Cost-effectiveness of osteoporosis screening strategies for hip fracture prevention in older Chinese people: a decision tree modeling study in the Mr. OS and Ms. OS cohort in Hong Kong.

Despite the high costs of hip fracture, many governments provide limited support for osteoporosis screening. We demonstrated that osteoporosis screening by dual-energy X-ray absorptiometry (DXA) with or without pre-screening by Fracture Risk Assessment Tool (FRAX) or calcaneal ultrasound are more cost-effective than no screening in Chinese people aged 65 or over in Hong Kong. INTRODUCTION: To examine the cost-effective potential osteoporosis screening strategies for hip fracture prevention in Hong Kong. METHODS: Decision tree models were constructed to evaluate the cost per quality-adjusted life years (QALYs) of the different osteoporosis screening strategies followed by subsequent 5-year treatment with alendronate compared to no screening (but treat if a hip fracture occurs). The multiple osteoporosis screening strategies were composed of alternative tests and initiation age groups were evaluated with a 10-year horizon, and treatment were assigned if central dual-energy X-ray absorptiometry (DXA) T-score (at either the hip or spine) is - 2.5 or less. Strategies included DXA for all people and pre-screening with the Fracture Risk Assessment Tool (FRAX) at specific thresholds or by calcaneal quantitative ultrasonography (QUS) before taking DXA examination. All the model inputs were based on the Mr. OS and Ms. OS Hong Kong cohort; data are obtained from the Social Welfare Department or the published literature. RESULTS: All of the screening strategies, including the universal screening with DXA and the pre-screening with FRAX or QUS before DXA, were consistently more cost-effective than no screening for people aged 65 years old or over. One-way sensitivity analysis with a more optimistic assumption on treatment adherence or inclusion of other major osteoporotic fractures did not change the results materially. Probabilistic sensitivity analyses showed a dominant role of pre-screening with FRAX followed by subsequent osteoporosis drug treatment in people aged 70 years old or over in Hong Kong. CONCLUSIONS: Osteoporosis screening strategies based on DXA with or without pre-screening are more cost-effective compared to no screening for Chinese people aged 65 or over in Hong Kong.

Reductions in all-cause and cause-specific mortality among HIV-infected individuals receiving antiretroviral therapy in British Columbia, Canada: 2001-2012.

OBJECTIVES: Since 2006, the British Columbia HIV/AIDS Drug Treatment Program (DTP) has expanded enrolment and dramatically increased its number of participants. We examined the effect this expansion has had on the underlying cause of death in HIV-infected individuals. METHODS: We analysed data from participants aged 18 years and older in the DTP to measure 2-year mortality rates and causes of death from 2001 to 2012. We conducted tests of trend for all-cause and cause-specific mortality, and compared demographics and characteristics of individuals. Cox proportional hazard models were used to determine the risk of death. RESULTS: A total of 8185 participants received antiretroviral therapy (ART) during the study period. Mortality declined from 3.88 per 100 person-years (PY) in 2001-2002 to 2.15 per 100 PY in 2011-2012 (P = 0.02). There were significant decreases in HIV-related deaths (2.34 to 0.56 per 100 PY; P = 0.02) and deaths attributable to chronic liver disease (0.20 to 0.09 per 100 PY; P = 0.01), cardiovascular disease (0.24 to 0.05 per 100 PY; P = 0.03) and suicides (0.47 to 0 per 100 PY; P = 0.003). Multivariate models, adjusted for age, gender, history of injecting drug use, AIDS diagnoses and baseline CD4 cell counts, demonstrated that initiation of ART in all time periods after 2001-2002 was independently associated with reduced mortality (P < 0.001). CONCLUSIONS: We observed declines in HIV-related mortality and certain non-HIV-related causes of death among participants in the BC DTP from 2001 to 2012. These findings suggest that there may be broader benefits to the increasingly liberal HIV treatment guidelines, including reductions in death caused by cardiovascular disease and chronic liver disease.

Tenofovir-based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir.

Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies--tenofovir (TDF) monotherapy and combination therapy of ETV+TDF--in CHB patients with ETV partial virological response. We conducted a retrospective study of 68 patients who had partial virological response to ETV, defined as having detectable HBV DNA following at least 12 months of ETV, and were switched to TDF monotherapy (n = 25) or ETV+TDF (n = 43). Patients were seen in seven US liver/community-based clinics and started on ETV between 2005 and 2009. The majority of patients were male; the vast majority were Asian and had positive hepatitis B e antigen (HBeAg). Patients in both groups had similar pretreatment characteristics. Complete viral suppression (CVS) rates with TDF monotherapy and ETV+TDF were similar after 6 months (71% vs 83%, P = 0.23) and 12 months (86% vs 84%, P = 0.85), and there was no statistically significant difference in CVS rates even when only patients with higher HBV DNA levels at switch (>1000 IU/mL) were evaluated. Multivariate analysis indicated that ETV+TDF was not an independent predictor of CVS compared to TDF monotherapy (OR = 1.19, P = 0.63). In conclusion, TDF monotherapy and ETV+TDF are comparable in achieving CVS in CHB patients with partial virological response to ETV. Long-term alternate therapy with one pill (TDF monotherapy) vs two pills (ETV+TDF) could lead to lower nonadherence rates and better treatment outcomes.

Modelling clinical progression and health care utilization of HIV-positive patients in British Columbia prior to death.

OBJECTIVES: The extent to which clinical progression of HIV-positive patients leads to an increase in health care utilization, especially prior to their death, is unknown. Thus, we modelled trends in CD4 cell count and emergency department utilization and the likelihood of an emergency department visit leading to a transfer to an acute care-level facility prior to a patient's death from nonaccidental causes. METHODS: Eligible patients initiated highly active antiretroviral therapy (HAART) in British Columbia between August 1996 and June 2006 (n = 457). Patients were followed until their death, which occurred on or before 30 June 2007 (period in which the emergency department visit data were available). Trends were modelled using generalized mixed effects. RESULTS: Patients experienced a significantly steep decline in CD4 cell count and a corresponding increase in the number of emergency department visits and transfers to acute-level facilities in the 5 years prior to death. For every 6-month interval prior to death, the CD4 cell count decreased by 13.22 cells/µL, the risk of experiencing an emergency department visit increased by 9%, and among those ever admitted, the odds ratio of being transferred to an acute care-level facility increased by 3%. CONCLUSIONS: We showed that patients experienced a steep decline in CD4 cell count, which was associated with an increase in health care utilization prior to their death. These findings highlight the substantial residual avoidable burden that unsuccessfully managed HIV disease poses, even in the HAART era. Further strategies to enhance sustained and successful engagement in care are urgently needed to mitigate high health care utilization.

Orolingual angioedema after alteplase therapy of acute ischaemic stroke: incidence and risk of prior angiotensin-converting enzyme inhibitor use.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) is an uncommon but potentially life-threatening complication of treatment with recombinant tissue plasminogen activator (rt-PA; alteplase) during acute ischaemic stroke. This study aimed to determine the incidence of rt-PA-related OA in an Asian stroke population and the risk of pre-stroke anti-hypertensive drug use for development of this complication. METHODS: A multi-center stroke registry was used to identify the pre-stroke medications of acute ischaemic stroke patients receiving intravenous rt-PA from January 2002 to December 2013. The clinical manifestations of rt-PA-related OA were recorded and the incidence of this complication was determined. The risks of pre-stroke use of different anti-hypertensive agents for the occurrence of rt-PA-related OA were determined from this study and from a meta-analysis. RESULTS: A total of 559 patients received intravenous rt-PA over a 12-year period. Five patients (two males) developed OA after rt-PA administration. The incidence of OA amongst these patients was 0.89% (95% confidence interval 0.29%-2.09%), which was lower than that obtained by meta-analysis (1.9%). Amongst pre-stroke anti-hypertensive medications, angiotensin-converting enzyme (ACE) inhibitors were found in this study to have the highest relative risk for rt-PA-related OA (17.1; 95% confidence interval 3.0-96.9). Meta-analysis also revealed that pre-stroke use of ACE inhibitors was associated with a high relative risk of OA after intravenous rt-PA (12.9; 95% confidence interval 4.5-37.0). CONCLUSIONS: The incidence of rt-PA-related OA in the Asian population is lower than that in the Caucasian population. Pre-stroke use of ACE inhibitors significantly increases the risk of this complication.

