Search

Purpose: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women., Methods: In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration., Results: Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy., Conclusion: Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients., Competing Interests: Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise Nur Aishah Mohd TaibConsulting or Advisory Role: Roche, AstraZeneca, MSD Veronique K.M. TanHonoraria: AstraZeneca (Inst), Roche (Inst)Consulting or Advisory Role: Bertis (Inst) Douglas F. EastonPatents, Royalties, Other Intellectual Property: Royalties from Boadicea risk prediction tool (Inst) Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. I may receive royalties if commercialization is realized (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, RocheNo other potential conflicts of interest were reported.

Objectives: This study seeks to provide an understanding of the changing experiences in caregivers of end-of-life patients in Hong Kong through exploring their caregiving journey., Methods: Using longitudinal individual qualitative interviews, a total of 14 caregivers of community-dwelling elderly patients receiving end-of-life care were recruited between 2015 and 2016. A series of in-depth interviews and observations were conducted in 14 cases during the end-of-life journey., Results: A thematic analysis revealed four sequential experiential stages, abbreviated as "CAPE" that caregivers confronted: Stage 1 Certainty, (1a) lack of certainty regarding the progression of decline at the end-stage of life (1b) feelings of despair as patients' function decreased; Stage 2 Ambivalence, (2a) feelings of ambivalence after decisions were made regarding EOL care, (2b) struggle over care responsibility within families; Stage 3 Perturbed, (3a) varied in quality of EOL care, (3b) depressed mood arisen from frequent exposure to the suffering of elderly patients; and Stage 4 Expectation, (4a) losing the caregiving role as patients showing signs of imminent death., Conclusions: These findings increase our understanding of caregivers' in-depth experience over time that arise within the structural context of end-of-life care. Our data highlights the need for end of life related knowledge and information, provision of a caring atmosphere and communication, and professional-led detachment in creating caregiving-friendly service in healthcare system, thus as to provide support and alleviate stress for caregivers with their critical responsibility and role during the course of end-of-life care.

Background and Aims: Arterial stiffness is a risk factor for chronic kidney disease progression (CKD). Pulse pressure is a surrogate marker of arterial stiffness. It is unclear if pulse pressure predicts CKD progression in type 2 diabetes mellitus., Methods: This was prospective study involving 1494 patients with estimated glomerular filtration rate (eGFR) ≥ 15 ml/min/1.73 m 2 . Carotid-femoral pulse wave velocity was measured using applanation tonometry. Pulse pressure was calculated as difference between systolic and diastolic blood pressures. CKD progression was defined as worsening of eGFR categories (stage 1, ≥ 90 ml/min/1.73 m 2 ; stage 2, 60-89 ml/min/1.73 m 2 ; stage 3a, 45-59 ml/min/1.73 m 2 ; stage 3b, 30-44 ml/min/1.73 m 2 ; stage 4; 15-29 ml/min/1.73 m 2 ; and stage 5, < 15 ml/min/1.73 m 2 ) with ≥ 25% decrease in eGFR from baseline., Results: After follow-up of up to 6 years, CKD progression occurred in 33.5% of subjects. Subjects in 2nd, 3rd and 4th quartiles of peripheral pulse pressure experienced higher risk of CKD progression with unadjusted hazard ratios (HRs) 1.55 [95% confidence interval (CI) 1.13-2.11; p = 0.006], 2.58 (1.93-3.45; p < 0.001) and 3.41 (2.58-4.52; p < 0.001). In the fully adjusted model, the association for 2nd, 3rd and 4th quartiles remained with HRs 1.40 (1.02-1.93; p = 0.038), 1.87 (1.37-2.56; p < 0.001) and 1.75 (1.25-2.44; p = 0.001) respectively. Similarly, 2nd, 3rd and 4th quartiles of aortic pulse pressure were associated with higher hazards of CKD progression with HRs 1.73 (1.25-2.40; p = 0.001), 1.65 (1.18-2.29; p = 0.003) and 1.81 (1.26-2.60; p = 0.001). Increasing urinary albumin-to-creatinine ratio accounted for 44.0% of the association between peripheral pulse pressure and CKD progression., Conclusions: Individuals with high pulse pressure were more susceptible to deterioration of renal function. Pulse pressure could potentially be incorporated in clinical practice as an inexpensive and readily available biomarker of renal decline in type 2 diabetes mellitus. Graphic abstract., (© 2021. Italian Society of Nephrology.)

