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Objective: Associations between single nucleotide polymorphisms (SNPs) and aspirin resistance (AR) have been studied with variable results. The associations of genetic variants with AR may be helpful to explain why some individuals demonstrate aspirin insensitivity with this anti-platelet therapy. The purpose of this research was to investigate the effect of different genotypes in candidate genes on aspirin response in patients taking long-term aspirin therapy by measuring the serum thromboxane B2 (TXB2) and platelet function using the Multiplate® analyser., Methods: A total of 266 patients with stable coronary heart disease (CHD) taking low-dose aspirin for long periods of time and without any other anti-platelet drugs medications were enrolled into the study. They were required to take 80 mg of aspirin every morning for a week including the day before blood tests. Blood samples were collected 24 h after the last dose. The 80 mg dose of aspirin was taken orally and blood samples were collected again 1 h later. The serum TXB2 levels were measured in samples at 24 h post-dose and 1 h post-dose using the EIA kit and platelet activity was determined using the Multiplate® Impedance Platelet Aggregometry (ASPI) assay. Genotyping assays were performed by the TaqMan SNP genotyping technique., Results: Of the 266 patients, only 251 patients were enrolled in the present study. The PTGS1/COX1 -1676 A  >  G (rs1330344) and the PTGS2/COX2 -765 G  >  C (rs20417) SNPs showed significant associations with the ASPI measurements in samples taken at 24 h post-dose, but not with the values at 1 h post-dose or with the TXB2 levels ( P  < 0.05)., Conclusions: Our results suggest that polymorphisms in the PTGS1/COX1 and the PTGS2/COX2 genes may be associated with reduced anti-aggregatory effects and increased the risk of AR, but future larger-scale cohort studies are necessary for further validation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Authors.)

Background: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese., Methods: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA 1c . We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour., Results: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86])., Conclusion: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.O.Y.L. has served as a member of advisory panel for Amgen, AstraZeneca, Boehringer Ingelheim and Sanofi and received research support from Amgen, Asia Diabetes Foundation, Bayer, Biogen, Boehringer Ingelheim, Lee’s Pharmaceutical, MSD, Novo Nordisk, Roche, Sanofi, Sugardown Ltd, Takeda, outside the submitted work. J.C.N.C. has received institutional grants and/or consultancy fees from Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Celltrion, Hua Medicine, Lee Powder, Lilly, Merck, MSD, Novartis, Pfizer, Sanofi, Servier, Viatris Pharmaceuticals and Zuelig Pharma; acts as CEO (probono) in Asia Diabetes Foundation and is a founding director of GemVCare, outside the submitted work. In addition, J.C.N.C. holds patents of using biogenetic markers for precision prevention and treatment of diabetes and its complications. A.P.S.K. has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli-Lilly, Kyowa Kirin, Merck Serono, Novo Nordisk, Pfizer and Sanofi, outside the submitted work. R.C.W.M. has received grants from AstraZeneca, Bayer, Pfizer, Novo Nordisk, Sanofi, Tricida Inc., speaker honorarium from AstraZeneca, Bayer and Boehringer Ingelheim, and has received support from the Hong Kong Government Innovation and Technology Commission and its Technology Start-up Support Scheme for Universities (TSSSU), as co-founder of a technology start-up GemVCare which provides genetic testing for diabetes and diabetes complications, outside the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO., Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m 2 ) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models., Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12)., Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management., Competing Interests: JC has received research grants through her affiliated institutions and/or honoraria for consultancy or giving lectures from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Eli-Lilly, Hua Medicine, Merck, Merck Sharp & Dohme, Novo Nordisk, Novartis, Pfizer, Servier, Sanofi, Viatris and ZP Therapeutics. AK has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo Nordisk, Pfizer, and Sanofi. RCWM reported receiving grants and/or honoraria for consultancy or giving lectures from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, and Takeda. AL reported receiving grants and/or honoraria for consultancy or giving lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi. EC has received institutional research support and/or honoraria for giving lectures for Sanofi, Novartis, Medtronic Diabetes, Powder Pharmaceuticals Inc. The proceeds have been donated to The Chinese University of Hong Kong, American Diabetes Association and other charity organizations to support diabetes research and education. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Yeung, Lee, Lau, Yung, Yang, Wu, Wong, Kong, Chow, Ma, Yeung, Loo, Ozaki, Luk, Lui and Chan.)