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Neighborhood Social Cohesion Associates with Loneliness Differently among Older People According to Subjective Social Status.

OBJECTIVES: To examine whether neighborhood social cohesion can alleviate the negative impact of low subjective social status on feelings of loneliness. DESIGN: Cross-sectional study. SETTING: Community, Hong Kong. PARTICIPANTS: Older people who participated in a cohort study on osteoporosis and general health in Hong Kong (MrOs study). METHODS: Data were sourced from the 14-year follow-up data of the MrOs study. Loneliness was measured using the 6-item De Jong Gierveld Loneliness Scale. Neighborhood social cohesion was measured by the Hong Kong version of Neighborhood Cohesion Instrument. Linear regression models were used to examine the associations between neighborhood social cohesion and loneliness, controlled for age, sex, marital status, educational level, lifestyle, number of diseases, and maximum lifetime income. The analyses were stratified by subjective social status as measured by a 10-rung self-anchoring scale. RESULTS: 1,037 participants with a mean age of 83 years were included in the study, of whom 72%, 83%, and 64% were classified as at risk of overall loneliness, emotional loneliness, and social loneliness, respectively. Those who were classified as at risk of overall loneliness reported lower subjective social status and had lower levels of neighborhood social cohesion. Linear regression models showed that higher levels of neighborhood social cohesion were associated with lower levels of overall and social loneliness. Stratified analyses showed that the associations between neighborhood social cohesion and loneliness vary across subjective social status groups. Among those with low/middle social status ranking, higher levels of neighborhood social cohesion were associated with lower overall (low-ranking B=-0.111, p=0.001; middle-ranking B=-0.057, p=0.026) and social (low-ranking B=-0.093, p<0.001; middle-ranking B=-0.073, p<0.001) loneliness scores. Among those with high ranking, higher levels of neighborhood social cohesion were associated with lower overall (B=-0.099, p=0.041) and emotional (B=-0.056, p=0.017) loneliness scores, but the associations became insignificant when controlling for maximum lifetime income. CONCLUSIONS AND IMPLICATIONS: Neighborhood social cohesion may operate differently in different social ranking groups. Interventions to alleviate feelings of loneliness should be subjective social status specific.

Fine mapping of the 9q31 Hirschsprung's disease locus.

Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.

Non-medically supervised treatment interruptions among participants in a universally accessible antiretroviral therapy programme.

BACKGROUND: We examined clinical outcomes, patient characteristics and trends over time of non-medically supervised treatment interruptions (TIs) from a free-of-charge antiretroviral therapy (ART) programme in British Columbia (BC), Canada. METHODS: Data from ART-naïve individuals > or =18 years old who initiated triple combination highly active antiretroviral therapy (HAART) between January 2000 and June 2006 were analysed. Participants having > or =3 month gap in HAART coverage were defined as having a TI. Cox proportional hazards modelling was used to examine factors associated with TIs and to examine factors associated with resumption of treatment. RESULTS: A total of 1707 participants were study eligible and 643 (37.7%) experienced TIs. TIs within 1 year of ART initiation decreased from 29% of individuals in 2000 to 19% in 2006 (P<0.001). TIs were independently associated with a history of injection drug use (IDU) (P=0.02), higher baseline CD4 cell counts (P<0.001), hepatitis C co-infection (P<0.001) and the use of nelfinavir (NFV) (P=0.04) or zidovudine (ZDV)/lamivudine (3TC) (P=0.009) in the primary HAART regimen. Male gender (P<0.001), older age (P<0.001), AIDS at baseline (P=0.008) and having a physician who had prescribed HAART to fewer patients (P=0.03) were protective against TIs. Four hundred and eighty-eight (71.9%) participants eventually restarted ART with male patients and those who developed an AIDS-defining illness prior to their TI more likely to restart therapy. Higher CD4 cell counts at the time of TI and unknown hepatitis C status were associated with a reduced likelihood of restarting ART. CONCLUSION: Treatment interruptions were associated with younger, less ill, female and IDU participants. Most participants with interruptions eventually restarted therapy. Interruptions occurred less frequently in recent years.

