Simultaneous precise editing of multiple genes in human cells

Abstract. When double-strand breaks are introduced in a genome by CRISPR they are repaired either by non-homologous end joining (NHEJ), which often results i

Development and application of a Japanese model of the WHO fracture risk assessment tool (FRAX™)

SUMMARY: The present study estimated the 10-year probability using the Japanese version of WHO fracture risk assessment tool (FRAX) in order to determine fracture probabilities that correspond to intervention thresholds currently used in Japan and to resolve some issues for its use in Japan. INTRODUCTION: The objective of the present study was to evaluate a Japanese version of the WHO fracture risk assessment (FRAX) tool to compute 10-year probabilities of osteoporotic fracture in Japanese men and women. Since lumbar spine bone mineral density (BMD) is used preferentially as a site for assessment, and densitometers use Japanese reference data, a second aim was to investigate the suitability and impact of this practice in Japan. METHODS: Fracture probabilities were computed from published data on the fracture and death hazards in Japan. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck BMD. Fracture probabilities were determined that were equivalent to intervention thresholds currently used in Japan. The difference between T-scores derived from international reference data and that using Japanese-specific normal ranges was estimated from published sources. The gradient of risk of BMD for fracture in Japan was compared to that for BMD at the lumbar spine in the Hiroshima cohort. RESULTS: The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current intervention thresholds ranged from approximately 5% at the age of 50 years to more than 20% at the age of 80 years. The use of femoral neck BMD predicts fracture as well as or better than BMD tests at the lumbar spine. There were small differences in T-scores between those used for the model and those derived from a Japanese reference population. CONCLUSIONS: The FRAX mark tool has been used to determine possible thresholds for therapeutic intervention, based on equivalence of risk with current guidelines. The approach will need to be supported by appropriate health economic analyses. Femoral neck BMD is suitable for the prediction of fracture risk among Japanese. However, when applying the FRAX model to Japan, T-scores and Z-scores should be converted to those derived from the international reference

Efficacy of weekly teriparatide does not vary by baseline fracture probability calculated using FRAX

Summary The aim of this study was to determine the efficacy of once-weekly teriparatide as a function of baseline fracture risk. Treatment with once-weekly teriparatide was associated with a statistically significant 79 % decrease in vertebral fractures, and in the cohort as a whole, efficacy was not related to baseline fracture risk. Introduction Previous studies have suggested that the efficacy of some interventions may be greater in the segment of the population at highest fracture risk as assessed by the FRAX® algorithms. The aim of the present study was to determine whether the antifracture efficacy of weekly teriparatide was dependent on the magnitude of fracture risk. Methods Baseline fracture probabilities (using FRAX) were computed from the primary data of a phase 3 study (TOWER) of the effects of weekly teriparatide in 542 men and postmenopausal women with osteoporosis. The outcome variable comprised morphometric vertebral fractures. Interactions between fracture probability and efficacy were explored by Poisson regression. Results The 10-year probability of major osteoporotic fractures (without BMD) ranged from 7.2 to 42.2 %. FRAX-based hip fracture probabilities ranged from 0.9 to 29.3 %. Treatment with teriparatide was associated with a 79 % (95 % CI 52–91 %) decrease in vertebral fractures assessed by semiquantitative morphometry. Relative risk reductions for the effect of teriparatide on the fracture outcome did not change significantly across the range of fracture probabilities (p = 0.28). In a subgroup analysis of 346 (64 %) participants who had FRAX probabilities calculated with the inclusion of BMD, there was a small but significant interaction (p = 0.028) between efficacy and baseline fracture probability such that high fracture probabilities were associated with lower efficacy. Conclusion Weekly teriparatide significantly decreased the risk of morphometric vertebral fractures in men and postmenopausal women with osteoporosis. Overall, the efficacy of teriparatide was not dependent on the level of fracture risk assessed by FRAX in the cohort as a whole

A high incidence of vertebral fracture in women with breast cancer

Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3–9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1–57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer. © 1999 Cancer Research Campaig