The early eluting peaks in the first minute of cation-exchange high-performance liquid chromatography (CE-HPLC) are often not analysed in haemoglobin pattern studies, except for haemoglobin (Hb) Bart's and Hb H peaks. In this study, we described the presence of a specific α-thalassaemia early eluting peak (αEEP) at the retention time of 0.24 min generated by Variant II CE-HPLC (β-Thalassaemia Short Program; Bio-Rad Laboratories). We have evaluated the utility of αEEP for the screening of α-thalassaemia trait in our local Chinese population in comparison to the Hb H inclusion body test. A total of 303 blood samples presenting with microcytosis were sent for haemoglobin pattern study and were analysed for the presence or absence of αEEP and Hb H inclusions. Twenty cases with a normal mean corpuscular volume were assessed as a control. Discordant results between the αEEP and the Hb H inclusion test were reviewed with the α-globin genotyping test performed. The concordance rate of the αEEP and the Hb H inclusion body test was 96.0% (κ=0.921, p<0.001). Eight of 303 cases (2.6%) were initially negative for the Hb H inclusion test but positive for the αEEP. All eight cases were found to have occasional Hb H inclusion bodies upon review. Four of 303 cases (1.3%) were negative for the αEEP but positive for the Hb H inclusion test. Of these four cases, two (50%) showed heterozygous Southeast Asian (SEA) type deletion, one (25%) showed Hb Quong Sze mutation, and one (25%) showed no mutation detected upon molecular testing. All the Hb E trait cases with no Hb H inclusions and the negative control group showed the absence of the αEEP. The sensitivity and specificity of αEEP for detecting SEA deletion were 93.8% and 100% respectively, which is superior to the Hb H inclusion test (sensitivity 81.3%, specificity 95.2%). The αEEP is found to be a more sensitive method than the Hb H inclusion body test in the screening of α-thalassaemia trait in our Chinese population, in which SEA type deletion is prevalent. Further study is needed to explore the utility of the αEEP in the screening of α-thalassaemia traits in other populations. The exact nature of the αEEP is yet to be defined., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Aims: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D)., Methods: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia., Results: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association., Conclusions: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D., Competing Interests: Declaration of competing interest Conflicts of interest were disclosed according to the disclosure form of International Committee of Medical Journal Editors. A.O. Luk declared (2) Grants or contracts from any entity (if not indicated in item #1 above): Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Lee Pharmaceutical, MSD, Novo Nordisk, Roche, Sanofi, Sugardown, Takeda; (5) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, MSD; (7) Support for attending meetings and/or travel: AstraZeneca, Boehringer Ingelheim, Eli Lilly; (10) Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Deputy Chair of the Joint-Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee Phase 1 Panel, Deputy Director of Clinical Research Management Office of the Chinese University of Hong Kong, Vice President of the Hong Kong Association on the Study of Obesity. R.C. Ma declared (2) Grants or contracts from any entity (if not indicated in item #1 above): Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18), Research Grants Council General Research Fund (Ref. 14118718), Innovation and Technology Fund (MPR/054/20X), Health and Medical Research Fund (CFS-CUHK2), Croucher Foundation, AstraZeneca, Bayer, Novo Nordisk, Pfizer, Tricida Inc., Roche Diagnostics (all the above payment to institution); (4) Consulting fees: Merck, Kyowa Kirin; (5) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic (all the above were donated to institution to support diabetes research); (8) Patents planned, issued or pending: Hold issued patents relating to genetic markers of diabetes or diabetes complications; (10) Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Council Member, Hong Kong College of Physicians (unpaid), Board Member, Asian Association for the Study of Diabetes (unpaid), Past Board Member of Worldwide Initiative for Diabetes Education (WorldWIDE Diabetes) (up to 3/2021), Member, FIGO Committee on the Impact of Pregnancy on Long-term Health (unpaid); (13) Other financial or non-financial interests: Cofounder of GemVCare, a technology start-up which provides genetic testing for diabetes and diabetes complications, established with support from the Hong Kong Government Technology Start-up Support Scheme for Universities (TSSSU) (No income or renumeration received from the company). J.C. Chan declared (2), (4), (5), (8), (10), (11): J.C. Chan reported receiving grants and/or honoraria for consultancy or giving lectures from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Eli Lilly, Hua Medicine, Lee Pharm, Merck Serono, Merck Sharp & Dohme, Pfizer, Sanofi, Servier and Viatris Pharmaceutical. She is the chief executive officer (pro bono) of the Asia Diabetes Foundation that designed and implemented the web-based JADE platform for data-driven diabetes management. She holds patents for using biomarkers to predict diabetes and its complications for precision care. She is the co-founder of GemVCare, a biotech start-up company, with partial support from the Hong Kong Government, which uses biogenetic markers and information technology in pursuit of prevention and precision care in diabetes through partnerships. Y.K. Wing declared (2) Grants or contracts from any entity (if not indicated in item #1 above): Grants from Research Grant Council General Research Fund (GRF) & Collaborative Research Fund (CRF) (received grants support for research projects which is outside the submitted work.); (4) Consulting fees: Consultation fee from Eisai Co., Ltd. (received personal fees from Eisai Co., Ltd., which is outside the submitted work); (5) Honorarium from Eisai Hong Kong (received personal fees from Eisai Co., Ltd. for lecture, which is outside the submitted work). A.P. Kong declared (4) Consulting fees: Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi (all the above payment to her); (5) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi (all the above payment to her); (7) Support for attending meetings and/or travel: Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, and Sanofi; (9) Participation on a Data Safety Monitoring Board or Advisory Board: Advisory Board member of Abbott, Astra Zeneca, Eli-Lilly, and Kyowa Kirin (all the above payment to her), (11) Stock or stock options: Aptorum. C. O, B.W. Siu, V.W. Leung, Y. Lin, C. Ding, E.S. Lau, J. Cheung, E.Y. Chow declared no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: We aimed to examine the impact of non-alcoholic fatty liver disease (NAFLD) on the clinical outcomes in patients with type 2 diabetes (T2D)., Methods: Between 2013 and 2014, 1,734 patients with T2D underwent transient elastography (TE) to assess liver status indicated by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Liver steatosis was defined by CAP ≥ 248 dB/m and advanced liver fibrosis by LSM ≥ 10 kPa. In 2019, we assessed their clinical outcomes including hospitalizations and mortality., Results: In this prospective cohort [56% men, mean (±standard deviation) age:60.8±11.5 years; glycated hemoglobin (HbA 1c )7.8±1.6 %], 798 patients had liver steatosis, 296 patients had advanced liver fibrosis and 640 patients had normal liver at baseline. T2D with advanced liver fibrosis had higher body mass index, waist circumference, waist-hip ratio, fasting plasma glucose, HbA 1c , blood pressure and lipid profiles than their counterparts with NAFLD or normal liver (all p < 0.05). After a median follow-up of 6.07 (interquartile range:5.84 to 6.30) years, there were 4,403 incident hospitalizations, 32,119 days of hospital stay, and 171 deaths. Using Cox regression analysis, advanced liver fibrosis was associated with increased risk of heart failure (hazard ratio [95% confidence interval] HR:3.07[1.08-8.68], p=0.035) and hospitalizations (HR:1.39[1.14-1.70], p=0.001) while liver steatosis was associated with reduced mortality (HR:0.60[0.41-0.87], p=0.007) compared to their counterparts with normal liver after adjustment for potential confounders., Conclusions: T2D comorbid with liver steatosis and advanced liver fibrosis are distinct clinical entities with differences in outcomes. Advanced liver fibrosis is an important predictor for worse outcomes including heart failure and hospitalizations in people with T2D., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Characterization of the subcellular distribution of RNA is essential for understanding the molecular basis of biological processes. Here, the subcellular nanopore direct RNA-sequencing (DRS) of four lung cancer cell lines (A549, H1975, H358, and HCC4006) is performed, coupled with a computational pipeline, Low-abundance Aware Full-length Isoform clusTEr (LAFITE), to comprehensively analyze the full-length cytoplasmic and nuclear transcriptome. Using additional DRS and orthogonal data sets, it is shown that LAFITE outperforms current methods for detecting full-length transcripts, particularly for low-abundance isoforms that are usually overlooked due to poor read coverage. Experimental validation of six novel isoforms exclusively identified by LAFITE further confirms the reliability of this pipeline. By applying LAFITE to subcellular DRS data, the complexity of the nuclear transcriptome is revealed in terms of isoform diversity, 3'-UTR usage, m6A modification patterns, and intron retention. Overall, LAFITE provides enhanced full-length isoform identification and enables a high-resolution view of the RNA landscape at the isoform level., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

