A radio-detected type Ia supernova with helium-rich circumstellar material.

Type Ia supernovae (SNe Ia) are thermonuclear explosions of degenerate white dwarf stars destabilized by mass accretion from a companion star1, but the nature of their progenitors remains poorly understood. A way to discriminate between progenitor systems is through radio observations; a non-degenerate companion star is expected to lose material through winds2 or binary interaction3 before explosion, and the supernova ejecta crashing into this nearby circumstellar material should result in radio synchrotron emission. However, despite extensive efforts, no type Ia supernova (SN Ia) has ever been detected at radio wavelengths, which suggests a clean environment and a companion star that is itself a degenerate white dwarf star4,5. Here we report on the study of SN 2020eyj, a SN Ia showing helium-rich circumstellar material, as demonstrated by its spectral features, infrared emission and, for the first time in a SN Ia to our knowledge, a radio counterpart. On the basis of our modelling, we conclude that the circumstellar material probably originates from a single-degenerate binary system in which a white dwarf accretes material from a helium donor star, an often proposed formation channel for SNe Ia (refs. 6,7). We describe how comprehensive radio follow-up of SN 2020eyj-like SNe Ia can improve the constraints on their progenitor systems.

Qualification of the Microsatellite Instability Analysis (MSA) for Bladder Cancer Detection: The Technical Challenges of Concordance Analysis.

Bladder cancer (here we refer to transitional carcinoma of bladder) is a major cause of morbidity and mortality in the Western world, and recent understanding of its etiology, the molecular characteristics associated with its progression, renders bladder cancer an ideal candidate for screening. Cystoscopy is invasive and sometimes carries unwanted complications, but it is the gold standard for the detection of bladder cancer. Urine cytology, while the most commonly used test as an initial screening tool, is of limited value due to its low sensitivity, particularly for low-grade tumors. Several new "molecular assays" for the diagnosis of urothelial cancer have been developed over the last two decades. Here, we have established our new bladder cancer test based on an assay established for the Early Detection Research Network (EDRN) study. As a part of the study, a quality control CLIA/College of American Pathology (CAP) accredited laboratory, (QA Lab), University of Maryland Baltimore Biomarker Reference Laboratory (UMB-BRL), performed quality assurance analysis. Quality assurance measures included a concordance study between the testing laboratory (AIBioTech), also CLIA/CAP accredited, and the QA lab to ensure that the assay was performed and the results were analyzed in a consistent manner. Therefore, following the technical transfer and training of the microsatellite analysis assay to the UMB-BRL and prior to the initiation of analysis of the clinical samples by the testing lab, a series of qualification studies were performed. This report details the steps taken to ensure qualification of the assay and illustrates the technical challenges facing biomarker validation of this kind.

Development of Multiplex Polymerase Chain Reaction (PCR)-Based MSA Assay for Bladder Cancer Detection.

Several studies have shown that microsatellite changes can be profiled in the urine to detect bladder cancer. Microsatellite analysis (MSA) of bladder cancer detection requires a comprehensive analysis of up to 15-20 markers based on amplifying and interpreting many individual MSA markers, which can be technically challenging. To develop fast, efficient, standardized, and less costly MSA to detect bladder cancer, we developed three multiplex polymerase chain reaction (PCR) based MSA assays, all of which were analyzed by a genetic analyzer. First, we selected 16 MSA markers based on nine publications. We developed MSA assays based on triplet or three-tube-based multiplex PCR (Triplet MSA assay) using samples from Johns Hopkins University (JHU Sample, first set of samples). In the second set of samples (samples from six cancer patients and fourteen healthy individuals), our Triplet Assay with 15 MSA markers correctly predicted all 6/6 cancer samples to be cancerous and 14/14 healthy samples to be healthy. Although we could improve our report with more clinical information from patient samples and an increased number of cancer patients, our overall results suggest that our Triplet MSA Assay combined with a genetic analyzer is a potentially time- and cost-effective genetic assay for bladder cancer detection and has potential use as a dependable assay in patient care.

