Use of allopurinol to manage skewed 6-mercaptopurine metabolism in pediatric maintenance acute lymphoblastic leukemia treatment.

BACKGROUND: 6-mercaptopurine is a cornerstone of maintenance therapy for pediatric ALL. Response to 6MP is typically determined by the ANC. Therapeutic ANC range while receiving 6MP is between 500 and 1500/µL. In addition to desired myelosuppression, 6MP is associated with multiple adverse drug effects. Increased doses of 6MP can lead to therapeutic ANC values; however, patients may experience adverse effects before obtaining therapeutic myelosuppression, often deemed "skewed metabolism." Allopurinol may potentially correct skewed 6MP metabolism. PROCEDURE: Pediatric patients with ALL with 6MMP and 6TGN metabolites drawn during maintenance therapy were analyzed for allopurinol use. The primary outcome evaluated the percentage of time spent in therapeutic ANC range before and after allopurinol initiation. In addition, the difference in 6MMP:6TGN ratios before and after allopurinol initiation, incidence of hepatotoxicity, and rates of relapse, were analyzed. RESULTS: Ninety-five patients were included for analysis. Thirty-two (34%) patients received allopurinol. There were no significant differences in baseline demographics between the patients who received allopurinol and those who did not. When comparing ANC values pre- and post-allopurinol initiation, a statistically significant increase in the percentage of time spent in therapeutic range was observed (27% vs. 43%; p = .03). In addition, when comparing metabolite ratios pre- and post-allopurinol initiation, a statistically significant decrease in 6MMP:6TGN metabolite ratio values was observed (86.7 vs. 3.6; p < .0001). CONCLUSIONS: Allopurinol significantly increased the percent time in therapeutic ANC range and can be safely utilized to significantly lower the ratio of 6MMP:6TGN metabolites, alleviating the undesirable side effects of 6MMP, and optimizing the anti-leukemic effects associated with 6TGN.

Childhood cancer presentation and initial outcomes in Ethiopia: Findings from a recently opened pediatric oncology unit.

There were no pediatric oncology centers in southwest Ethiopia prior to 2016. This study aims to describe presenting diagnoses and initial outcomes at Jimma University Medical Center (JUMC), the first pediatric oncology unit (POU) in southwest Ethiopia, provide initial insights into regional pediatric cancer epidemiology, illustrate the rapid growth of pediatric cancer services, and highlight ongoing challenges. We used a retrospective descriptive approach to assess the epidemiologic pattern and initial treatment outcomes of pediatric cancer at JUMC POU from August 2016 through December 2022. During the study period, 749 children were diagnosed with cancer at JUMC. The mean age was 7.2 years (20 days-18 years). Acute lymphoblastic leukemia was the most common diagnosis (16.4%), followed by non-Hodgkin lymphoma (12.4%), Wilms tumor (11.1%), soft tissue sarcoma (8.8%), Hodgkin lymphoma (8.4%), and retinoblastoma (8.3%). Brain tumors accounted for only 2.7% of the diagnoses. Of the 703 patients that were not referred elsewhere, 42% of the patients abandoned treatment, 29% died, 17% completed treatment, and 7% remained on treatment at the time of this assessment. The findings emphasize the growth in the diagnosis and treatment of children with cancer in the southwest region of Ethiopia. The data suggests a different epidemiologic profile of childhood cancer cases diagnosed at the JUMC POU compared to high-income countries and neighbouring countries in Africa. Treatment abandonment remains a barrier to care. Ongoing areas of focus include establishment of a hospital-based cancer registry, reduction of treatment abandonment, improvement of diagnostic capacity, and increased access to advanced supportive care.

Real-world effectiveness of upadacitinib in Crohn's disease: a UK multicentre retrospective cohort study.

