Discovery of a conserved translationally repressive upstream open reading frame within the iron-deficiency response regulator IDEF2.

BACKGROUND: Iron (Fe) deficiency affects 30-50% of the world's population. Genetic biofortification of staple crops is a promising strategy for improving human nutrition, but the number of effective precision breeding targets for Fe biofortification is small. Upstream open reading frames (uORFs) are cis-regulatory elements within the 5' leader sequence (LS) of genes that generally repress translation of the main open reading frame (mORF). RESULTS: We aligned publicly available rice (Oryza sativa L.) ribo-seq datasets and transcriptomes to identify putative uORFs within important Fe homeostasis genes. A dual luciferase assay (DLA) was used to determine whether these uORFs cause repression of mORF translation and pinpoint LS regions that can be mutated for mORF derepression. A translationally repressive uORF region was identified in two positive regulators of the Fe-deficiency response: IDEF1 and IDEF2. The IDEF2-uORF peptide was highly conserved among monocots and a mutation series in the 5' LS of the wheat (Triticum aestivum L.) TaIDEF2-A1 gene demonstrated variable mORF derepression. CONCLUSIONS: Together these results reveal a possible regulatory mechanism by which IDEF2 transcription factors modulate the Fe deficiency response in monocots, and highlight novel precision breeding targets to improve crop nutrition and abiotic stress tolerance.

Polyphenol-Rich Aronia melanocarpa Fruit Beneficially Impact Cholesterol, Glucose, and Serum and Gut Metabolites: A Randomized Clinical Trial.

Polyphenol-rich Aronia fruits have great potential as a functional food with anti-inflammatory, hypolipidemic, and hypoglycemic biologic activities. However, clinical intervention trials investigating the impact of Aronia fruit consumption on human health are limited. A randomized, controlled, double-blinded, parallel intervention trial was conducted using 14 human subjects who ingested either 0 mL or 100 mL of Aronia juice daily for 30 days. Anthropometric measurements, fasting, and postprandial measures of glucose and lipid metabolism and inflammation, 16S rRNA fecal microbial composition data, and mass spectrometry-acquired serum and fecal metabolomic data were collected before and after the intervention period. Data were analyzed using general linear models, ANOVA, and t-tests. Daily consumption of Aronia prevented a rise in cholesterol levels (ß = -0.50, p = 0.03) and reduced postprandial glucose (ß = -3.03, p < 0.01). No difference in microbial community composition by condition was identified at any taxonomic level, but a decrease (ß = -18.2, p = 0.04) in microbial richness with Aronia was detected. Serum and fecal metabolomic profiles indicated shifts associated with central carbon and lipid metabolism and decreases in pro-inflammatory metabolites. Our study further informs the development of polyphenol-based dietary strategies to lower metabolic disease risk.

Timely targeted testing for hereditary cancer syndromes - Importance of clinician-facilitated cascade testing in the first year post-diagnosis.

OBJECTIVE: Cascade testing for hereditary cancer syndromes allows relatives to estimate cancer risk and pursue prevention and early detection strategies. The current paradigm relies on patient coordinated care, resulting in only one-third of relatives successfully completing testing. Studies suggest that team-based approaches, where clinicians facilitate testing, can increase uptake. As institutions consider implementing such programs, understanding patient characteristics associated with interest is crucial for resource allocation. We aim to assess interest in clinician-facilitated testing and evaluate barriers. METHODS: Patients with cancer-associated pathogenic variants seen at a gynecologic oncology clinic were offered clinician-facilitated cascade testing. Patient interest and demographic variables were recorded and patients that declined were interviewed regarding the decision. RESULTS: From 11/2023-4/2024, 139 patients were offered clinician-facilitated cascade testing. Median patient age was 43 years (IQR 17), 97 (69.8 %) self-identified as White and 101 (72.7 %) as non-Hispanic. Fifty-six (40.3 %) patients harbored a BRCA1 pathogenic variant, 37 (26.6 %) BRCA2, and 46 (33.1 %) other cancer-associated genes. Fifty-seven (41.0 %) patients expressed interest in the intervention. Interested patients were more likely to have been diagnosed in the prior year vs. patients who were not interested on univariate (OR 4.6, 95 % CI 2.0-10.2, P = 0.0002) and multivariable analyses (adjusted OR 3.8, 95 % CI 1.622-9.009, P = 0.0022). CONCLUSIONS: Our study demonstrates that patients are almost five time more likely to be interested in cascade genetic testing within the first year of diagnosis of a pathogenic variant. Given the utility of such programs and their resource requirements, targeting this population could maximize effectiveness and uptake of cascade services.