Objectives: To investigate whether there were any socioeconomic disparities in utilisation of hospital care services during end of life in Hong Kong., Methods: Secondary data analyses were conducted using frequency of the accident and emergency (A&E) department visits and hospital admissions during the last year of life in all public hospitals from 2004 to 2014 in Hong Kong. A total of 1 237 044 A&E records from 357 853 patients, and 1 878 982 admission records from 375 506 patients were identified for analyses. In total, 395 019 unique deceased patients were identified from both datasets., Results: Regression analyses showed that comprehensive social security assistance (CSSA) recipients used A&E services 1.29 times more than the non-recipients. Being either a CSSA recipient or an elderly home resident was more likely to be admitted to hospitals and stayed longer. Elderly home residents tended to stay longer than those from the community in the earlier months during the last year of life regardless of CSSA status; however, non-elderly home residents surpassed the residents in the duration of stay at hospitals towards the later months of the last year of life. There were also significant differences in hospital utilisation across various districts of residence., Conclusions: People of lower socioeconomic position tend to have higher emergency visits and hospitalisation during their last year of life in Hong Kong, implying the presence of health inequality during end of life. However, due to Hong Kong's largely pro-rich primary care system, the predominantly public A&E and inpatient services may inadvertently act as a mitigator of such health inequalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Key Points: Chemogenetic activation of medial vestibular nucleus-projecting 5-HT neurons resulted in deficits in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. The 5-HT 1A receptor mediates the vestibular-related behavioural effects of 5-HT in the vestibular nucleus. 5-HT 1A receptor activation attenuated evoked excitatory postsynaptic currents and evoked inhibitory postsynaptic currents via a presynaptic mechanism in the vestibular nucleus., Abstract: While the anxiolytic effects of serotonergic neuromodulation are well studied, its role in sensorimotor coordination and postural control is unclear. In this study, we show that an increase of serotonin (5-hydroxytryptamine, 5-HT) at the medial vestibular nucleus (MVN), a brainstem centre for vestibulospinal coordination, by either direct cannula administration or chemogenetic stimulation of MVN-projecting serotonergic neurons, adversely affected performance of rats in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. Application of the 5-HT 1 and 5-HT 7 receptor co-agonist 8-hydroxy-2-(di-n-propylamino) tetralin recapitulated the effect of 5-HT, while co-administration of the specific 5-HT 1A receptor antagonist WAY 100135 effectively abolished all 5-HT-induced behavioural deficits. This indicated that 5-HT 1A receptors mediated the effects of 5-HT in the rat MVN. Using whole-cell patch-clamp recording, we demonstrated that 5-HT 1A receptor activation attenuated both evoked excitatory and evoked inhibitory postsynaptic currents through a presynaptic mechanism in the rat MVN. The results thus highlight the 5-HT 1A receptor as the gain controller of vestibular-related brainstem circuits for posture and balance., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Aim: To examine correlation between vascular measures and cognitive performance in type 2 diabetes (T2D)., Methods: This was a cross-sectional study on patients (N = 1167) aged ≥45 years attending Diabetes Centre in a tertiary hospital and primary care polyclinic. The following vascular measures were measured: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), pulse wave velocity (PWV) and augmentation index (AI). Cognition was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine relationships between vascular measures and cognition, adjusting for demographics, education, depression, clinical covariates and presence of APOE Ɛ 4 allele., Results: In unadjusted analyses, all the vascular measures, except for MAP, were associated with RBANS total score. In fully adjusted analyses, the association with RBANS total score persisted for peripheral PP, aortic PP and aortic DBP with βs -0.05 (95%CI -0.07 to -0.02; p = 0.001), -0.04 (95%CI -0.06 to -0.01; p = 0.002) and 0.05 (95%CI 0.00 to 0.09; p = 0.033). Association between peripheral and aortic PP and RBANS total score was unaffected by age-stratification (age <60 and ≥60 years). In contrast, significant association between aortic DBP and RBANS total score was only observed for those ≥60 years. Peripheral and aortic PP (which estimate pulsatility) are negatively associated with attention, visuospatial/constructional and language ability., Conclusions: Peripheral and aortic PP, and aortic DBP were independently correlated with cognitive performance globally and in multiple domains. Further research should be conducted to establish the clinical relevance and importance., Competing Interests: Declaration of competing interest The authors report no potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To investigate the association between baseline plasma zinc-α2-glycoprotein and non-albuminuric chronic kidney disease progression in type 2 diabetes., Methods: Adults with normoalbuminuria at entry (n=341; age 57±10 years, 52% men) were analysed. Chronic kidney disease progression was defined as a decrease in chronic kidney disease stage and a decline of ≥25% in estimated GFR from baseline. Baseline plasma zinc-α2-glycoprotein levels were quantified by immunoassay, and analysed either as a continuous variable or by tertiles in Cox proportional hazards models. Model discrimination was assessed using Harrell's C-index. A sensitivity analysis was performed on a subset of individuals who maintained normoalbuminuria during follow-up., Results: Chronic kidney disease progression occurred in 54 participants (16%). Zinc-α2-glycoprotein levels were elevated in chronic kidney disease progressors (P = 0.011), and more progressors were assigned to the higher zinc-α2-glycoprotein tertile than non-progressors. In the unadjusted Cox model, zinc-α2-glycoprotein, both as a continuous variable (hazard ratio 1.72, 95% CI 1.08-2.75) and tertile 3 (vs tertile 1; hazard ratio 2.14, 95% CI 1.10-4.17), predicted chronic kidney disease progression. The association persisted after multivariable adjustment. The C-index of the Cox model increased significantly after incorporation of zinc-α2-glycoprotein into a base model comprising renin-angiotensin system antagonist usage. Sensitivity analysis showed that zinc-α2-glycoprotein independently predicted chronic kidney disease progression among individuals who maintained normoalbuminuria during follow-up., Conclusions: Plasma zinc-α2-glycoprotein is associated with chronic kidney disease progression, and may serve as a useful early biomarker for predicting non-albuminuric chronic kidney disease progression in type 2 diabetes., (© 2020 Diabetes UK.)