Background: Upadacitinib is a Janus kinase inhibitor, which has recently been approved for treating Crohn's disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn's disease. Objective: Our aim was to evaluate the outcomes of upadacitinib in a real-world Crohn's disease cohort. Methods: We conducted a retrospective, multicentre, cohort study over a 2-year period across National Health Service (NHS) Lothian and Royal Devon University Healthcare NHS Foundation Trust. The primary outcome was treatment persistence at week 24. Secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index (HBI)<5) and biomarker remission (C-reactive protein (CRP)≤5 mg/L and faecal calprotectin (FCAL)<250 µg/g) at 12, 24 and 52 weeks. We recorded adverse events. Results: 135 patients commenced upadacitinib as of the 1 January 2024, of which 93 patients with active Crohn's disease were included with a minimum of 12 weeks follow-up. The median follow-up time was 25 weeks (IQR 15-42 weeks). 82% of the cohort had exposure to at least two classes of advanced therapies, and 52% had exposure to at least three classes of advanced therapies. Treatment persistence was 87.1% at week 12, 81.7% at week 24 and 62.8% at week 52. Rates of clinical remission were 64% (42/66), 48% (22/46) and 38% (8/21) at weeks 12, 24 and 52, respectively. Significant reductions in HBI, CRP and FCAL were observed during follow-up. 14% (13/91) had a hospitalisation due to Crohn's disease. Adverse events occurred in 40% (37/93) of the cohort, of which 12% (11/93) were serious. Conclusion: Upadacitinib was effective in a real-world, highly refractory, Crohn's disease cohort with good persistence.

Evaluation of germicidal UV-C light for suppression of grape powdery mildew and Botrytis bunch rot in Western Oregon.

Germicidal ultraviolet light (UV-C) has been shown to effectively suppress several plant pathogens, as well as some arthropod pests. Recent reports describe the efficacy of nighttime applications of UV-C at doses from 100 to 200 J/m2 in vineyards to reduce grape powdery mildew (Erysiphe necator). Our in vitro studies confirmed efficacy of UV-C to inhibit germination of E. necator and Botrytis cinerea conidia, demonstrated a range of tolerances to UV-C within a collection of E. necator isolates, and showed growth stage-specific effects of UV-C on B. cinerea. Nighttime use of UV-C was evaluated at 48 to 96 J/m2 in small plot trials (<1,000 vines) from 2020 to 2023. Once or twice weekly UV-C applications significantly reduced the incidence of foliar powdery mildew compared to non-UV-C-treated controls (P < 0.02). Suppression of powdery mildew on fruit was less consistent, where once or twice weekly UV-C exposure reduced powdery mildew disease severity in 2020 (P = 0.04), 2021 (P = 0.02) and 2023 (P =0.003), but less so in 2022 (P = 0.07). Bunch rot severity was not significantly reduced with UV-C treatment in any year of the study. Application of UV-C until the onset of fruit color change (veraison) also had a minimal effect on the fruit soluble solids, pH, anthocyanins, or phenolics in harvested fruit at any UV-C dose or frequency (P > 0.10). Suppression of powdery mildew by nighttime application UV-C at lower doses in small plots suggests that such treatments merit further evaluation in larger-scale studies in Western Oregon.

Population density and receipt of care for common mental disorders: a cross-sectional analysis of English household data from the 2014 Adult Psychiatric Morbidity Survey.

OBJECTIVES: People living in less urban areas in the UK may have reduced access to mental healthcare compared with people in urban areas. Although this was not reported in the 2000 Adult Psychiatric Morbidity Survey (APMS) data, subsequent changes to mental health provision and economic recession may have impacted care inequalities. We re-examined this, hypothesising that those living in less urban areas of England received less antidepressant medication and psychological interventions, compared with those living in urban areas, after adjusting for covariates including common mental disorders (CMDs) and socioeconomic status. DESIGN: National cross-sectional study. SETTING: Households in England. PARTICIPANTS: We analysed data from 7455 participants aged 16 and above from the 2014 English APMS. EXPOSURES: Residence in an urban or less urban area. PRIMARY OUTCOME: Current receipt of any antidepressant medication or any psychological intervention. RESULTS: Participants living in less urban areas were half as likely to be in receipt of any psychological intervention relative to those living in urban areas (adjusted OR (aOR) 0.49; 95% CI 0.30 to 0.79; p=0.004). There was no association between urbanisation and antidepressant receipt (aOR 1.01; 95% CI 0.81 to 1.25; p=0.944). CONCLUSION: People living in less urban areas have a lower likelihood of being in receipt of psychological treatment for CMDs, which may indicate barriers to care access. Our findings differ from the results of a study using a comparable sample conducted 14 years previously. While Improving Access to Psychological Therapies services have increased therapy access nationwide, this may have had more impact in urban areas, potentially widening urban/rural inequalities. Further research is needed to understand how to address such geographical inequalities in access to mental healthcare.

SYNY: a pipeline to investigate and visualize collinearity between genomes.

