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Secondary spinal cord injury is the inflammatory damage to surrounding tissues caused by activated microglial-mediated neuroinflammatory responses. The nuclear factor-κB (p65/p50) pathway and PU.1 are closely correlated with inflammatory responses; thus, we examined the relationship and function between PU.1 and p50 in secondary spinal cord injury. In this study, we established an adult rat acute spinal cord injury model to simulate the pathological process of spinal cord injury. We found that the expression of PU.1 was significantly increased at three days after spinal cord injury and mainly expressed in activated microglia. Bcl-2 inhibitor Moreover, p-p50 expression was increased in SCI rats and the protein interacted with PU.1. Lipopolysaccharide was used to induce microglia activation in vitro. The results showed that PU.1 and p-p50 expression was significantly increased and PU.1 interacted with p50 in the nucleus. The levels of tumor necrosis factor-α and interleukin-1β secreted by microglia were detected by enzyme-linked immunosorbent assay. The results showed that when both PU.1 and p50 were overexpressed, tumor necrosis factor-α and interleukin-1β secretion was significantly increased to levels higher than in cells overexpressing PU.1 or p50 alone. These results suggest that PU.1 and p50 interact to promote p65 transcription and the expression of inflammatory factors, which is an important mechanism of the microglial-mediated inflammatory response to secondary injury after spinal cord injury.

To examine the impact of increasing multi-target stool DNA test (mt-sDNA [Cologuard]) utilization for colorectal cancer (CRC) screening in cohorts aged 50-75 and 45-75 years old with varying levels of adherence from the perspectives of integrated delivery networks (IDNs) and payers.

We developed a budget impact model that simulates CRC screening with colonoscopy over a 10-year time horizon, fecal immunochemical test (FIT), and mt-sDNA according to the United States Preventive Services Task Force and American Cancer Society guidelines for average risk adults. We evaluated varying levels of screening adherence for a status quo scenario and for an increased mt-sDNA utilization scenario, from the IDN and payer perspectives. The IDN perspective included CRC screening program costs, whereas the payer perspective did not. Conversely, stool-based screening test and bowel preparation costs were unique to the payer perspective.

The increased mt-sDNA scenarios yielded cost savings relative to the status quo under on yielded cost-savings.

Among all adherence scenarios, perspectives, and age ranges, increased mt-sDNA utilization yielded cost-savings.Introduction New diagnostics may be useful in clinical practice, especially in contexts of high prevalence of multidrug-resistant organisms (MDRO). However, misuse of diagnostic tools may lead to increased costs and worse patient outcome. Conventional and new techniques should be appropriately positioned in diagnostic algorithms to guide an appropriate use of antimicrobial therapy.Areas covered A panel of experts identified 4 main areas in which the implementation of diagnostic stewardship is needed. Among chronic infections, bone and prosthetic joint infections and subacute-chronic intravascular infections and endocarditis represent common challenges for clinicians. Among acute infections, bloodstream infections and community-acquired pneumonia may be associated with high mortality and require appropriate diagnostic approach.Expert opinion Diagnostic stewardship aims to improve the appropriate use of microbiological diagnostics to guide therapeutic decisions through appropriate and timely diagnostic testing. Here, diagnostic algorithms based on different patient profiles are proposed for chronic and acute clinical syndromes. In each clinical scenario, combining conventional and new diagnostic techniques is crucial to make a rapid and accurate diagnosis and to guide the selection of antimicrobial therapy. Barriers related to the implementation of new rapid diagnostic tools, such as high initial costs, may be overcome through their rational and structured use.Background Cancer patients are more vulnerable to Coronavirus disease-2019 (COVID-19) and have a higher risk of adverse outcomes than the general population. Therefore, it is necessary to evaluate whether anti-cancer therapies such as surgery, chemotherapy, immunotherapy, and targeted therapy will increase the severity and mortality of cancer patients with COVID-19.Methods Relevant articles were retrieved from PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI). The search time was from December 1, 2019 to January 23, 2021. Meta-analysis was conducted using Revman 5.3 statistical software.Results A total of 26 studies were included in this meta-analysis, involving 5571 cancer patients infected with SARS-CoV-2. Meta-analysis showed that surgery, chemotherapy, immunotherapy and targeted therapy were not associated with disease severity or mortality (107/688, OR =1.30, 95% CI[0.79, 2.13], P =0.30; 1956/2674, OR =1.27, 95% CI [0.95, 1.69], P =0.10; 342/1455, OR =1.20, 95% CI [0.90, 1.61], P =0.21; 503/1378, OR =0.92, 95% CI [0.72, 1.19], P =0.54, respectively).Conclusion In cancer patients with COVID-19, anti-cancer therapy had no adverse effect on disease severity or mortality. Further research is necessary to determine the complex interrelationship between anti-cancer therapy, particularly chemotherapy, and COVID-19.KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.Introduction Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.Expert opinion While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug-drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10-40 mg and ezetimibe 10 mg enables considerable reductions in LDL-C (up to 60-75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed-dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.Introduction The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus has been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials, and some have been approved as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors over the past 4 years. We review the selectivity and potency of 47 PI3K inhibitors. Structural determinants for increasing selectivity toward PI3K subtype-selectivity or mutant selectivity are discussed. Future research direction and current clinical development in combination therapy of inhibitors involved in PI3Ks are also discussed.Area covered This review covers clinical trial reports and patent literature on PI3K inhibitors and their selectivity published between 2016 and 2020.Expert opinion To PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. It is also necessary to develop subtype-selective PI3Kα inhibitors to minimize toxicity. To reduce drug resistance and to improve efficacy, future studies should include combination therapy of PI3K inhibitors with existing anticancer drugs from different pathways.Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD.This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 (n = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates.Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD.Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.