Health care services utilization stratified by virological and immunological markers of HIV: evidence from a universal health care setting.

OBJECTIVE: The aim of the study was to determine rates of utilization of in-patient, out-patient and laboratory services stratified by virological and immunological markers of HIV disease among patients on antiretroviral treatment in British Columbia, Canada. METHODS: We estimated resource utilization for in-patient visits, out-patient visits, and laboratory tests among patients initiating antiretroviral treatment between 1 April 1994 and 31 December 2000, with follow-up to 31 March 2001. Resource use was stratified by CD4 cell count and plasma HIV viral load (pVL) at the time of utilization and rates per 100 patient-years were calculated for each health care resource. RESULTS: A total of 2718 patients were included in our analyses. The overall rates of in-patient visits, out-patient visits, and laboratory tests were 902, 3001 and 840 per 100 patient-years, respectively. Utilization was higher for patients with low CD4 cell counts and high pVLs when compared with patients with high CD4 cell counts and low pVLs. CONCLUSIONS: Patients with low CD4 cell counts and high pVLs had the highest use of health care services. Regular follow-up with health care providers in an out-patient setting, allowing for proper monitoring and maintenance of HIV care, is important in minimizing unnecessary and potentially costly in-patient care.

Time-resolved three-dimensional concentration measurements in a gas jet.

Turbulence can greatly influence reaction and heat transfer rates in fluids. The topology of the three-dimensional interface between mixing fluids directly determines the location and degree of reaction. The time-resolved measurement of the three-dimensional concentration field in a transitional gas jet is reported. A thin sheet of laser light was swept through the flow volume by a rotating mirror in a time brief enough that motion of the gas was minimal. The light sheet illuminated different parallel planes within the flow, and light scattered from particles seeding the jet was imaged onto a detector. The series of two-dimensional measurements made during one scan of the flow volume constituted a full three-dimensional mapping of structures within the flow. Computer graphics software was used to reconstruct and visualize three-dimensional surfaces of constant concentration and the magnitude of the concentration gradient vector over such surfaces.

Development of a marine fish model for studying in vivo molecular responses in ecotoxicology.

A protocol for fixation and processing of whole adult marine medaka (Oryzias melastigma) was developed in parallel with in situ hybridization (ISH) and immunohistochemistry (IHC) for molecular analysis of in vivo gene and protein responses in fish. Over 200 serial sagittal sections (5microm) can be produced from a single adult medaka to facilitate simultaneous localization and quantification of gene-specific mRNAs and proteins in different tissues and subcellular compartments of a single fish. Stereological analysis (as measured by volume density, V(v)) was used to quantify ISH and IHC signals on tissue sections. Using the telomerase reverse transcriptase (omTERT) gene, omTERT and proliferating cell nuclear antigen (PCNA) proteins as examples, we demonstrated that it is possible to localize, quantify and correlate their tissue expression profiles in a whole fish system. Using chronic hypoxia (1.8+/-0.2 mgO(2)L(-1) for 3 months) as an environmental stressor, we were able to identify significant alterations in levels of omTERT mRNA, omTERT protein, PCNA (cell proliferation marker) and TUNEL (apoptosis) in livers of hypoxic O. melastigma (p<0.05). Overall, the results suggest that O. melastigma can serve as a model marine fish for assessing multiple in vivo molecular responses to stresses in the marine environment.