Elevated risk of multimorbidity post-COVID-19 infection: protective effect of vaccination.

BACKGROUND: It is unclear how the coronavirus disease 2019 (Covid-19) pandemic has affected multimorbidity incidence among those with one pre-existing chronic condition, as well as how vaccination could modify this association. AIM: To examine the association of Covid-19 infection with multimorbidity incidence among people with one pre-existing chronic condition, including those with prior vaccination. DESIGN: Nested case-control study. METHODS: We conducted a territory-wide nested case-control study with incidence density sampling using Hong Kong electronic health records from public healthcare facilities and mandatory Covid-19 reports. People with one listed chronic condition (based on a list of 30) who developed multimorbidity during 1 January 2020-15 November 2022 were selected as case participants and randomly matched with up to 10 people of the same age, sex and with the same first chronic condition without having developed multimorbidity at that point. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) of multimorbidity. RESULTS: In total, 127 744 case participants were matched with 1 230 636 control participants. Adjusted analysis showed that there were 28%-increased odds of multimorbidity following Covid-19 [confidence interval (CI) 22% to 36%] but only 3% (non-significant) with prior full vaccination with BNT162b2 or CoronaVac (95% CI -2% to 7%). Similar associations were observed in men, women, older people aged 65 or more, and people aged 64 or younger. CONCLUSIONS: We found a significantly elevated risk of multimorbidity following a Covid-19 episode among people with one pre-existing chronic condition. Full vaccination significantly reduced this risk increase.

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study.

To determine denosumab's effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. INTRODUCTION: After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among real-world postmenopausal women. METHODS: This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. RESULTS: In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52-0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. CONCLUSION: The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial. REGISTRATION: EnCePP registration number: EUPAS26372; registration date: 12/11/2018.

Hip fractures are preventable: a proposal for osteoporosis screening and fall prevention in older people.

Osteoporosis is highly prevalent but underdiagnosed and undertreated in Hong Kong. Fragility fractures associated with osteoporosis often result in loss of independence and increased mortality for home-dwelling patients, imposing a high socio-economic burden on society. This issue requires urgent attention given the rapid growth of the elderly population in Hong Kong by approximately 4.3% each year. To address this situation, a group of experts convened to discuss practical ways to reduce the burden of fractures and formulated three recommendations: first, all men (aged ≥70 years) and women (aged ≥65 years) should receive universal dual-energy X-ray absorptiometry assessment for osteoporosis. Second, all men (aged ≥70 years) and women (aged ≥65 years) with a fracture-risk assessment-derived 10-year risk (hip fracture with bone mineral density) ≥3% should receive ≥3 years of anti-osteoporotic treatment. Third, comprehensive structured assessment (including dual-energy X-ray absorptiometry) should be conducted in older patients with a history of falling. By implementing these recommendations, we estimate that we could prevent 5234 hip fractures in 10 years, an annual incidence reduction of approximately 7%, and save HK$425 million in direct medical costs plus substantial indirect savings. Ample clinical and cost-effectiveness data support these recommendations, and studies in Hong Kong and abroad could serve as models on how to implement them. We are confident that by applying these recommendations rigorously and systematically, a significant reduction in hip fractures in Hong Kong is achievable.

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.

Serum calcium and incident diabetes: an observational study and meta-analysis.

