Citations

Objective Grip strength is a well-characterised measure of weakness and of poor muscle performance, but there is a lack of consensus on its prognostic implications in terms of cardiac adverse events in patients with cardiac disorders. Methods Articles were searched in PubMed, Cochrane Library, BioMed Central and EMBASE. The main inclusion criteria were patients with cardiac disorders (ischaemic heart disease, heart failure (HF), cardiomyopathies, valvulopathies, arrhythmias); evaluation of grip strength by handheld dynamometer; and relation between grip strength and outcomes. The endpoints of the study were cardiac death, all-cause mortality, hospital admission for HF, cerebrovascular accident (CVA) and myocardial infarction (MI). Data of interest were retrieved from the articles and after contact with authors, and then pooled in an individual patient meta-analysis. Univariate and multivariate logistic regression was performed to define predictors of outcomes. Results Overall, 23 480 patients were included from 7 studies. The mean age was 62.3±6.9 years and 70% were male. The mean follow-up was 2.82±1.7 years. After multivariate analysis grip strength (difference of 5 kg, 5× kg) emerged as an independent predictor of cardiac death (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001), all-cause death (OR 0.87, 95% CI 0.85 to 0.89, p<0.0001) and hospital admission for HF (OR 0.88, 95% CI 0.84 to 0.92, p<0.0001). On the contrary, we did not find any relationship between grip strength and occurrence of MI or CVA. Conclusion In patients with cardiac disorders, grip strength predicted cardiac death, all-cause death and hospital admission for HF. Trial registration number CRD42015025280.

Increased amino acids in the dysbiotic gut influences susceptibility to Clostridioides difficile infection in mice and humans.

AbstractVariable tumor cellularity can limit sensitivity and precision in comparative genomics because differences in tumor content can result in misclassifying truncal mutations as region‐specific private mutations in stroma‐rich regions, especially when studying tissue specimens of mediocre tumor cellularity such as lung adenocarcinomas (LUADs). To address this issue, we refined a nuclei flow‐sorting approach by sorting nuclei based on ploidy and the LUAD lineage marker thyroid transcription factor 1 and applied this method to investigate genome‐wide somatic copy number aberrations (SCNAs) and mutations of 409 cancer genes in 39 tumor populations obtained from 16 primary tumors and 21 matched metastases. This approach increased the mean tumor purity from 54% (range 7–89%) of unsorted material to 92% (range 79–99%) after sorting. Despite this rise in tumor purity, we detected limited genetic heterogeneity between primary tumors and their metastases. In fact, 88% of SCNAs and 80% of mutations were propagated from primary tumors to metastases and low allele frequency mutations accounted for much of the mutational heterogeneity. Even though the presence of SCNAs indicated a history of chromosomal instability (CIN) in all tumors, metastases did not have more SCNAs than primary tumors. Moreover, tumors with biallelic TP53 or ATM mutations had high numbers of SCNAs, yet they were associated with a low interlesional genetic heterogeneity. The results of our study thus provide evidence that most macroevolutionary events occur in primary tumors before metastatic dissemination and advocate for a limited degree of CIN over time and space in this cohort of LUADs. Sampling of primary tumors thus may suffice to detect most mutations and SCNAs. In addition, metastases but not primary tumors had seeded additional metastases in three of four patients; this provides a genomic rational for surgical treatment of such oligometastatic LUADs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The objective of this study is to describe the pharmacokinetics of lacosamide in a critically ill adult during continuous venovenous hemofiltration (CVVH). A 78-year-old male developed sepsis and acute kidney injury following cardiac surgery. He was initially treated with intermittent hemodialysis but developed nonconvulsive status epilepticus at the end of the first session and was subsequently initiated on CVVH. In addition to lorazepam boluses, levetiracetam, and midazolam infusion, he was loaded with lacosamide 400 mg intravenously and started on 200 mg intravenously twice daily as maintenance therapy. Noncompartmental modeling of lacosamide pharmacokinetics revealed significant extracorporeal removal, a volume of distribution of 0.69 L/kg, elimination half-life of 13.6 hours, and peak and trough concentrations of 7.4 and 3.7 mg/L, respectively (goal trough, 5-10 mg/L). We found significant extracorporeal removal of serum lacosamide during CVVH, which was higher than previously reported. This led to subtherapeutic concentrations and decreased overall antiepileptic drug exposure. The relationship between serum lacosamide concentrations and clinical efficacy is not well understood; thus, therapeutic drug monitoring is not routinely recommended. Yet, we demonstrated that measuring serum lacosamide concentrations in the critically ill population during continuous renal replacement therapy may be useful to individualize dosing programs. Further pharmacokinetic studies of lacosamide may be necessary to generate widespread dosing recommendations.

Although the Sensititre Yeast-One (SYO) and Etest methods are widely utilized, interpretive criteria are not available for triazole susceptibility testing of Candida or Aspergillus species. We collected fluconazole, itraconazole, posaconazole, and voriconazole SYO and Etest MICs from 39 laboratories representing all continents for (method/agent-dependent) 11,171 Candida albicans , 215 C. dubliniensis , 4,418 C. glabrata species complex, 157 C. guilliermondii ( Meyerozyma guilliermondii ), 676 C. krusei ( Pichia kudriavzevii ), 298 C. lusitaniae ( Clavispora lusitaniae ), 911 C. parapsilosis sensu stricto , 3,691 C. parapsilosis species complex, 36 C. metapsilosis , 110 C. orthopsilosis , 1,854 C. tropicalis , 244 Saccharomyces cerevisiae , 1,409 Aspergillus fumigatus , 389 A. flavus , 130 A. nidulans , 233 A. niger , and 302 A. terreus complex isolates.

Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials.