A secular increase in BMD in Chinese women.

Population-based studies have revealed a decline in the incidence of age-adjusted hip fractures in southern Chinese women during the past decade. To determine whether there was a secular change in population characteristics that accounted for this decline, we compared the bone mineral density (BMD) and lifestyle habits of two cohorts of women who were more than 50 years of age and who were recruited from 1995 to 2000 and 2005 to 2010. The BMD levels in the 2005-2010 cohort were significantly higher at the spine and hip and ranged from 3.6 to 17.8% among the different age groups. Additionally, a significantly lower prevalence of subjects with osteoporosis and osteopenia was observed. Longer reproductive years, higher levels of physical activity, higher estradiol and 25(OH) vitamin D levels, and lower alkaline phosphatase levels were found in the 2005-2010 cohort. After adjusting for bone-determining factors, significant differences were detected in the BMD levels at the lumbar spine, femoral neck, and total hip (4.17, 9.02, and 9.34%, respectively) in women >50 years of age but not in women ≤50 years of age. The secular increase in BMD and healthier lifestyles most likely led to the decline in the incidence of age-adjusted fractures.

A novel respiratory tracking system for smart-gated PET acquisition.

PURPOSE: In this study, the authors validated a novel respiratory tracking device, the multidimensional respiratory tracking (MDRT) system, that was designed to assist in correcting for respiratory motion in PET/CT images. The authors also investigated a novel PET acquisition technique, smart gating (SG), that enables to acquire motion-free PET data prospectively, with minimum user interference and with no additional postprocessing of the PET data. METHODS: MDRT uses visual tracking techniques to track simultaneously the two-dimensional (in the vertical plane) motion of multiple fiducial markers using a standard video camera. A threshold window is set at the breathing amplitude of interest using the MDRT GUI. A trigger is generated at a rate of 250 Hz as long as the breathing signal is within the threshold window. The triggers are fed into the PET scanner to initialize one single bin of a gated acquisition every 4 ms. No triggers are delivered as the breathing signal drifts outside the threshold window. Consequently, PET data are acquired only whenever the breathing signal is confined within the amplitude threshold window, thus resulting into a motion-free image set. The accuracy of MDRT in tracking the breathing signal was assessed (1) by comparing the period of an oscillating phantom, as measured by MDRT, to that measured with a photogate timer and (2) by comparing the MDRT output to that of the real-time position management (RPM) in ten patients. The SG PET/CT acquisition was validated in phantoms and in two stereotactic body radiosurgery (SBRS) lung DIBH-PET/CT patients. RESULTS: MDRT was in agreement with the photogate timer in determining the period of motion to less than 2%. The percent errors between MDRT and RPM in the positions of the peaks and troughs of the ten patients' breathing signals were within 10%. In phantoms, SG technique enables to correct for motion-induced artifacts in the PET images and improve the accuracy of PET quantitation. For the SBRS application, in one patient, the patient's CT lesion was not detected in the corresponding clinical PET images, while it exhibited an SUV of 1.8 in the DIBH image set. In the second patient, DIBH-PET images showed an improved PET-to-CT spatial matching and a 52% increase in the lesion SUV. CONCLUSIONS: MDRT has been shown to be accurate in tracking breathing motion and assisted in implementing a smart-gating PET acquisition technique that allowed to acquire prospectively motion-free PET images.

A transient radio source consistent with a merger-triggered core collapse supernova.

A core collapse supernova occurs when exothermic fusion ceases in the core of a massive star, which is typically caused by exhaustion of nuclear fuel. Theory predicts that fusion could be interrupted earlier by merging of the star with a compact binary companion. We report a luminous radio transient, VT J121001+495647, found in the Very Large Array Sky Survey. The radio emission is consistent with supernova ejecta colliding with a dense shell of material, potentially ejected by binary interaction in the centuries before explosion. We associate the supernova with an archival x-ray transient, which implies that a relativistic jet was launched during the explosion. The combination of an early relativistic jet and late-time dense interaction is consistent with expectations for a merger-driven explosion.

The Financial Impact on Reimbursement of Moderately Hypofractionated Postoperative Radiation Therapy for Breast Cancer: An International Consortium Report.

AIMS: Moderately hypofractionated breast irradiation has been evaluated in several prospective studies, resulting in wide acceptance of shorter treatment protocols for postoperative breast irradiation. Reimbursement for radiation therapy varies between private and public systems and between countries, impacting variably financial considerations in the use of hypofractionation. The aim of this study was to evaluate the financial impact of moderately hypofractionated breast irradiation by reimbursement system in different countries. MATERIALS AND METHODS: The study was designed by an international group of radiation oncologists. A web-questionnaire was distributed to representatives from each country. The participants were asked to involve the financial consultant at their institution. RESULTS: Data from 13 countries from all populated continents were collected (Europe: Denmark, France, Italy, the Netherlands, Spain, UK; North America: Canada, USA; South America: Brazil; Africa: South Africa; Oceania: Australia; Asia: Israel, Taiwan). Clinicians and/or departments in most of the countries surveyed (77%) receive remuneration based on the number of fractions delivered to the patient. The financial loss per patient estimated resulting from applying moderately hypofractionated breast irradiation instead of conventional fractionation ranged from 5-10% to 30-40%, depending on the healthcare provider. CONCLUSION: Although a generalised adoption of moderately hypofractionated breast irradiation would allow for a considerable reduction in social and economic burden, the financial loss for the healthcare providers induced by fee-for-service remuneration may be a factor in the slow uptake of these regimens. Therefore, fee-for-service reimbursement may not be preferable for radiation oncology. We propose that an alternative system of remuneration, such as bundled payments based on stage and diagnosis, may provide more value for all stakeholders.

Clonal gammopathies following alemtuzumab-based reduced intensity conditioning haematopoietic stem cell transplantation: association with chronic graft-versus-host disease and improved overall survival.

The presence of clonal gammopathies (CG) has been reported following both conventional myeloablative and autologous haematopoietic stem cell transplantation (HSCT). We monitored the occurrence of CG in a cohort of patients with myeloid malignancies receiving FBC (fludarabine-busulphan-alemtuzumab)-based reduced intensity conditioned (RIC) HSCT, and assessed its correlation with infections, graft-versus-host disease (GvHD) and survival. Serial serum protein electrophoresis was analysed in a total of 138 patients and CG were detected in 49 patients (36%). The predominant Ig isotype was IgG (82%). There was no difference in the incidence of viral infections between patient groups. However, patients with gammopathies were more likely to have had prior chronic GvHD (OR 2.7, 95% CI 1.3-5.5, P<0.001). On multivariate analysis, the only factors that were found to influence overall survival (OS) were presence of gammopathies, which was associated with an improved OS (OR 0.35 95% CI 0.14-0.86, P=0.02) as well as disease stage, patients with advanced disease having a higher risk of death (OR 2.20 95% CI 1.18-4.11, P=0.02). Disease stage was the only variable that influenced relapse incidence on multivariate analysis (OR 4.22 95% CI 1.82-9.78, P<0.01). Clonal gammopathies are a frequent but benign occurrence following alemtuzumab-based RIC HSCT, and their appearance may define a group of patients with a favourable overall outcome.

Long-distance movement of phosphate starvation-responsive microRNAs in Arabidopsis.

Plant microRNAs are small RNAs that are important for genetic regulation of processes such as plant development or environmental responses. Specific microRNAs accumulate in the phloem during phosphate starvation, and may act as long-distance signalling molecules. We performed quantitative PCR on Arabidopsis hypocotyl micrograft tissues of wild-type and hen1-6 mutants to assess the mobility of several phosphate starvation-responsive microRNA species. In addition to the previously confirmed mobile species miR399d, the corresponding microRNA* (miR399d*) was identified for the first time as mobile between shoots and roots. Translocation by phosphate-responsive microRNAs miR827 and miR2111a between shoots and roots during phosphate starvation was evident, while their respective microRNA*s were not mobile. The results suggest that long-distance mobility of microRNA species is selective and can occur without the corresponding duplex strand. Movement of miR399d* and root-localised accumulation of miR2111a* opens the potential for persisting microRNA*s to be mobile and functional in novel pathways during phosphate starvation responses.

A radio counterpart to a neutron star merger.

Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.

Illuminating gravitational waves: A concordant picture of photons from a neutron star merger.

Merging neutron stars offer an excellent laboratory for simultaneously studying strong-field gravity and matter in extreme environments. We establish the physical association of an electromagnetic counterpart (EM170817) with gravitational waves (GW170817) detected from merging neutron stars. By synthesizing a panchromatic data set, we demonstrate that merging neutron stars are a long-sought production site forging heavy elements by r-process nucleosynthesis. The weak gamma rays seen in EM170817 are dissimilar to classical short gamma-ray bursts with ultrarelativistic jets. Instead, we suggest that breakout of a wide-angle, mildly relativistic cocoon engulfing the jet explains the low-luminosity gamma rays, the high-luminosity ultraviolet-optical-infrared, and the delayed radio and x-ray emission. We posit that all neutron star mergers may lead to a wide-angle cocoon breakout, sometimes accompanied by a successful jet and sometimes by a choked jet.

Early relapse post autologous transplant is a stronger predictor of survival compared with pretreatment patient factors in the novel agent era: analysis of the Singapore Multiple Myeloma Working Group.

The clinical outcome of multiple myeloma is heterogeneous. Both the depth of response to induction and transplant as well as early relapse within a year are correlated with survival, but it is unclear which factor is most relevant in Southeast Asian patients with multiple myeloma. We retrospectively analyzed outcomes of 215 patients who were treated with upfront autologous transplant in Singapore between 2000 and 2014. In patients who received novel agent (NA)-based induction, achieving only partial response (PR) post-induction was associated with poorer OS (HR 1.95, P=0.047) and PFS (HR 2.9, P<0.001), while achieving only PR post-transplant was strongly correlated with both OS (HR 3.3, P=0.001) and PFS (HR 7.6, P<0.001), compared with patients who achieved very good partial response (VGPR) or better. Early relapse was detected in 18% of all patients, although nearly half had initially achieved VGPR or better post-transplant. Early relapse after NA-based induction led to significantly shorter OS (median 22 months vs not reached, P<0.001), and was strongly associated with OS (HR 13.7, P<0.001). The impact of suboptimal post-transplant response and early relapse on survival may be more important than pretransplant factors, such as International Staging System or cytogenetics, and should be considered in risk stratification systems to rationalize therapy.

HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis.

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

Genetic and environmental determinants of bone mineral density in Chinese women.

BMD is a complex trait determined by genetic and lifestyle factors. To assess the genetic and environmental determinants of BMD in southern Chinese women, we studied a community-based cohort of 531 pre- and postmenopausal southern Chinese women and assessed the influence of 12 candidate gene loci and lifestyle risk factors on spine and hip BMD. The candidate genes studied include estrogen receptor alpha (ESR1) and beta (ESR2), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Ialpha1 (COLIA1), and LDL receptor-related protein 5 (LRP5). Social, medical, reproductive history, dietary habits and lifestyle factors were determined using a structured questionnaire. Single nucleotide polymorphisms (SNPs) of the COLIA1 and LRP5 gene in Chinese were determined by direct sequencing. Nucleotide (nt) -1363C/G and -1997 G/T of COLIA1, nt 266A/G, 2220C/T and 3989C/T of LRP5 gene were analyzed. Using stepwise multiple linear regression analyses, body weight was the strongest predictor for BMD in premenopausal women (n = 262), which accounted for 15.9% of the variance at the spine, 20% at femoral neck, 17.1% at trochanter, 24.3% at total hip and 10.9% at the Ward's triangle. Other significant predictors were ESR1 Ivs1-397T/C genotype (2.2% at the spine); LRP5 2220C/T genotype (1.3% at the spine, 1.6% at the trochanter); LRP5 266A/G genotype (1.1% at Ward's triangle); age at menarche (1.3% at trochanter) and age (2.0% at Ward's triangle). As for postmenopausal women (n = 269), body weight ( approximately 25% at various sites) and age (approximately 16% at femoral neck, trochanter, total hip and Ward's triangle sites) were the strongest predictors of BMD. Other significant predictors were age at menarche (4.4% at spine, 0.7% at femoral neck, 1.4% at trochanter, and 1.4% at Ward's triangle); weight bearing physical activity (2.1% at trochanter and 1% at total hip); calcium intake (1.1% at femoral neck, 0.9% at trochanter, and 1.7% at total hip) ; height (0.7% at trochanter); and ESR2 1082A/G genotype (0.8% at trochanter). We conclude that BMD at various sites and at different time span of a woman is modified by different genetic and lifestyle factors, suggesting that BMD is highly dependent on gene-environmental interactions.

Estrogen receptor beta gene polymorphisms are associated with higher bone mineral density in premenopausal, but not postmenopausal southern Chinese women.

Bone mineral density (BMD), the main determining risk factor for osteoporotic fractures, has a strong genetic component. Estrogen and its receptors play a critical role in both skeletal maturity and bone loss. We investigated the association between dinucleotide (cytosine-adenine; CA) repeat polymorphisms located in the flanking region of the estrogen receptor beta gene and bone mineral density (BMD) in 325 healthy southern Chinese women. BMD at the lumbar spine and hip region were measured using dual-energy X-ray absorptiometry (DEXA). The number of the repeats observed in our population ranged from 16 to 28. After adjusting for age, height, weight, and years of estrogen exposure, we observed that premenopausal subjects (n = 120) bearing at least one allele of 20 CA repeats had significantly higher BMD at the L2-4 lumbar spine (1.049 +/- 0.016 vs. 0.984 +/- 0.015; p = 0.01), total hip (0.836 +/- 0.014 vs. 0.813 +/- 0.013; p < 0.02), femoral neck (0.773 +/- 0.014 vs. 0.728 +/- 0.013; p = 0.02), trochanter (0.665 +/- 0.013 vs. 0.614 +/- 0.012; p = 0.01), and Ward's triangle (0.715 +/- 0.017 vs. 0.651 +/- 0.016; p = 0.02). There was no difference in the vertebral area of L-3 and femoral neck width in these premenopausal women with or without 20 CA repeats. However, in postmenopausal women (n = 205), Estrogen receptor beta (ER beta) gene polymorphisms were not related to BMD at any skeletal site. We conclude that ER beta gene polymorphisms are associated with higher BMD in premenopausal women, suggesting that the ER beta gene may have a modulatory role in bone metabolism in young adulthood.

Immune tolerance therapy for haemophilia.

The development of anti-factor VIII and anti-factor IX allo-antibodies in haemophilia A and B, respectively, remains a serious complication of treatment for these two X-linked haemostatic disorders, with major clinical and economic consequences. Treatment of this potentially fatal complication remains one of the greatest challenges facing haematologists at the beginning of the 21st century. Immune tolerance induction (ITI) therapy has been generally accepted as the best available treatment, extinguishing the inhibitor and permitting a resumption of standard dosing schedules. Although there have been several established protocols for ITI therapy developed over the last quarter century, the optimal scheme in terms of safety, clinical efficacy and pharmacoeconomic considerations has yet to be determined.

Reduced-intensity rituximab-BEAM-CAMPATH allogeneic haematopoietic stem cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions.

The indolent non-Hodgkin's lymphomas are theoretically curable through allogeneic haematopoietic stem cell transplantation (allo-HSCT). The applicability of standard conditioning allo-HSCT is, however, restricted by its toxicity. Recently, reduced-intensity conditioning regimens have demonstrated efficacy with significantly reduced early morbidity and mortality. We examined the safety and efficacy of rituximab-BEAM-CAMPATH as reduced-intensity conditioning for allo-HSCT in follicular lymphomas. Minimal residual disease was assessed by polymerase chain reaction (PCR) for bcl-2/IgH translocations, and chimerism by X,Y-FISH or PCR amplification of short tandem repeat sequences. At a median follow-up of 521 days (371-719), four of five patients were alive and three were in complete molecular remission. Three patients required pre-emptive treatment for CMV reactivation. One succumbed to a perforated viscus and one had slowly progressive disease. A graft-versus-lymphoma effect was demonstrable and quantitative PCR for bcl-2/IgH may allow better accuracy in scheduling post-allograft rituximab and/or donor lymphocyte infusions. Although follow-up is short, reduced-intensity allo-HSCT with BEAM-CAMPATH conditioning appears to be safe, effective in inducing a molecular remission and is potentially curative. Further recruitment and much longer follow-up will be necessary to determine if this impacts favourably upon disease-free and overall survival.

Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT).

An idiopathic hyperammonaemia syndrome has been reported in, and following chemotherapy for, various haematological malignancies as well as following bone marrow transplantation. It should be considered in the differential diagnosis of any neurological deterioration, and we describe a further case associated with an allogeneic peripheral blood progenitor cell transplant (allo-PBPCT).

Fatal donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disorder following reduced intensity volunteer-unrelated bone marrow transplant for myelodysplastic syndrome.

Post-transplant lymphoproliferative disorders (PTLD) are a well recognised complication of conventional haemopoietic stem cell transplantation (HSCT). Reduced intensity HSCT involves intensive immunosuppression to permit engraftment. Thirty reduced intensity transplants with the FBC (fludarabine 150 mg/m2, busulphan 8 mg/m2, CAMPATH-1H 100 mg) protocol have been performed at our centre, with one confirmed EBV-positive PTLD. The female recipient developed a perforated viscus day +191 following HSCT from a volunteer unrelated male donor. A large caecal mass and a retroperitoneal abscess were excised, revealing an EBV-positive diffuse large B cell lymphoma confirmed by FISH to be of donor origin. More experience is required before the risk of PTLD in this setting can be assessed.

An ion-selective electrode system for continuously monitoring cyanide ion, based on a computerized gran plot technique.

A procedure for the continuous monitoring of cyanide ion with an ion-selective electrode is described, based on the use of the Gran plot standard-addition technique. The mean concentration of the sample reservoir is measured continuously during a time span of 6 min. The use of a computer programme facilitates calculation of the results. Because the combined weights of several data points are used to calculate the unknown concentration, random errors tend to be eliminated and in addition there is no need for reference calibration curves.

A fully automated procedure for the determination of sodium hypochlorite and hydrogen peroxide, based on the use of a porous catalytic silver electrode.

A new approach to the automated determination of sodium hypochlorite and hydrogen peroxide is described, based on the use of a porous catalytic silver electrode. The principle of both methods involves the quantitative liberation of oxygen, which is measured coulometrically by the electrode. The procedures are suitable for the continuous monitoring of the contents of bleaching baths.

Clinical presentation of herpes zoster in a Singapore hospital.

BACKGROUND: There is a direct correlation between increasing age and incidence of herpes zoster. There is an increased risk of complications in the elderly and the immunocompromised. OBJECTIVE: To study the clinical epidemiology of hospitalised patients with herpes zoster. METHODS: Medical records of all patients hospitalised with zoster were respectively analysed. RESULTS: Sixty-seven patients (3% of total admissions) were studied. There were 35 males and 32 females with a mean age of 50.35 +/- 21.71. There was an increased proportion of older patients in the study cohort. Nineteen patients (28.4%) were immunocompromised with malignancy occurring in 9 patients. Thirteen had been on cytotoxic and/or steroid therapy. The commonest symptoms were rash, pain and fever. Eighty-five percent of the patients had complications (bacterial super-infection in (61%), dissemination (31%), ocular involvement (5%) and post-herpetic neuralgia (13.4%). There was an increasing frequency of duration of pain with increasing age in the patients with post-herpetic neuralgia. Forty-three patients were treated with acyclovir. The median time to healing of lesions was 11 days. The 41 patients with bacterial super-infection received antibiotics with median time to healing of 12 days. CONCLUSION: Increasing age and immunocompromised state appear to be risk factors for developing herpes zoster in hospitalised patients.