Investigating collinearity between chromosomes is often used in comparative genomics to help identify gene orthologs, pinpoint genes that might have been overlooked as part of annotation processes and/or perform various evolutionary inferences. Collinear segments, also known as syntenic blocks, can be inferred from sequence alignments and/or from the identification of genes arrayed in the same order and relative orientations between investigated genomes. To help perform these analyses and assess their outcomes, we built a simple pipeline called SYNY (for synteny) that implements the two distinct approaches and produces different visualizations. The SYNY pipeline was built with ease of use in mind and runs on modest hardware. The pipeline is written in Perl and Python and is available on GitHub (https://github.com/PombertLab/SYNY) under the permissive MIT license.

Geographical and socioeconomic disparities in post-transcatheter aortic valve replacement pacemaker placement.

INTRODUCTION: Pacemaker (PPM) implantation is indicated for conduction abnormalities which can develop post-transcatheter aortic valve replacement (TAVR). However, whether post-TAVR PPM risk is associated with the geographical location of the hospital and socioeconomic status of the patient is not well established. Our goal was to explore geographical and socioeconomic disparities in post-TAVR PPM implantation. METHODS: A retrospective cohort analysis was conducted using the National Inpatient Sample 2016-2020 with respective ICD-10 codes for TAVR and PPM implantation. A weighted multivariate logistic regression model was used to analyze prognostic outcomes. RESULTS: The number of patients hospitalized for undergoing TAVR was 296,740, out of which 28,265 patients had PPM implantation (prevalence 9.5 %). Patients' demographics including sex, ethnicity, household income, and insurance were not associated with risk of post-TAVR PPM except age (OR 1.01, CI 1.07-12.5, p < 0.001). Compared to rural hospitals, urban non-teaching hospitals were associated with a higher risk of post-TAVR PPM (OR 2.09, 1.3-3.43, p = 0.003). Compared to New England hospitals (ME, NH, VT, MA, RI, CT), middle Atlantic hospitals (NY, NJ, PA) were associated with highest post-TAVR PPM risk (OR 1.54, CI 1.2-1.98, p < 0.001), followed by Pacific (AK, WA, OR, CA, HI), mountain (ID, MT, WY, NV, UT, CO, AZ, NM) and east north central US. CONCLUSION: Patients' demographics including sex, ethnicity, household income, and insurance were not associated with the risk of post-TAVR PPM except for age. Compared to New England hospitals, Middle Atlantic hospitals were associated with the highest post-TAVR PPM risk followed by Pacific, Mountain, and East North Central US. Prospective studies with data on TAVR wait times, expertise of the interventional staff, and post-TAVR management and discharge planning are required to further explore the observed regional distribution of TAVR outcomes.

An Assessment of Open Fracture Management in Hospitals in Malawi Before and Immediately After Implementing Open Fracture Guidelines.

Background: Open fractures, a common consequence of road traffic collisions, are associated with a high risk of complications. The introduction of standard guidelines has been shown to improve patient care and reduce the risk of complications in several countries. In September 2021, the Malawi Orthopaedic Association/Arbeitsgemeinschaft für Osteosynthesefragen Alliance (MOA/AOA) guidelines and standards for open fracture management were introduced in Malawi. This study aimed to assess the management of open fractures in hospitals in Malawi, before and after implementing a training course on the MOA/AOA open fracture guidelines. Methods: This was a descriptive and quantitative, before-and-after study that reviewed the medical files of patients with open fractures at Zomba Central Hospital and Mulanje, Salima, and Mangochi district hospitals over two 3-month periods. Variables included initial assessment; antibiotic prophylaxis; place of debridement; type of anesthesia; treatment of the open fracture in the emergency department, operating room, and wards; and short-term complications requiring hospital treatment. Results: A total of 88 open-fracture case files were reviewed; 43 were prior and 45 were subsequent to the implementation of the open fracture guidelines. The overall median patient age was 36 years (interquartile range, 27 to 45 years), and 91% (80) were male. Limb neurovascular status assessment and documentation improved from 26% (11) of the patients before the guidelines to 62% (28) afterward (p = 0.0002). The percentage who underwent debridement in the operating room significantly increased from 19% (8) to 69% (31) (p = 0.01). The percentage who underwent debridement under general or spinal anesthesia significantly increased from 5% (2) to 38% (17) and from 12% (5) to 29% (13), respectively (p= 0.001). The wound infection rate decreased from 21% to 11%, but this was not significant, and there was no change in the overall complication rate (p = 0.152). Conclusions: This study suggests that training on the MOA/AOA open fracture management guidelines followed by their implementation can lead to at least temporary improvement in the management of open fractures. Nevertheless, additional studies need to be performed to understand the effect on long-term patient outcomes. Levels of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Improving the management of open tibia fractures, Malawi.

