+)-Aristolochene ( 10 ) exhibited selective activity against the fungal strains Aspergillus fumigatus ATCC46645 and Candida albicans ATCC64124 at 471 µM.

Objective: Although the differences in short-term outcomes between male and female patients in abdominal aortic aneurysm (AAA) repair have been well studied, it remains unclear if these sex disparities extend to other long-term adverse outcomes after AAA repair, such as reintervention and late rupture., Methods: We performed a retrospective cohort study of 13,007 patients who underwent either endovascular (EVAR) or open AAA repair (OAR) between 2003 and 2015 using data from the Vascular Quality Initiative registries. Eligible patients were linked to fee-for-service Medicare claims to identify late outcomes of rupture and aneurysm-specific reintervention., Results: The mean age of our cohort was 76 ± 6.7 years, 22% were female, 94% were White, and 77% underwent EVAR. The 10-year rupture incidence was slightly higher for women at 4.8 per 1000 person-years, vs 3.9 for men, but this difference was not statistically significant after risk adjustment (hazard ratio [HR] = 1.13, 95% confidence interval [CI]: 0.74-1.73). Likewise, we found no sex difference in reintervention rates (5.1 vs 4.8 in women per 1000 person-years) even after risk adjustment (HR = 0.95, 95% CI: 0.83-1.09). Regression models suggest effect modification by repair type for reintervention, where women who underwent index EVAR had a higher risk of reintervention than men (HR = 1.08, 95% CI: 0.93-1.26), whereas women who underwent OAR were at a lower risk of reintervention than men (HR = 0.79, 95% CI: 0.58-1.08); however, neither effect reached statistical significance within each subgroup. In addition, we found that the risk of reintervention for women vs men varied by clinical presentation, where women were less likely to undergo reintervention after an elective or symptomatic AAA repair but were more likely to undergo reintervention after a repair for AAA rupture (HR = 1.70, 95% CI: 1.05-2.75)., Conclusions: Male and female patients who underwent AAA repair had similar rates of reintervention and late aneurysm rupture in the 10 years after their procedure. However, our findings suggest that repair type and clinical presentation may affect the role of sex in clinical outcomes and warrant further exploration in these subgroups., (Copyright © 2023 Society for Vascular Surgery. All rights reserved.)

Introduction: We used New Hampshire Colonoscopy Registry data to examine the association between postcolonoscopy colorectal cancer (PCCRC) and sessile serrated detection rates (SSLDRs)., Methods: We included patients with either a colonoscopy or a CRC diagnosis in the NH State Cancer Registry. PCCRC was any CRC diagnosed ≥ 6 months after index examination., Results: Of 26,901 patients, 162 were diagnosed with PCCRC. The hazard ratio for PCCRC was lowest for patients whose endoscopists had the highest SSLDR quintile (≥6%) (hazard ratio 0.29; 95% confidence interval 0.16-0.50)., Discussion: Endoscopists with higher SSLDRs had lower risks of PCCRC. These data validate SSLDR as a clinically relevant quality measure., (Copyright © 2023 by The American College of Gastroenterology.)

Objective: Fat-infiltrated axillary lymph nodes (LNs) are unique sites for ectopic fat deposition. Early studies showed a strong correlation between fatty LNs and obesity-related diseases. Confirming this correlation requires large-scale studies, hindered by scarce labeled data. With the long-term goal of developing a rapid and generalizable tool to aid data labeling, we developed an automated deep learning (DL)-based pipeline to classify the status of fatty LNs on screening mammograms., Methods: Our internal data set included 886 mammograms from a tertiary academic medical institution, with a binary status of the fat-infiltrated LNs based on the size and morphology of the largest visible axillary LN. A two-stage DL model training and fine-tuning pipeline was developed to classify the fat-infiltrated LN status using the internal training and development data set. The model was evaluated on a held-out internal test set and a subset of the Digital Database for Screening Mammography., Results: Our model achieved 0.97 (95% CI: 0.94-0.99) accuracy and 1.00 (95% CI: 1.00-1.00) area under the receiver operator characteristic curve on 264 internal testing mammograms, and 0.82 (95% CI: 0.77-0.86) accuracy and 0.87 (95% CI: 0.82-0.91) area under the receiver operator characteristic curve on 70 external testing mammograms., Conclusion: This study confirmed the feasibility of using a DL model for fat-infiltrated LN classification. The model provides a practical tool to identify fatty LNs on mammograms and to allow for future large-scale studies to evaluate the role of fatty LNs as an imaging biomarker of obesity-associated pathologies., Advances in Knowledge: Our study is the first to classify fatty LNs using an automated DL approach., Competing Interests: Competing interestsThe authors declare no competing interests.

