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.

Unusual mammalian usage of TGA stop codons reveals that sequence conservation need not imply purifying selection.

The assumption that conservation of sequence implies the action of purifying selection is central to diverse methodologies to infer functional importance. GC-biased gene conversion (gBGC), a meiotic mismatch repair bias strongly favouring GC over AT, can in principle mimic the action of selection, this being thought to be especially important in mammals. As mutation is GC→AT biased, to demonstrate that gBGC does indeed cause false signals requires evidence that an AT-rich residue is selectively optimal compared to its more GC-rich allele, while showing also that the GC-rich alternative is conserved. We propose that mammalian stop codon evolution provides a robust test case. Although in most taxa TAA is the optimal stop codon, TGA is both abundant and conserved in mammalian genomes. We show that this mammalian exceptionalism is well explained by gBGC mimicking purifying selection and that TAA is the selectively optimal codon. Supportive of gBGC, we observe (i) TGA usage trends are consistent at the focal stop codon and elsewhere (in UTR sequences); (ii) that higher TGA usage and higher TAA→TGA substitution rates are predicted by a high recombination rate; and (iii) across species the difference in TAA <-> TGA substitution rates between GC-rich and GC-poor genes is largest in genomes that possess higher between-gene GC variation. TAA optimality is supported both by enrichment in highly expressed genes and trends associated with effective population size. High TGA usage and high TAA→TGA rates in mammals are thus consistent with gBGC's predicted ability to "drive" deleterious mutations and supports the hypothesis that sequence conservation need not be indicative of purifying selection. A general trend for GC-rich trinucleotides to reside at frequencies far above their mutational equilibrium in high recombining domains supports the generality of these results.

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.

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.

The genetic basis and cell of origin of mixed phenotype acute leukaemia.

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.

Evaluation of Germicidal UV-C Light for Suppression of Grape Powdery Mildew and Botrytis Bunch Rot in Western Oregon.

Germicidal UV 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 the 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 with 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 of UV-C at lower doses in small plots suggests that such treatments merit further evaluation in larger-scale studies in Western Oregon.

Position of Beta-blockers in the Treatment of Hypertension Today: An Indian Consensus.

BACKGROUND: Management of essential hypertension (HTN) remains challenging, with contemporary control being achieved in <1/10 of the cases, especially when aligned with the recently updated guidelines of American College of Cardiology (ACC) or International Society of Hypertension (ISH). The place and positioning of beta-blockers have been evolving, with recent focused updates, such as the European Society of Hypertension (ESH) 2023 guidelines, that may hold relevance for the Indian phenotypic traits of premature cardiovascular disease (CVD), fragile coronary architecture, and/or high resting heart rate. To further develop consensus on the clinical role and relevance of beta-blockers, including nebivolol, an Indian consensus was evolved with graded recommendations on their clinical role in HTN, HTN with additional cardiovascular (CV) risk, or type 2 diabetes mellitus (T2DM). METHODOLOGY: An expert review panel was constituted, comprising interventional and clinical cardiologists as experts, to synthesize the literature for the development of a validated knowledge, attitude, and practice (KAP) survey questionnaire. Research databases, including Cochrane Systematic Reviews, PubMed, and Google Scholar, were accessed for contemporary information and guidelines on beta-blockers updated until Dec 2023. Delphi rounds were conducted to develop graded recommendations based on the strength, quality of evidence, and the agreement among the panelists (n = 9). Consensus was achieved on the graded recommendations, with ≥70% of national panelists in agreement. RESULTS: Ninety-six percent of respondents opined that the new ESH HTN guidelines (2023) help gain confidence in using beta-blockers, which are considered first-line drugs for the treatment of HTN. Beta-blockers, including nebivolol, can be recommended in patients with HTN with high resting heart rates, including young hypertensive patients under 40 years of age. For people under 60 years old with HTN, regardless of whether they have comorbid diseases, beta-blockers are the recommended drug choice. Ninety-five percent of respondents opined that nebivolol is the preferred beta-blocker in hypertensive patients with T2DM, followed by bisoprolol and metoprolol. More than 90% of respondents opined that the three most commonly preferred beta-blockers by experts in patients with angina were nebivolol, metoprolol, and bisoprolol. CONCLUSION: Beta-blockers, including nebivolol, can be considered initial-line therapy for HTN management in real-life settings in India and nebivolol is preferred because of its two important properties: highest beta-1 selectivity and endothelial-dependent vasodilation.

Telomere-to-Telomere genome assemblies of human-infecting Encephalitozoon species.