Molecular Markers for Bladder Cancer Screening: An Insight into Bladder Cancer and FDA-Approved Biomarkers.

Bladder cancer is one of the most financially burdensome cancers globally, from its diagnostic to its terminal stages. The impact it imposes on patients and the medical community is substantial, exacerbated by the absence of disease-specific characteristics and limited disease-free spans. Frequent recurrences, impacting nearly half of the diagnosed population, require frequent and invasive monitoring. Given the advancing comprehension of its etiology and attributes, bladder cancer is an appealing candidate for screening strategies. Cystoscopy is the current gold standard for bladder cancer detection, but it is invasive and has the potential for undesired complications and elevated costs. Although urine cytology is a supplementary tool in select instances, its efficacy is limited due to its restricted sensitivity, mainly when targeting low-grade tumors. Although most of these assays exhibit higher sensitivity than urine cytology, clinical guidelines do not currently incorporate them. Consequently, it is necessary to explore novel screening assays to identify distinctive alterations exclusive to bladder cancer. Thus, integrating potential molecular assays requires further investigation through more extensive validation studies. Within this article, we offer a comprehensive overview of the critical features of bladder cancer while conducting a thorough analysis of the FDA-approved assays designed to diagnose and monitor its recurrences.

Results Obtained from a Pivotal Validation Trial of a Microsatellite Analysis (MSA) Assay for Bladder Cancer Detection through a Statistical Approach Using a Four-Stage Pipeline of Modern Machine Learning Techniques.

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer.

Prospective Randomized Study Using Pharmacogenetics to Customize Postoperative Pain Medication Following Hip and Knee Arthroplasty.

BACKGROUND: The purpose of this study is to determine whether pharmacogenetic testing could be used to effectively customize postoperative pain medicine following total joint replacement. METHODS: Buccal swabs were collected preoperatively from 107 patients. Pharmacogenetic testing was performed for genetic variants on a panel of 16 genes, including CYP2D6, CYP2C9, OPRM1, and CYP1A2, which affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and many opioids. Patients were randomized to a control group or custom group and blinded to their group. The control group was prescribed oxycodone, tramadol, and celecoxib for postoperative pain management. If any of those were not normally metabolized, they were not prescribed to the patients in the custom group, who were given an alternative drug (hydromorphone for narcotics, meloxicam for non-steroidal anti-inflammatory drugs). Patients recorded their pain level (0-10 numeric scale) and all medications taken daily for the first 10 days following surgery. Medication was converted to milligram morphine equivalents (MMEs). RESULTS: Genetic variations to medications in our standard postoperative pain management protocol occurred in 24 of the 107 patients (22.4%). The 10-day MME consumed by patients in the control group with genetic variants was 162.6 mg. Patients with variants who had custom postoperative medication consumed only 86.7 MME in the same timeframe (P = .126). The control group demonstrated a higher 10-day average pain level of 4.2 vs the custom group pain level of only 3.1 (P < .05). CONCLUSION: With custom postoperative pain prescriptions based on pharmacogenetic testing, patients were able to achieve lower pain levels while reducing the consumption of pain medication.

Microsatellite Instability Analysis (MSA) for Bladder Cancer: Past History and Future Directions.

Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, colorectal, and bladder cancers; yet a landscape of instability events across a wider variety of cancer types is beginning to be discovered. The epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches to the detection of the MSI phenotype of tumors using NGS have been developed. Bladder cancer (here we refer to transitional carcinoma of the bladder) is a major cause of morbidity and mortality in the Western world. Cystoscopy, a gold standard for the detection of bladder cancer, is invasive and sometimes carries unwanted complications, while its cost is relatively high. Urine cytology is of limited value due to its low sensitivity, particularly to low-grade tumors. Therefore, over the last two decades, several new "molecular assays" for the diagnosis of urothelial cancer have been developed. Here, we provide an update on the development of a microsatellite instability assay (MSA) and the development of MSA associated with bladder cancers, focusing on findings obtained from urine analysis from bladder cancer patients as compared with individuals without bladder cancer. In our review, based on over 18 publications with approximately 900 sample cohorts, we provide the sensitivity (87% to 90%) and specificity (94% to 98%) of MSA. We also provide a comparative analysis between MSA and other assays, as well as discussing the details of four different FDA-approved assays. We conclude that MSA is a potentially powerful test for bladder cancer detection and may improve the quality of life of bladder cancer patients.