Purpose: Cervical artery dissection (CeAD), which includes both vertebral artery dissection (VAD) and carotid artery dissection (CAD), is the most serious safety concern associated with cervical spinal manipulation (CSM). We evaluated the association between CSM and CeAD among US adults., Methods: Through analysis of health claims data, we employed a case-control study with matched controls, a case-control design in which controls were diagnosed with ischemic stroke, and a case-crossover design in which recent exposures were compared to exposures in the same case that occurred 6-7 months earlier. We evaluated the association between CeAD and the 3-level exposure, CSM versus office visit for medical evaluation and management (E&M) versus neither, with E&M set as the referent group., Results: We identified 2337 VAD cases and 2916 CAD cases. Compared to population controls, VAD cases were 0.17 (95% CI 0.09 to 0.32) times as likely to have received CSM in the previous week as compared to E&M. In other words, E&M was about 5 times more likely than CSM in the previous week in cases, relative to controls. CSM was 2.53 (95% CI 1.71 to 3.68) times as likely as E&M in the previous week among individuals with VAD than among individuals experiencing a stroke without CeAD. In the case-crossover study, CSM was 0.38 (95% CI 0.15 to 0.91) times as likely as E&M in the week before a VAD, relative to 6 months earlier. In other words, E&M was approximately 3 times more likely than CSM in the previous week in cases, relative to controls. Results for the 14-day and 30-day timeframes were similar to those at one week., Conclusion: Among privately insured US adults, the overall risk of CeAD is very low. Prior receipt of CSM was more likely than E&M among VAD patients as compared to stroke patients. However, for CAD patients as compared to stroke patients, as well as for both VAD and CAD patients in comparison with population controls and in case-crossover analysis, prior receipt of E&M was more likely than CSM., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6)., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In a survey to evaluate the potential of lichens associated with gypsum areas as sources of new antifungal metabolites, six species of lichens were collected in the gypsum outcrops of the Sorbas Desert ( Diploschistes ocellatus and Seirophora lacunosa ) and the Tabernas Desert ( Cladonia foliacea , Acarospora placodiformis , Squamarina lentigera and Xanthoparmelia pokornyi ) in southern Spain. Raw lichen acetone extracts were tested against a panel of seven phytopathogenic fungi, including Botrytis cinerea , Colletotrichum acutatum , Fusarium oxysporum f.sp cubense TR4, Fusarium ploriferaum , Magnaporthe grisea , Verticillium dahliae and Zymoseptoria tritici . Active extracts of Cladonia foliacea , Xanthoparmelia pokornyi and Squamarina lentigera were analyzed by HPLC-MS/MS and Molecular Networking to identify possible metabolites responsible for the antifungal activity. A total of ten depside-like metabolites were identified by MS/MS dereplication and NMR experiments, of which one was a new derivative of fumaroprotocetraric acid. The compounds without previously described biological activity were purified and tested against the panel of fungal phytopathogens. Herein, the antifungal activity against fungal phytopathogens of 4'-O-methylpaludosic acid, divaricatic acid and stenosporic acid is reported for the first time. Stenosporic and divaricatic acids displayed a broad antifungal spectrum against seven relevant fungal phytopathogens in a micromolar range, including the extremely resistant fungus F. oxysporum f. sp. cubense Tropical Race 4 (TR4). 4'-O-methylpaludosic acid exhibited specific antifungal activity against the wheat pathogen Z. tritici , with an IC50 of 38.87 µg/mL (87.1 µM) in the absorbance-based assay and 24.88 µg/mL (55.52 µM) in the fluorescence-based assay.

Antimicrobial resistance can be considered a hidden global pandemic and research must be reinforced for the discovery of new antibiotics. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, compounds displaying different antibiotic activities. Three marine Micromonospora strains (CA-214671, CA-214658 and CA-218877), identified as phocoenamicins producers, were chosen to scale up their production and LC/HRMS analyses proved that EtOAc extracts from their culture broths produce several structurally related compounds not disclosed before. Herein, we report the production, isolation and structural elucidation of two new phocoenamicins, phocoenamicins D and E ( 1 - 2 ), along with the known phocoenamicin, phocoenamicins B and C ( 3 - 5 ), as well as maklamicin ( 7 ) and maklamicin B ( 6 ), the latter being reported for the first time as a natural product. All the isolated compounds were tested against various human pathogens and revealed diverse strong to negligible activity against methicillin-resistant Staphylococcus aureus , Mycobacterium tuberculosis H37Ra, Enterococcus faecium and Enterococcus faecalis . Their cell viability was also evaluated against the human liver adenocarcinoma cell line (Hep G2), demonstrating weak or no cytotoxicity. Lastly, the safety of the major compounds obtained, phocoenamicin ( 3 ), phocoenamicin B ( 4 ) and maklamicin ( 7 ), was tested against zebrafish eleuthero embryos and all of them displayed no toxicity up to a concentration of 25 μM.

Cancer is considered one of the main causes of human death worldwide, being characterized by an alteration of the oxidative metabolism. Many natural compounds from plant origin with anti-tumor attributes have been described. Among them, capsaicin, which is the molecule responsible for the pungency in hot pepper fruits, has been reported to show antioxidant, anti-inflammatory, and analgesic activities, as well as anti-proliferative properties against cancer. Thus, in this work, the potential anti-proliferative activity of pepper ( Capsicum annuum L.) fruits from diverse varieties with different capsaicin contents (California < Piquillo < Padrón < Alegría riojana) against several tumor cell lines (lung, melanoma, hepatoma, colon, breast, pancreas, and prostate) has been investigated. The results showed that the capsaicin content in pepper fruits did not correspond with their anti-proliferative activity against tumor cell lines. By contrast, the greatest activity was promoted by the pepper tissues which contained the lowest capsaicin amount. This indicates that other compounds different from capsaicin have this anti-tumor potentiality in pepper fruits. Based on this, green fruits from the Alegría riojana variety, which has negligible capsaicin levels, was used to study the effect on the oxidative and redox metabolism of tumor cell lines from liver (Hep-G2) and pancreas (MIA PaCa-2). Different parameters from both lines treated with crude pepper fruit extracts were determined including protein nitration and protein S-nitrosation (two post-translational modifications (PTMs) promoted by nitric oxide), the antioxidant capacity, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), among others. In addition, the activity of the NADPH-generating enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and NADP-isocitrate dehydrogenase (NADP-ICDH) was followed. Our data revealed that the treatment of both cell lines with pepper fruit extracts altered their antioxidant capacity, enhanced their catalase activity, and considerably reduced the activity of the NADPH-generating enzymes. As a consequence, less H 2 O 2 and NADPH seem to be available to cells, thus avoiding cell proliferation and possibly triggering cell death in both cell lines.