UNLABELLED: The study aimed to prospectively evaluate if serum calcium is related to diabetes incidence in Hong Kong Chinese. The results showed that serum calcium has a significant association with increased risk of diabetes. The result of meta-analysis reinforced our findings. INTRODUCTION: This study aimed to evaluate the association of serum calcium, including serum total calcium and albumin-corrected calcium, with incident diabetes in Hong Kong Chinese. METHODS: We conducted a retrospective cohort study in 6096 participants aged 20 or above and free of diabetes at baseline. Serum calcium was measured at baseline. Incident diabetes was determined from several electronic databases. We also searched relevant databases for studies on serum calcium and incident diabetes and conducted a meta-analysis using fixed-effect modeling. RESULTS: During 59,130.9 person-years of follow-up, 631 participants developed diabetes. Serum total calcium and albumin-corrected calcium were associated with incident diabetes in the unadjusted model. After adjusting for demographic and clinical variables, the association remained significant only for serum total calcium (hazard ratio (HR), 1.32 (95 % confidence interval (CI), 1.02-1.70), highest vs. lowest quartile). In a meta-analysis of four studies including the current study, both serum total calcium (pooled risk ratio (RR), 1.38 (95 % CI, 1.15-1.65); I (2) = 5 %, comparing extreme quantiles) and albumin-corrected calcium (pooled RR, 1.29 (95 % CI, 1.03-1.61); I (2) = 0 %, comparing extreme quantiles) were associated with incident diabetes. Penalized regression splines showed that the association of incident diabetes with serum total calcium and albumin-correlated calcium was non-linear and linear, respectively. CONCLUSIONS: Elevated serum calcium concentration is associated with incident diabetes. The mechanism underlying this association warrants further investigation.

Possible FRAX-based intervention thresholds for a cohort of Chinese postmenopausal women.

SUMMARY: A total of 2,266 postmenopausal Chinese women were followed for 4.5 years to determine the incidence of new fractures. The positive predictive value, negative predictive value, sensitivity and specificity of different treatment strategies were compared. Using a fixed optimal threshold calculated from receiver operating characteristics (ROC) curve had the highest sensitivity but lowest specificity. INTRODUCTION: There is no specific intervention threshold based on FRAX to guide treatment for Asian populations. This prospective study sought to determine the impact of applying different intervention thresholds to a cohort of Chinese postmenopausal women. METHODS: This study was part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment-naïve postmenopausal women underwent clinical risk factor and BMD assessments. The subjects were followed to assess fractures. We calculated the FRAX probability of major osteoporotic fractures corresponding to women with prior fractures but no other clinical risk factors. Different treatment strategies which include treating women with prior fractures, women with age-specific FRAX probability corresponding to those with prior fractures, women with osteoporosis as well as women with FRAX probability above a fixed cut-off based on optimizing sensitivity and specificity on the ROC curve were compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years, and the mean follow-up time was 4.5 ± 2.8 years. One hundred six new major osteoporotic fractures were reported. An optimal (FRAX, with BMD) cut-off point of 9.95 % was identified. All strategies had negative predictive value of >90 %. Using a fixed cut-off had the highest sensitivity (62.3 %) but lowest specificity (73.5 %) and positive predictive value (10.3 %). Using a fixed cut-off would direct treatment from younger women with lower absolute risk to elderly women with higher absolute risk. CONCLUSION: Targeting only women with prior fractures is unlikely to reduce fracture burden. Other treatment strategies with higher sensitivity need to be considered but they have different shortcomings.

Randomized clinical trial of chronic pain after the transinguinal preperitoneal technique compared with Lichtenstein's method for inguinal hernia repair.

BACKGROUND: Preliminary experience has suggested that preperitoneal mesh positioning causes less chronic pain than Lichtenstein's technique for inguinal hernia repair. Therefore, a randomized clinical trial was conducted with the aim of evaluating the incidence of postoperative chronic pain after transinguinal preperitoneal (TIPP) mesh repair versus Lichtenstein's technique. METHODS: Patients with a primary unilateral inguinal hernia were randomized to either TIPP or Lichtenstein's repair in two training hospitals. The primary outcome was the number of patients with chronic pain after surgery. Secondary outcomes were adverse events. Follow-up was scheduled after 14 days, 3 months and 1 year. Patients and outcome assessors were blinded. RESULTS: A total of 302 patients were randomized to TIPP (143) or Lichtenstein (159) repair. Baseline characteristics were comparable in the two groups. Some 98.0 per cent of the patients were included in the analysis (141 in the TIPP group and 155 in the Lichtenstein group). Significantly fewer patients in the TIPP group had continuous chronic pain 1 year after surgery: five patients (3.5 per cent) versus 20 patients (12.9 per cent) in the Lichtenstein group (P = 0.004). An additional 12 patients (8.5 per cent) in the TIPP group and 60 (38.7 per cent) in the Lichtenstein group experienced pain during activity (P = 0.001). There were two patients with recurrence in the TIPP group and four in the Lichtenstein group, but no significant differences were found in other severe adverse events between the groups. CONCLUSION: Fewer patients had continuous chronic pain at 1 year after the TIPP mesh inguinal hernia repair compared with Lichtenstein's repair.

Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk.

SUMMARY: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future. INTRODUCTION: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis. METHODS: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA). RESULTS: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA. CONCLUSIONS: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.

Meta-analysis of gene-based genome-wide association studies of bone mineral density in Chinese and European subjects.

UNLABELLED: Gene-based association approach could be regarded as a complementary analysis to the single SNP association analysis. We meta-analyzed the findings from the gene-based association approach using the genome-wide association studies (GWAS) data from Chinese and European subjects, confirmed several well established bone mineral density (BMD) genes, and suggested several novel BMD genes. INTRODUCTION: The introduction of GWAS has greatly increased the number of genes that are known to be associated with common diseases. Nonetheless, such a single SNP GWAS has a lower power to detect genes with multiple causal variants. We aimed to assess the association of each gene with BMD variation at the spine and hip using gene-based GWAS approach. METHODS: We studied 778 Hong Kong Southern Chinese (HKSC) women and 5,858 Northern Europeans (dCG); age, sex, and weight were adjusted in the model. The main outcome measure was BMD at the spine and hip. RESULTS: Nine genes showed suggestive p value in HKSC, while 4 and 17 genes showed significant and suggestive p values respectively in dCG. Meta-analysis using weighted Z-transformed test confirmed several known BMD genes and suggested some novel ones at 1q21.3, 9q22, 9q33.2, 20p13, and 20q12. Top BMD genes were significantly associated with connective tissue, skeletal, and muscular system development and function (p < 0.05). Gene network inference revealed that a large number of these genes were significantly connected with each other to form a functional gene network, and several signaling pathways were strongly connected with these gene networks. CONCLUSION: Our gene-based GWAS confirmed several BMD genes and suggested several novel BMD genes. Genetic contribution to BMD variation may operate through multiple genes identified in this study in functional gene networks. This finding may be useful in identifying and prioritizing candidate genes/loci for further study.

Ethnic difference of clinical vertebral fracture risk.

UNLABELLED: Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. This study observed that Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians, but the vertebral fracture rates were higher, resulting in a high vertebral-to-hip fracture ratio. As a result, estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate. INTRODUCTION: Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. The aim of this study was to report the incidence of clinical vertebral fractures among the Chinese and to compare the vertebral-to-hip fracture risk to other ethnic groups. METHODS: Four thousand, three hundred eighty-six community-dwelling Southern Chinese subjects (2,302 women and 1,810 men) aged 50 or above were recruited in the Hong Kong Osteoporosis Study since 1995. Baseline demographic characteristics and medical history were obtained. Subjects were followed annually for fracture outcomes with a structured questionnaire and verified by the computerized patient information system of the Hospital Authority of the Hong Kong Government. Only non-traumatic incident hip fractures and clinical vertebral fractures that received medical attention were included in the analysis. The incidence rates of clinical vertebral fractures and hip fractures were determined and compared to the published data of Swedish Caucasian and Japanese populations. RESULTS: The mean age at baseline was 62 ± 8.2 years for women and 68 ± 10.3 years for men. The average duration of follow-up was 4.0 ± 2.8 (range, 1 to 14) years for a total of 14,733 person-years for the whole cohort. The incidence rate for vertebral fracture was 194/100,000 person-years in men and 508/100,000 person-years in women, respectively. For subjects above the age of 65, the clinical vertebral fracture and hip fracture rates were 299/100,000 and 332/100,000 person-years, respectively, in men, and 594/100,000 and 379/100,000 person-years, respectively, in women. Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians. At the age of 65 or above, the hip fracture rates for Asian (Hong Kong Chinese and Japanese) men and women were less than half of that in Caucasians, but the vertebral fracture rate was higher in Asians, resulting in a high vertebral-to-hip fracture ratio. CONCLUSIONS: The incidences of vertebral and hip fractures, as well as the vertebral-to-hip fracture ratios vary in Asians and Caucasians. Estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate.