RNA G-quadruplex (rG4) structures in the 5' untranslated region (5'UTR) play crucial roles in fundamental cellular processes. ADAR is an important enzyme that binds to double-strand RNA and accounts for the conversion of Adenosine to Inosine in RNA editing. However, so far there is no report on the formation and regulatory role of rG4 on ADAR expression. Here, we identify and characterize a thermostable rG4 structure within the 5'UTR of the ADAR1 mRNA and demonstrate its formation and inhibitory role on translation in reporter gene and native gene constructs. We reveal rG4-specific helicase DHX36 interacts with this rG4 in vitro and in cells under knockdown and knockout conditions by GTFH (G-quadruplex-triggered fluorogenic hybridization) probes and modulates translation in an rG4-dependent manner. Our results further substantiate the rG4 structure-DHX36 protein interaction in cells and highlight rG4 to be a key player in controlling ADAR1 translation., (© 2022 Wiley-VCH GmbH.)

Japanese eels (Anguilla japonica) are commercially important species, harvested extensively for food. Currently, this and related species (American and European eels) are challenging to breed on a commercial basis. As a result, the wild stock is used for aquaculture. Moreover, climate change, habitat loss, water pollution, and altered ocean currents affect eel populations negatively. Accordingly, the International Union for Conservation of Nature lists Japanese eels as endangered and on its red list. Here we presented a high-quality genome assembly for Japanese eels and demonstrated that large chromosome reorganizations occurred in the events of third-round whole-genome duplications (3R-WRDs). Several chromosomal fusions and fissions have reduced the ancestral protochromosomal number of 25 to 19 in the Anguilla lineage. A phylogenetic analysis of the expanded gene families showed that the olfactory receptors (group δ and ζ genes) and voltage-gated Ca2+ channels expanded significantly. Both gene families are crucial for olfaction and neurophysiology. Additional tandem and proximal duplications occurred following 3R-WGD to acquire immune-related genes for an adaptive advantage against various pathogens. The Japanese eel assembly presented here can be used to study other Anguilla species relating to evolution and conservation., (© The Author(s) 2022. Published by Oxford University Press GigaScience.)

Background: RNA G-quadruplexes (rG4s) are non-canonical structural motifs that have diverse functional and regulatory roles, for instance in transcription termination, alternative splicing, mRNA localization and stabilization, and translational process. We recently developed the RNA G-quadruplex structure sequencing (rG4-seq) technique and described rG4s in both eukaryotic and prokaryotic transcriptomes. However, rG4-seq suffers from a complicated gel purification step and limited PCR product yield, thus requiring a high amount of RNA input, which limits its applicability in more physiologically or clinically relevant studies often characterized by the limited availability of biological material and low RNA abundance. Here, we redesign and enhance the workflow of rG4-seq to address this issue., Results: We developed rG4-seq 2.0 by introducing a new ssDNA adapter containing deoxyuridine during library preparation to enhance library quality with no gel purification step, less PCR amplification cycles and higher yield of PCR products. We demonstrate that rG4-seq 2.0 produces high-quality cDNA libraries that support reliable and reproducible rG4 identification at varying RNA inputs, including RNA mounts as low as 10 ng. rG4-seq 2.0 also improved the rG4-seq calling outcome and nucleotide bias in rG4 detection persistent in rG4-seq 1.0. We further provide in vitro mapping of rG4 in the HEK293T cell line, and recommendations for assessing RNA input and sequencing depth for individual rG4 studies based on transcript abundance., Conclusions: rG4-seq 2.0 can improve the identification and study of rG4s in low abundance transcripts, and our findings can provide insights to optimize cDNA library preparation in other related methods., (© 2022. The Author(s).)

The clinical efficacy of continuous subcutaneous insulin infusion (CSII) therapy combined with six classes of oral glucose-lowering drugs (GLDs) (TZDs/metformin/acarbose/GLP-1 receptor agonist/SGLT-2 inhibitor/DPP-4 inhibitor) was evaluated by a network meta-analysis to provide an evidence-based reference in making a clinical decision on CSII combined with drugs in the treatment of type 2 diabetes. Data were retrieved from eight databases: the Chinese Journal Full-Text Database (CNKI), VIP Chinese Science and Technology Periodicals Full-Text Database (VP-CSFD), Wanfang Data Journal Paper Resource (WANFANG), China Biomedical Database (CBM), PubMed, Embase, Cochrane Library, and Web of Science. The retrieval period dated from the library's construction to 27 June 2021. The search was for randomized, controlled trial studies (RCT) on insulin infusion (CSII) combined with oral hypoglycemic drugs (TZDs/metformin/acarbose/GLP-1 receptor agonist/SGLT-2 inhibitor/DPP-4 inhibitor) in the treatment of type 2 diabetes. Quality evaluation and data extraction were performed on the studies included, and network meta-analysis was performed with R4.0.1 software. A total of 56 publications was included in the final network meta-analysis, with a total sample size of 4395. Results based on the network meta-analysis were that CSII combined with a metformin works best on fasting blood glucose (FBG) and 2 h postprandial blood glucose (2hPG) and improves insulin resistance (lower HOMA-IR levels). CSII combined with a DPP-4 inhibitor had the best clinical effect in reducing glycosylated hemoglobin levels. Treatment with CSII combined with a DPP-4 inhibitor was the fastest way to achieve the blood glucose standard. In terms of insulin dosage, an insulin pump (CSII) combined with the GLP-1 receptor agonist can significantly reduce insulin dosage. Network meta-analysis evidence suggests that an insulin infusion (CSII) combined with oral hypoglycemic drugs can improve clinical efficacy in controlling blood sugar and improving insulin resistance, insulin dosage, and standard time. However, the most outstanding performance was that of insulin infusion (CSII) combined with metformin, which had the best clinical effect in controlling blood sugar and improving insulin resistance.

Competing Interests: The authors declare that they have no conflict of interest.

Background and Aims: Skin autofluorescence (SAF) can non-invasively assess the accumulation of tissue AGEs. We investigated the association between SAF and kidney dysfunction in participants with T2D., Methods: Of 4030 participants consecutively measured SAF at baseline, 3725 participants free of end-stage kidney disease (ESKD) were included in the analyses. The association of SAF with incident ESKD or ≥30% reduction in estimated glomerular filtration rate (eGFR) was examined with Cox regression, linear mixed-effects model for the association with annual eGFR decline, and mediation analyses for the mediating roles of renal markers., Results: During a median (IQR) 1.8 (1.1-3.1) years of follow-up, 411 participants developed the outcome. SAF was associated with progression of kidney disease (hazard ratio 1.15 per SD, 95% confidence interval [CI] [1.04, 1.28]) and annual decline in eGFR (β -0.39 per SD, 95% CI [-0.71, -0.07]) after adjustment for risk factors, including baseline eGFR and urinary albumin-creatinine ratio (UACR). Decreased eGFR (12.9%) and increased UACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome., Conclusions: SAF is independently associated with progression of kidney disease. More than half of its effect is independent of renal markers. SAF is of potential to be a prognostic marker for kidney dysfunction., Competing Interests: Declaration of competing interest This study was supported by the Research Grants Council Theme-based Research Scheme (T12-402/13N), and the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Fund, and the RGC Research Impact Fund (R4012-18). RCWM and AJJ acknowledge support from the Internationalization Faculty Mobility Schemes (Outbound Research Mobility Scheme 2015–2016 and Inbound Research Mobility Scheme 2015–2016, respectively) from the Office of Academic Links, Chinese University of Hong Kong. We acknowledge Diagnoptics and Chong Lap (H.K.) Co. Ltd for providing access to the AGE Reader. The funders or companies had no involvement or input into the study design, data analyses or manuscript preparation. RCWM received research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Pfizer, Sanofi and Tricida Inc. for carrying out clinical trials, speaker honorarium or consultancy in advisory boards. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

G-quadruplexes are non-helical secondary structures that can fold in vivo in both DNA and RNA. In human cells, they can influence replication, transcription and telomere maintenance in DNA, or translation, transcript processing and stability of RNA. We have previously showed that G-quadruplexes are detectable in the DNA of the malaria parasite Plasmodium falciparum, despite a very highly A/T-biased genome with unusually few guanine-rich sequences. Here, we show that RNA G-quadruplexes can also form in P. falciparum RNA, using rG4-seq for transcriptome-wide structure-specific RNA probing. Many of the motifs, detected here via the rG4seeker pipeline, have non-canonical forms and would not be predicted by standard in silico algorithms. However, in vitro biophysical assays verified formation of non-canonical motifs. The G-quadruplexes in the P. falciparum transcriptome are frequently clustered in certain genes and associated with regions encoding low-complexity peptide repeats. They are overrepresented in particular classes of genes, notably those that encode PfEMP1 virulence factors, stress response genes and DNA binding proteins. In vitro translation experiments and in vivo measures of translation efficiency showed that G-quadruplexes can influence the translation of P. falciparum mRNAs. Thus, the G-quadruplex is a novel player in post-transcriptional regulation of gene expression in this major human pathogen., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

G-quadruplexes (G4s) are non-classical DNA or RNA secondary structures that have been first observed decades ago. Over the years, these four-stranded structural motifs have been demonstrated to have significant regulatory roles in diverse biological processes, but challenges remain in detecting them globally and reliably. Compared to DNA G4s (dG4s), the study of RNA G4s (rG4s) has received less attention until recently. In this review, we will summarize the innovative high-throughput methods recently developed to detect rG4s on a transcriptome-wide scale, highlight the many novel and important functions of rG4 being discovered in vivo across the tree of life, and discuss the key biological questions to be addressed in the near future., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: A growing interest exists in the relationship between diet and skin disease, with many recent studies identifying a role for omega-3 fatty acids (O3FAs) in various dermatological conditions., Objective: Our objective was to identify the spectrum of uses for O3FA supplementation reported in literature and to evaluate the current level of evidence for its clinical application in skin disease prevention and management., Methods: A search was conducted using Ovid MEDLINE for primary literature that examined O3FA intake and skin health. A manual search of reference lists was performed to identify additional articles for inclusion., Results: A total of 38 studies met eligibility for review, reporting benefits for O3FA supplementation in the treatment of psoriasis, atopic dermatitis, acne, and skin ulcers. Additionally, a reduced incidence of skin cancer and a decrease in the severity of drug-associated mucocutaneous side effects were reported with O3FA supplementation., Conclusion: This review yielded many well-studied benefits of O3FA uses in dermatology. Given its high safety profile, low cost, and ease of supplementation, O3FA is a reasonable supplement that may benefit patients wishing to improve inflammatory skin conditions through diet. Areas of particular clinical interest where supplementation may be valuable include O3FAs for systemic UV photoprotection, as well as adjuvant treatment for acne to reduce both inflammatory lesion count and the severity of mucocutaneous side effects associated with isotretinoin use.

We recently developed the rG4-seq method to detect and map in vitro RNA G-quadruplex (rG4s) structures on a transcriptome-wide scale. rG4-seq of purified human HeLa RNA has revealed many non-canonical rG4s and the effects adjacent sequences have on rG4 formation. In this study, we aimed to improve the outcomes and false-positive discrimination in rG4-seq experiments using a bioinformatic approach. By establishing connections between rG4-seq library preparation chemistry and the underlying properties of sequencing data, we identified how to mitigate indigenous sampling errors and background noise in rG4-seq. We applied these findings to develop a novel bioinformatics pipeline named rG4-seeker (https://github.com/TF-Chan-Lab/rG4-seeker), which uses tailored noise models to autonomously assess and optimize rG4 detections in a replicate-independent manner. Compared with previous methods, rG4-seeker exhibited better false-positive discrimination and improved sensitivity for non-canonical rG4s. Using rG4-seeker, we identified novel features in rG4 formation that were missed previously. rG4-seeker provides a reliable and sensitive approach for rG4-seq investigations, laying the foundations for further elucidation of rG4 biology.

Background: Advances in sequencing technologies have greatly improved our understanding of long noncoding RNA (lncRNA). These transcripts with lengths of >200 nucleotides may play significant regulatory roles in various biological processes. Importantly, the dysregulation of better characterized lncRNAs has been associated with multiple types of cancers, including hepatocellular carcinoma (HCC). There are many studies on altered lncRNA expression levels, very few, however, have focused on their subcellular localizations, from which accumulating evidences have indicated their close relationships to lncRNA functions. A transcriptome-wide investigation of the subcellular distributions of lncRNAs might thus provide new insights into their roles and functions in cancers. Results: In this study, we subjected eight patient-derived HCC cell lines to subcellular fractionation and independently sequenced RNAs from the nuclear and cytoplasmic compartments. With the integration of tumor and tumor-adjacent RNA-seq datasets of liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA), de novo transcriptome assembly and differential expression analysis were conducted successively and identified 26 nuclear-enriched HCC-associated lncRNAs shared between the HCC samples and the TCGA datasets, including the reported cancer driver PXN-AS1 . The majority of nuclear-enriched HCC-associated lncRNAs were associated with the survival outcomes of HCC patients, exhibited characteristics similar to those of many experimentally supported HCC prognostic lncRNAs, and were co-expressed with protein-coding genes that have been linked to disease progression in various cancer types. Conclusion: We adopted a fractionation-then-sequencing approach on multiple patient-derived HCC samples and identified nuclear-enriched, HCC-associated lncRNAs that could serve as important targets for HCC diagnosis and therapeutic development. This approach could be widely applicable to other studies into the disease etiologies of lncRNA., (Copyright © 2019 Chow, Zhang, Qin and Chan.)

cDNA library preparation is important for many high-throughput sequencing applications, such as RNA G-quadruplex structure sequencing (rG4-seq). A systematic evaluation of the procedures of the experimental pipeline, however, is lacking. Herein, we perform a comprehensive assessment of the 5 key experimental steps involved in the cDNA library preparation of rG4-seq, and identify better reaction conditions and/or enzymes to carry out each of these key steps. Notably, we apply the improved methods to fragmented cellular RNA, and show reduced RNA input requirement, lower transcript abundance variations between biological replicates, as well as lower transcript coverage bias when compared to prior arts. In addition, the time to perform these steps is substantially reduced to hours. Our method and results can be directly applied in protocols that require cDNA library preparation, and provide insights to the further development of simple and efficient cDNA library preparation for different biological applications.

Background: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project., Results: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10-15, empirical P = 2.00 × 10-5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs., Conclusion: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population.

Platelet factor 4 (PF4) is an angiostatic chemokine that suppresses tumor growth and metastasis. We previously revealed frequent transcriptional silencing of PF4 in multiple myeloma, but the functional roles of this chemokine are still unknown. We studied the apoptotic effects of PF4 on myeloma cell lines and primary myeloma in vitro, and investigated the involved signaling pathway. The in vivo effects were also studied using a mouse model. PF4 not only suppressed myeloma-associated angiogenesis, but also inhibited growth and induced apoptosis in myeloma cells. We found that PF4 negatively regulated STAT3 and concordantly inhibited constitutive and interleukin-6-induced phosphorylation of STAT3, and down-regulated the expression of STAT3 target genes (Mcl-1, survivin and VEGF). Overexpression of constitutively activated STAT3 could rescue PF4-induced apoptotic effects. Furthermore, we found that PF4 induced the expression of SOCS3, a STAT3 inhibitor, and gene silencing of SOCS3 abolished its ability to inhibit STAT3 activation, suggesting a critical role of SOCS3 in PF4-induced STAT3 inhibition. Knockdown of LRP1, a putative PF4 receptor, could also abolish PF4-induced apoptosis and STAT3 inhibition. Finally, the tumor growth inhibitory effect of PF4 was confirmed by in vivo mouse models. Immunostaining of rabbit bone xenografts from PF4-treated mice showed induction of apoptosis of myeloma cells and inhibition of angiogenesis, which was associated with suppression of STAT3 activity. Together, our preclinical data indicate that PF4 may be a potential new targeting agent for the treatment of myeloma.

As implantable devices gain more widespread use, medical device manufacturers are constantly looking for novel materials that increase and improve capability and functionality. The packaging needs to be biocompatible, but it is also highly desirable for it to be radio transparent to facilitate wireless telemetry and remote powering. Low temperature co-fired ceramics (LTCC) provide a viable solution that meets these desired specifications while also having characteristics that support ease of manufacturing such as the ability for molding, shaping, and even embedding components within the material. In this work, inductor coils used for wireless telemetry and powering are integrated into the walls of the LTCC-based package to maximize the size of the passive component while optimizing the miniaturization of the implant. The package designed and fabricated in this work consisted of inductors approximating 20 mH with a quality factor of 7.8 at 2 MHz. When compared to similar devices in the literature the LTCC inductor out performed these devices when a power-link figure of merit is used for comparison.

Glaucoma is a detrimental disease that causes blindness in millions of people worldwide. There are numerous treatments to slow the condition but none are totally effective and all have significant side effects. Currently, a continuous monitoring device is not available, but its development may open up new avenues for treatment. This work focuses on the design and fabrication of an active glaucoma intraocular pressure (IOP) monitor that is fully wireless and implantable. Major benefits of an active IOP monitoring device include the potential to operate independently from an external device for extended periods of time and the possibility of developing a closed-loop monitoring and treatment system. The fully wireless operation is based off using gigahertz-frequency electromagnetic wave propagation, which allows for an orientation independent transfer of power and data over reasonable distances. Our system is comprised of a micro-electromechanical systems (MEMS) pressure sensor, a capacitive power storage array, an application-specific integrated circuit designed on the Texas Instruments (TI) 130 nm process, and a monopole antenna all assembled into a biocompatible liquid-crystal polymer-based tadpole-shaped package.

Haemoglobin (Hb) Bonn is a newly described benign Hb variant that causes falsely depressed oxygen saturation as measured by pulse oximetry. It was found to be associated with mild haemolysis. Since its first report in a German family, no further cases have been documented in the literature. We report the first Chinese family with this Hb variant and confirm its unusual clinical presentation. No evidence of haemolysis was seen. The absence of consistent abnormalities in routine Hb tests such as high-performance liquid chromatography and gel electrophoresis means that spurious hypoxaemia is the only clue to its presence, and genotypic analysis is the preferred method for definitive diagnosis. Its positive identification is important for counselling and will help to avoid unnecessary investigation and treatment for this benign condition.

This paper presents a fully wireless cardiac pressure sensing system. Food and Drug Administration (FDA) approved medical stents are explored as radiating structures to support simultaneous transcutaneous wireless telemetry and powering. An application-specific integrated circuit (ASIC), designed and fabricated using the Texas Instruments 130-nm CMOS process, enables wireless telemetry, remote powering, voltage regulation, and processing of pressure measurements from a microelectromechanical systems (MEMS) capacitive sensor. This paper demonstrates fully wireless-pressure-sensing functionality with an external 35-dB.m RF powering source across a distance of 10 cm. Measurements in a regulated pressure chamber demonstrate the ability of the cardiac system to achieve pressure resolutions of 0.5 mmHg over a range of 0-50 mmHg using a channel data-rate of 42.2 kb/s.

Background: The 2006 Canadian Dermatology Association (CDA) member survey tracked the Canadian dermatology workforce. Information on use of nondermatologist extenders, impact of financial burden on practice style, and wait times was collected in the survey., Objective: To survey Canadian dermatologists for specialty-specific physician resource information including demographics, workload, and future career plans and compare it to results from the 2001 survey. In addition, to explore three other areas not covered in the previous survey: patient access to dermatologic care through wait times, the use of nondermatologist extenders, and potential impact of educational financial debt on practice styles., Methods: CDA members in 2006 were surveyed by mail. Follow-up mailings were done for nonresponders. Survey results were compared to those of the 2001 survey., Results: Thirty-six percent (216 of 602) of Canadian dermatologists responded (70% in 2001). The national distribution was identical between surveys. The median age increased to 55 years; two-thirds of dermatologists are male. The median retirement age remained at 65 years. There was a shift from rural to urban practice locations; 78% practice in private offices. Three-fifths of dermatologists do mainly medical dermatology, a decrease between surveys. Pediatric dermatology decreased 10%, whereas surgical dermatology increased 52% between surveys. Fewer practitioners perform noninsured services, and half as many perform research or hospital consultations or teach medical students. Financial debt burden had no impact on selection of practice style. Median wait times for nonurgent consultations doubled from 5 to 10 weeks; follow-up visits increased from 4 to 5 weeks; noninsured consultations increased from 4 to 5 weeks. The national median wait time for a third available consultation appointment was 42 days (range 7-161 days). Seventeen percent of dermatologists reported using nondermatologist extenders. Training programs produce only 60% of new practitioners needed to replace retirees over the next 5 years. Existing training programs are at full capacity, and only the creation of new programs can expand training capacity., Conclusions: Although the face of Canadian dermatology shows a productive specialty committed to patient care, teaching, and research, the demographics of the Canadian baby boom generation will have a major negative impact on the effectiveness of Canadian dermatology in the service of the Canadian population. The attrition rate predicted in the 2001 survey and validated by the 2006 survey spotlights the critical imperative for the specialty to adapt to the future of a shrinking workforce in the face of expanding demand for its services.

There is often a strong correlation between elevated levels of intraocular pressure (IOP) and glaucoma; however, the underlying mechanisms that lead to blindness are not well understood. The key may lie in the study of genetic factors which determine IOP and lead to glaucoma-related blindness. Mice are typically used for genetic research due to their short generation time and accelerated lifespan, manageability, the availability of established and pure lines, and the ability to manipulate the genome. Post genetic manipulation, IOP monitoring at regular intervals is needed and for large scale testing, on the order of thousands of mice, it is crucial to have at least a partially automated data collection scheme. This work presents a fully wireless system on a chip that measures 300 µm in its widest dimension, has a wireless microwave-based data and power link, and is capable of relaying digitized pressure recordings to a nearby base-station.

Wireless telemetry is crucial for long-term implantable neural recording systems. RF-encoded neurological signals often require high data-rates to transmit information from multiple electrodes with a sufficient sampling frequency and resolution. In this work, we quantify the effects of interferers and tissue attenuation on a wireless link for optimal design of future systems. The wireless link consists of an external receiver capable of demodulating FSK/OOK transmission at speeds up to 8 Mbps, with <1e-5 bit-error rate (BER) without error correction, and a fully implanted transmitter consuming about 1.05 mW. The external receiver is tested with the transmitter in vivo to show demodulation efficacy of the transcutaneous link at high data-rates. Transmitter/Receiver link BER is quantified in typical and controlled RF environments for ex vivo and in vivo performance.

Chronic recording electrodes are a vital tool for brain research and neural prostheses. Despite decades of advances in recording technology, probe structures and implantation methods have changed little over time. Then as now, compressive insertion methods require probes to be constructed from hard, stiff materials, such as silicon, and contain a large diameter shank to penetrate the brain, particularly for deeper structures. The chronic presence of these probes results in an electrically isolating glial scar, degrading signal quality over time. This work demonstrates a new magnetic tension-based insertion mechanism that allows for the use of soft, flexible, and thinner probe materials, overcoming the materials limitations of modern electrodes. Probes are constructed from a sharp magnetic tip attached to a flexible tether. A pulsed magnetic field is generated in a coil surrounding a glass pipette containing the electrode. The applied field pulls the electrode tip forward, accelerating the probe into the neural tissue with a penetration depth that is calibrated against the charge voltage. Mathematical modeling and agar gel insertion testing demonstrate that the electrode can be implanted to a predictable depth given system specific parameters. Trial rodent implantations resulted in discernible single-unit activity on one of the probes. The current prototype demonstrates the feasibility of a tension based, magnetically driven implantation system and opens the door to a wide variety of new minimally invasive probe materials and configurations.