We explore the intergenerational pattern of resource transfer and possible associated factors. A scoping review was conducted of quantitative, peer-reviewed, English-language studies related to intergenerational transfer or interaction. We searched AgeLine, PsycINFO, Social Work Abstracts, and Sociological Abstracts for articles published between Jane 2008 and December 2018. Seventy-five studies from 25 countries met the inclusion criteria. The scoping review categorised resource transfers into three types: financial, instrumental, and emotional support. Using an intergenerational solidarity framework, factors associated with intergenerational transfer were placed in four categories: (1) demographic factors (e.g., age, gender, marital status, education, and ethno-cultural background); (2) needs and opportunities factors, including health, financial resources, and employment status; (3) family structures, namely, family composition, family relationship, and earlier family events; and (4) cultural-contextual structures, including state policies and social norms. Those factors were connected to the direction of resource transfer between generations. Downward transfers from senior to junior generations occur more frequently than upward transfers in many developed countries. Women dominate instrumental transfers, perhaps influenced by traditional gender roles. Overall, the pattern of resource transfer between generations is shown, and the impact of social norms and social policy on intergenerational transfers is highlighted. Policymakers should recognise the complicated interplay of each factor with different cultural contexts. The findings could inform policies that strengthen intergenerational solidarity and support.

Background: In response to population aging, there is a need for health systems to focus on care for chronic disease, specifically palliative care, while focusing on people-centered care. The objective of this study is to explore the healthcare system enablers and barriers to the provision of quality palliative and end-of-life care from the perspective of healthcare professionals., Materials and Methods: Using purposive sampling, fifteen focus group interviews and nine individual interviews involving 72 healthcare providers were conducted. Primary qualitative data were collected between May 2016 and July 2017. All recorded discussions were transcribed verbatim and analyzed. A thematic framework was developed., Results: The provision of quality palliative and end-of-life care is influenced by the interaction and integration of nine sub-themes under four identified themes: (1) political context; (2) organization setting; (3) support to patients, caregivers, and family members, and (4) healthcare workers and the public., Conclusions: Integration of palliative and end-of-life care is an important pillar of healthcare service to improve quality of life by addressing patients' values, wishes and preference, and assist their family to handle challenges at the end stage of life. Further improvements to the service framework would be required, specifically in the political framework, multidisciplinary approach, and readiness and competence in healthcare workers and community. These were highlighted in our study as key components in service provision to ensure that patients can receive continuous and integrated care between hospitals and the community as well as dignified care at the end stage of life.

End-of-life (EOL) care for terminal illness and life-limiting conditions is a sector in the health service spectrum that is drawing increased attention. Despite having the world's longest life expectancy and an ever-escalating demand for long-term care, Hong Kong's EOL care was underdeveloped. The current study aims to provide a holistic picture of gaps and issues to EOL care in Hong Kong. Data collection was conducted using a multi-method qualitative approach that included focus groups and in-depth interviews with key informants and stakeholders, and longitudinal case studies with patients and families. Deductive thematic analysis was used to examine service gaps in current EOL care through the lens of a socioecological model where gaps and issues in various nested, hierarchical levels of care as well as the relationships between these levels were studied in detail. Using the model, we identified gaps and issues of EOL care among older populations in Hong Kong at the policy, legal, community, institutional, as well as intrapersonal and interpersonal levels. These include but are not limited to a lack of overarching EOL care policy framework, ambiguity in the legal basis for mental incapacity, legislative barriers for advance directives, inadequate capacity, resources, and support in the community to administer EOL care, inadequate knowledge, training, and resources for EOL care in health and social care sectors, inadequate medical-social interface, general reluctance and fear of death and dying, as well as the cultural interpretation of filial piety that may lengthen the suffering of the dying patients. Findings highlight the multi-level gaps and issues of EOL care in a place where western and eastern culture meet, and shed light on how best to design more effective and comprehensive policy interventions that will likely have a more sustainable and instrumental impact on facilitating person-centered EOL care during the end of life.

Objective: In this cross-sectional analysis, we sought to assess the relationship of adiposity and forearm microvascular reactivity with cognitive dysfunction among older Asians with type 2 diabetes (T2D)., Methods: Subjects with T2D aged ≥ 55 years were analyzed (N = 907). Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Mini-Mental State Exam (MMSE). Visceral fat area (VFA) was estimated by tetrapolar multi-frequency bioimpedance. Forearm microvascular endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) were assessed by laser Doppler imaging with iontophoresis., Results: RBANS total score was correlated with VFA, EDV, and EIV (all P < .05). However, VFA was correlated with EIV, but not with EDV. Multivariable linear regression showed significant association between VFA and RBANS total score (B = -0.02, 95% CI= -0.03 to -0.01) or memory (immediate and delayed) index scores. These associations were attenuated after adjustment for EIV. Mediation analysis showed that EIV partially mediated the relationship between visceral adiposity and RBANS scores (all Sobel tests P < .05). EIV also mediated the relationship between VFA and MMSE score., Conclusions: Impaired endothelium-independent vascular smooth muscle reactivity may exert a mediatory effect on the association between increased visceral adiposity and decreased cognitive performance in older adults with T2D., (© 2020 John Wiley & Sons Ltd.)