Multi-source connectivity as the driver of solar wind variability in the heliosphere.

The ambient solar wind that fills the heliosphere originates from multiple sources in the solar corona and is highly structured. It is often described as high-speed, relatively homogeneous, plasma streams from coronal holes and slow-speed, highly variable, streams whose source regions are under debate. A key goal of ESA/NASA's Solar Orbiter mission is to identify solar wind sources and understand what drives the complexity seen in the heliosphere. By combining magnetic field modelling and spectroscopic techniques with high-resolution observations and measurements, we show that the solar wind variability detected in situ by Solar Orbiter in March 2022 is driven by spatio-temporal changes in the magnetic connectivity to multiple sources in the solar atmosphere. The magnetic field footpoints connected to the spacecraft moved from the boundaries of a coronal hole to one active region (12961) and then across to another region (12957). This is reflected in the in situ measurements, which show the transition from fast to highly Alfvénic then to slow solar wind that is disrupted by the arrival of a coronal mass ejection. Our results describe solar wind variability at 0.5 au but are applicable to near-Earth observatories.

Tobacco-cannabis co-use among cancer patients and survivors: findings from 2 US cancer centers.

BACKGROUND: Cannabis use is prevalent among cancer patients and survivors and may provide some therapeutic benefits for this population. However, benefits may be attenuated when cannabis is co-used with tobacco, which is associated with more severe tobacco and cannabis use and adverse outcomes in noncancer populations. We compared cannabis use, primary mode of use, and therapeutic and/or nontherapeutic use among 3 groups of patients and survivors based on cigarette smoking status. METHODS: Survey data was collected from patients and survivors with cancer (n = 1732) at 2 US National Cancer Institute-designated cancer centers in states with varying cannabis regulatory policy. Prevalence of cannabis use (prior to diagnosis, after diagnosis, before treatment, after treatment), primary mode of use, and therapeutic and/or nontherapeutic use were assessed by cigarette smoking status (current, former, never) within and across centers using weighted bivariate analyses and multivariable logistic regression, controlling for demographic and clinical variables. RESULTS: Current cigarette use was associated with greater rates of cannabis use prior to diagnosis, after diagnosis, during treatment, and after treatment within each center (all P < .001) and in pooled analyses across centers (all P < .001). Primary mode of use, knowledge of cannabis products, and therapeutic and/or nontherapeutic use also statistically differed by tobacco status and study site. CONCLUSIONS: Results illustrate the importance of conducting assessments for both tobacco and cannabis use among cancer patients during and after cancer treatment, regardless of the cannabis regulatory environment. Given previous data indicating harms from co-use and continued tobacco use during cancer treatment, this issue introduces new priorities for cancer care delivery and research.

Flexible decision-making is related to strategy learning, vicarious trial and error, and medial prefrontal rhythms during spatial set-shifting.

Flexible decision-making requires a balance between exploring features of an environment and exploiting prior knowledge. Behavioral flexibility is typically measured by how long it takes subjects to consistently make accurate choices after reward contingencies switch or task rules change. This measure, however, only allows for tracking flexibility across multiple trials, and does not assess the degree of flexibility. Plus, although increases in decision-making accuracy are strong indicators of learning, other decision-making behaviors have also been suggested as markers of flexibility, such as the on-the-fly decision reversals known as vicarious trial and error (VTE) or switches to a different, but incorrect, strategy. We sought to relate flexibility, learning, and neural activity by comparing choice history-derived evaluation of strategy use with changes in decision-making accuracy and VTE behavior while recording from the medial prefrontal cortex (mPFC) in rats. Using a set-shifting task that required rats to repeatedly switch between spatial decision-making strategies, we show that a previously developed strategy likelihood estimation procedure could identify putative learning points based on decision history. We confirm the efficacy of learning point estimation by showing increases in decision-making accuracy aligned to the learning point. Additionally, we show increases in the rate of VTE behavior surrounding identified learning points. By calculating changes in strategy likelihoods across trials, we tracked flexibility on a trial-by-trial basis and show that flexibility scores also increased around learning points. Further, we demonstrate that VTE behaviors could be separated into indecisive and deliberative subtypes depending on whether they occurred during periods of high or low flexibility and whether they led to correct or incorrect choice outcomes. Field potential recordings from the mPFC during decisions exhibited increased beta band activity on trials with VTE compared to non-VTE trials, as well as increased gamma during periods when learned strategies could be exploited compared to prelearning, exploratory periods. This study demonstrates that increased behavioral flexibility and VTE rates are often aligned to task learning. These relationships can break down, however, suggesting that VTE is not always an indicator of deliberative decision-making. Additionally, we further implicate the mPFC in decision-making and learning by showing increased beta-based activity on VTE trials and increased gamma after learning.

