An evaluation of clinical risk factors for estimating fracture risk in postmenopausal osteoporosis using an electronic medical record database.

SUMMARY: Many of the clinical risk factors used in fracture risk assessment (FRAX) calculator are available in electronic medical record (EMR) databases and are good sources of osteoporosis risk factor information. The EPIC EMR database showed a lower prevalence of FRAX risk factors and, consequently, proportion of patients who would be deemed "high risk." INTRODUCTION: The FRAX tool is underutilized for osteoporosis screening. Many of the clinical risk factors for FRAX may be available in EMR databases and may enable health systems to perform fracture risk assessments. We intended to identify variables in an EMR database for calculating FRAX score in a cohort of postmenopausal women, to estimate absolute fracture risk, and to determine the proportions of women whose absolute fracture risks exceed the National Osteoporosis Foundation (NOF) thresholds. METHODS: Our cohort was selected using an EMR database with demographic, inpatient, outpatient, and clinical information for female patients age≥50 in a family practice, internal medicine, or obstetrics/gynecology clinic in 2007-2008. The latest physician encounter was the index date. Variables, problem and medication lists, diagnosis codes, and histories from the EMR were used to populate the 11 clinical risk factor variables used in the FRAX. These risk factor prevalence and treatment-eligible proportions were compared to those of published epidemiology studies. RESULTS: The study included 345 patients. Mean (SD) 10-year risk for any major fracture was 11.1% (6.8) when bone mineral density (BMD) was used and 11.2% (6.5) when BMI was used. About 10.1% of the cohort exceeded the NOF's 20% major fracture risk threshold and 32.5% exceeded the NOF's 3% hip fracture risk threshold when BMD was used. Overall, the number of treatment-eligible patients was slightly lower when FRAX was calculated using BMD versus BMI (13.6 and 36.8%). CONCLUSION: Our cohort using EMR data most likely underestimated the mean 10-year probability of any major fracture compared to other cohorts in published literature. The difference may be in the nature of EMRs for supporting only passive data collection of risk factor information.

A[H1N1] flu and refractory hypoxaemia: is extracorporeal lung support the holy grail?

There is a call for methodologically robust randomised clinical trials in adult extracorporeal membrane oxygenation for its routine implementation for patients with "failing" conventional ventilation. Adherence to lung protective ventilation strategies, along with fluid balance [if required early renal replacement therapy] and inotropes to support the circulation to minimise ventilator-induced lung injury, may mitigate deterioration requiring extracorporeal lung support. Currently there is no convincing evidence to routinely advocate extracorporeal lung support in failed conventional ventilation, and a prospective trial is needed to define standard best practice and to tailor extracorporeal lung support referral criteria in young patient cohort with severe refractory respiratory failure.

Drotrecogin alfa (activated): diffusion from clinical trials to clinical practice.

BACKGROUND AND OBJECTIVE: Although the PROWESS trial demonstrated a mortality benefit, subsequent studies in different patient populations have not reproduced the effect. As a result, concerns have been expressed about the clinical effectiveness of drotrecogin alfa (activated). Therefore the aim of this audit was to review the clinical impact of drotrecogin alfa (activated) when used outside clinical trials. METHODS: A retrospective review of ICU charts and medical records of patients who had received drotrecogin alfa (activated) in the five largest users of drotrecogin alfa (activated) in England. Patients characteristics details at ICU admission and vital status at hospital discharge were recorded. The severity of illness was assessed by the APACHE II score (using first 24 h admission data) and the number of organ dysfunctions. Adverse incidents were recorded and any sequence effect explored. RESULTS: In all, 351 patients received drotrecogin alfa (activated) between December 2002 and November 2005. Of those, 201 (57.2%) were male, and 177 (50.4%) were admitted after recent surgery. The patients' average age was 61.8 yr. The mean admission APACHE II score was 23.3 and the average number of dysfunctional organs on admission was 3.3. The hospital mortality was 46.7% (164 deaths). The expected number of deaths calculated by using the APACHE II risk of death was 173 (49.3%) and by number of sepsis induced organ failures 210 (59.7%). Overall, there were 33 (9.4%) adverse incidents. CONCLUSIONS: Expected mortality derived from both the APACHE II score and organ dysfunctions suggests that drotrecogin alfa (activated) does reduce mortality. Serious adverse incidents occurred in 5.1% patients; however, the direct contributing effect of drotrecogin alfa (activated) cannot be established from this type of audit.

The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice.

Regulation of the cell cycle is a critical aspect of cellular proliferation, differentiation, and transformation. In many cell types, the differentiation process is accompanied by a loss of proliferative capability, so that terminally differentiated cells become postmitotic and no longer progress through the cell cycle. In the experiments described here, the ocular lens has been used as a system to examine the role of the retinoblastoma protein (pRb) family in regulation of the cell cycle during differentiation. The ocular lens is an ideal system for such studies, since it is composed of just two cell types: epithelial cells, which are capable of proliferation, and fiber cells, which are postmitotic. In order to inactivate pRb in viable mice, genes encoding either a truncated version of simian virus 40 large T antigen or the E7 protein of human papillomavirus were expressed in a lens-specific fashion in transgenic mice. Lens fiber cells in the transgenic mice were found to incorporate bromodeoxyuridine, implying inappropriate entry into the cell cycle. Surprisingly, the lens fiber cells did not proliferate as tumor cells but instead underwent programmed cell death, resulting in lens ablation and microphthalmia. Analogous lens alterations did not occur in mice expressing a modified version of the truncated T antigen that was mutated in the binding domain for the pRb family. These experimental results indicate that the retinoblastoma protein family plays a crucial role in blocking cell cycle progression and maintaining terminal differentiation in lens fiber cells. Apoptotic cell death ensues when fiber cells are induced to remain in or reenter the cell cycle.

