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Meningioma because host for advanced breast cancer: An infrequent incidence significant therapeutic effect.
Objectives. To test whether distortions in the age distribution of deaths can track pandemic activity. Methods. We compared weekly distributions of all-cause deaths by age during the COVID-19 pandemic in the United States from March to December 2020 with corresponding prepandemic weekly baseline distributions derived from data for 2015 to 2019. We measured distortions via Kolmogorov-Smirnov (K-S) and χ2 goodness-of-fit statistics as well as deaths among individuals aged 65 years or older as a percentage of total deaths (PERC65+). We computed bivariate correlations between these measures and the number of recorded COVID-19 deaths for the corresponding weeks. Results. Elevated COVID-19-associated fatalities were accompanied by greater distortions in the age structure of mortality. Distortions in the age distribution of weekly US COVID-19 deaths in 2020 relative to earlier years were highly correlated with COVID fatalities (K-S r = 0.71, P  less then  .001; χ2 r = 0.90, P  less then  .001; PERC65+ r = 0.85, P  less then  .001). Conclusions. A population-representative sample of age-at-death data can serve as a useful means of pandemic activity surveillance when precise cause-of-death data are incomplete, inaccurate, or unavailable, as is often the case in low-resource environments. (Am J Public Health. 2022;112(1)165-168. https//doi.org/10.2105/AJPH.2021.306567).We implemented the HIV preexposure prophylaxis (PrEP) care continuum among individuals receiving medication for opioid use disorder (MOUD). We screened HIV-negative MOUD participants for PrEP eligibility by assessing injection drug use risk factors and sexual behaviors. Implementation of the PrEP care continuum was challenging; less than a third of MOUD participants were aware of PrEP, and very few initiated PrEP. Findings should promote the development of effective interventions to increase engagement in PrEP during MOUD treatment. (Am J Public Health. 2022;112(1)34-37. https//doi.org/10.2105/AJPH.2021.306566).We conducted a community seroprevalence survey in Arizona, from September 12 to October 1, 2020, to determine the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used the seroprevalence estimate to predict SARS-CoV-2 infections in the jurisdiction by applying the adjusted seroprevalence to the county's population. The estimated community seroprevalence of SARS-CoV-2 infections was 4.3 times greater (95% confidence interval = 2.2, 7.5) than the number of reported cases. Field surveys with representative sampling provide data that may help fill in gaps in traditional public health reporting. (Am J Public Health. 2022;112(1)38-42. https//doi.org/10.2105/AJPH.2021.306568).Objectives. To evaluate universal access to clean drinking water by characterizing relationships between community sociodemographics and water contaminants in California domestic well areas (DWAs) and community water systems (CWSs). Methods. We integrated domestic well locations, CWS service boundaries, residential parcels, building footprints, and 2013-2017 American Community Survey data to estimate sociodemographic characteristics for DWAs and CWSs statewide. We derived mean drinking and groundwater contaminant concentrations of arsenic, nitrate, and hexavalent chromium (Cr[VI]) between 2011 and 2019 and used multivariate models to estimate relationships between sociodemographic variables and contaminant concentrations. Results. We estimated that more than 1.3 million Californians (3.4%) use domestic wells and more than 370 000 Californians rely on drinking water with average contaminant concentrations at or above regulatory standards for 1 or more of the contaminants considered. Higher proportions of people of color were associated with greater drinking water contamination. Conclusions. Poor water quality disproportionately impacts communities of color in California, with the highest estimated arsenic, nitrate, and Cr(VI) concentrations in areas of domestic well use. Domestic well communities must be included in efforts to achieve California's Human Right to Water. (Am J Public Health. 2022;112(1)88-97. buy Bromopyruvic https//doi.org/10.2105/AJPH.2021.306561).Children's environmental health (CEH) has a 25-year history at the US Environmental Protection Agency (EPA), during which the agency has advanced CEH through research, policy, and programs that address children's special vulnerability to environmental harm. However, the Trump administration took many actions that weakened efforts to improve CEH. The actions included downgrading or ignoring CEH concerns in decision-making, defunding research, sidelining the Children's Health Protection Advisory Committee, and rescinding regulations that were written in part to protect children. To improve CEH, federal environmental statutes should be reviewed to ensure they are sufficiently protective. The administrator should ensure the EPA's children's health agenda encompasses the most important current challenges and that there is accountability for improvement. Guidance documents should be reviewed and updated to be protective of CEH and the federal lead strategy refocused on primary prevention. The Office of Children's Health Protection's historically low funding and staffing should be remedied. Finally, the EPA should update CEH data systems, reinvigorate the role of the Children's Health Protection Advisory Committee, and restore funding for CEH research that is aligned with environmental justice and regulatory decision-making needs. (Am J Public Health. 2022;112(1)124-134. https//doi.org/10.2105/AJPH.2021.306537).The prevalence of multidrug-resistant bacteria has been increasing rapidly worldwide, a trend that poses great risk to human and animal health and creates urgent need for pharmaceutical and nonpharmaceutical approaches to stop the spread of disease due to antimicrobial resistance. Here, we found that alanine, aspartate, and glutamate metabolism was inactivated, and glutamine was repressed in multidrug-resistant uropathogenic Escherichia coli using a comparative metabolomics approach. Exogenous glutamine promoted β-lactam–, aminoglycoside-, quinolone-, and tetracycline-induced killing of uropathogenic E. coli and potentiated ampicillin to eliminate multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella peneumoniae, Edwardsiella tarda, Vibrio alginolyticus, and Vibrio parahaemolyticus. Glutamine-potentiated ampicillin-mediated killing was effective against biofilms of these bacteria in a mouse urinary tract infection model and against systemic infection caused by E. coli, P. aeruginosa, A. baumannii, or K. peneumoniae in a mouse model. Exogenous glutamine stimulated influx of ampicillin, leading to the accumulation of intracellular antibiotic concentrations that exceeded the amount tolerated by the multidrug-resistant bacteria. Furthermore, we demonstrated that exogenous glutamine promoted the biosynthesis of nucleosides including inosine, which in turn interacted with CpxA/CpxR and up-regulated OmpF. We validated the physiological relevance of the mechanism by showing that loss of purF, purH, cpxA, or ompF elevated antibiotic resistance in antibiotic-sensitive strains. In addition, glutamine retarded the development of ampicillin resistance. These results may facilitate future development of effective approaches for preventing or managing chronic, multidrug-resistant bacterial infections, bacterial persistence, and difficult-to-treat bacterial biofilms.Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against liver flukes of the Fasciola genus. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we use ligand- and target-based methods to demonstrate that PZQ activates a transient receptor potential melastatin ion channel (TRPMPZQ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage sensor–like domain of the channel to cause calcium entry and worm paralysis. PZQ activates TRPMPZQ homologs in other PZQ-sensitive flukes, but not Fasciola hepatica. However, a single amino acid change in the F. hepatica TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved.Chimeric antigen receptor (CAR) T cells induce durable responses in patients with refractory hematological tumors. However, low CAR T cell activity, poor engraftment, or short in-patient persistence can lead to tumor progression or relapse. Furthermore, excessive CAR T cell expansion and activation can result in life-threatening cytokine release syndrome (CRS). Thus, in-patient control of the CAR T cell population is essential. Interleukin-2 (IL-2) is a critical cytokine for T cell proliferation and effector function, but its clinical use is limited by immune-mediated toxicity. Here, we report on an orthogonal IL-2 receptor and ligand system that enables specific in vivo control of CAR T cell expansion and activation, wherein an orthogonal human IL-2 (STK-009) selectively pairs with an orthogonal human IL-2Rβ (hoRb) expressed on CAR T cells. STK-009 expands hoRb-expressing CAR T cells in the presence and absence of tumor antigen and maintains the presence of stem cell memory T cells (TSCM) and effector T cells. In preclinical models of human CAR-refractory lymphoma, STK-009 treatment resulted in systemic and intratumoral expansion and activation of hoRb-expressing anti–CD19-CD28ζ CAR T cells (SYNCAR). The orthogonal IL-2 receptor/ligand system delivers complete responses in large subcutaneous lymphomas, even with substantially reduced CAR T cell doses, by selectively expanding and activating CAR T cells in vivo. STK-009 withdrawal allowed normal CAR T cell contraction, thereby limiting CRS induced by tumor antigen–specific T cell activation. These data suggest that the orthogonal IL-2 receptor/ligand system provides the in vivo control necessary to maximize efficacy of CAR T therapies.Although systemic antibiotics are critical in controlling infections and reducing morbidity and mortality, overuse of antibiotics is presumed to contribute to negative repercussions such as selection of antimicrobial-resistant organisms and collateral damage to commensal microbes. In a prospective, randomized study of four clinically relevant antibiotic regimens [doxycycline (20 mg or 100 mg), cephalexin, or trimethoprim/sulfamethoxazole], we investigated microbial alterations on skin after administration of systemic antibiotics to healthy human volunteers. Samples from different skin and oral sites, as well as stool, were collected before, during, and up to 1 year after antibiotic use, and shotgun metagenomic sequencing was performed. Taxonomic analysis showed that subjects receiving doxycycline 100 mg and trimethoprim/sulfamethoxazole (TMP/SMX) exhibited greater changes to their skin microbial communities, as compared to those receiving other regimens or untreated controls. Oral and stool microbiota also demonstrated fluctuations after antibiotics.
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