BACKGROUND: Microsporidia are diverse spore forming, fungal-related obligate intracellular pathogens infecting a wide range of hosts. This diversity is reflected at the genome level with sizes varying by an order of magnitude, ranging from less than 3 Mb in Encephalitozoon species (the smallest known in eukaryotes) to more than 50 Mb in Edhazardia spp. As a paradigm of genome reduction in eukaryotes, the small Encephalitozoon genomes have attracted much attention with investigations revealing gene dense, repeat- and intron-poor genomes characterized by a thorough pruning of molecular functions no longer relevant to their obligate intracellular lifestyle. However, because no Encephalitozoon genome has been sequenced from telomere-to-telomere and since no methylation data is available for these species, our understanding of their overall genetic and epigenetic architectures is incomplete. METHODS: In this study, we sequenced the complete genomes from telomere-to-telomere of three human-infecting Encephalitozoon spp. -E. intestinalis ATCC 50506, E. hellem ATCC 50604 and E. cuniculi ATCC 50602- using short and long read platforms and leveraged the data generated as part of the sequencing process to investigate the presence of epigenetic markers in these genomes. We also used a mixture of sequence- and structure-based computational approaches, including protein structure prediction, to help identify which Encephalitozoon proteins are involved in telomere maintenance, epigenetic regulation, and heterochromatin formation. RESULTS: The Encephalitozoon chromosomes were found capped by TTAGG 5-mer telomeric repeats followed by telomere associated repeat elements (TAREs) flanking hypermethylated ribosomal RNA (rRNA) gene loci featuring 5-methylcytosines (5mC) and 5-hemimethylcytosines (5hmC), themselves followed by lesser methylated subtelomeres and hypomethylated chromosome cores. Strong nucleotide biases were identified between the telomeres/subtelomeres and chromosome cores with significant changes in GC/AT, GT/AC and GA/CT contents. The presence of several genes coding for proteins essential to telomere maintenance, epigenetic regulation, and heterochromatin formation was further confirmed in the Encephalitozoon genomes. CONCLUSION: Altogether, our results strongly support the subtelomeres as sites of heterochromatin formation in Encephalitozoon genomes and further suggest that these species might shutdown their energy-consuming ribosomal machinery while dormant as spores by silencing of the rRNA genes using both 5mC/5hmC methylation and facultative heterochromatin formation at these loci.

Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL.

Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.

Association between serum uric acid levels and cardiovascular risk factors among adults in India.

BACKGROUND AND AIM: The objective of this study was to explore the association between serum uric acid (SUA) levels and cardiovascular risk factors in the Indian population. METHODS AND RESULTS: This was a cross-sectional, population-based study. The study enrolled adults aged 20 years and above residing in rural, sub-urban, and urban. All participants completed a detailed questionnaire, underwent anthropometric measurements, and had blood samples collected. Participants were divided into three tertiles based on their SUA concentrations. A total of 2976 participants were included in this study, with 865 from rural, 1030 from sub-urban, and 1081 from urban populations. The mean values of cardiovascular risk factors were significantly higher in tertile 3 (p < 0.001) as compared to the other tertiles. However, we observed a negative trend between the increase of SUA and SUA/Scr ratio and HbA1c levels (Pearson correlation r = -0.068; p < 0.001 and r = -0.140; p < 0.001, respectively). The healthy and prediabetic groups did not show any significant change in HbA1c with increasing SUA levels, while an inverse trend was observed in diabetics. In the diabetic population, both men and women showed an inverse trend between increasing SUA levels and HbA1c in both known and newly diagnosed diabetes (p < 0.001). CONCLUSIONS: The study found a positive association between SUA levels and cardiovascular risk factors. However, HbA1c was inversely correlated with increasing SUA tertiles in both known and newly diagnosed diabetes, as compared to the general population. Additionally, both men and women with diabetes consistently showed an inverse relationship between increasing SUA/SCr ratio and HbA1c levels.

Processes and perceptions of chemotherapy supply chain in Ethiopia: A mixed-method study.

BACKGROUND: The impact and downstream effects of the chemotherapy supply chain in Ethiopia are not well understood. The purpose of this study was to identify perceived gaps in supply chain and characterize their impact on patient care. METHODS: A concurrent mixed-method study was conducted at a large academic cancer center in Ethiopia. In-depth interviews (IDIs) and surveys were completed in collaboration with external stakeholders with knowledge about chemotherapy supply chain in Ethiopia. Thematic coding was used for qualitative analysis of IDI and descriptive statistics were used to summarize quantitative survey data. RESULTS: Six stakeholders participated in the IDIs and seven completed surveys. IDIs revealed that most chemotherapeutic agents are purchased by the Ethiopian Pharmaceutical Supply Agency (EPSA) and are distributed to cancer treatment centers. A free-market purchasing option also exists, but for chemotherapy obtained outside of government-subsidized channels, the potential for substandard or falsified chemotherapy was a concern. Participants expressed confidence that the correct treatment was administered to patients, but viewpoints on reliability and consistency of medication supply were variable. Quantitative data from the survey showed that participants were not confident that medications are prepared safely and correctly. Improper storage and manipulation of high-risk medications remain a significant risk to staff. CONCLUSIONS: This study provides insight from a healthcare staff perspective on how gaps in the chemotherapy supply chain process impact patient care in a low-income country. Inventory management, disruptions in supply chain, and product integrity were perceived as the largest gaps in the current chemotherapy supply chain structure.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Acral Skin Rash Caused by Altered Mercaptopurine Metabolism in Maintenance Therapy for B-Cell Acute Lymphoblastic Leukemia.