Objective: To assess the impact of an open fracture intervention bundle on clinical management and patient outcomes of adults in Malawi with open tibia fractures. Methods: We conducted a before-and-after implementation study in Malawi in 2021 and 2022 to assess the impact of an open fracture intervention bundle, including a national education course for clinical officers and management guidelines for open fractures. We recruited 287 patients with open tibia fractures. The primary outcome was a before-and-after comparison of the self-reported short musculoskeletal function assessment score, a measure of patient function. Secondary outcomes included clinical management; and clinician knowledge and implementation evaluation outcomes of 57 health-care providers attending the course. We also constructed multilevel regression models to investigate associations between clinical knowledge, patient function, and implementation evaluation before and after the intervention. Findings: The median patient function score at 1 year was 6.8 (interquartile range, IQR: 1.5 to 14.5) before intervention and 8.4 (IQR: 3.8 to 23.2) after intervention. Compared with baseline scores, we found clinicians' open fracture knowledge scores improved 1 year after the intervention was implemented (mean posterior difference: 1.6, 95% highest density interval: 0.9 to 2.4). However, we found no difference in most aspects of clinicians' open fracture management practice. Conclusion: Despite possible improvement in clinician knowledge and positive evaluation of the intervention implementation, our study showed that there was no overall improvement in clinical management, and weak evidence of worsening patient function 1 year after injury, after implementation of the open fracture intervention bundle.

Correction: Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness.

[This corrects the article DOI: 10.1371/journal.pone.0287412.].

Encoding a magic state with beyond break-even fidelity.

To run large-scale algorithms on a quantum computer, error-correcting codes must be able to perform a fundamental set of operations, called logic gates, while isolating the encoded information from noise1-8. We can complete a universal set of logic gates by producing special resources called magic states9-11. It is therefore important to produce high-fidelity magic states to conduct algorithms while introducing a minimal amount of noise to the computation. Here we propose and implement a scheme to prepare a magic state on a superconducting qubit array using error correction. We find that our scheme produces better magic states than those that can be prepared using the individual qubits of the device. This demonstrates a fundamental principle of fault-tolerant quantum computing12, namely, that we can use error correction to improve the quality of logic gates with noisy qubits. Moreover, we show that the yield of magic states can be increased using adaptive circuits, in which the circuit elements are changed depending on the outcome of mid-circuit measurements. This demonstrates an essential capability needed for many error-correction subroutines. We believe that our prototype will be invaluable in the future as it can reduce the number of physical qubits needed to produce high-fidelity magic states in large-scale quantum-computing architectures.

Transforming healthcare documentation: harnessing the potential of AI to generate discharge summaries.

BACKGROUND: Hospital discharge summaries play an essential role in informing GPs of recent admissions to ensure excellent continuity of care and prevent adverse events; however, they are notoriously poorly written, time-consuming, and can result in delayed discharge. AIM: To evaluate the potential of artificial intelligence (AI) to produce high-quality discharge summaries equivalent to the level of a doctor who has completed the UK Foundation Programme. DESIGN & SETTING: Feasibility study using 25 mock patient vignettes. METHOD: Twenty-five mock patient vignettes were written by the authors. Five junior doctors wrote discharge summaries from the case vignettes (five each). The same case vignettes were input into ChatGPT. In total, 50 discharge summaries were generated; 25 by Al and 25 by junior doctors. Quality and suitability were determined through both independent GP evaluators and adherence to a minimum dataset. RESULTS: Of the 25 AI-written discharge summaries 100% were deemed by GPs to be of an acceptable quality compared with 92% of the junior doctor summaries. They both showed a mean compliance of 97% with the minimum dataset. In addition, the ability of GPs to determine if the summary was written by ChatGPT was poor, with only a 60% accuracy of detection. Similarly, when run through an AI-detection tool all were recognised as being very unlikely to be written by AI. CONCLUSION: AI has proven to produce discharge summaries of equivalent quality to a junior doctor who has completed the UK Foundation Programme; however, larger studies with real-world patient data with NHS-approved AI tools will need to be conducted.