A Descriptive and Geospatial Analysis of Environmental Factors Attributing to Sudden Unexpected Infant Death.

This study examined medicolegal death investigation records and autopsy reports of a medical examiner's office to identify the circumstances surrounding sudden unexpected infant deaths (SUID) and geospatial analyses to pinpoint areas of infant death concentration. Analysis of 732 records of SUID deaths occurring in a 10-year span resulted in the conclusion that environmental factors associated with the sudden death were to some extent modifiable. Co-sleeping (sharing a sleeping surface, or bed-sharing) on various surfaces (mattress, pallet, couch) occurred in 53.4% of the infant deaths. Geographic areas where the largest number of deaths occurred were characterized as areas of high poverty level. The inclusion of additional information at the time of investigation (eg, alcohol and tobacco use of co-sleepers, illness of others in household, exceptions to normal sleep routine of infant) may aid in identifying modifiable circumstances to reduce infant mortality attributable to sudden infant death.

One Foot After Another-Fungal Foot Issues in Expedition Adventure Racing.

Skin infections are an important issue among participants in expedition-length adventure races. Prolonged stress, scant sleep, and water exposure mean that competitors are at risk of uncommon manifestations of infections. Ulcerative tinea pedis is an example of this. We present a case with characteristic clinical manifestations, including the "sandpaper symptom." There is limited literature exploring infectious foot complaints in expedition adventure racers. Beyond this case report, more research is needed to better understand incidence rates, risk factors, diagnostic measures, treatment, and prevention options.

The strength of plants: theory and experimental methods to measure the mechanical properties of stems.

From the stems of agricultural crops to the structural trunks of trees, studying the mechanical behaviour of plant stems is critical for both commerce and science. Plant scientists are also increasingly relying on mechanical test data for plant phenotyping. Yet there are neither standardized methods nor systematic reviews of current methods for the testing of herbaceous stems. We discuss the architecture of plant stems and highlight important micro- and macrostructural parameters that need to be controlled and accounted for when designing test methodologies, or that need to be understood in order to explain observed mechanical behaviour. Then, we critically evaluate various methods to test structural properties of stems, including flexural bending (two-, three-, and four-point bending) and axial loading (tensile, compressive, and buckling) tests. Recommendations are made on best practices. This review is relevant to fundamental studies exploring plant biomechanics, mechanical phenotyping of plants, and the determinants of mechanical properties in cell walls, as well as to application-focused studies, such as in agro-breeding and forest management projects, aiming to understand deformation processes of stem structures. The methods explored here can also be extended to other elongated, rod-shaped organs (e.g. petioles, midribs, and even roots).

ROS mediated selection for increased NADPH availability in Escherichia coli.

The economical production of chemicals and fuels by microbial processes remains an intense area of interest in biotechnology. A key limitation in such efforts concerns the availability of key co-factors, in this case NADPH, required for target pathways. Many of the strategies pursued for increasing NADPH availability in Escherichia coli involve manipulations to the central metabolism, which can create redox imbalances and overall growth defects. In this study we used a reactive oxygen species based selection to search for novel methods of increasing NADPH availability. We report a loss of function mutation in the gene hdfR appears to increase NADPH availability in E. coli. Additionally, we show this excess NADPH can be used to improve the production of 3HP in E. coli.

Capacity planning for maternal-fetal medicine using discrete event simulation.