Introduction: Diabetic peripheral neuropathy (DPN) is a common microvascular complication in patients with type 2 diabetes (T2D). Apart from hyperglycemia, few modifiable risk factors have been identified. Endothelin-1 is a potent vasoconstrictor peptide, implicated in the causal pathway of microangiopathy. We investigated whether baseline plasma endothelin-1 and other metabolic and vascular risk factors predicted the incidence of DPN., Design: This is a 3-year observational, cohort study., Methods: In patients with T2D (n = 2057), anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements. Forearm cutaneous endothelial reactivity was assessed by iontophoresis and laser Doppler flowmetry/imaging. Measurements were repeated on follow-up. Incident DPN was considered present if an abnormal finding in monofilament (<8 of 10 points) or neurothesiometer testing was ≥25 volts on either foot at 3-year follow-up, but normal at baseline. Plasma endothelin-1 was assessed by ELISA., Results: At baseline, mean age of patients was 57.4 ± 10.8 years old and prevalence of DPN was 10.8%. Of the 1767 patients without DPN, 1250 patients returned for follow-up assessment ((2.9 ± 0.7) years), with a 10.7% incidence of DPN. Patients with incident DPN had significantly higher baseline endothelin-1 (1.43 (1.19-1.73) vs 1.30 (1.06-1.63)) pg/mL, P < 0.0001. Multivariable Cox proportional hazards ratio showed a 1-s.d. increase in log endothelin-1 (adjusted HR: 4.345 (1.451-13.009), P = 0.009), systolic blood pressure (per 10-unit) (adjusted HR: 1.107 (1.001-1.223), P = 0.047) and diabetes duration (adjusted HR: 1.025 (1.004-1.047), P = 0.017) predicted incident DPN, after adjustment for glycemic control, eGFR, albuminuria, peripheral arterial disease and retinopathy status., Conclusion: Higher baseline endothelin-1, blood pressure and diabetes duration were significant and independent predictors for incident DPN. Validation of our findings in independent cohorts and molecular mechanistic studies will help better our understanding on the role of endothelin-1 in DPN.

Literature evaluating the relationship between central obesity and cognitive deficits in type 2 diabetes (T2DM) remains scarce. This cross-sectional analysis explored the association of novel and traditional central obesity measures with cognitive performance in older (aged ≥60 years) non-demented multi-ethnic Asians with T2DM, including a stratified analysis by body mass index (BMI). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Central obesity measures including visceral fat area (VFA), waist circumference, waist:hip ratio, waist:height ratio, abdominal volume index, body roundness index and conicity index were measured and/or computed. In our cohort (N = 677; mean age = 67 ± 5 years, 51.7% men), VFA emerged as an associate of overall cognitive performance after covariate adjustment and Bonferroni correction (β = -.10, 95% CI = -0.18, -0.03), outperforming the other adiposity indices. Specifically, VFA was inversely associated with delayed memory and language scores. Additionally, compared with normal-weight individuals, excess visceral obesity (VFA ≥100 cm 2 ) was independently associated with lower cognitive scores to a greater extent in normal BMI (<23 kg/m 2 ) adults than in those with high BMI (≥23 kg/m 2 ). Assessment and management of visceral adiposity may help to prevent cognitive decline in older people with T2DM, and reduce the global burden of dementia in ageing populations., (© 2020 World Obesity Federation.)

Aims: Poor glycaemic control elevates the risk for vascular complications. Biomarkers for predicting susceptibility to glycaemic worsening are lacking. This 3-year prospective analysis assessed the utility of several circulating diabetes-related biomarkers for predicting loss of glycaemic control, and their contribution to albuminuria progression in type 2 diabetes mellitus (T2DM)., Methods: T2DM subjects with adequately-controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 859). Baseline plasma levels of osteoprotegerin (OPG), C-reactive protein (CRP), adiponectin, intercellular-cell adhesion molecule-1, and vascular-cell adhesion molecule-1 were quantified using immunoassay. Definitions for development of uncontrolled diabetes and albuminuria progression were HbA1c ≥ 8.0% and increase in albuminuria category at follow-up, respectively., Results: At follow-up, 185 subjects developed uncontrolled diabetes. Higher baseline CRP and OPG levels were observed in the high-risk individuals, and predicted increased risk for developing uncontrolled diabetes. OPG, but not CRP, was associated with albuminuria progression after multivariable adjustment. The relationship was attenuated following adjustment for development of uncontrolled diabetes, which emerged as a significant associate. Mediation analysis revealed that loss of glycaemic control explained 64.5% of the relationship between OPG and albuminuria progression., Conclusions: OPG outperformed other diabetes-related biomarkers to be a potentially useful biomarker for predicting loss of glycaemic control and its associated albuminuria deterioration., 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 © 2020 Elsevier B.V. All rights reserved.)