Paws and Pathogens: A Multidisciplinary Approach Through Bartonella henselae Endocarditis and Hepatosplenic T-Cell Lymphoma.

Bartonella species are gram-negative coccobacilli that are globally recognized as significant pathogens causing zoonotic infections. Among Bartonella species, B. henselae, B. quintana, and B. bacilliformis are prominent pathogens causing infections in humans, often manifesting as infective endocarditis. Bartonella endocarditis can pose diagnostic challenges due to its indolent presentation and limitations of standard microbiological culture techniques to identify the organism. We report a case of a 23-year-old male, who initially presented with the manifestations of hepatosplenic T-cell lymphoma, later diagnosed with blood culture-negative endocarditis caused by B. henselae. The patient had a complicated clinical course including pancytopenia, hepatosplenomegaly, and severe aortic valve regurgitation. Despite negative blood cultures, diagnostic clues included persistent fevers and bicuspid aortic valve with abscess. High Bartonella IgG titers (>1:800) supported the diagnosis. This case underscores the importance of considering Bartonella species in patients with suspected endocarditis, particularly in those with predisposing factors and negative blood cultures. Diagnosis relies heavily on serologic assays due to low sensitivity of conventional culture methods. Treatment involves a multidisciplinary approach with antibiotics and surgical intervention for optimal outcomes. Timely recognition and management are crucial to mitigate the high mortality associated with Bartonella endocarditis, and we hope this article offers insight for clinicians.

Rats exposed to Alternaria toxins in vivo exhibit altered liver activity highlighted by disruptions in riboflavin and acylcarnitine metabolism.

Natural toxins produced by Alternaria fungi include the mycotoxins alternariol, tenuazonic acid and altertoxins I and II. Several of these toxins have shown high toxicity even at low levels including genotoxic, mutagenic, and estrogenic effects. However, the metabolic effects of toxin exposure from Alternaria are understudied, especially in the liver as a key target. To gain insight into the impact of Alternaria toxin exposure on the liver metabolome, rats (n = 21) were exposed to either (1) a complex culture extract with defined toxin profiles from Alternaria alternata (50 mg/kg body weight), (2) the isolated, highly genotoxic altertoxin-II (ATX-II) (0.7 mg/kg of body weight) or (3) a solvent control. The complex mixture contained a spectrum of Alternaria toxins including a controlled dose of ATX-II, matching the concentration of the isolated ATX-II. Liver samples were collected after 24 h and analyzed via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Authentic reference standards (> 100) were used to identify endogenous metabolites and exogenous compounds from the administered exposures in tandem with SWATH-acquired MS/MS data which was used for non-targeted analysis/screening. Screening for metabolites produced by Alternaria revealed several compounds solely isolated in the liver of rats exposed to the complex culture, confirming results from a previously performed targeted biomonitoring study. This included the altersetin and altercrasin A that were tentatively identified. An untargeted metabolomics analysis found upregulation of acylcarnitines in rats receiving the complex Alternaria extract as well as downregulation of riboflavin in rats exposed to both ATX-II and the complex mixture. Taken together, this work provides a mechanistic view of Alternari toxin exposure and new suspect screening insights into hardly characterized Alternaria toxins.

Addressing Substance Use in the Adolescent Transplant Population.

Adolescence is a unique period of physical and psychosocial changes as youth transition, over many years, to adulthood. The psychosocial changes that accompany adolescence include emotional separation from parents, greater influence of peer groups, an interest in self-identification and autonomy, and increased risk-taking behaviors. Substance use is a common form of risk-taking behavior in the adolescent developmental stage. Alcohol, nicotine, and cannabis are the most common types of substances used in the United States. In the adolescent transplant population, rates of substance use appear to be at, or slightly below, their peer counterparts. Substance use can lead to deleterious health outcomes for adolescent transplant patients as a result of impaired decision-making, reduction in medication and clinic visit compliance, increases in mental health disorders, and risk for developing dependence and a substance use disorder. Given the close relationship that many pediatric transplant providers have with their patients and families, transplant care teams are in an excellent position to help their patients by addressing adolescent substance use. This narrative review describes how providers can use proactive standardized approaches to identify and intervene with substance use behavior.

