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.

Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium.

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies.

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

Health-care providers' perception of knowledge, skills and preparedness for disaster management in primary health-care centres in Jordan.

This survey in primary health-care centres in north Jordan aimed to assess health-care providers' perceptions of their knowledge, skills and preparedness for disaster management. A multistage random sample was used to recruit nurses and physicians from 57 health centres. A total of 207 participants completed the Arabic version of the Disaster Preparedness Evaluation Tool. Participants perceived themselves as having moderate preparation for disaster management [mean score 74.9 (SD 21.6)], moderate knowledge [mean 49.9 (SD 12.3)] and moderate to weak skills in disaster management [mean 35.3 (SD 12.7)]. Significant differences were revealed in participants' perceptions of their disaster preparedness, knowledge and skills according to their sex, specialty and exposure to a real disaster situation. Further education and training courses are needed to enhance providers' preparedness for disaster management in Jordan.

Evaluation of dental extractions, suturing and INR on postoperative bleeding of patients maintained on oral anticoagulant therapy.

OBJECTIVES: To examine the consequences of temporary withdrawal of warfarin and/or suturing on bleeding and healing pattern following dental extractions. METHODS: Two hundred and fourteen patients on long-term oral anticoagulation (warfarin) therapy scheduled for dental extraction were randomly divided into four groups: no suturing and discontinued (group 1) or continued warfarin (group 2), and suturing and discontinued (group 3) or continued warfarin (group 4). International normalised ratio (INR) was determined at different time points (baseline, days 1, 3 and 7). RESULTS: Discontinuing warfarin reduced INR level significantly at day 1, which subsequently reached <1.5 in 96 out of 104 patients (group 1 and 3). Statistical comparisons among the different treatment groups did not reveal any significant difference regarding bleeding status or healing pattern. Interestingly, patients who received sutures showed higher but insignificant incidence of bleeding postoperatively compared to their respective controls. CONCLUSION: Dental extractions may be safely performed for patients on anticoagulation therapy provided the INR level is kept <3.0 and effective measures of local haemostasis are administered. The decision to suture should be made on case-by-case basis, as the trauma associated with soft tissue handling might outweigh its advantages in certain situations like simple extractions.

Distribution of atrial natriuretic peptide and its effects on contraction and intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rat.

The distribution of atrial natriuretic peptide (ANP) in blood plasma and cardiac muscle and its effects on ventricular myocyte contraction and intracellular free calcium concentration [Ca2+]i in the streptozotocin (STZ)-induced diabetic rat have been investigated. Blood plasma concentration and heart atrial and ventricular contents of ANP were significantly increased in STZ-treated rats compared to age-matched controls. STZ treatment increased the number of ventricular myocytes immunolabeled with antibodies against ANP. In control myocytes the percentage of cells that labeled positively and negatively were 17% versus 83%, respectively. However, in myocytes from STZ-treated rat the percentages were 52% versus 53%. Time to peak (TPK) shortening was significantly and characteristically prolonged in myocytes from STZ-treated rats (360+/-5 ms) compared to controls (305+/-5 ms). Amplitude of the Ca2+ transient was significantly increased in myocytes from STZ-treated rats compared to controls (0.39+/-0.02 versus 0.29+/-0.02 fura-2 RU in controls) and treatment with ANP reduced the amplitude of the Ca2+ transient to control levels. ANP may have a protective role in STZ-induced diabetic rat heart.

Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes.

CD4(+) (Th) and CD8(+) (Tc) T and NK lymphocytes can be divided into type 1 and 2 subsets according to their cytokine secretion profile. Studies on the role of lymphocyte subsets in human diseases have been hampered by the lack of stable surface markers to define them. Recently, we reported that ST2L and IL-18R are stably expressed on murine Th2 and Th1 cells, respectively. In this study, we generated Abs to human homologues of ST2L and IL-18R and tested them against Th1/Th2, Tc1/Tc2, and NK1/NK2 lines and PBMCs from healthy individuals. We show for the first time that ST2L and IL-18R are stable selective cell surface markers for human Th2/Tc2/NK2 and Th1/Tc1/NK1 lymphocytes, respectively. We then investigated PBMCs from HIV-infected patients and HIV-negative individuals, to test whether Abs to these two surface markers could be used directly to monitor lymphocyte subset distribution in human diseases. We found a clear Th1 to Th2 shift in the HIV-infected individuals, thus settling a long-standing controversy and include, for the first time, Tc and NK cells as well. Therefore, these cell surface molecules could serve as important determinants of the immune status of human diseases in general, and thereby could be useful for therapeutic monitoring and intervention.

Augmentation of bone mineral density in hirsute women.

Hirsutism is associated with both hyperandrogenism and oligomenorrhea or amenorrhea, which have opposing effects on bone mineral density (BMD). We tested the hypothesis that hyperandrogenism in hirsute women counteracts the osteopenic effects of menstrual dysfunction. Using dual energy x-ray absorptiometry, we measured BMD and total bone mineral content (BMC) in 32 young women referred for hirsutism. The control group consisted of 25 matched, nonhirsute women. Among the hirsute women, 21 reported regular menses, and 11 gave a history of oligomenorrhea; all members of the control group reported regular menses. Compared with controls, hirsute women had higher total BMD (1.202 +/- 0.02 vs. 1.116 +/- 0.02 g/cm2, P < 0.01), lumbar spine BMD (1.183 +/- 0.02 vs. 1.125 +/- 0.02 g/cm2, P < 0.01), and total BMC (2700 +/- 66 vs. 2400 +/- 70 g, P < 0.001). Serum total testosterone levels were similar, but androstenedione levels were higher (11.7 +/- 0.80 vs. 7.9 +/- 0.79 nmol/L, P < 0.005) and sex hormone binding globulin levels lower (22.0 +/- 3.0 vs. 57.6 +/- 8.5 nmol/L, P < 0.001) in hirsute women than controls. Oligomenorrheic hirsute women had higher BMD than nonhirsute women, although the augmentation was less pronounced than in eumenorrheic hirsute women. These results indicate that hirsutism is associated with higher bone density and mineral content, consistent with a net positive effect of hyperandrogenism on skeletal mass.