Lower extremity skeletal muscle mass (LESM) in Type 2 Diabetes (T2D) has been linked to adverse clinical events, but it is not known whether it is associated with cognitive difficulties. We conducted a cross-sectional study on 1,235 people (mean age 61.4 ± 8.0 years) with T2D under primary and secondary care in Singapore. Bioelectrical impedance analyses (BIA) measures of upper extremity skeletal muscle mass (UESM), LESM and appendicular skeletal muscle index (SMI) were related to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measures of cognition, in multiple linear regression. In multivariable models, tertile 1 LESM (b = -2.62 (-3.92 to -1.32)) and tertile 2 LESM (b = -1.73 (-2.73 to -0.73)), referenced to tertile 3) were significantly associated with decreased RBANS total score. Significant associations of LESM with cognitive domain performances were observed for tertile 1 (b = -3.75 (-5.98 to -1.52)) and tertile 2 (b = -1.98 (-3.69 to -0.27)) with immediate memory, and for tertile 1 (b = -3.05 (-4.86 to -1.24)) and tertile 2 (b = -1.87 (-3.25 to -0.48)) with delayed memory, and for tertile 1 (b = -2.99 (-5.30 to -0.68)) with visuospatial/constructional ability. Tertile 1 SMI (b = -1.94 (-3.79 to -0.08) and tertile 2 SMI (b = -1.75 (-3.14 to -0.37)) were also associated with delayed memory. There were no associations between UESM with cognitive performance. Lower LESM may be a useful marker of possible co-occuring cognitive dysfunction.

Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders., Competing Interests: The authors have declared that no competing interests exist.

The kinesin I family of motor proteins are crucial for axonal transport, but their roles in dendritic transport and postsynaptic function are not well-defined. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates, but it is not clear whether and how they exhibit functional specificity. Here we show that knockdown of KIF5A or KIF5B differentially affects excitatory synapses and dendritic transport in hippocampal neurons. The functional specificities of the two kinesins are determined by their diverse carboxyl-termini, where arginine methylation occurs in KIF5B and regulates its function. KIF5B conditional knockout mice exhibit deficits in dendritic spine morphogenesis, synaptic plasticity and memory formation. Our findings provide insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in regulating postsynaptic function., Competing Interests: JZ, AF, RF, PK, HC, LL, YC, WY, JH, CL, KL No competing interests declared, (© 2020, Zhao et al.)

Aims: Increased adiposity confers elevated risk for diabetic kidney disease (DKD) progression in type 2 diabetes mellitus (T2DM). This 3-year prospective study examined whether worsening of metabolic control e.g. development of uncontrolled diabetes mediated the relationship between increased adiposity and DKD deterioration., Methods: T2DM subjects who had adequately controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 853). HbA1c ≥ 8% at follow-up was classified as development of uncontrolled T2DM. Absolute changes in body weight (ΔWeight), body mass index (ΔBMI), and body fat mass (ΔBFM) were calculated by subtracting baseline from follow-up values. DKD deterioration (outcome) was defined as an increase in the composite ranking of relative risk by glomerular filtration rate and albuminuria levels (Kidney Disease: Improving Global Outcomes 2009)., Results: Subjects with deteriorated DKD displayed lower reduction in body composition at follow-up than those who remained stable or/improved (all P < 0.05). In separate regression models, ΔWeight (risk ratio (RR):1.04, 95% CI:1.01-1.06), ΔBMI (RR:1.07, 95% CI:1.01-1.13), and ΔBFM (RR:1.03, 95% CI:1.01-1.06) were independently associated with worsened DKD. The associations were attenuated after accounting for the loss of glycaemic control. Binary mediation analysis revealed that the development of uncontrolled diabetes explained 41.7%, 45.4% and 39.7%, respectively, of the effects of ΔWeight, ΔBMI and ΔBFM on the outcome., Conclusions: Among T2DM individuals who had adequately-controlled T2DM at initial recruitment, the relationship between gain in adiposity and DKD deterioration is mediated by the development of poor glycaemic control over time. Therefore, preventing worsening adiposity and hyperglycaemia is pivotal to impede DKD progression., (Copyright © 2019. Published by Elsevier B.V.)

Background: This study evaluated the association between gain in adiposity and renal decline in a large prospective multiethnic South-east Asian cohort with type 2 diabetes mellitus (T2DM)., Methods: Three years after the baseline visit, 2057 T2DM subjects were recalled for reassessment. The final cohort comprised 1014 subjects and was categorized into tertiles based on changes in body weight (ΔWt), body mass index (ΔBMI), visceral fat area (ΔVFA), and BMI-adjusted VFA (ΔVFA BMI ). Outcomes included annual and rapid (≥3 mL/min per 1.73 m 2 per year) decline in estimated glomerular filtration rate (eGFR) and progression of albuminuria., Results: Participants (mean [±SD] age 57 ± 11 years, 48.8% women, BMI 27.7 ± 5.4 kg/m 2 ) exhibited a median annual decline in eGFR of 1.0 mL/min per 1.73 m 2 . Compared with the lower tertiles, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI had the highest anthropometric increase, albeit of modest magnitude, and this was accompanied by the worst renal outcomes (all P < 0.05). The relationship between annual eGFR decline and Tertile 3 of ΔWt, ΔBMI, and ΔVFA BMI persisted after multivariate adjustment in men but not in women. In addition, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFA BMI predicted rapid eGFR decline. Anthropometric gains were also associated with progression of albuminuria., Conclusions: Modest longitudinal gain in adiposity was associated with progressive renal decline in T2DM patients, suggesting that increased adiposity over time adversely affects renal outcomes. Therefore, a carefully designed weight-neutral or -loss antidiabetic treatment regimen is important when managing T2DM in the clinic., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Perineuronal nets (PN) restrict neuronal plasticity in the adult brain. We hypothesize that activity-dependent consolidation of PN is required for functional maturation of behavioral circuits. Using the postnatal maturation of brainstem vestibular nucleus (VN) circuits as a model system, we report a neonatal period in which consolidation of central vestibular circuitry for graviception is accompanied by activity-dependent consolidation of chondroitin sulfate (CS)-rich PN around GABAergic neurons in the VN. Postnatal onset of negative geotaxis was used as an indicator for functional maturation of vestibular circuits. Rats display negative geotaxis from postnatal day (P) 9, coinciding with the condensation of CS-rich PN around GABAergic interneurons in the VN. Delaying PN formation, by removal of primordial CS moieties on VN with chondroitinase ABC (ChABC) treatment at P6, postponed emergence of negative geotaxis to P13. Similar postponement was observed following inhibition of GABAergic transmission with bicuculline, in line with the reported role of PN in increasing excitability of parvalbumin neurons. We further reasoned that PN-CS restricts bioavailability of plasticity-inducing factors such as semaphorin 3A (Sema3A) to bring about circuit maturation. Treatment of VN explants with ChABC to liberate PN-bound Sema3A resulted in dendritic growth and arborization, implicating structural plasticity that delays synapse formation. Evidence is thus provided for the role of PN-CS-Sema3A in regulating structural and circuit plasticity at VN interneurons with impacts on the development of graviceptive postural control.