Robotic performance metrics model fellow proficiency in living donor nephrectomy.

We investigated the use of robotic objective performance metrics (OPM) to predict number of cases to proficiency and independence among abdominal transplant fellows performing robot-assisted donor nephrectomy (RDN). 101 RDNs were performed by 5 transplant fellows from September 2020 to October 2023. OPM included fellow percent active control time (%ACT) and handoff counts (HC). Proficiency was defined as ACT ≥ 80% and HC ≤ 2, and independence as ACT ≥ 99% and HC ≤ 1. Case number was significantly associated with increasing fellow %ACT, with proficiency estimated at 14 cases and independence at 32 cases (R2 = 0.56, p < 0.001). Similarly, case number was significantly associated with decreasing HC, with proficiency at 18 cases and independence at 33 cases (R2 = 0.29, p < 0.001). Case number was not associated with total active console time (p = 0.91). Patient demographics, operative characteristics, and outcomes were not associated with OPM, except for donor estimated blood loss (EBL), which positively correlated with HC. Abdominal transplant fellows demonstrated proficiency at 14-18 cases and independence at 32-33 cases. Total active console time remained unchanged, suggesting that increasing fellow autonomy does not impede operative efficiency. These findings may serve as a benchmark for training abdominal transplant surgery fellows independently and safely in RDN.

Clinical outcomes in patients infected with ertapenem-only-resistant Enterobacterales versus multi-carbapenem-resistant Enterobacterales.

BACKGROUND: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). OBJECTIVES: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. METHODS: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. RESULTS: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. CONCLUSIONS: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections.

Patient and Family Financial Burden in Cancer: A Focus on Differences across Four Provinces, and Reduced Spending Including Decisions to Forego Care in Canada.

GOAL: This study aimed to examine provincial differences in patient spending for cancer care and reductions in household spending including decisions to forego care in Canada. METHODS: Nine-hundred and one patients with cancer, from twenty cancer centers across Canada, completed a self-administered questionnaire (P-SAFE version 7.2.4) (344 breast, 183 colorectal, 158 lung, and 216 prostate) measuring direct and indirect costs and spending changes. RESULTS: Provincial variations showed a high mean out-of-pocket cost (OOPC) of CAD 938 (Alberta) and a low of CAD 280 (Manitoba). Differences were influenced by age and income. Income loss was highest for Alberta (CAD 2399) and lowest for Manitoba (CAD 1126). Travel costs were highest for Alberta (CAD 294) and lowest for British Columbia (CAD 67). Parking costs were highest for Ontario (CAD 103) and lowest for Manitoba (CAD 53). A total of 41% of patients reported reducing spending, but this increased to 52% for families earning

Evaluation of hospital-onset bacteraemia and fungaemia in the USA as a potential healthcare quality measure: a cross-sectional study.

BACKGROUND: Hospital-onset bacteraemia and fungaemia (HOB) is being explored as a surveillance and quality metric. The objectives of the current study were to determine sources and preventability of HOB in hospitalised patients in the USA and to identify factors associated with perceived preventability. METHODS: We conducted a cross-sectional study of HOB events at 10 academic and three community hospitals using structured chart review. HOB was defined as a blood culture on or after hospital day 4 with growth of one or more bacterial or fungal organisms. HOB events were stratified by commensal and non-commensal organisms. Medical resident physicians, infectious disease fellows or infection preventionists reviewed charts to determine HOB source, and infectious disease physicians with training in infection prevention/hospital epidemiology rated preventability from 1 to 6 (1=definitely preventable to 6=definitely not preventable) using a structured guide. Ratings of 1-3 were collectively considered 'potentially preventable' and 4-6 'potentially not preventable'. RESULTS: Among 1789 HOB events with non-commensal organisms, gastrointestinal (including neutropenic translocation) (35%) and endovascular (32%) were the most common sources. Overall, 636/1789 (36%) non-commensal and 238/320 (74%) commensal HOB events were rated potentially preventable. In logistic regression analysis among non-commensal HOB events, events attributed to intravascular catheter-related infection, indwelling urinary catheter-related infection and surgical site infection had higher odds of being rated preventable while events with neutropenia, immunosuppression, gastrointestinal sources, polymicrobial cultures and previous positive blood culture in the same admission had lower odds of being rated preventable, compared with events without those attributes. Of 636 potentially preventable non-commensal HOB events, 47% were endovascular in origin, followed by gastrointestinal, respiratory and urinary sources; approximately 40% of those events would not be captured through existing healthcare-associated infection surveillance. DISCUSSION: Factors identified as associated with higher or lower preventability should be used to guide inclusion, exclusion and risk adjustment for an HOB-related quality metric.

Carbapenem-resistant Acinetobacter baumannii complex in the United States-An epidemiological and molecular description of isolates collected through the Emerging Infections Program, 2019.

BACKGROUND: Understanding the epidemiology of carbapenem-resistant A. baumannii complex (CRAB) and the patients impacted is an important step toward informing better infection prevention and control practices and improving public health response. METHODS: Active, population-based surveillance was conducted for CRAB in 9 U.S. sites from January 1 to December 31, 2019. Medical records were reviewed, isolates were collected and characterized including antimicrobial susceptibility testing and whole genome sequencing. RESULTS: Among 136 incident cases in 2019, 66 isolates were collected and characterized; 56.5% were from cases who were male, 54.5% were from persons of Black or African American race with non-Hispanic ethnicity, and the median age was 63.5 years. Most isolates, 77.2%, were isolated from urine, and 50.0% were collected in the outpatient setting; 72.7% of isolates harbored an acquired carbapenemase gene (aCP), predominantly blaOXA-23 or blaOXA-24/40; however, an isolate with blaNDM was identified. The antimicrobial agent with the most in vitro activity was cefiderocol (96.9% of isolates were susceptible). CONCLUSIONS: Our surveillance found that CRAB isolates in the U.S. commonly harbor an aCP, have an antimicrobial susceptibility profile that is defined as difficult-to-treat resistance, and epidemiologically are similar regardless of the presence of an aCP.

Cost-effectiveness of BRCA1 testing at time of obstetrical prenatal carrier screening for cancer prevention.

BACKGROUND: Improved technologies paired with an increase in access to genetic testing have led to the availability of expanded carrier screening evaluating hundreds of disorders. Currently, most autosomal dominant mutations, such as BRCA1, are not included in expanded carrier assays. Screening pregnant or preconception reproductive-aged women for BRCA1 may present a unique opportunity to perform population-based screening for patients at a time when precancer screening, chemoprevention, and/or risk-reducing surgery may be beneficial. OBJECTIVE: This study aimed to inform clinical decision-making as to whether the universal incorporation of BRCA1 testing at the time of obstetrical prenatal carrier screening is cost-effective. STUDY DESIGN: A decision analysis and Markov model was created. The initial decision point in the model was BRCA1 testing at the time of expanded carrier screening. Model probabilities, cost, and utility values were derived from published literature. For BRCA1-positive patients, the model simulated breast cancer screening and risk-reducing surgical interventions. A cycle length of 1 year and a time horizon of 47 years were used to simulate the lifespan of patients. The setting was obstetrical clinics in the United States, and the participants were a theoretical cohort of 1,429,074 pregnant patients who annually underwent expanded carrier screening. RESULTS: Among our cohort, BRCA1 testing resulted in the identification of an additional 3716 BRCA1-positive patients, the prevention of 1394 breast and ovarian cancer cases, and 1084 fewer deaths. BRCA1 testing was a cost-effective strategy compared with no BRCA1 testing with an incremental cost-effectiveness ratio of $86,001 per quality-adjusted life years. In a 1-way sensitivity analysis, we varied the prevalence of BRCA1 in the population from 0.00% to 20.00% and found that BRCA1 testing continued to be the cost-effective strategy until the prevalence rate was reduced to 0.16%. Multiple additional sensitivity analyses did not substantially affect the cost-effectiveness. CONCLUSION: The addition of BRCA1 testing to obstetrical prenatal carrier screening is a cost-effective management strategy to identify at-risk women at a time when cancer screening and preventive strategies can be effective. Despite the burden of additional genetic counseling, prenatal care represents a unique opportunity to implement population-based genetic testing.