The impact of extreme heat on morbidity in Milwaukee, Wisconsin

Given predictions of increased intensity and frequency of heat waves, it is important to study the effect of high temperatures on human mortality and morbidity. Many studies focus on heat wave-related mortality; however, heat-related morbidity is often overlooked. The goals of this study are to examine the historical observed relationship between temperature and morbidity (illness), and explore the extent to which observed historical relationships could be used to generate future projections of morbidity under climate change. We collected meteorological, air pollution, and hospital admissions data in Milwaukee, Wisconsin, for the years 1989-2005, and employed a generalized additive model (GAM) to quantify the relationship between morbidity (as measured by hospital admissions) and high temperatures with adjustment for the effects of potential confounders. We also estimated temperature threshold values for different causes of hospital admissions and then quantified the associated percent increase of admissions per degree above the threshold. Finally, the future impact of higher temperatures on admissions for the years 2059-2075 was examined. Our results show that five causes of admission (endocrine, genitourinary, renal, accidental, and self-harm) and three age groups (15-64, 75-84, > 85 years) were affected by high temperatures. Future projections indicate a larger number of days above the current temperature threshold leading to an increase in admissions. Our results indicate that climate change may increase heat-related hospital admissions in the US urban mid-West and that health systems should include heat wave planning

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-{kappa}B (NF-{kappa}B) pathway, whereas insensitive cell lines displayed activation of the alternative NF-{kappa}B pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-{kappa}B pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-{kappa}B pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-{kappa}B or NIK-NF-{kappa}B pathways in MCL and provide critical insights into patient stratification strategies for NF-{kappa}B pathway-targeted agents