Incidence, attributable mortality, and healthcare and out-of-pocket costs of Clostridioides difficile infection in US Medicare Advantage Enrollees

BACKGROUND: US attributable Clostridioides difficile infection (CDI) mortality and cost data are primarily from Medicare fee-for-service populations, and little is known about Medicare Advantage Enrollees (MAEs). This study evaluated CDI incidence among MAEs from 2012 to 2019 and determined attributable mortality and costs by comparing MAEs with and without CDI occurring in 2018. METHODS: This retrospective cohort study assessed CDI incidence and associated mortality and costs for eligible MAEs ≥65 years of age using the de-identified Optum Clinformatics Data Mart database (Optum; Eden Prairie, Minnesota, USA). Outcomes included mortality, healthcare utilization, and costs, which were assessed via a propensity score-matched cohort using 2018 as the index year. Outcome analyses were stratified by infection acquisition and hospitalization status. RESULTS: From 2012 to 2019, overall annual CDI incidence declined from 609 to 442 per 100 000 person-years. Although the incidence of healthcare-associated CDI declined overall (2012, 53.2%; 2019, 47.2%), community-associated CDI increased (2012, 46.8%; 2019, 52.8%). The 1-year attributable mortality was 7.9% (CDI cases, 26.3%; non-CDI controls, 18.4%). At the 2-month follow-up, CDI-associated excess mean total healthcare and out-of-pocket costs were $13 476 and$396, respectively. Total excess mean healthcare costs were greater among hospitalized (healthcare-associated, $28 762; community-associated,$28 330) than nonhospitalized CDI patients ($5704 and$2320, respectively), whereas total excess mean out-of-pocket cost was highest among community-associated hospitalized CDI patients ($970). CONCLUSIONS: CDI represents an important public health burden in the MAE population. Preventive strategies and treatments are needed to improve outcomes and reduce costs for healthcare systems and this growing population of older US adults

Simulating Spatiotemporal Dynamics of Sichuan Grassland Net Primary Productivity Using the CASA Model and In Situ Observations

Net primary productivity (NPP) is an important indicator for grassland resource management and sustainable development. In this paper, the NPP of Sichuan grasslands was estimated by the Carnegie-Ames-Stanford Approach (CASA) model. The results were validated with in situ data. The overall precision reached 70%; alpine meadow had the highest precision at greater than 75%, among the three types of grasslands validated. The spatial and temporal variations of Sichuan grasslands were analyzed. The absorbed photosynthetic active radiation (APAR), light use efficiency (ε), and NPP of Sichuan grasslands peaked in August, which was a vigorous growth period during 2011. High values of APAR existed in the southwest regions in altitudes from 2000 m to 4000 m. Light use efficiency (ε) varied in the different types of grasslands. The Sichuan grassland NPP was mainly distributed in the region of 3000–5000 m altitude. The NPP of alpine meadow accounted for 50% of the total NPP of Sichuan grasslands

Liver immune microenvironment and metastasis from colorectal cancer‐pathogenesis and therapeutic perspectives

A drastic difference exists between the 5‐year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver‐colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver‐resident cells including Kupffer cells, hepatic stellate cells, and liver‐sinusoidal endothelial cells are co‐opted by the recruited cells, such as myeloid‐derived suppressor cells and tumor‐associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis‐prone liver immune microenvironment should open new immuno‐oncology avenues for liver metastasis intervention

Outstanding hydrogen evolution reaction catalyzed by porous nickel diselenide electrocatalysts

To relieve our strong reliance on fossil fuels and to reduce greenhouse effects, there is an ever-growing interest in using electrocatalytic water splitting to produce green, renewable, and environment-benign hydrogen fuel via the hydrogen evolution reaction. For commercially feasible water electrolysis, it is imperative to develop electrocatalysts that perform as efficiently as Pt but using only earth-abundant commercial materials. However, the highest performance current catalysts consist of nanostructures made by using complex methods. Here we report a porous nickel diselenide (NiSe_2) catalyst that is superior for water electrolysis, exhibiting much better catalytic performance than most first-row transition metal dichalcogenide-based catalysts, well-studied MoS_2, and WS_2-based catalysts. Indeed NiSe2 performs comparably to the state-of-the-art Pt catalysts. We fabricate NiSe_2 directly from commercial nickel foam by acetic acid-assisted surface roughness engineering. To understand the origin of the high performance, we use first-principles calculations to identify the active sites. This work demonstrates the commercial possibility of hydrogen production via water electrolysis using porous bulk NiSe_2 catalysts