Obesity-Induced Hyperglycemia and Heart Failure Preserved Ejection Fraction: Uncharted Territories to Remission.

Until the end of World War II, food security was a global challenge. Consequently, in 1948, type 2 diabetes was relatively uncommon, with the majority of cases being type 1 diabetes requiring insulin therapy. Since then, food has become increasingly palatable and readily available, leading to a rise in obesity across all age groups. Understanding the impact of obesity on our health has become crucial for optimizing healthcare. In this context, we draw attention to two significant, yet relatively uncharted pathogenic effects associated with obesity: Hyperglycemia and Heart Failure with Preserved Ejection Fraction (HFpEF). Thorough pathophysiologic, hemodynamic, and echocardiographic characterization have revealed the existence of a distinct phenotype known as "obese HFpEF" within the broader HFpEF population, and "obesity-induced hyperglycemia" within the diabetes population. In these phenotypes, patients often present with higher Body Mass Index and experience clinical symptoms decades earlier. Recent insights have enhanced our understanding of the mechanisms underlying obesity-mediated heart failure preserved ejection fraction and hyperglycemia. Early detection offers the potential for reversibility of many pathologies associated with obesity through adequate weight reduction. The objective of this review is to provide a deeper insight into these uncharted territories and explore the potential for improved outcomes by reframing these two narratives toward achieving remission. Such a shift has the potential to positively impact individual engagement with healthier lifestyles.

Coronary Artery Calcium Scoring in Asymptomatic Patients.

Coronary artery calcium (CAC) scoring is an important prognostic tool for personalized cardiovascular preventive care and has recently been incorporated into American College of Cardiology/American Heart Association guidelines. CAC provides direct visualization and quantification of CAC burden for risk stratification and primary prevention of cardiovascular events in an asymptomatic population. CAC scoring is recommended for individuals with intermediate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and selective populations with borderline ASCVD risk. In this review, we outline the interpretation of CAC scores for predicting the risk of cardiovascular events, and we highlight the guidelines for starting statin and potentially starting aspirin therapy. A CAC score of 0 is the strongest negative predictive factor for cardiovascular disease (CVD), and a 0 score can successfully de-risk a patient. On the contrary, higher CAC scores correlate with worse cardiovascular prognostic outcomes. The CAC scan is a widely available and reproducible means for an early look at the atherosclerotic burden, and it can help strategize early interventions. The CAC interpretation and the decision to start treatment need to be personalized based on individual risk factors. We believe the emerging literature supports our contention that the CAC score can be used more broadly to improve the prophylaxis and treatment of a wider range of apparently healthy patients.

Atrial Fibrillation: Rate Versus Rhythm Control.

Description Atrial fibrillation (AF) remains the most common arrhythmia worldwide and is expected to affect approximately 12 million individuals in the United States alone by 2030. Thromboembolic events remain a feared complication of AF and should be treated and risk-stratified utilizing the CHA2DS2-VASc scoring system. Other complications of AF span a wide spectrum from impaired quality of life (QoL) to an increase in all-cause mortality. Rate control strategies consist of controlling the ventricular rate and have been shown to be a safe and effective strategy for asymptomatic AF patients. In patients who are plagued with symptoms leading to impaired QoL or a decrease in exercise capacity, rhythm control with antiarrhythmic drugs or catheter ablation may be suitable options. Mortality benefits when comparing rate versus rhythm control remain equivocal when comparing multiple studies over the past decade.

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness.

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

Our Hidden Enemy: Ultra-Processed Foods, Inflammation, and the Battle for Heart Health.

Over the past few decades, we have witnessed unprecedented growth in new data that has fundamentally changed our traditional understanding of the progression of atherosclerotic plaques, as well as our strategies for preventing cardiovascular diseases, especially atherosclerosis. It was once believed that atherosclerosis was primarily caused by abnormal lipid buildup in the vessel intima, leading to plaque growth and luminal stenosis, with or without rupture. This perspective has now evolved to encompass more complex pathways, wherein the accumulation of abnormal products of oxidation and inflammation are the most likely factors mediating the growth of atherosclerotic plaques. The review aims to provide a comprehensive and detailed exploration of the relationship between ultra-processed foods, chronic inflammation, cardiovascular diseases, obesity, insulin resistance, and the role of the gut microbiota. It touches on several important aspects of modern diet and health.