A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections

Antimicrobial resistance is a global threat. As “proof-of-concept, ” we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Cerebrospinal fluid TRH immunoreactivity in anorexia nervosa

Central nervous system (CNS) thyrotropin-releasing hormone (TRH) activity is of interest in patients with anorexia nervosa. First, anorexics have peripheral thyroid abnormalities that appear to be related to weight and nutritional status. Second, CNS TRH activity may effect many other physiologic systems that are known to be disturbed in patients with anorexia nervosa. We found that anorexic patients, when both underweight and studied after attaining goal weight, had significantly reduced CSF TRH concentrations in comparison to controls. These data suggest that weight gain or increased caloric intake, in contrast to its large effect on peripheral thyroid function, has relatively little effect on CNS TRH activity. The reason for reduced CSF TRH in goal weight anorexics is not known but could be trait related, a persistent defect slow to normalize after weight gain, or related to these patients still being at a weight lower than controls. Finally, in terms of CSF TRH concentrations, this study suggests that anorexia nervosa has a different pathophysiology than major depressive disorder

Evaluating 1 Thessalonians: an outline of holistic approaches to 1 Thessalonians in the last 25 years

This article focuses on works that have been produced within the last 25 years which attempt to provide a holistic approach to the understanding and interpretation of 1 Thessalonians, such as: epistolary, rhetorical, theological, linguistic, and various combinations of the above. Proponents of each view and their perspectives will be outlined along with their structural division of the text. This article attempts to provide a general map of particular approaches to 1 Thessalonians, but also provides a brief outline of some of the critiques and weaknesses of the different methodologies. This article concludes with a brief statement regarding the trajectory of current studies