Inhibition of NF-κB Signaling Pathway by Resveratrol Improves Spinal Cord Injury

Spinal cord injury (SCI) can have a significant impact on an individual’s life. Herein, we discuss how resveratrol improves SCI by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Evidences show resveratrol suppresses NF-κB signaling pathway to exert its beneficial effects on various diseases. NF-κB signaling pathway plays a significant role in the pathophysiological mechanisms of SCI including increase in inflammation, augmentation of damage caused by free radicals and lipid peroxidation as well as facilitation of apoptosis and axonal demyelination. We also discuss mechanisms between resveratrol and NF-κB signaling pathway in the wake of SCI, which can be potential targets for resveratrol to treat SCI

Efficient hydrogen evolution by ternary molybdenum sulfoselenide particles on self-standing porous nickel diselenide foam

With the massive consumption of fossil fuels and its detrimental impact on the environment, methods of generating clean power are urgent. Hydrogen is an ideal carrier for renewable energy; however, hydrogen generation is inefficient because of the lack of robust catalysts that are substantially cheaper than platinum. Therefore, robust and durable earth-abundant and cost-effective catalysts are desirable for hydrogen generation from water splitting via hydrogen evolution reaction. Here we report an active and durable earth-abundant transition metal dichalcogenide-based hybrid catalyst that exhibits high hydrogen evolution activity approaching the state-of-the-art platinum catalysts, and superior to those of most transition metal dichalcogenides (molybdenum sulfide, cobalt diselenide and so on). Our material is fabricated by growing ternary molybdenum sulfoselenide particles on self-standing porous nickel diselenide foam. This advance provides a different pathway to design cheap, efficient and sizable hydrogen-evolving electrode by simultaneously tuning the number of catalytic edge sites, porosity, heteroatom doping and electrical conductivity

Twist Promotes Tumor Metastasis in Basal-Like Breast Cancer by Transcriptionally Upregulating ROR1

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients. Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients. Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells

Mixed methods to explore factors associated with the decline of patients in the methadone maintenance treatment program in Shanghai, China

BACKGROUND: This study was to characterize the Methadone Maintenance Treatment (MMT) in Shanghai, China, and to explore factors associated with the decline of patients in MMT during 2005-2016. METHODS: Both qualitative and quantitative methods were used in this study. Based on the data from Shanghai Centers for Disease Control (CDC), we described the changes in the number of patients who received MMT, and new enrollment each year from 2005 to 2016. Focus groups were conducted with 22 patients, and in-depth interviews were conducted with 9 service providers. RESULTS: Quantitative data demonstrate that the number of new enrollment began to decline in 2009, and the number of patients receiving MMT began to decline in 2012. The main reasons for dropout include (1) discontinuing medication due to unknown reasons (25%), (2) criminal activities other than drug-related crimes (20%), (3) relapse to heroin use (16%), and (4) physical disease (10%). Qualitative assessment results indicate that the major reasons for the decline of patients in MMT are as follows: (1) the increase of Amphetamine-type stimulants (ATS) use in recent years, (2) limited knowledge about MMT in both patients and MMT staff, (3) complicated enrollment criteria, and (4) discrimination against drug use. CONCLUSION: Various reasons to explain the decline of patients in MMT in Shanghai, China, were identified. Government agencies, service providers, and other stakeholders need to work together and overcome identified barriers to support MMT programs in China

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy

PD1-based DNA vaccine amplifies HIV-1 GAG-specific CD8+ T cells in mice

Viral vector-based vaccines that induce protective CD8+ T cell immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety have impeded their implementation in HIV-1. Here, we report the development of what we believe to be a novel antigen-targeting DNA vaccine strategy that exploits the binding of programmed death-1 (PD1) to its ligands expressed on dendritic cells (DCs) by fusing soluble PD1 with HIV-1 GAG p24 antigen. As compared with non-DC-targeting vaccines, intramuscular immunization via electroporation (EP) of the fusion DNA in mice elicited consistently high frequencies of GAG-specific, broadly reactive, polyfunctional, long-lived, and cytotoxic CD8+ T cells and robust anti-GAG antibody titers. Vaccination conferred remarkable protection against mucosal challenge with vaccinia GAG viruses. Soluble PD1-based vaccination potentiated CD8+ T cell responses by enhancing antigen binding and uptake in DCs and activation in the draining lymph node. It also increased IL-12-producing DCs and engaged antigen cross-presentation when compared with anti-DEC205 antibody-mediated DC targeting. The high frequency of durable and protective GAG-specific CD8+ T cell immunity induced by soluble PD1-based vaccination suggests that PD1-based DNA vaccines could potentially be used against HIV-1 and other pathogens.published_or_final_versio