Discriminative value of FRAX for fracture prediction in a cohort of Chinese postmenopausal women.

UNLABELLED: We followed 2,266 postmenopausal Chinese women for 4.5 years to determine which model best predicts osteoporotic fracture. A model that contains ethnic-specific risk factors, some of which reflect frailty, performed as well as or better than the well-established FRAX model. INTRODUCTION: Clinical risk assessment, with or without T-score, can predict fractures in Chinese postmenopausal women although it is unknown which combination of clinical risk factors is most effective. This prospective study sought to compare the accuracy for fracture prediction using various models including FRAX, our ethnic-specific clinical risk factors (CRF) and other simple models. METHODS: This study is part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment naïve postmenopausal women underwent clinical risk factor and bone mineral density assessment. Subjects were followed up for outcome of major osteoporotic fracture and receiver operating characteristic (ROC) curves for different models were compared. The percentage of subjects in different quartiles of risk according to various models who actually fractured was also compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years and mean follow-up time was 4.5 ± 2.8 years. A total of 106 new major osteoporotic fractures were reported, of which 21 were hip fractures. Ethnic-specific CRF with T-score performed better than FRAX with T-score (based on both Chinese normative and National Health and Nutrition Examination Survey (NHANES) databases) in terms of AUC comparison for prediction of major osteoporotic fracture. The two models were similar in hip fracture prediction. The ethnic-specific CRF model had a 10% higher sensitivity than FRAX at a specificity of 0.8 or above. CONCLUSION: CRF related to frailty and differences in lifestyle between populations are likely to be important in fracture prediction. Further work is required to determine which and how CRF can be applied to develop a fracture prediction model in our population.

Influence of prolonged cold ischemia in renal transplantation.

AIM: To determine to what extent current cold ischemia times (CITs) affect the results of renal transplantation in the Netherlands. METHODS: Retrospective survey of the Dutch Organ Transplant Registry concerning transplants from deceased donors between 1990 and 2007. RESULTS: A total of 6322 recipients were identified, of whom 5306 received a kidney from deceased heartbeating (HBD) and 1016 from donors after cardiac death (DCD). Mean CIT was 24.0 ± 7.9 h in HBD and 21.6 ± 6.7 h in DCD. The percentage delayed graft function (DGF) was 12.3 and 50.4, respectively (p < 0.001). Primary non-function (PNF) occurred in, respectively, 1.7% and 5.0% (p < 0.001). Serum creatinine after three months was 166 µM in HBD and 213 µM in DCD (p < 0.001). Five-yr graft survival was 79.5% and 78.3%, respectively (p = ns). In multivariate analysis, CIT proved to be an independent risk factor for DGF and PNF. Shorter CIT was associated with better graft survival in both groups with a hazard ratio of 1.024 (1.011-1.037, 95% CI)/h. CIT <20 h was associated with a graft survival benefit of 3% after five yr in HBD and CIT of <16 h with a benefit of 10% in DCD. CONCLUSIONS: Longer CITs are associated with the occurrence of DGF, PNF and decreased graft survival in the Netherlands.

Reassortment of pandemic H1N1/2009 influenza A virus in swine.

The emergence of pandemic H1N1/2009 influenza demonstrated that pandemic viruses could be generated in swine. Subsequent reintroduction of H1N1/2009 to swine has occurred in multiple countries. Through systematic surveillance of influenza viruses in swine from a Hong Kong abattoir, we characterize a reassortant progeny of H1N1/2009 with swine viruses. Swine experimentally infected with this reassortant developed mild illness and transmitted infection to contact animals. Continued reassortment of H1N1/2009 with swine influenza viruses could produce variants with transmissibility and altered virulence for humans. Global systematic surveillance of influenza viruses in swine is warranted.

Establishment of an H6N2 influenza virus lineage in domestic ducks in southern China.

Multiple reassortment events between different subtypes of endemic avian influenza viruses have increased the genomic diversity of influenza viruses circulating in poultry in southern China. Gene exchange from the natural gene pool to poultry has contributed to this increase in genetic diversity. However, the role of domestic ducks as an interface between the natural gene pool and terrestrial poultry in the influenza virus ecosystem has not been fully characterized. Here we phylogenetically and antigenically analyzed 170 H6 viruses isolated from domestic ducks from 2000 to 2005 in southern China, which contains the largest population of domestic ducks in the world. Three distinct hemagglutinin lineages were identified. Group I contained the majority of isolates with a single internal gene complex and was endemic in domestic ducks in Guangdong from the late 1990s onward. Group II was derived from reassortment events in which the surface genes of group I viruses were replaced with novel H6 and N2 genes. Group III represented H6 viruses that undergo frequent reassortment with multiple virus subtypes from the natural gene pool. Surprisingly, H6 viruses endemic in domestic ducks and terrestrial poultry seldom reassort, but gene exchanges between viruses from domestic ducks and migratory ducks occurred throughout the surveillance period. These findings suggest that domestic ducks in southern China mediate the interaction of viruses between different gene pools and facilitate the generation of novel influenza virus variants circulating in poultry.

[Cold ischaemia time and outcome of renal transplantation]. / Koude-ischemietijd en resultaat niertransplantatie. Nederland, 1990-2007.

OBJECTIVE: To determine the effect of cold ischaemia time (CIT) on the outcome of cadaveric renal transplantation in the Netherlands. DESIGN: Retrospective, comparative. METHODS: We studied data from the Netherlands organ transplant registry of cadaveric renal transplants from 1990-2007. RESULTS: 6322 cadaveric renal transplant recipients were studied, of whom 5306 were from heart-beating donors (HBD) and 1016 from non-heart-beating donors (NHBD). The mean CIT was 24.0 h in the HBD group and 21.6 h in the NHBD group. The rate of delayed graft function (DGF) was 12.3% in the HBD group and 50.4% in the NHBD group. Multivariate analysis showed that prolonged CIT was an independent risk factor for graft failure. Prolonged CIT was also associated with the more frequent occurrence of DGF and primary non-function (PNF). Recipients of renal allografts from HBD with CIT

The development and genetic diversity of H5N1 influenza virus in China, 1996-2006.

Since it was first detected in 1996, the Goose/Guangdong/1/1996 (Gs/GD) H5N1 influenza virus and its reassortants have spread to over 60 countries, with over 20 distinct genetic reassortants previously recognized. However, systematic analysis of their interrelationship and the development of genetic diversity have not been explored. As each of those reassortants was first detected in China, here 318 full-length H5N1 virus genomes isolated from 1996 to 2006 in this region were phylogenetically analyzed. Our findings revealed two major group reassortment events in 2001 and 2002 that were responsible for the generation of the majority of the 44 distinct Gs/GD genotypes identified, excepting those 1997 variants. Genotype replacement and emergence occurred continually, with 34 transient genotypes detected while only 10 variants were persistent. Two major replacements of predominant genotypes were also observed: genotype B replaced by Z in 2002 and then genotype Z replaced by the now predominant genotype V in 2005.

Estrogen receptor alpha CA dinucleotide repeat polymorphism is associated with rate of bone loss in perimenopausal women and bone mineral density and risk of osteoporotic fractures in postmenopausal women.

