HIV and Hepatitis C Mortality in Massachusetts, 2002–2011: Spatial Cluster and Trend Analysis of HIV and HCV Using Multiple Cause of Death

Background: Infectious diseases, while associated with a much smaller proportion of deaths than they were 50 years ago, still play a significant role in mortality across the state of Massachusetts. Most analysis of infectious disease mortality in the state only take into account the underlying cause of death, rather than contributing causes of death, which may not capture the full extent of mortality trends for infectious diseases such as HIV and the Hepatitis C virus (HCV). Methods: In this study we sought to evaluate current trends in infectious disease mortality across the state using a multiple cause of death methodology. We performed a mortality trend analysis, identified spatial clusters of disease using a 5-step geoprocessing approach and examined spatial-temporal clustering trends in infectious disease mortality in Massachusetts from 2002–2011, with a focus on HIV/AIDS and HCV. Results: Significant clusters of high infectious disease mortality in space and time throughout the state were detected through both spatial and space time cluster analysis. The most significant clusters occurred in Springfield, Worcester, South Boston, the Merrimack Valley, and New Bedford with other smaller clusters detected across the state. Multiple cause of death mortality rates were much higher than underlying cause mortality alone, and significant disparities existed across race and age groups. Conclusions: We found that our multi-method analyses, which focused on contributing causes of death, were more robust than analyses that focused on underlying cause of death alone. Our results may be used to inform public health resource allocation for infectious disease prevention and treatment programs, provide novel insight into the current state of infectious disease mortality throughout the state, and benefited from approaches that may more accurately document mortality trends

Proportion of physicians who treat patients with greater social and clinical risk and physician inclusion in Medicare Advantage networks

IMPORTANCE: Medicare Advantage (MA) plans are expanding rapidly, now serving 50% of all Medicare enrollees. Little is known about how inclusion rates of physicians in MA plan networks vary by the social and clinical risks of their patients. OBJECTIVE: To examine the association of physicians caring for patients with higher levels of social and clinical risk in traditional Medicare (TM) with the likelihood of inclusion in MA plan networks. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study evaluated the number of patients of physicians participating in TM Part B in 2019. The data analysis was conducted between June 2022 and March 2023. EXPOSURES: Quintiles of the proportion of patients who were dually eligible for Medicare and Medicaid and average beneficiary hierarchical condition category (HCC) score (a measure of a patient\u27s chronic disease burden that is used in risk adjustment and MA plan payment, where higher scores indicate higher risk) in the Part B TM program. MAIN OUTCOMES AND MEASURES: The main outcomes were the proportion of MA plans and enrollees for which physicians were in network. RESULTS: The analysis sample included 259 932 physicians billing Medicare Part B in 2019. After adjusting for physician, patient, and county characteristics, physicians with the highest quintile of patients with dual eligibility were associated with a lower likelihood of being included in MA plans and being in network with MA enrollees than the lowest quintile physicians (MA inclusion rate, -3.0% [95% CI, -3.2% to -2.8%]; P \u3c .001; in-network enrollee proportion, -6.5% [95% CI, -7.0% to -6.0%]; P \u3c .001). Similarly, physicians with the highest quintile HCC score were associated with a lower likelihood of being included in MA plans and being in network with MA enrollees than the lowest quintile physicians (MA inclusion rate, -7.5% [95% CI, -7.9% to -7.2%]; P \u3c .001; in-network enrollee proportion, -18.7% [95% CI, -19.5% to -18.1%]; P \u3c .001). Physicians in medical specialties in the highest clinical risk group (highest quintile HCC score) were associated with a significantly lower likelihood of being in network with MA enrollees than those in the lowest clinical risk group (in-network enrollee proportion, -20.4% [95% CI, -21.1% to -19.8%]; P \u3c .001). CONCLUSIONS AND RELEVANCE: This cross-sectional study of physicians participating in TM Part B in 2019 found that physicians with higher numbers of patients with social and medical risks in TM were significantly less likely to be associated with MA plans

Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr)

There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs

Projecting Need for a COVID-19 Alternative Care Site (ACS) Austin, TX

To support the city of Austin and Travis County in responding to the threatening rise in COVID-19 hospitalizations, we used a data-driven model of COVID-19 transmission in the Austin-Round Rock MSA to project hospitalizations until February 4th, estimate the risk that cases will exceeding local capacity, and determine effective triggers for opening an alternative care site (ACS) to expand capacity. Note that the results presented herein are based on multiple assumptions about the transmission rate and age-specific severity of COVID-19 and do not represent the full range of uncertainty. Rather, they are meant to provide plausible scenarios for COVID-19 healthcare demand and inform decisions that balance the high costs of establishing an ACS with the risks of outstripping local healthcare capacity.Integrative Biolog

Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma

Buckling Testing and Analysis of Honeycomb Sandwich Panel Arc Segments of a Full-Scale Fairing Barrel

Four honeycomb sandwich panel types, representing 1/16th arc segments of a 10-m diameter barrel section of the Heavy Lift Launch Vehicle (HLLV), were manufactured and tested under the NASA Composites for Exploration program and the NASA Constellation Ares V program. Two configurations were chosen for the panels: 6-ply facesheets with 1.125 in. honeycomb core and 8-ply facesheets with 1.000 in. honeycomb core. Additionally, two separate carbon fiber/epoxy material systems were chosen for the facesheets: in-autoclave IM7/977-3 and out-of-autoclave T40-800b/5320-1. Smaller 3- by 5-ft panels were cut from the 1/16th barrel sections. These panels were tested under compressive loading at the NASA Langley Research Center (LaRC). Furthermore, linear eigenvalue and geometrically nonlinear finite element analyses were performed to predict the compressive response of each 3- by 5-ft panel. This manuscript summarizes the experimental and analytical modeling efforts pertaining to the panels composed of 6-ply, IM7/977-3 facesheets (referred to as Panels B-1 and B-2). To improve the robustness of the geometrically nonlinear finite element model, measured surface imperfections were included in the geometry of the model. Both the linear and nonlinear models yield good qualitative and quantitative predictions. Additionally, it was correctly predicted that the panel would fail in buckling prior to failing in strength. Furthermore, several imperfection studies were performed to investigate the influence of geometric imperfections, fiber angle misalignments, and three-dimensional (3-D) effects on the compressive response of the panel

Transient study using LoTSS -- framework development and preliminary results

We present a search for transient radio sources on time-scales of seconds to hours at 144 MHz using the LOFAR Two-metre Sky Survey (LoTSS). This search is conducted by examining short time-scale images derived from the LoTSS data. To allow imaging of LoTSS on short time-scales, a novel imaging and filtering strategy is introduced. This includes sky model source subtraction, no cleaning or primary beam correction, a simple source finder, fast filtering schemes and source catalogue matching. This new strategy is first tested by injecting simulated transients, with a range of flux densities and durations, into the data. We find the limiting sensitivity to be 113 and 6 mJy for 8 second and 1 hour transients respectively. The new imaging and filtering strategies are applied to 58 fields of the LoTSS survey, corresponding to LoTSS-DR1 (2% of the survey). One transient source is identified in the 8 second and 2 minute snapshot images. The source shows one minute duration flare in the 8 hour observation. Our method puts the most sensitive constraints on/estimates of the transient surface density at low frequencies at time-scales of seconds to hours; $<4.0\cdot 10^{-4} \; \text{deg}^{-2}$ at 1 hour at a sensitivity of 6.3 mJy; $5.7\cdot 10^{-7} \; \text{deg}^{-2}$ at 2 minutes at a sensitivity of 30 mJy; and $3.6\cdot 10^{-8} \; \text{deg}^{-2}$ at 8 seconds at a sensitivity of 113 mJy. In the future, we plan to apply the strategies presented in this paper to all LoTSS data.Comment: submitted to MNRA

COVID-19 alert stages, healthcare projections and mortality patterns in Austin, Texas, May 2021

To support public health decision-making in Austin, Texas, we project COVID-19 healthcare demand as vaccines continue to roll out, and we provide retrospective estimates for in-hospital COVID-19 mortality during surge and non-surge periods of the pandemic. The projections indicate that a return to COVID-19 Alert Stage 2 in May 2021 would be unlikely to cause a healthcare surge that exceeds local ICU capacity. However, our retrospective estimates of in-hospital COVID-19 mortality suggest that even modest surges may increase the COVID-19 fatality rate and that, throughout the pandemic, in-hospital mortality has disproportionately occurred in communities with overlapping socioeconomic, occupational, and health risks. The analyses are based on multiple assumptions about the transmission rate, age-specific severity of COVID-19, and efficacy of vaccines, and thus do not represent the full range of uncertainty that the city of Austin may encounter. We are posting these results prior to peer review to provide insights regarding changing COVID-19 risks as vaccination coverage continues to increase and to guide the relaxation of COVID-19 mitigation measures in the spring and summer of 2021.Integrative Biolog