Background: Fluctuation of kidney function may signify intra-glomerular microvascular hemodynamic instability. We aim to examine the association of long-term serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy., Methods: We included type 2 diabetes mellitus patients who attended the Diabetes Centre in 2011-2014 and were followed up (median = 3.2 years). Digital colour fundus photographs were assessed for diabetic retinopathy at follow-up. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. We conducted a nested case-control study involving 177 diabetic retinopathy (118 non-proliferative diabetic retinopathy, 50 proliferative diabetic retinopathy) and 327 age- and gender-matched non-diabetic retinopathy. Serum creatinine measured before follow-up visit was obtained (⩾3 readings/patient). Variability was calculated as intra-individual standard deviation/√ n/( n - 1)., Results: Diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-diabetic retinopathy [9.1 (4.9-21.6) vs 5.4 (3.4-10.1) µM, p < 0.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratio = 1.47, 95% confidence interval (1.02-2.10), p = 0.04]. The area under the curve increased significantly after adding adjusted-serum creatinine-standard deviation [0.70 (0.65-0.75) vs 0.72 (0.68-0.77), p < 0.03]. Proliferative diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-proliferative diabetic retinopathy [15.5 (6.6-39.7) vs 7.47 (4.52-17.8) µM, p < 0.001]. After adjustment, adjusted-serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04-2.12), p = 0.03] and proliferative diabetic retinopathy [2.43 (1.34-4.39), p = 0.003; p-trend = 0.002]. Similar findings were observed for estimated glomerular filtration rate variability., Conclusion: Serum creatinine and estimated glomerular filtration rate variability is associated with the presence and severity of diabetic retinopathy independent of intra-individual means. This may inform novel therapeutic strategies aiming to achieve stable renal function in type 2 diabetes mellitus.

Aim: Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m 2 ) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m 2 )., Methods: This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002-2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline., Results: Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21-5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06-8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline., Conclusion: Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

Objectives: According to the 2015 Quality of Death Index published by the Intelligence Unit of the Economist, Hong Kong is ranked 22nd in terms of quality of palliative care in the world, behind many other major developed countries in Asia, including Taiwan, Singapore, Japan, and South Korea. The objectives of the present study were to describe the knowledge, attitude, and preferences of the general Hong Kong adult population across different age groups regarding end-of-life (EOL) care decisions, place of care and death, as well as advance directive (AD)., Methods: This was a population-based cross-sectional survey conducted by telephone. A total of 1067 adults over 30 years old were contacted through residential telephone lines using a random sampling method and were interviewed. Information on sociodemographic factors, general health status, chronic diseases, knowledge, attitude and preferences of advance decisions, EOL care, and place of death were collected., Results: A total of 85.7% had not heard of AD, but 60.9% would prefer to make their own AD if legislated after explanation; and for those who did not prefer to have an AD, the predominant concern was the possible change of mind afterward. Adjusted logistic regression suggested that female participants were less willing to make an AD, whereas those with prior knowledge of do-not-attempt-cardiopulmonary-resuscitation significantly increased the chance of making an AD. In terms of life-sustaining treatments, a predominant 87.6% preferred to receive appropriate palliative care that gives comfort rather than to prolong life if being diagnosed to be terminally ill; 43% disagreed that doctors should generally try to keep patients alive for as long as possible; and 86.2% agreed that the patient's own wishes should determine what treatment he/she should receive. Adjusted logistic regression showed that palliative care was more preferred by age groups 50 years or above but was less preferred by those who did not care for their family members with chronic diseases. Regarding place of death, 31.2% of the participants would choose to die at home, and among those, 19.5% would still prefer to die at home even if they did not have sufficient support. Adjusted logistic regression showed a decreased trend for all older age groups from 40-49 years to 80+ years, as well as having poor self-rated health, to prefer to die at home. Being a female participant and having education level of tertiary or above, however, had higher preference for death at home., Conclusions: This is the first population-representative survey of the general Hong Kong adult population on the knowledge, attitude, and preferences of AD, EOL care, and place of care/death. The main implication of this study was that preferences to have autonomy over own EOL care, to receive palliative care, and to die at home were greater than the actual practice currently, highlighting the service gaps for better EOL care in the future., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors., Methods: Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts., Results: Compared to Caucasian women, percent density was 2.0% higher among Asian women (p < 0.001), and dense volume was 5.7 cm 3 higher among pre-menopausal Asian women (p < 0.001). Dense volume was 3.0 cm 3 lower among post-menopausal Asian women (p = 0.009) compared to post-menopausal Caucasian women, and this difference was attributed to population differences in height, weight, and parity (p < 0.001)., Conclusions: Our analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.

