A meta-analysis of trabecular bone score in fracture risk prediction and its relationship to FRAX

Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. This article is protected by copyright. All rights reserved.

Protective and risk factors in amateur equestrians and description of injury patterns: A retrospective data analysis and a case - control survey

Background In Switzerland there are about 150,000 equestrians. Horse related injuries, including head and spinal injuries, are frequently treated at our level I trauma centre. Objectives To analyse injury patterns, protective factors, and risk factors related to horse riding, and to define groups of safer riders and those at greater risk Methods We present a retrospective and a case-control survey at conducted a tertiary trauma centre in Bern, Switzerland. Injured equestrians from July 2000 - June 2006 were retrospectively classified by injury pattern and neurological symptoms. Injured equestrians from July-December 2008 were prospectively collected using a questionnaire with 17 variables. The same questionnaire was applied in non-injured controls. Multiple logistic regression was performed, and combined risk factors were calculated using inference trees. Results Retrospective survey A total of 528 injuries occured in 365 patients. The injury pattern revealed as follows: extremities (32%: upper 17%, lower 15%), head (24%), spine (14%), thorax (9%), face (9%), pelvis (7%) and abdomen (2%). Two injuries were fatal. One case resulted in quadriplegia, one in paraplegia. Case-control survey 61 patients and 102 controls (patients: 72% female, 28% male; controls: 63% female, 37% male) were included. Falls were most frequent (65%), followed by horse kicks (19%) and horse bites (2%). Variables statistically significant for the controls were: Older age (p = 0.015), male gender (p = 0.04) and holding a diploma in horse riding (p = 0.004). Inference trees revealed typical groups less and more likely to suffer injury. Conclusions Experience with riding and having passed a diploma in horse riding seem to be protective factors. Educational levels and injury risk should be graded within an educational level-injury risk index.

Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. LAY ABSTRACT: Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

The Risk of Paradoxical Embolism (RoPE) Study: initial description of the completed database

BACKGROUND: Detecting a benefit from closure of patent foramen ovale in patients with cryptogenic stroke is hampered by low rates of stroke recurrence and uncertainty about the causal role of patent foramen ovale in the index event. A method to predict patent foramen ovale-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. AIMS: The aim of this study was to develop a database to support modeling of patent foramen ovale-attributable recurrence risk by combining extant data sets. METHODS: We identified investigators with extant databases including subjects with cryptogenic stroke investigated for patent foramen ovale, determined the availability and characteristics of data in each database, collaboratively specified the variables to be included in the Risk of Paradoxical Embolism database, harmonized the variables across databases, and collected new primary data when necessary and feasible. RESULTS: The Risk of Paradoxical Embolism database has individual clinical, radiologic, and echocardiographic data from 12 component databases, including subjects with cryptogenic stroke both with (n = 1925) and without (n = 1749) patent foramen ovale. In the patent foramen ovale subjects, a total of 381 outcomes (stroke, transient ischemic attack, death) occurred (median follow-up 2·2 years). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. CONCLUSION: While individual studies are inadequate for modeling patent foramen ovale-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a patent foramen ovale-related stroke recurrence who may have the greatest potential benefit from patent foramen ovale closure.

Framingham risk score and alternatives for prediction of coronary heart disease in older adults

Background Guidelines for the prevention of coronary heart disease (CHD) recommend use of Framingham-based risk scores that were developed in white middle-aged populations. It remains unclear whether and how CHD risk prediction might be improved among older adults. We aimed to compare the prognostic performance of the Framingham risk score (FRS), directly and after recalibration, with refit functions derived from the present cohort, as well as to assess the utility of adding other routinely available risk parameters to FRS. Methods Among 2193 black and white older adults (mean age, 73.5 years) without pre-existing cardiovascular disease from the Health ABC cohort, we examined adjudicated CHD events, defined as incident myocardial infarction, CHD death, and hospitalization for angina or coronary revascularization. Results During 8-year follow-up, 351 participants experienced CHD events. The FRS poorly discriminated between persons who experienced CHD events vs. not (C-index: 0.577 in women; 0.583 in men) and underestimated absolute risk prediction by 51% in women and 8% in men. Recalibration of the FRS improved absolute risk prediction, particulary for women. For both genders, refitting these functions substantially improved absolute risk prediction, with similar discrimination to the FRS. Results did not differ between whites and blacks. The addition of lifestyle variables, waist circumference and creatinine did not improve risk prediction beyond risk factors of the FRS. Conclusions The FRS underestimates CHD risk in older adults, particularly in women, although traditional risk factors remain the best predictors of CHD. Re-estimated risk functions using these factors improve accurate estimation of absolute risk.

