Complications following hip fracture: Results from the World Hip Trauma Evaluation cohort study.

INTRODUCTION: Hip fractures are common in people over 60 years of age, and are associated with significant disability, morbidity and mortality. The aim of this study was to record the incidence of complications in the first 120 days following hip fracture. METHODS: The World Hip Trauma Evaluation (WHiTE) study is a multicentre, prospective cohort study conducted in National Health Service (NHS) hospitals in England and Wales. Participants are 60 years and older who received operative treatment for a hip fracture. We report the incidence of complications recorded by hospital staff until discharge from hospital and by participants at 120-days post-surgery. RESULTS: An analysis of 8673 consecutive participants enrolled in the WHiTE study revealed the following risks of complications within the first 120 days: signs of wound infection (3.1%); dislocation (0.5%); failure of fixation (0.6%); peri­prosthetic fracture (0.3%); overall revision surgery (0.9%); blood loss requiring transfusion (6.1%); chest infection (6.3%); urinary tract infection (5.0%); deep vein thrombosis/pulmonary embolus (1.8%); cerebrovascular accident (0.6%); acute coronary syndrome/myocardial infarction (0.6%); acute kidney injury (1.3%). CONCLUSION: The rates of complications reported here provide a reference range against which future studies might be assessed. Registration: ISRCTN63982700.

Prescribing and adherence to bone protection medications following hip fracture in the United Kingdom: results from the World Hip Trauma Evaluation (WHiTE) cohort study.

AIMS: Bone health assessment and the prescription of medication for secondary fracture prevention have become an integral part of the acute management of patients with hip fracture. However, there is little evidence regarding compliance with prescription guidelines and subsequent adherence to medication in this patient group. PATIENTS AND METHODS: The World Hip Trauma Evaluation (WHiTE) is a multicentre, prospective cohort of hip fracture patients in NHS hospitals in England and Wales. Patients aged 60 years and older who received operative treatment for a hip fracture were eligible for inclusion in WHiTE. The prescription of bone protection medications was recorded from participants' discharge summaries, and participant-reported use of bone protection medications was recorded at 120 days following surgery. RESULTS: Of 5456 recruited patients with baseline data, 2853 patients (52%) were prescribed bone protection medication at discharge, of which oral bisphosphonates were the most common, 4109 patients (75%) were prescribed vitamin D or calcium, and 606 patients (11%) were not prescribed anything. Of those prescribed a bone protection medication, only 932 patients (33%) reported still taking their medication 120 days later. CONCLUSION: These data provide a reference for current prescription and adherence rates. Adherence with oral medication remains poor in patients with hip fracture. Cite this article: Bone Joint J 2019;101-B:1402-1407.

Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells.

The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment.

A microRNA-operated switch of asymmetric-to-symmetric cancer stem cell divisions.

Defective asymmetric cell divisions of stem and progenitor cells are associated with tumorigenesis by a largely unknown mechanism. A signalling axis involving Snail, microRNA-146a and Numb is now shown to regulate the switch between symmetric and asymmetric cell division in colorectal cancer stem cells.

Asymmetric cell division of stem and progenitor cells during homeostasis and cancer.

Stem and progenitor cells are characterized by their ability to self-renew and produce differentiated progeny. A fine balance between these processes is achieved through controlled asymmetric divisions and is necessary to generate cellular diversity during development and to maintain adult tissue homeostasis. Disruption of this balance may result in premature depletion of the stem/progenitor cell pool, or abnormal growth. In many tissues, including the brain, dysregulated asymmetric divisions are associated with cancer. Whether there is a causal relationship between asymmetric cell division defects and cancer initiation is as yet not known. Here, we review the cellular and molecular mechanisms that regulate asymmetric cell divisions in the neural lineage and discuss the potential connections between this regulatory machinery and cancer.

A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.

Within the central nervous system (CNS), the hypothalamus senses and integrates information on the nutrient state of the body. However, the molecular mechanisms translating nutrient sensing into changes in gene expression and, ultimately, nutrient intake remain unclear. A crucial function for the cyclic AMP-response element binding protein (CREB) co-activator CREB-regulated transcription co-activator 2 (CRTC2) in maintaining glucose homeostasis has been shown in the liver. Here, we report CRTC2 expression in distinct areas of the CNS, including hypothalamic neurons. We show that hypothalamic CRTC2 phosphorylation and subcellular localization is altered by nutrient state. Specifically, glucose regulates hypothalamic CRTC2 activity via AMP-activated protein kinase (AMPK)-mediated phosphorylation of CRTC2. Hypothalamic AMPK controls the expression of the cAMP response element (CRE) gene, insulin receptor substrate 2 (Irs2), by regulating CRTC2 occupancy of the Irs2 promoter. Indeed, CRTC2 is required for the appropriate expression of specific hypothalamic CRE genes. Our data identify CRTC2 as a new hypothalamic AMPK target and highlight a role for CRTC2 in the mechanisms linking hypothalamic glucose sensing with CRE gene regulation.