BACKGROUND: Maternal-fetal medicine is a rapidly growing field requiring collaboration from many subspecialties. We provide an evidence-based estimate of capacity needs for our clinic, as well as demonstrate how simulation can aid in capacity planning in similar environments. METHODS: A Discrete Event Simulation of the Center for Fetal Diagnosis and Treatment and Special Delivery Unit at The Children's Hospital of Philadelphia was designed and validated. This model was then used to determine the time until demand overwhelms inpatient bed availability under increasing capacity. FINDINGS: No significant deviation was found between historical inpatient censuses and simulated censuses for the validation phase (p = 0.889). Prospectively increasing capacity was found to delay time to balk (the inability of the center to provide bed space for a patient in need of admission). With current capacity, the model predicts mean time to balk of 276 days. Adding three beds delays mean time to first balk to 762 days; an additional six beds to 1,335 days. CONCLUSION: Providing sufficient access is a patient safety issue, and good planning is crucial for targeting infrastructure investments appropriately. Computer-simulated analysis can provide an evidence base for both medical and administrative decision making in a complex clinical environment.

Predictors of Serious Psychological Distress in an Urban Population.

While there are state and national estimates of serious psychological distress (SPD), these are not useful for targeting local mental health interventions or for addressing the needs of sub-populations at increased risk for SPD. This cross-sectional study uses data from the population-based 2010 Health of Houston Survey (n = 5,116) to examine (1) the prevalence of SPD and its determinants in Houston area and (2) predictors of the utilization of mental health services among people with SPD. The prevalence of SPD among the Houston area adult population was 7 %, more than twice the national average. Correlates of SPD included: being female, under 65, lacking emotional support, smoking, having poor health status and financial distress. The odds of utilizing health services by those with SPD were affected by financial distress, insurance, employment and perceived need for services, among other factors. Interventions should be tailored to mitigate risk factors for SPD and to improve access to mental health services in the SPD sub-population.

Nutritional rickets masquerading as spinal muscular atrophy type III.

Muscle atrophy, weakness, and loss of ambulation in the pediatric population are signs of progressive neuromuscular diseases. Rapid identification of such diseases is important to prevent further progression. In pediatric neurology, it is well understood to include neuromuscular disorders in the differential for such presentations. We report a case of severe nutritional rickets that mimicked the presentation of spinal muscular atrophy type III and discuss the importance of including rickets in the differential for muscle atrophy and loss of ambulation. A 33-month-old African American boy with several months of gait abnormality was referred to outpatient neurology. The initial diagnostic evaluation focused primarily on neuromuscular disorders, specifically SMA type III, given the absence of reflexes on examination and the history of prior ambulation. After an unfruitful genetic workup, it was elucidated that the child had very poor dietary intake and minimal sun exposure causing nutritional rickets that improved with intervention.

Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice.

The purpose of the present study was to determine the effect of Akt gene ablation on Akt/Forkhead Box O (FOXO) signaling and atrogene expression. This was accomplished by studying wild-type (WT) and isoform-specific Akt knockout (Akt1(-/-) and Akt2(-/-)) mice. The ability of insulin to promote Akt phosphorylation on Ser(473) was significantly lower in extensor digitorum longus (EDL) and soleus muscles from Akt1(-/-) and Akt2(-/-) mice compared with WT mice. Total Akt1 protein levels were significantly lower in EDL muscles of Akt2(-/-) mice compared with WT mice, a process that appears to be posttranscriptionally regulated as Akt1 mRNA levels were unchanged. The loss of Akt1 protein in EDL muscles of Akt2(-/-) mice does not appear to be due to insulin resistance because 4 mo of a high-fat diet failed to reduce Akt1 protein levels in muscles of WT mice. Although FOXO3a phosphorylation and atrogin-1 expression were unaltered in muscles of Akt1(-/-) and Akt2(-/-) mice, the expression of the atrogenes Bnip3 and gabarapl were significantly elevated in muscles of both Akt1 and Akt2 knockout mice. Finally, the expression of striated activator of Rho signaling was significantly increased in muscles of Akt2(-/-) mice compared with Akt1(-/-) and WT mice. Our results demonstrate that the ablation of Akt isoforms disassociates insulin action and Akt/FOXO signaling to atrogenes.

Life without Proteinase Activated Receptor 2 (PAR2) Alters Body Composition and Glucose Tolerance in Mice.