6-mercaptopurine is a mainstay of acute lymphoblastic leukemia treatment. It has a narrow therapeutic window, dictated by its metabolite, thioguanine and 6-methylmercaptopurine. Skin manifestations usually consist of mild facial rash or hypersensitivity exanthems. We report a child who developed a painful acral rash and mucositis while undergoing maintenance therapy for B-cell acute lymphoblastic leukemia without infectious or known drug etiology. Thiopurine metabolites were skewed toward 6-methylmercaptopurine. Two weeks after allopurinol was added and 6-mercaptopurine (6-MP) dose adjusted, the cutaneous manifestations and other constitutional symptoms resolved. We posit that the rash was because of 6-MP toxicity related to skewed metabolism, adding to the growing list of toxicity related to altered 6-MP metabolism.

Infusion Therapy in the Treatment of Neuropathic Pain.

PURPOSE OF REVIEW: Neuropathic pain is a prevalent and burdensome condition. While oral medical therapies are the first-line treatment for refractory neuropathic pain, in some cases, infusion therapy may be employed. This article is a systematic review of recent publications regarding epidemiologic, pathophysiologic, diagnostic, and therapeutic advancements in the treatment of neuropathic pain using intravenous infusion therapy. Special consideration will be given to relevant and practically used agents and available information on outcomes. RECENT FINDINGS: Individuals with neuropathic pain from various etiologies (e.g. trigeminal neuralgia, post-herpetic neuralgia, diabetic neuropathy) often find short-term relief from infusion therapies. However, it is difficult to generalize the findings of these studies to form a standard treatment regimen. The purpose of this paper is to provide clinicians an up-to-date summary of recent literature regarding several infusion therapies in treating neuropathic pain.

Resource and Infrastructure-Appropriate Management of ST-Segment Elevation Myocardial Infarction in Low- and Middle-Income Countries.

The 143 low- and middle-income countries (LMICs) of the world constitute 80% of the world's population or roughly 5.86 billion people with much variation in geography, culture, literacy, financial resources, access to health care, insurance penetration, and healthcare regulation. Unfortunately, their burden of cardiovascular disease in general and acute ST-segment-elevation myocardial infarction (STEMI) in particular is increasing at an unprecedented rate. Compounding the problem, outcomes remain suboptimal because of a lack of awareness and a severe paucity of resources. Guideline-based treatment has dramatically improved the outcomes of STEMI in high-income countries. However, no such focused recommendations exist for LMICs, and the unique challenges in LMICs make directly implementing Western guidelines unfeasible. Thus, structured solutions tailored to their individual, local needs, and resources are a vital need. With this in mind, a multicountry collaboration of investigators interested in LMIC STEMI care have tried to create a consensus document that extracts transferable elements from Western guidelines and couples them with local realities gathered from expert experience. It outlines general operating principles for LMICs focused best practices and is intended to create the broad outlines of implementable, resource-appropriate paradigms for management of STEMI in LMICs. Although this document is focused primarily on governments and organizations involved with improvement in STEMI care in LMICs, it also provides some specific targeted information for the frontline clinicians to allow standardized care pathways and improved outcomes.

Deep learning in cancer pathology: a new generation of clinical biomarkers.

Clinical workflows in oncology rely on predictive and prognostic molecular biomarkers. However, the growing number of these complex biomarkers tends to increase the cost and time for decision-making in routine daily oncology practice; furthermore, biomarkers often require tumour tissue on top of routine diagnostic material. Nevertheless, routinely available tumour tissue contains an abundance of clinically relevant information that is currently not fully exploited. Advances in deep learning (DL), an artificial intelligence (AI) technology, have enabled the extraction of previously hidden information directly from routine histology images of cancer, providing potentially clinically useful information. Here, we outline emerging concepts of how DL can extract biomarkers directly from histology images and summarise studies of basic and advanced image analysis for cancer histology. Basic image analysis tasks include detection, grading and subtyping of tumour tissue in histology images; they are aimed at automating pathology workflows and consequently do not immediately translate into clinical decisions. Exceeding such basic approaches, DL has also been used for advanced image analysis tasks, which have the potential of directly affecting clinical decision-making processes. These advanced approaches include inference of molecular features, prediction of survival and end-to-end prediction of therapy response. Predictions made by such DL systems could simplify and enrich clinical decision-making, but require rigorous external validation in clinical settings.

Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Differential risk factor profile of diabetes and atherosclerosis in rural, sub-urban and urban regions of South India: The KMCH-Non-communicable disease studies.

AIMS: South Asia has emerged rapidly as an epicentre of non-communicable diseases (NCDs) specifically diabetes and cardiovascular diseases. The prevalence rate, risk factors and aetiology of NCDs in different socio-demographic settings are not clearly understood. This study was performed to assess the prevalence of diabetes and atherosclerosis and their risk factors in urban, sub-urban and rural communities of South India. METHODS: Three communities [Nallampatti (rural), Thadagam (sub-urban) and Kalapatti (urban)] in South India were selected for participation in the KMCH-NCD Studies. Study volunteers were administered a detailed questionnaire, underwent anthropometric measurements, clinical measurements including blood pressure, glycated haemoglobin (HbA1c ), non-fasting lipid profile and serum creatinine. Carotid intima-media thickness was measured using B-mode ultrasound. Multiple logistic regression analyses were performed to understand the association of risk factors with diabetes and atherosclerosis. RESULTS: A total of 2976 native participants, ≥20 years of age were screened. The prevalence of diabetes was 16%, 26% and 23% respectively in the rural, sub-urban and urban study populations. Association of obesity with diabetes was observed in only urban population while hypertension and dyslipidaemia showed association in both urban and semi-urban populations. Association of diabetes with atherosclerosis was observed in urban and semi-urban populations. Hypertension in semi-urban and obesity and dyslipidaemia in urban population showed association with atherosclerosis. CONCLUSIONS: Diabetes and atherosclerosis burden reported in the three different communities were higher than previous reports, especially in rural and sub-urban regions. No traditional risk factor is identified to be associated with prevalence of diabetes and atherosclerosis in rural population. These findings suggest an urgent need for investigation into the role of non-traditional risk factors like environmental or occupational exposures may help to better understand the aetiology of diseases in non-urbanized communities.

Mixed Phenotype Acute Leukemia: Current Approaches to Diagnosis and Treatment.

PURPOSE OF REVIEW: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia with features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The review examines current definitions and controversies in classification of MPAL, new insights into genomic drivers and pathogenesis, recent evidence to support treatment recommendations, and opportunities for future research. RECENT FINDINGS: Recent collaborative efforts have made progress in understanding the genomic landscape and optimal therapy for MPAL. The preponderance of retrospective data supports beginning therapy with ALL directed regimens. Differences in prognosis for adult and children with MPAL have led to divergent approaches for therapy intensity, including use of stem cell transplantation consolidation. MPAL remains a challenging leukemia to understand, research, and treat due to low incidence, shifting and subjective approaches to classification, and innate biological heterogeneity. Ongoing research hopes to surmount these obstacles through prospective studies within large cooperative groups to provide new insight into targetable biology and further refine optimal therapy.

Results of a pre-implementation analysis of Ethiopia's National Pediatric Cancer Registry.

In Ethiopia, cancer accounts for about 5.8% of total national mortality, with an estimated annual incidence of cancer of approximately 60,960 cases and an annual mortality of over 44,000 persons. This is likely an underestimation. Survival rates for pediatric malignancies are likewise suboptimal although exact figures are unknown since a national cancer registry is unavailable. The World Health Organization (WHO) provides recommendations for the creation of cancer registries to track such data. Here we describe our pharmacist-led, pre-implementation assessment of introducing an enhanced national pediatric cancer registry in Ethiopia. Our assessment project had three specific aims around which the methods were designed: 1) characterization of the current spreadsheet-based tool across participating sites, including which variables were being collected, how these variables compared to standards set by the WHO, and a description of how the data were entered and its completeness; 2) assessment of the perceptions of an enhanced registry from hospital staff; and 3) evaluation of workflow gaps regarding documentation. The hospital staff and leadership have generally positive perceptions of an enhanced pediatric cancer registry, which were further improved by our interactions. The workflow assessment revealed several gaps, which were addressed systematically using a three-phase implementation science approach. The assessment also demonstrated that the existing spreadsheet-based tool was missing WHO-recommended variables and had inconsistent completion due to the workflow gaps. A pediatric oncology summary sheet will be implemented in upcoming trips in patient charts to better summarize the patients' journey starting from diagnosis. This document will be used by the data clerks in an enhanced-spreadsheet to have a more complete data set.