Ways of coping and biomarkers of an increased atherothrombotic cardiovascular disease risk in elderly individuals

Objective. To investigate the relationship between coping and atherothrombotic biomarkers of an increased cardiovascular disease (CVD) risk in the elderly. Methods. We studied 136 elderly caregiving and noncaregiving men and women who completed the Ways of Coping Checklist to assess problem-focused coping, seeking social support (SSS), blamed self, wishful thinking, and avoidance coping. They had circulating levels of 12 biomarkers measured. We also probed for potential mediator and moderator variables (chronic stress, affect, health behavior, autonomic activity) for the relation between coping and biomarkers. Results. After controlling for demographic and CVD risk factors, greater use of SSS was associated with elevated levels of serum amyloid A (P = 0.001), C-reactive protein (CRP) (P = 0.002), vascular cellular adhesion molecule (VCAM)-1 (P = 0.021), and D-dimer (P = 0.032). There were several moderator effects. For instance, greater use of SSS was associated with elevated VCAM-1 (P < 0.001) and CRP (P = 0.001) levels in subjects with low levels of perceived social support and positive affect, respectively. The other coping styles were not significantly associated with any biomarker. Conclusions. Greater use of SSS might compromise cardiovascular health through atherothrombotic mechanisms, including elevated inflammation (i.e., serum amyloid A, CRP, VCAM-1) and coagulation (i.e., D-dimer) activity. Moderating variables need to be considered in this relationship.

Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C

Aim To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. Patients and Methods Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. Results A total of 472 (83% M, 17% F) patients were eligible. The median age at admission was 31 years (Interquartile range (IQR) 27–35 years), and the median duration of drug use was 10 years (IQR 5.5–15 years). Unhealthy drinking (>50 grams/day) was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76–1.87) than in the HCV-monoinfected patients (0.75, IQR 0.56–1.11) (p<0.001). In the multivariate analysis, unhealthy drinking (p = 0.034), lower total cholesterol (p = 0.042), serum albumin (p<0.001), higher GGT (p<0.001) and a longer duration of addiction (p = 0.005) were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001), a lower CD4 cell count (p = 0.006), higher total bilirubin (p<0.001) and a longer drug addiction duration (p<0.001) were significantly associated with higher FIB-4 values. Conclusions Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations.

Predicting perceived vulnerability for breast cancer among women with an average breast cancer risk

OBJECTIVES: The purpose of the present study was to investigate predictors of perceived vulnerability for breast cancer in women with an average risk for breast cancer. On the basis of empirical findings that suggested which variables might be associated with perceived vulnerability for breast cancer, we investigated whether knowledge of breast cancer risk factors, cancer worry, intrusions about breast cancer, optimism about not getting cancer and perceived health status have a predictive value for perceived breast cancer vulnerability. DESIGN: In a 3-step approach, we recruited 292 women from the general public in Germany who had neither a family history of breast cancer nor breast cancer themselves. After receiving an initial informational letter about study objectives, the women were interviewed by telephone and then asked to fill in a self-administered questionnaire. METHODS: We used structural equation modelling and hypothesized that each of the included variables has a direct influence on perceived vulnerability for breast cancer. RESULTS: We found a valid model with acceptable fit indices. Optimism about not getting cancer, intrusions about breast cancer and women's perceived health status explained 32% of the variance of perceived vulnerability for breast cancer. Cancer worry and knowledge about breast cancer did not influence perceived vulnerability for breast cancer. CONCLUSION: Perceived vulnerability for breast cancer is associated with health-related variables more than with knowledge about breast cancer risk factors.

Risk factors for reperfusion injury after lung transplantation

OBJECTIVE: To assess the influence of recipient's and donor's factors as well as surgical events on the occurrence of reperfusion injury after lung transplantation. DESIGN AND SETTING: Retrospective study in the surgical intensive care unit (ICU) of a university hospital. METHODS: We collected data on 60 lung transplantation donor/recipient pairs from June 1993 to May 2001, and compared the demographic, peri- and postoperative variables of patients who experienced reperfusion injury (35%) and those who did not. RESULTS: The occurrence of high systolic pulmonary pressure immediately after transplantation and/or its persistence during the first 48[Symbol: see text]h after surgery was associated with reperfusion injury, independently of preoperative values. Reperfusion injury was associated with difficult hemostasis during transplantation (p[Symbol: see text]=[Symbol: see text]0.03). Patients with reperfusion injury were more likely to require the administration of catecholamine during the first 48[Symbol: see text]h after surgery (p[Symbol: see text]=[Symbol: see text]0.014). The extubation was delayed (p[Symbol: see text]=[Symbol: see text]0.03) and the relative odds of ICU mortality were significantly greater (OR 4.8, 95% CI: 1.06, 21.8) in patients with reperfusion injury. Our analysis confirmed that preexisting pulmonary hypertension increased the incidence of reperfusion injury (p[Symbol: see text]<[Symbol: see text]0.01). CONCLUSIONS: Difficulties in perioperative hemostasis were associated with reperfusion injury. Occurrence of reperfusion injury was associated with postoperative systolic pulmonary hypertension, longer mechanical ventilation and higher mortality. Whether early recognition and treatment of pulmonary hypertension during transplantation can prevent the occurrence of reperfusion injury needs to be investigated.