The potential role of proteinase activated receptor 2 (PAR2) in the development of age-related obesity and insulin resistance is not well-understood. To address the hypothesis that deletion of PAR2 might ameliorate age-related obesity and impaired glucose homeostasis, we assessed body composition and insulin action in 18-month-old male PAR2 knockout (PAR2KO-AG), age-matched (AG) and young C57BL6 (YG, 6-month-old) mice. Body composition was measured by magnetic resonance spectroscopy (MRS) and insulin action was assessed by glucose tolerance (GT), insulin tolerance (IT) and AICAR tolerance (AT) testing. AG mice weighed significantly more than YG mice (p = 0.0001) demonstrating age-related obesity. However, PAR2KO-AG mice weighed significantly more than AG mice (p = 0.042), indicating that PAR2 may prevent a portion of age-related obesity. PAR2KO-AG and AG mice had greater fat mass and body fat percentage than YG mice. Similar to body weight, fat mass was greater in PAR2KO-AG mice compared to AG mice (p = 0.045); however, only a trend for greater body fat percentage in PAR2KO-AG compared to AG mice was observed (p = 0.09). No differences existed in lean body mass among the PAR2KO-AG, AG, and YG mice (p = 0.58). With regard to insulin action, the area under the curve (AUC) for GT was lower in PAR2KO-AG compared to AG mice (p = 0.0003) and YG mice (p = 0.001); however, no differences existed for the AUC for IT or AT. Our findings indicate that age-related obesity is not dependent on PAR2 expression.

Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort.

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. SIGNIFICANCE: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483.

Socioeconomic status, health care use, and outcomes: persistence of disparities over time.

PURPOSE: To determine the persistence of disparities in health care use and outcomes in socioeconomically diverse populations of epilepsy patients. METHODS: We followed patients for a year at one clinic in Houston and two in New York City that serve predominantly low-income, minority, Medicaid-insured, or uninsured patients, and a fourth clinic in Houston that serves a more balanced racial/ethnic and higher socioeconomic status (SES) population. We interviewed the patients several times regarding health care use, seizures, side effects, and outcomes, and examined differences between the patients at the three low-SES clinics and the patients at the high-SES clinic. KEY FINDINGS: After controlling for patients' age, gender, race/ethnicity, marital status, seizures, and side effects we found that low SES patients had consistently higher use of the hospital emergency room and more visits to a general practitioner. Hospitalizations were also consistently higher but the differences were not significant in most periods. Neurologist visits were relatively similar. Patients at the low SES sites also had a greater likelihood of having uncontrolled seizures, drug-related side effects, to be stigmatized, and have a lower overall quality of life throughout the study period. SIGNIFICANCE: These findings suggest the persistence of SES-related disparities in health care use and outcomes among patients with epilepsy who are receiving regular care.

Posterior reversible encephalopathy syndrome (PRES) with immune system activation, VEGF up-regulation, and cerebral amyloid angiopathy.

The case of a 75-year-old man with a history of lymphoma, recent upper respiratory tract infection, and a protracted course of encephalopathy is presented. Radiologically, findings were consistent with posterior reversible encephalopathy syndrome. A brain biopsy revealed evidence of endothelial activation, T-cell trafficking, and vascular endothelial growth factor expression, suggesting that systemic immune system activation may be involved with triggering posterior reversible encephalopathy syndrome. In addition, underlying cerebral amyloid angiopathy may have contributed to the initial nonclassical edema distribution by compromising autoregulatory blood flow mechanisms.

Posterior Reversible Encephalopathy Syndrome Following Failure of Conservative Management in Renal Trauma: Case Report.

Blunt renal trauma is relatively common in children. Conservative management has become the mainstay of treatment. A 4-year-old boy presented following a fall onto his right abdomen resulting in renal trauma. Initial conservative management was followed by complete embolization of the kidney. The resulting continued hypertension, as well as endothelial disruption, resulted in PRES as manifested by a single instance of generalized seizure. The patient regained normal neurological function following nephrectomy. Better understanding of the potential for acute hypertensive crisis resulting in PRES in the urology community may result in more urgent and effective management in these scenarios.