FRAX- vs. T-score-based intervention thresholds for osteoporosis

Many current guidelines for the assessment of osteoporosis, including those in Kuwait, initiate fracture risk assessment in men and women using BMD T-score thresholds. We compared the Kuwaiti guidelines with FRAX-based age-dependent intervention thresholds equivalent to that in women with a prior fragility fracture. FRAX-based intervention thresholds identified women at higher fracture probability than fixed T-score thresholds, particularly in the elderly. PURPOSE: A FRAX® model been recently calibrated for Kuwait, but guidance is needed on how to utilise fracture probabilities in the assessment and treatment of patients. METHODS: We compared age-specific fracture probabilities, equivalent to women with no clinical risk factors and a prior fragility fracture (without BMD), with the age-specific fracture probabilities associated with femoral neck T-scores of -2.5 and -1.5 SD, in line with current guidelines in Kuwait. Upper and lower assessment thresholds for BMD testing were additionally explored using FRAX. RESULTS: When a BMD T-score of -2.5 SD was used as an intervention threshold, FRAX probabilities of a major osteoporotic fracture in women aged 50 years were approximately twofold higher than those in women of the same age but with an average BMD. The increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 83 years or more, a T-score of -2.5 SD was associated with a lower probability of fracture than that of the age-matched general population with no clinical risk factors. The same phenomenon was observed from the age of 66 years at a T-score of -1.5 SD. A FRAX-based intervention threshold, defined as the 10-year probability of a major osteoporotic fracture in a woman of average BMI with a previous fracture, rose with age from 4.3% at the age of 50 years to 23%, at the age of 90 years, and identified women at increased risk at all ages. Qualitatively comparable findings were observed in the case of hip fracture probability and in men. CONCLUSION: Intervention thresholds based on BMD alone do not optimally target women at higher fracture risk than those on age-matched individuals without clinical risk factors, particularly in the elderly. In contrast, intervention thresholds based on fracture probabilities equivalent to a 'fracture threshold' consistently target women at higher fracture risk, irrespective of age

FRAX™ and the assessment of fracture probability in men and women from the UK

SUMMARY: A fracture risk assessment tool (FRAX) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. INTRODUCTION: The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. METHODS: Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. RESULTS: Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m(2)) ranged from 0.2% at the age of 50 years for women without CRF's to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. CONCLUSION: The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD

On Improving the Memorability of System-Assigned Recognition-Based Passwords

User-chosen passwords reflecting common strategies and patterns ease memorization but offer uncertain and often weak security, while system-assigned passwords provide higher security guarantee but suffer from poor memorability. We thus examine the technique to enhance password memorability that incorporates a scientific understanding of long-term memory. In particular, we examine the efficacy of providing users with verbal cues—real-life facts corresponding to system-assigned keywords. We also explore the usability gain of including images related to the keywords along with verbal cues. In our multi-session lab study with 52 participants, textual recognition-based scheme offering verbal cues had a significantly higher login success rate (94.23%) compared to the control condition, i.e., textual recognition without verbal cues (61.54%). We found that when users were provided with verbal cues, adding images contributed to faster recognition of the assigned keywords, and thus had an overall improvement in usability. So, we conducted a field study with 54 participants to further examine the usability of graphical recognition-based scheme offering verbal cues, which showed an average login success rate of 98% in a real-life setting and an overall improvement in login performance with more login sessions. These findings show a promising research direction to gain high memorability for system-assigned passwords

Periferne osteoporotske frakture osim kuka - epidemiologija i značenje

Fractures are the most serious consequence of osteoporosis. Non-vertebral and non-hip fractures are seldom recognised as important, even though they account for the majority of all fractures. The most prevalent localisations are distal radius, proximal humerus, ribs, clavicle, and the pelvis. According to the results from large phase III clinical trials for placebo groups, their incidence ranges from 4.9 % to 12.0 %. Hospital morbidity data in Croatia in 2006 show that peripheral non-hip fractures ranked among the leading fifteen injuries, accounting for 23.7 % of all injuries in patients aged 60 years and above. Risk factors for non-hip and non-vertebral fractures are similar to other osteoporotic fractures, and the main are low bone mineral density and earlier fractures. Quality of life is considerably affected by these fractures, and medical costs are very high, soaring as high as 36.9 % of all national medical costs in the USA. Nonvertebral non-hip fractures need more attention, which was also recognised by the European regulatory bodies that approve use of anti-osteoporotic drugs.Prijelomi su najozbiljnija posljedica osteoporoze. Iako čine većinu svih fraktura, nevertebralne frakture osim kuka rijetko se prepoznaju kao značajne. Najčešće lokalizacije tih prijeloma su: distalni dio radijusa, proksimalni dio humerusa, rebra, klavikula i zdjelica. Prema rezultatima iz placebo-grupa III. faze velikih kliničkih ispitivanja raspon njihove incidencije iznosi između 4,9 % i 12,0 %. Prema podacima bolničkog pobolijevanja za 2006. g. u Hrvatskoj, među 15 vodećih ozljeda u dobnoj grupi 60 i više godina 23,7 % bile su periferne frakture osim kuka. Čimbenici rizika za nevertebralne frakture osim onih kuka slični su kao i za druge osteoporotske frakture gdje središnje mjesto imaju niska mineralna gustoća kosti i prethodne frakture. Ove frakture imaju velik utjecaj na kvalitetu `ivota, a njihovi su troškovi vrlo visoki, tako da u SAD-u iznose čak 36.9 % svih nacionalnih medicinskih troškova. Nevertebralne frakture osim kuka zahtijevaju veću pozornost, što su i prepoznala europska regulatorna tijela koja odobravaju upotrebu antiosteoporotskih lijekova