Uncovering clinical research trends allows us to understand the direction of healthcare services and is essential for longer-term healthcare planning. The Hospital Authority Convention is a mainstream annual healthcare conference that gathers up-to-date Hong Kong medical research. We propose to use state-of-the-art medical document mining and topic modelling methods to uncover latent themes and structures in the publications. We collected 742 articles from HA Convention from the year 2013 to 2016 and selected 56 publications from the category of "Clinical Safety and Quality Service" for further analysis. Applying natural language processing and Latent Dirichlet Allocation (LDA) methods, we identified 7 potential topics, namely: surgical operation, hospital discharge, medical error, nursing procedure, service performance assessment, patient and staff engagement, and admission algorithm and standardisation. This exploratory study demonstrates that key themes exist in the annual HA Convention and we observe potential changes in healthcare services focus over the years in the selected category.

Background: APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system., Methods: In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT., Results: The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values < 0.05). Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells (P < 0.001)., Conclusions: Taken together, our data suggests that tumour-infiltrating immune cells may be an important feature of breast cancers arising in women with APOBEC3B germline deletion, and that this may be of particular interest in Asian women where the germline deletion is more common.

Aims: Physiological equivalent temperature (PET) is a widely used index to assess thermal comfort of the human body. Evidence on how thermal stress-related health effects vary with small geographical areas is limited. The objectives of this study are (i) to explore whether there were significant patterns of geographical clustering of thermal stress as measured by PET and mortality and (ii) to assess the association between PET and mortality in small geographical areas., Methods: A small area ecological cross-sectional study was conducted at tertiary planning units (TPUs) level. Age-standardized mortality rates (ASMR) and monthly deaths at TPUs level for 2006 were calculated for cause-specific diseases. A PET map with 100 m × 100 m resolution for the same period was derived from Hong Kong Urban Climatic Analysis Map data and the annual and monthly averages of PET for each TPU were computed. Global Moran's I and local indicator of spatial association (LISA) analyses were performed. A generalized linear mixed model was used to model monthly deaths against PET adjusted for socio-economic deprivation., Results: We found positive spatial autocorrelation between PET and ASMR. There were spatial correlations between PET and ASMR, particularly in the north of Hong Kong Island, most parts of Kowloon, and across New Territories. A 1°C change in PET was associated with an excess risk (%) of 2.99 (95% CI: 0.50-5.48) for all natural causes, 4.75 (1.14-8.36) for cardiovascular, 7.39 (4.64-10.10) for respiratory diseases in the cool season, and 4.31 (0.12 to 8.50) for cardiovascular diseases in the warm season., Conclusions: Variations between TPUs in PET had an important influence on cause-specific mortality, especially in the cool season. PET may have an impact on the health of socio-economically deprived population groups. Our results suggest that targeting policy interventions at high-risk areas may be a feasible option for reducing PET-related mortality., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: A significant increase in mortality was observed during cold winters in many temperate regions. However, there is a lack of evidence from tropical and subtropical regions, and the influence of ambient temperatures on seasonal variation of mortality was not well documented., Methods: This study included 213,737 registered deaths from January 2003 to December 2011 in Guangzhou, a subtropical city in Southern China. Excess winter mortality was calculated by the excess percentage of monthly mortality in winters over that of non-winter months. A generalized linear model with a quasi-Poisson distribution was applied to analyze the association between monthly mean temperature and mortality, after controlling for other meteorological measures and air pollution., Results: The mortality rate in the winter was 26% higher than the average rate in other seasons. On average, there were 1,848 excess winter deaths annually, with around half (52%) from cardiovascular diseases and a quarter (24%) from respiratory diseases. Excess winter mortality was higher in the elderly, females and those with low education level than the young, males and those with high education level, respectively. A much larger winter increase was observed in out-of-hospital mortality compared to in-hospital mortality (45% vs. 17%). We found a significant negative correlation of annual excess winter mortality with average winter temperature (rs=-0.738, P=0.037), but not with air pollution levels. A 1 °C decrease in monthly mean temperature was associated with an increase of 1.38% (95% CI:0.34%-2.40%) and 0.88% (95% CI:0.11%-1.64%) in monthly mortality at lags of 0-1 month, respectively., Conclusion: Similar to temperate regions, a subtropical city Guangzhou showed a clear seasonal pattern in mortality, with a sharper spike in winter. Our results highlight the role of cold temperature on the winter mortality even in warm climate. Precautionary measures should be strengthened to mitigate cold-related mortality for people living in warm climate.