UNLABELLED: The association between a newly identified CA repeat polymorphism of the estrogen receptor alpha gene (ESR1) with osteoporosis was investigated. Postmenopausal women with <18 CA repeats had low BMD, increased rate of bone loss and increased fracture risk. INTRODUCTION: Studies have shown that intronic dinucleotide repeat polymorphisms in some genes are associated with disease risk by modulating mRNA splicing efficiency. D6S440 is a newly identified intronic CA repeat polymorphism located downstream of the 5'-splicing site of exon 5 of ESR1. METHODS: The associations of D6S440 with bone mineral density (BMD), rate of bone loss and fracture risk were evaluated in 452 pre-, 110 peri- and 622 postmenopausal southern Chinese women using regression models. RESULTS: Post- but not premenopausal women with less CA repeats had lower spine and hip BMD. The number of CA repeats was linearly related to hip BMD in postmenopausal women (beta=0.008; p=0.004). Postmenopausal women with CA repeats <18 had higher risks of having osteoporosis (BMD T-score< -2.5 at the spine: OR 2.46, 95% CI 1.30-4.65; at the hip: OR 3.79(1.64-8.74)) and low trauma fractures (OR 2.31(1.29-4.14)) than those with >or= 18 repeats. Perimenopausal women with <18 CA repeats had significantly greater bone loss in 18 months at the hip than those with >or= 18 repeats (-1.96% vs. -1.61%, p = 0.029). CONCLUSIONS: ESR1 CA repeat polymorphism is associated with BMD variation, rate of bone loss and fracture risk, and this may be a useful genetic marker for fracture risk assessment.

Establishment of influenza A virus (H6N1) in minor poultry species in southern China.

An H6N1 virus, A/teal/Hong Kong/W312/97 (W312), was isolated during the "bird flu" incident in Hong Kong in 1997. Genetic analysis suggested that this virus might be the progenitor of the A/Hong Kong/156/97 (HK/97) H5N1 virus, as seven of eight gene segments of those viruses had a common source. Continuing surveillance in Hong Kong showed that a W312-like virus was prevalent in quail and pheasants in 1999; however, the further development of H6N1 viruses has not been investigated since 2001. Here we report influenza virus surveillance data collected in southern China from 2000 to 2005 that show that H6N1 viruses have become established and endemic in minor poultry species and replicate mainly in the respiratory tract. Phylogenetic analysis indicated that all H6N1 isolates had W312-like hemagglutinin and neuraminidase genes. However, reassortment of internal genes between different subtype virus lineages, including H5N1, H9N2, and other avian viruses, generated multiple novel H6N1 genotypes in different types of poultry. These novel H6N1/N2 viruses are double, triple, or even quadruple reassortants. Reassortment between a W312-like H6N1 virus and an A/quail/Hong Kong/G1/97 (HK/97)-like H9N2 virus simultaneously generated novel H6N2 subtype viruses that were persistent in poultry. Molecular analyses suggest that W312-like viruses may not be the precursors of HK/97 virus but reassortants from an HK/97-like virus and another unidentified H6 subtype virus. These results provide further evidence of the pivotal role of the live poultry market system of southern China in generating increased genetic diversity in influenza viruses in this region.

Effects of low-dose naloxone on opioid therapy in pediatric patients: a retrospective case-control study.

OBJECTIVE: To develop novel therapies that prevent opioid tolerance in critically ill children we examined the effects of low-dose naloxone infusions on patients' needs for analgesia or sedation. DESIGN AND SETTING: Matched case-control study in a pediatric intensive care unit at a university children's hospital. PATIENTS: We compared 14 pediatric ICU patients receiving low-dose naloxone and opioid infusions with 12 matched controls receiving opioid infusions. MEASUREMENTS AND MAIN RESULTS: Opioid analgesia and sedative requirements were assessed as morphine- and midazolam-equivalent doses, respectively. No differences were observed between groups in opioid doses at baseline or during naloxone, but in the postnaloxone period opioid doses tended to be lower in the naloxone group. Compared to baseline the naloxone group required more opioids during naloxone but fewer opioids after naloxone. Total sedative doses were comparable at baseline in both groups, with no differences in the postnaloxone period. The naloxone group required less sedation after naloxone but sedation doses were unchanged in controls. The two groups did not differ in pain scores, sedation scores, or opioid side effects. CONCLUSIONS: Naloxone did not reduce the need for opioid during the infusion period but tended to reduce opioid requirements in the postnaloxone period without additional need for sedation. Randomized clinical trials may examine the effects of low-dose naloxone on opioid tolerance and side effects in pediatric ICU patients requiring prolonged opioid analgesia.