Summary Background International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT ), SHH (MBSHH ), group 3 (MBGrp3 ), and group 4 (MBGrp4 ), each defined by their ...characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. Methods In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Findings Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant ; n=65) and childhood patients (≥4·3 years; MBSHH-Child ; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR n=65 and MBGrp4-HR n=85) and low-risk (MBGrp3-LR n=50 and MBGrp4-LR n=73) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 25% of 215 patients; 91% survival 95% CI 82–100); standard risk (50 23% patients; 81% survival 70–94); high-risk (82 38% patients; 42% survival 31–56); and very high-risk (29 13% patients; 28% survival 14–56). Interpretation The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Funding Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and ...clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.
Detection of bioaerosols, or primary biological aerosol particles (PBAPs), has become increasingly important for a wide variety of research communities and scientific questions. In particular, ...real-time (RT) techniques for autonomous, online detection and characterization of PBAP properties in both outdoor and indoor environments are becoming more commonplace and have opened avenues of research. With advances in technology, however, come challenges to standardize practices so that results are both reliable and comparable across technologies and users. Here, we present a critical review of major RT instrument classes that have been applied to PBAP research, especially with respect to environmental science, allergy monitoring, agriculture, public health, and national security. Eight major classes of RT techniques are covered, including the following: (i) fluorescence spectroscopy, (ii) elastic scattering, microscopy, and holography, (iii) Raman spectroscopy, (iv) mass spectrometry, (v) breakdown spectroscopy, (vi) remote sensing, (vii) microfluidic techniques, and (viii) paired aqueous techniques. For each class of technology we present technical limitations, misconceptions, and pitfalls, and also summarize best practices for operation, analysis, and reporting. The final section of the article presents pressing scientific questions and grand challenges for RT sensing of PBAP as well as recommendations for future work to encourage high-quality results and increased cross-community collaboration.
Objective
To quantify the impact of Medicaid enrollment on access to care and adherence to recommended preventive services.
Data Source
2005‐2015 Medical Expenditure Panel Survey Household Component.
...Study Design
We examined several access measures and utilization of several preventive services within the past year and within the time frame recommended by the United States Preventive Services Task Force, if more than a year. We estimated local average treatment effects of Medicaid enrollment using a new, two‐stage regression model developed by Nguimkeu, Denteh, and Tchernis. This model accounts for both endogenous and underreported Medicaid enrollment by using a partial observability bivariate probit regression as the first stage. We identify the model with an exogenous measure of Medicaid eligibility, the simulated Medicaid eligibility rate by state, year, and parents vs childless adults. A wide range of changes in Medicaid eligibility occurred during the time period studied.
Data Collection/Extraction methods
Sample of low‐income, nonelderly adults not receiving disability benefits.
Principal Findings
Medicaid enrollment decreased the probability of having unmet needs for medical care by 7.5 percentage points and the probability of experiencing delays getting prescription drugs by 7.7 percentage points. Medicaid enrollment increased the probability of having a usual source of care by 16.5 percentage points, the probability of having a routine checkup by 17.1 percentage points, and the probability of having a flu shot in past year by 12.6 percentage points.
Conclusion
Medicaid enrollment increased access to care and use of some preventive services. Additional research is needed on impacts for subgroups, such as parents, childless adults, and the smaller and generally older populations for whom screening tests are recommended.
The United States offers two markedly different subsidy structures for private health insurance. When covered through employer-based plans, employees and their dependents benefit from the exclusion ...from taxable income of the premiums. Individuals without access to employer coverage may obtain subsidies for Marketplace coverage. This paper seeks to understand how the public subsidies embedded in the privately financed portion of the U.S. healthcare system impact the payments families are required to make under both ESI and Marketplace coverage, and the implications for finance equity.
Using the Household Component of the Medical Expenditure Panel Survey (MEPS-HC) and Marketplace premium data, we assess horizontal and vertical equity by calculating public subsidies for and expected family spending under each coverage source and using Lorenz curves and Gini and concentration coefficients. Our study pooled the 2018 and 2019 MEPS-HC to achieve a sample size of 10,593 observations. Our simulations showed a marked horizontal inequity for lower-income families with access to employer coverage who cannot obtain Marketplace subsidies. Relative to both the financing of employer coverage and earlier Marketplace tax credits, the more generous Marketplace premium subsidies, first made available in 2021 under the American Rescue Plan Act, substantially increased the vertical equity of Marketplace financing. While Marketplace subsidies have clearly improved equity within the United States, we conclude with a comparison to other OECD countries highlighting the persistence of inequities in the U.S. stemming from its noteworthy reliance on employer-based private health insurance.
•United States uses employer and individual private health insurance coverage.•No recent investigations of horizontal and vertical equity of U.S. private coverage.•Analysis of Gini coefficients and Lorenz curves suggests regressivity.•Public policies including insurance subsidies can reduce inequities.
Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict ...patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.
In the twenty-three states that have decided against expanding Medicaid under the Affordable Care Act, uninsured adults who would have been eligible for Medicaid and have incomes at or above the ...federal poverty guidelines are generally eligible for Marketplace (insurance exchange) premium tax credits and plans with generous benefits. This study compared estimated out-of-pocket spending for care and premiums, as well as the financial burdens they impose, for the families of these adults under two simulation scenarios: obtaining coverage through a silver plan with subsidized cost sharing and enrolling in expanded Medicaid. Compared with Marketplace coverage, Medicaid would more than halve average annual out-of-pocket spending ($938 versus $1,948), while dramatically reducing the percentage of adults in families with out-of-pocket expenses exceeding 10 percent or 20 percent of income (6.0 percent versus 17.1 percent and 0.9 percent versus 3.7 percent, respectively). Larger reductions would be seen for families with smokers, who under Medicaid would no longer be subject to Marketplace tobacco user surcharges. Medicaid expansion may offer a greater opportunity than access to Marketplace insurance to promote the financial well-being of previously uninsured low-income adults.
The Affordable Care Act provides tax credits for Marketplace insurance, but before 2021, families with incomes above four times the federal poverty level did not qualify for tax credits and could ...face substantial financial burdens when purchasing coverage. As a measure of affordability, we calculated potential Marketplace premiums as a percentage of family income among families with incomes of 401600 percent of poverty. In 2015 half of this middle-class population would have paid at least 7.7 percent of their income for the lowest-cost bronze plan; in 2019 they would have paid at least 11.3 percent of their income. By 2019 half of the near-elderly ages 55-64 would have paid at least 18.9 percent of their income for the lowest-cost bronze plan in their area. The American Rescue Plan Act temporarily expanded tax credit eligibility for 2021 and 2022, but our results suggest that families with incomes of 401-600 percent of poverty will again face substantial financial burdens after the temporary subsidies expire.
The Affordable Care Act (ACA) allows insurers to charge tobacco users who have nongroup coverage up to 50 percent more than nonusers of tobacco. In this study we used 2014-19 administrative data on ...enrollees in the federally facilitated ACA Marketplace, HealthCare.gov, to examine the relationships among surcharge rates, total Marketplace enrollment, and enrollment by tobacco users. We found that the tobacco surcharge rate averaged approximately 14 percent and that it was associated with lower total enrollment as well as a reduced share of total enrollees who reported any tobacco use. Our analysis also found that tobacco surcharges have a significantly larger effect on tobacco users' share of enrollment in rural areas than in urban areas, which may in turn contribute to urban-rural health disparities. Given that tobacco surcharges may decrease Marketplace enrollment overall and shift the composition of enrollment away from tobacco users, our findings suggest that reducing tobacco surcharges may increase total Marketplace enrollment.
Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying ...shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.
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