Association between cannabis use and sexual risk behavior among young heterosexual adults

To study the association between cannabis use and frequent sexual risk behavior, we tested the hypothesis of a situational influence of cannabis use in sexual encounters using a combination of global association study and event-level analysis and examined possible mediator variables, including the personality trait of hedonism/risk preference, psychosocial stress, and HIV-related beliefs, using mediation models. The results of a computer-assisted telephone interview of a random sample of 2790 heterosexual men and women aged 16-24 years showed that risky sexual behavior was more frequent in cannabis-using men and women than in non-using persons. The results did not support a situational effect of cannabis intoxication on sexual risk behavior. The more frequent sexual risk behavior among cannabis users was mediated by decreased intentions to use HIV protection, by lower HIV-self-efficacy, and higher risk preference/hedonism. Only among women psychosocial stress was a partial mediator. The findings show that HIV prevention programs for cannabis-using young adults should emphasize the role of person variables instead of situation variables.

Prediction of hip fracture risk by quantitative ultrasound in more than 7000 Swiss women > or =70 years of age: comparison of three technologically different bone ultrasound devices in the SEMOF study

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women > or =70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. INTRODUCTION: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. MATERIALS AND METHODS: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women > or =70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. RESULTS: From the 7609 women who were included in the study, 7062 women 75.2 +/- 3.1 (SD) years of age were prospectively followed for 2.9 +/- 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). CONCLUSIONS: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Risk factors for early catheter-related infections in cancer patients

BACKGROUND: Early catheter-related infection is a serious complication in cancer treatment, although risk factors for its occurrence are not well established. The authors conducted a prospective study to identify the risk factors for developing early catheter-related infection. METHODS: All consecutive patients with cancer who underwent insertion of a central venous catheter were enrolled and were followed prospectively during 1 month. The study endpoint was occurrence of early catheter-related infection. RESULTS: Over 10,392 catheter-days of follow-up, 14 of 371 patients had early catheter-related infections (14 patients in 10,392 catheter-days or 1.34 per 1000 catheter-days). The causative pathogens were gram positive in 11 of 14 patients. In univariate analysis, the risk factors for early catheter-related infection were aged <10 years (P = .0001), difficulties during insertion (P < 10(-6)), blood product administration (P < 10(-3)), parenteral nutrition (P < 10(-4)), and use >2 days (P < 10(-6)). In multivariate analysis, 3 variables remained significantly associated with the risk of early catheter-related infection: age <10 years (odds ratio [OR], 18.4; 95% confidence interval [95% CI], 1.9-106.7), difficulties during insertion procedure (OR, 25.6; 95% CI, 4.2-106), and parenteral nutrition (OR, 28.5; 95% CI, 4.2-200). CONCLUSIONS: On the day of insertion, 2 variables were identified that were associated with a high risk of developing an early catheter-related infection: young age and difficulties during insertion. The results from this study may be used to identify patients who are at high risk of infection who may be candidates for preventive strategies.

Risk prediction of fever in neutropenia in children with cancer: a step towards individually tailored supportive therapy?

BACKGROUND: Fever in severe chemotherapy-induced neutropenia (FN) is the most frequent manifestation of a potentially lethal complication of current intensive chemotherapy regimens. This study aimed at establishing models predicting the risk of FN, and of FN with bacteremia, in pediatric cancer patients. METHODS: In a single-centre cohort study, characteristics potentially associated with FN and episodes of FN were retrospectively extracted from charts. Poisson regression accounting for chemotherapy exposure time was used for analysis. Prediction models were constructed based on a derivation set of two thirds of observations, and validated based on the remaining third of observations. RESULTS: In 360 pediatric cancer patients diagnosed and treated for a cumulative chemotherapy exposure time of 424 years, 629 FN were recorded (1.48 FN per patient per year, 95% confidence interval (CI), 1.37-1.61), 145 of them with bacteremia (23% of FN; 0.34; 0.29-0.40). More intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central venous access device (CVAD), and prior FN were significantly and independently associated with a higher risk to develop both FN and FN with bacteremia. The prediction models explained more than 30% of the respective risks. CONCLUSIONS: The two models predicting FN and FN with bacteremia were based on five easily accessible clinical variables. Before clinical application, they need to be validated by prospective studies.