Analysis of possible WT1 RNA processing in primary Wilms tumors.

WT1 RNA processing abnormalities have been suggested to play a role in the development of Wilms tumor by reports of editing at codon 280 in the rat WT1 transcript (codon 281 in humans) and aberrant splicing of exon 2 in WT1 transcripts from Wilms tumor xenograft cell lines. Both events result in a functionally changed WT1 protein and are potential mechanisms of altering normal protein function in the absence of WT1 DNA mutations. To determine whether either of these RNA processing events occurs in primary Wilms tumors, we analysed WT1 mRNA from 15 primary tumors. There was no evidence of WT1 RNA editing at codon 281, and only one primary tumor displayed aberrant splicing of exon 2. Sequence and Southern analysis of DNA from this tumor did not reveal any alteration in or around exon 2. These results suggest that neither RNA editing at codon 281 nor aberrant exon 2 splicing is a frequent mechanism of WT1 alteration during tumorigenesis.

Retroviral delivery of DNA into the livers of transgenic mice bearing premalignant and malignant hepatocellular carcinomas.

To develop gene therapy for hepatocellular carcinoma (HCC), we infused mice through the portal vein with retrovirus carrying the Escherichia coli beta-galactosidase reporter gene under the transcriptional control of the viral long terminal repeat (LTR) and the promoter from the mouse multidrug resistance gene mdr1b. Two transgenic mouse HCC models were used, one bearing the human hepatitis B viral envelope protein and the other SV40 T antigen. These animals develop HCC with predictable pathological manifestations. The viral transduction efficiency appeared to depend upon the stage of the disease in the animals. The most efficient transduction occurred when the livers had developed microscopic nodular hyperplasia; in some cases as many as 0.01-0.1 copies/cell were transduced. The transduction efficiency was lower in the late stage of the disease when livers had a heavy tumor burden and in the early stage when no lesion was evident. Low viral transduction efficacy was also seen in nontransgenic animals but was significantly increased by partial hepatectomy. The expression of the reporter gene in these animals was very low, as determined by histological staining. These results suggest that hepatocarcinogenesis can enhance retroviral delivery of foreign genes into the liver. Further development by increasing the viral transducing efficiency and the level of expression of transduced gene is required.

Analysis of the promoter region of human cartilage oligomeric matrix protein (COMP).

Cartilage oligomeric matrix protein (COMP) is an extracellular matrix protein expressed in cartilage, ligament, and tendon. The importance of COMP in the matrix of these cells is underscored by the discovery that mutations in COMP cause the skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Here, we present the first report on the analysis of the human COMP promoter region in cartilage, ligament, and tendon cells. A 1.7-kb region of the COMP promoter has been cloned and sequenced and no TATA or CAAT boxes were found. Primer extension identified multiple transcription start sites. All four transcription start sites were utilized in chondrocytes with only three of them utilized in tendon and ligament cells. Differential regulation was observed for different parts of this 1.7-kb region with the 370-bp proximal region conveying the strongest promoter activity. The highest activity was observed in tendon and ligament. Finally, we provide evidence that the DNA binding protein SP1 plays a role in the regulation of COMP expression. These results indicate that COMP expression within these cells is regulated in a unique manner that differs from the expression of other extracellular matrix genes.

Prostacyclin but not phentolamine increases oxygen consumption and skin microvascular blood flow in patients with sepsis and respiratory failure.

Inadequate tissue oxygenation may occur in critically ill patients with sepsis despite an apparently adequate O2 transport (QO2), and this may contribute to the development of an O2 debt and also to multiple organ failure. It has been shown that increasing QO2 by infusing a vasodilator may reveal this O2 debt in septic patients. To investigate whether the site of action of vasodilators may be of importance in unmasking such an O2 debt, we administered prostacyclin, a prostaglandin with a preferential effect on the microcirculation, and phentolamine, an arteriolar vasodilator, in 11 patients studied during the first 48 hours after the onset of sepsis, and compared their effect on whole body oxygen consumption (VO2) and skin microvascular blood flow. The results demonstrated that increasing QO2 by prostacyclin but not by phentolamine significantly increases VO2 in critically ill patients with sepsis. The site of action of vasodilators may therefore play an important role in their ability to unmask an O2 debt.

Nosocomial H1N1 infection during 2010-2011 pandemic: a retrospective cohort study from a tertiary referral hospital.

This study aimed to estimate the incidence of hospital transmission of influenza A subtype H1N1 [A(H1N1)], to identify high-risk areas for such transmission and to evaluate common characteristics of affected patients. In this single-centre retrospective cohort study, 10 patients met the criteria for hospital-acquired A(H1N1) infection over a three-month period. All affected patients required an escalation of their care and the mortality rate was 20%. Clinicians should be aware of the risk of nosocomial A(H1N1) infection that exists despite routine infection control measures and should consider additional control measures including vaccination of hospital inpatients and healthcare staff.