Raynorstorm3513

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. PBIT Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations.

We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory conaCT 2012-004383-22.Scholars acknowledge that friends shape youth civic engagement, but the relative contribution of peer influence and critical beliefs to civic behaviors has yet to be disaggregated. Informed by sociopolitical development and critical consciousness theories, the present study used longitudinal social network analysis to examine peer socialization and adolescents' awareness of systemic inequities in relation to participation in service and activist activities at a high school serving primarily low-income Latinx youth. Students were surveyed in May 2019 and May 2020 (N = 354; 51% female; in 2019, Mage = 15.9, age range 14.4 to 18.5). The results yielded evidence of peer influence on service activities, but not activism or perceptions of inequities. In contrast, adolescents' perception of inequities predicted their activist behavior, but not service, after controlling for network effects and individual covariates. The school provided scaffolding for service activities, but not activist activities, potentially explaining the salience of service participation in youth friendship networks.

This paper aimed to summarise existing literature on strategies to improve the healthiness of retail food environments in the East Asia and Pacific (EAP) region, and propose a prioritised research agenda on this topic.

Little research on retail food environments has been conducted in the EAP region. Several approaches for measuring retail food environments were identified, although none have been tailored to the EAP context. A small number of policies and initiatives to promote healthy retail food environments have been implemented in EAP. Lessons learnt from successful implementation of initiatives in other regions could be applied in EAP. Retail food environments have a strong influence on food choices and health outcomes. Research can contribute to efforts to improve the healthiness of retail food environments in EAP by (1) describing the current state of retail food environments to highlight areas of good practice and concern and (2) identifying policies and initiatives that are likely to be effective, and mechanisms for their successful implementation.

Little research on retail food environments has been conducted in the EAP region. Several approaches for measuring retail food environments were identified, although none have been tailored to the EAP context. A small number of policies and initiatives to promote healthy retail food environments have been implemented in EAP. Lessons learnt from successful implementation of initiatives in other regions could be applied in EAP. Retail food environments have a strong influence on food choices and health outcomes. Research can contribute to efforts to improve the healthiness of retail food environments in EAP by (1) describing the current state of retail food environments to highlight areas of good practice and concern and (2) identifying policies and initiatives that are likely to be effective, and mechanisms for their successful implementation.

To analyse if postoperative complications constitute a predictor for the risk of developing long-term groin pain.

Population-based prospective cohort study of 30,659 patients operated for inguinal hernia 2015-2017 included in the Swedish Hernia Register. Registered post-operative complications were categorised into hematomas, surgical site infections, seromas, urinary tract complications, and acute post-operative pain. A questionnaire enquiring about groin pain was distributed to all patients 1year after surgery. Multivariable logistic regression analysis was used to find any association between postoperative complications and reported level of pain 1year after surgery.

The response rate was 64.5%. In total 19,773 eligible participants responded to the questionnaire, whereof 73.4% had undergone open anterior mesh repair and 26.6% had undergone endo-laparoscopic mesh repair. Registered postoperative complications were 750 hematomas (2.3%), 516 surgical site infections (1.6%), 395 seromas (1.2%), 1216 urillowing open anterior hernia repair, although the rate of reported postoperative complications was low.Graph-based causal models are a flexible tool for causal inference from observational data. In this paper, we develop a comprehensive framework to define, identify, and estimate a broad class of causal quantities in linearly parametrized graph-based models. The proposed method extends the literature, which mainly focuses on causal effects on the mean level and the variance of an outcome variable. For example, we show how to compute the probability that an outcome variable realizes within a target range of values given an intervention, a causal quantity we refer to as the probability of treatment success. We link graph-based causal quantities defined via the do-operator to parameters of the model implied distribution of the observed variables using so-called causal effect functions. Based on these causal effect functions, we propose estimators for causal quantities and show that these estimators are consistent and converge at a rate of [Formula see text] under standard assumptions. Thus, causal quantities can be estimated based on sample sizes that are typically available in the social and behavioral sciences. In case of maximum likelihood estimation, the estimators are asymptotically efficient. We illustrate the proposed method with an example based on empirical data, placing special emphasis on the difference between the interventional and conditional distribution.

Defining immune mechanisms leading to multiple sclerosis (MS) is difficult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS.

To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab.

A two-center observational cohort of patients treated with alemtuzumab underwent immune profiling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up.

After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatorylemtuzumab have an early immune reconstitution dominated by NK cells.In oncology, and especially in the treatment of non-small-cell lung cancer (NSCLC), dose optimization is often a neglected part of precision medicine. Many drugs are still being administered in "one dose fits all" regimens or based on parameters that are often only minor determinants for systemic exposure. These dosing approaches often introduce additional pharmacokinetic variability and do not add to treatment outcomes. Fortunately, pharmacological knowledge is increasing, providing valuable information regarding the potential of, for example, therapeutic drug monitoring. This article focuses on the evidence for the most promising and easily implemented optimized dosing approaches for the small-molecule inhibitors, chemotherapeutic agents, and monoclonal antibodies as treatment options currently approved for NSCLC. Despite limitations such as investigations having been conducted in oncological diseases other than NSCLC or the retrospective origin of many analyses, an alternative dosing regimen could be beneficial for treatment outcomes, prescriber convenience, or financial burden on healthcare systems. This review of the literature provides recommendations on the implementation of dose optimization and advice regarding promising strategies that deserve further research in NSCLC.

Approximately 15% of clinically localised conventional renal cell carcinomas (cRCC) develop metastases within 5years of follow-up. Sarcomatous cRCC is a highly malignant cancer of the kidney. The aim of our study was to identify biomarkers for estimating the postoperative progression of cRCCs.

Global microarray-based gene expression analysis of RCCs with and without sarcomatous changes revealed that a high MMP12 expression was associated with a sarcomatous histology. Additionally, we analysed MMP12 expression using a multi-tissue array comprising 736 cRCC patients without metastasis at the time of surgery. The median follow-up time was 66 ± 29months.

Immunohistochemistry revealed MMP12 expression in 187 of 736 cRCCs with good follow-up data. Subsequent Kaplan-Meier analysis revealed that patients with MMP12 positive tumours exhibited a significantly shorter tumour-free survival (p < 0.001). In multivariate Cox regression analysis a weak to strong MMP12 expression indicated a 2.4-2.8 times higher risk of postoperative tumour relapse (p < 0.