Continuous monitoring of blood pressure from a minimally invasive device in the pulmonary artery can serve as a diagnostic and early warning system for cardiac health. The foremost challenge in such a device is the wireless transfer of data and power from within the blood vessel to an external device while maintaining unrestricted flow through the artery. We present a miniaturized system, which is attached to the outer surface of a regular or drug-eluting FDA-approved stent. When expanded, the stent maintains a patent vessel lumen while allowing contact between the electronic sensors and the blood supply. The stent-based antenna can be used for both wireless telemetry and power transfer for the implanted electronics. Using the stent platform as both a radiating antenna and a structural support allows us to take advantage of an FDA-approved device whose safety and surgical procedure are well established. The electronics package has been reduced to an area of less than 1 mm(2), with a thickness under 300 mum. A minimally invasive implantation procedure allows the delivery of the stent-based implant in nearly any major vessel of the body. This article describes an initial prototype with two stents configured as a single dipole, a 2.4-GHz transmitter microchip, and a battery, and validates transcutaneous transmission through ex vivo and in vivo porcine studies. The results demonstrate the feasibility of a stent-based wireless platform for continuous monitoring of blood pressure.

Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an immune response gene, both located on chromosome 19p13.3, were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS infection caused by the novel coronavirus (SARS-CoV) was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P=.0067; odds ratio [OR], 4.31 [95% confidence interval {CI}, 1.37-13.56]) and lower total white blood cell counts (P=.022; OR, 0.30 [95% CI, 0.10-0.89]) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS.

Background: Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms of RANTES, IP-10 and Mig affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS)., Methods: We tested the polymorphisms of RANTES, IP-10 and Mig for their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls., Results: RANTES -28 G allele was associated with SARS susceptibility in Hong Kong Chinese (P < 0.0001, OR = 2.80, 95%CI:2.11-3.71). Individuals with RANTES -28 CG and GG genotypes had a 3.28-fold (95%CI:2.32-4.64) and 3.06-fold (95%CI:1.47-6.39) increased risk of developing SARS respectively (P < 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (P = 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11-4.06) and 4.01-fold (95% CI: 1.30-12.4) increased risk. For the replication of RANTES data in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64-11.1) and GG (OR = 3.34, 95%CI:0.37-30.7) were associated with admission to intensive care units or death due to SARS (P = 0.011)., Conclusion: RANTES -28 G allele plays a role in the pathogenesis of SARS.

The aim of this study was to determine serological prevalence for Salmonella in 90 Alberta finishing swine farms over a 5-month period; to evaluate the correlation between the detection of Salmonella by bacteriological culture and serology; and to identify risk factors for Salmonella seroprevalence. Participating farms were visited 3 times. A total of 30 blood and 15 fecal samples were collected from finishing pigs on each farm. VetScreen Salmonella covalent mix-ELISA (Svanovir) and conventional culture were performed. The apparent Salmonella seroprevalences at the sample and farm level were 13.2% (95% confidence interval [CI], 10.5-15.5%) and 83.3% (95% CI, 74-90.4%), respectively. Most of the farms had within-farm seroprevalence of

A province-wide cross-sectional seroprevalence and agroecological risk factor study of Mycobacterium avium subspecies paratuberculosis (MAP) and Neospora caninum (NC) infection among cattle in 100 cow-calf herds in Alberta was conducted. The seroprevalence of MAP in adult cattle was 1.5% across all herds. Using a widely accepted herd test cutpoint of 2 or more seropositive cows out of 30 animals tested, 7.9% of herds were estimated to be infected (95% confidence interval (CI): 2.3-23.4%). Seroprevalence of MAP differed by agroecological region; specifically, cattle and herds in areas with high soil pH (> 7.0), southern latitudes, and arid climates had a moderately reduced risk of infection (P < 0.10). Seroprevalence of NC infection was 9.7% among adult beef cattle province-wide--these levels also varied by agroecological region--with 91.0% of herds infected overall.

Background: Host genetic factors are important determinants in tuberculosis (TB). The SLC11A1 (or NRAMP1) gene has been studied extensively for genetic association with TB, but with inconsistent findings. In addition, no study has yet looked into the effect of sex and age on the relationship between SLC11A1 polymorphisms and TB., Methods: A case-control study was conducted. In total, 278 pulmonary TB patients and 282 sex- and age-matched controls without TB were recruited. All subjects were ethnic Chinese. On the basis of linkage disequilibrium pattern, three genetic markers from SLC11A1 and one from the nearby IL8RB locus were selected and examined for association with TB susceptibility. These markers were genotyped using single strand conformation polymorphism analysis or fragment analysis of amplified products., Results: Statistically significant differences in allele (P = 0.0165, OR = 1.51) and genotype (P = 0.0163, OR = 1.59) frequencies of the linked markers SLC6a/b (classically called D543N and 3'UTR) of the SLC11A1 locus were found between patients and controls. With stratification by sex, positive associations were identified in the female group for both allele (P = 0.0049, OR = 2.54) and genotype (P = 0.0075, OR = 2.74) frequencies. With stratification by age, positive associations were demonstrated in the young age group (age < or =65 years) for both allele (P = 0.0047, OR = 2.52) and genotype (P = 0.0031, OR = 2.92) frequencies. All positive findings remained significant even after correction for multiple comparisons. No significant differences were noted in either the male group or the older age group. No significant differences were found for the other markers (one SLC11A1 marker and one IL8RB marker) either., Conclusion: This study confirmed the association between SLC11A1 and TB susceptibility and demonstrated for the first time that the association was restricted to females and the young age group.

A high-frequency transmitter has been designed for high data-rate biomedical telemetry. Although high frequencies face greater attenuation, transcutaneous transmission was successfully tested and verified using a 3.76 mm thick sample of porcine skin. The structure transmits over 440 microW of power, consumes about 4.9 mA of current from a 1.8 V supply, and achieves a phase noise of -72 dBc/Hz at 100 KHz. The transmitter operates at around 6.7 GHz with a 50 MHz tuning range and is fully integrated on the CMOS IBM7RF 0.18 microm process.

An indirect enzyme-linked immunosorbent assay (IELISA) was developed for the detection of equine serum antibodies to lipopolysaccharide of Salmonella enterica subsp. enterica serovar Abortusequi (LPS), a causative organism of Equine Paratyphoid. The data presented demonstrates that horses immunized with S. abortusequi LPS developed antibodies detectable by the IELISA. By comparison, the tube agglutination test (TAT) did not detect antibody to S. abortusequi LPS as consistently as the IELISA. The data suggests that the IELISA may be a more suitable test for the detection of serum antibodies to S. abortusequi than the TAT.

A province-wide, cross-sectional seroprevalence and agroecological risk factor study of Mycobacterium avium subspecies paratuberculosis (MAP), Neospora caninum (NC), Bovine leukemia virus (BLV), and Bovine viral diarrhea virus (BVDv) genotypes 1 and 2 (BVDv1 and BVDv2) infection in dairy cattle herds in Alberta was conducted. Among adults, the seroprevalence of MAP, NC, and BLV was 9.1%, 18.5%, and 26.9%, respectively. For MAP, based on a herd test cutpoint of 2 or more seropositive cows, 58.8% of herds were infected. Herd-level seroprevalence for NC and BLV was 98.7% and 86.7%, respectively, based on a herd-test cutpoint of 1 seropositive cow. Among unvaccinated dairy heifers, the seroprevalence for BVDv1 and BVDv2 infection was 28.4% and 8.9%, respectively, while herd-level infection was 53.4% and 19.7%. Seroprevalence for MAP varied moderately by agroecological region, whereas that for NC, BLV, and BVDv1 and BVDv2 did not. For MAP, aridity and soil pH (correlated features of the region) were also important.

Background: Cytokines play important roles in antiviral action. We examined whether polymorphisms of IFN-gamma,TNF-alpha and IL-10 affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS)., Methods: A case-control study was carried out in 476 Chinese SARS patients and 449 healthy controls. We tested the polymorphisms of IFN-gamma,TNF-alpha and IL-10 for their associations with SARS., Results: IFN-gamma +874A allele was associated with susceptibility to SARS in a dose-dependent manner (P < 0.001). Individuals with IFN-gamma +874 AA and AT genotype had a 5.19-fold (95% Confidence Interval [CI], 2.78-9.68) and 2.57-fold (95% CI, 1.35-4.88) increased risk of developing SARS respectively. The polymorphisms of IL-10 and TNF-alpha were not associated with SARS susceptibility., Conclusion: IFN-gamma +874A allele was shown to be a risk factor in SARS susceptibility.

We report the first case of Hb Phnom Penh where a molecular study was done on the patient's sample. The result confirmed the predicted DNA sequence change involved in the mutation, which was delineated by another group in 1998 using amino acid analysis.

Little is known about the innate immune response to severe acute respiratory syndrome (SARS) coronavirus (CoV) infection. Mannose-binding lectin (MBL), a key molecule in innate immunity, functions as an ante-antibody before the specific antibody response. Here, we describe a case-control study that included 569 patients with SARS and 1188 control subjects and used in vitro assays to investigate the role that MBL plays in SARS-CoV infection. The distribution of MBL gene polymorphisms was significantly different between patients with SARS and control subjects, with a higher frequency of haplotypes associated with low or deficient serum levels of MBL in patients with SARS than in control subjects. Serum levels of MBL were also significantly lower in patients with SARS than in control subjects. There was, however, no association between MBL genotypes, which are associated with low or deficient serum levels of MBL, and mortality related to SARS. MBL could bind SARS-CoV in a dose- and calcium-dependent and mannan-inhibitable fashion in vitro, suggesting that binding is through the carbohydrate recognition domains of MBL. Furthermore, deposition of complement C4 on SARS-CoV was enhanced by MBL. Inhibition of the infectivity of SARS-CoV by MBL in fetal rhesus kidney cells (FRhK-4) was also observed. These results suggest that MBL contributes to the first-line host defense against SARS-CoV and that MBL deficiency is a susceptibility factor for acquisition of SARS.

Enzyme-linked immunosorbent assay (ELISA) and culture are 2 common diagnostic tests for detecting Mycobacterium avium subsp. paratuberculosis (Map) in Johne's disease, but they are not as sensitive as polymerase chain reaction (PCR). However, inhibitors can coextract with the target DNA and cause interference in PCR. Development of an immune capture assay followed by PCR amplification can alleviate this problem. In this study, we were able to induce an immune response in chickens using heat or formalin inactivated Map. The purified immunoglobulin (Ig)Y has a molecular weight of 160 kDa. The titers were at 1:6400 and 1:12 800 at weeks 5 to 6 and 8 to 9, respectively, as determined by the IDEXX modified ELISA kit for Johne's disease. The IgY produced from inactivated bacterial cells had no effect on its ability to recognize live Map cells as illustrated by immunofluorescence assay and immune capture PCR results.

Background/aims: Jumping translocations are rare cytogenetic aberrations in haematological malignancies, the pathogenesis of which remains to be fully characterised. We investigated the mechanism of formation of jumping translocations in a case of adult common acute lymphoblastic leukaemia (ALL) positive for the Ph translocation., Methods: Interphase and metaphase fluorescence in situ hybridisation (FISH) was performed using several probe systems. Results were correlated with findings on conventional cytogenetics. Granulocytes, T-cells and leukaemic B-cells in peripheral blood were sorted by immunomagnetic method and the terminal restriction fragment (TRF) length of these cellular populations was determined by Southern blot analysis., Results: Duplicated BCR-ABL fusion signals were found on a dic(14;22)der(22)t(9;22) chromosome. Clonal jumping translocations, existing as evolutionary changes, involved the donor chromosomal segment distal to 1q12 jumping onto the telomere ends of 11q, 15p, 19p and 20p. Telomere length was decreased in the neoplastic B-cell population and contributed to the formation of the dicentric chromosome that showed absence of telomere repeats at fusion ends. Subsequent pericentromeric heterochromatin decondensation of chromosome 1q occurred, and this donor segment was randomly fused to the shortened telomere ends of non-homologous chromosomes., Conclusions: Both telomere shortening and pericentromeric heterochromatin decondensation contribute to the formation of jumping translocations, which is most probably a multi-stage process.

Osteonecrosis is a debilitating bone disease affecting adults who have recovered from severe acute respiratory syndrome in Hong Kong and China, but there are no data on its prevalence in children. We report 5 children with magnetic resonance imaging evidence of osteonecrosis. In view of the high prevalence and asymptomatic presentation of osteonecrosis, we suggest magnetic resonance imaging screening for osteonecrosis in children with severe acute respiratory syndrome.