Background: To complement available information on mortality in a population Standard Expected Years of Life Lost (SEYLL), an indicator of premature mortality, is increasingly used to calculate the mortality-associated disease burden. SEYLL consider the age at death and therefore allow a more accurate view on mortality patterns as compared to routinely used measures (e.g. death counts). This study provides a comprehensive assessment of disease and injury SEYLL for Hong Kong in 2010., Methods: To estimate the SEYLL, life-expectancy at birth was set according to the 2004 Global Burden of Disease study at 82.5 and 80 years for females and males, respectively. Cause of death data for 2010 were corrected for misclassification of cardiovascular and cancer causes. In addition to the baseline estimates, scenario analyses were performed using alternative assumptions on life-expectancy (Hong Kong standard life-expectancy), time-discounting and age-weighting. To estimate a trend of premature mortality a time-series analysis from 2001 to 2010 was conducted., Results: In 2010 524,706.5 years were lost due to premature death in Hong Kong with 58.3% of the SEYLL attributable to male deaths. The three overall leading single causes of SEYLL were "trachea, bronchus and lung cancers", "ischaemic heart disease" and "lower respiratory infections" together accounting for about 29% of the overall SEYLL. Further, self-inflicted injuries (5.6%; ranked 5) and liver cancer (4.9%; ranked 7) were identified as important causes not adequately captured by classical mortality measures. Scenario analyses highlighted that by using a 3% time-discount rate and non-uniform age-weights the SEYLL dropped by 51.6%. Using Hong Kong's standard life-expectancy values resulted in an overall increase of SEYLL by 10.8% as compared to the baseline SEYLL. Time-series analysis indicates an overall increase of SEYLL by 6.4%. In particular, group I (communicable, maternal, perinatal and nutritional) conditions showed highest increases with SEYLL-rates per 100,000 in 2010 being 1.4 times higher than 2001., Conclusions: The study stresses the mortality impact of diseases and injuries that occur in earlier stages of life and thus presents the SEYLL measure as a more sensitive indicator compared to classical mortality indicators. SEYLL provide useful additional information and supplement available death statistics.

Background: Populations in Asia are not only at risk of harm to their health through environmental degradation as a result of worsening pollution problems but also constantly threatened by recurring and emerging influenza epidemics and. pandemics. Situated in the area with the world's fastest growing economy and close to hypothetical epicenters of influenza transmission, Hong Kong offers a special opportunity for testing environmental management and public health surveillance in the region. In the Public Health and Air Pollution in Asia (PAPA*) project, the Hong Kong research team assessed the health effects of air pollution and influenza as well as the interaction between them. The team also assessed disparities in the health effects of air pollution between relatively deprived and more affluent areas in Hong Kong. The aim was to provide answers to outstanding research questions relating to the short-term effects of air pollution on mortality and hospital admissions; the health effects of influenza with a view to validating different measures of influenza activity according to virologic data; the confounding effects of influenza on estimates of the health effects of air pollution; the modifying effects of influenza on the health effects of air pollution; and the modifying effects of neighborhood social deprivation on the health effects of air pollution., Data: Data on mortality and hospital admissions for all natural causes, as well as the subcategories of cardiovascular diseases (CVD) and respiratory diseases (RD), were derived from the Hong Kong Census and Statistics Department and the Hospital Authority. Daily concentrations of nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter with an aerodynamic diameter < or = 10 pm (PM10); and ozone (O3) were derived from eight monitoring stations with hourly data that were at least 75% complete during the study period. Three measures of influenza and respiratory syncytial virus (RSV) activity were derived from positive isolates of specimens in the virology laboratory of Queen Mary Hospital (QMH), the main clinical teaching center at The University of Hong Kong and part of the Hong Kong Hospital Authority network of teaching hospitals: influenza intensity (defined as the weekly proportion of positive isolates of influenza in the total number of specimens received for diagnostic tests); the presence of influenza epidemic (defined as a period when the weekly frequency of these positive isolates is > or = 4% of the annual total number of positive isolates [i.e., twice the expected mean value] in two or more consecutive weeks); and influenza predominance (defined as a period of influenza epidemic when the weekly frequency of RSV was less than 2% for two or more consecutive weeks). The weekly proportion of positive isolates of RSV in total specimens was determined in the same way as for influenza intensity. A social deprivation index (SDI) was defined by taking the average of the proportions of households or persons with the following six characteristics in each geographic area using the census statistics: unemployment; household income < U.S. $250 per month; no schooling at all; never-married status; one-person household; and subtenancy. A Poisson regression with quasi-likelihood to account for overdispersion was used to develop core models for daily health outcomes, with a natural spline smoothing function to filter out seasonal patterns and long-term trends in this time-series study of daily mortality and hospital admissions, and with adjustment for days of the week, temperature, and relative humidity (RH). Air pollutant concentration values were entered into the core model to assess the health effects of specific pollutants. The possible confounding effects of influenza were assessed by observing changes in magnitude of the effect estimate when each influenza measurement was entered into the model; and interactions between air pollution and influenza were assessed by entering the terms for the product of the air pollutant concentration and a measurement of influenza activity into the model. A Poisson regression analysis was performed to assess the effects of air pollution in each area belonging to low, middle, or high social deprivation strata according to the tertiles of the SDI. The differences in air pollution effects were tested by a case-only approach. RESULTS The excess risk (ER) estimates for the short-term effects of air pollution on mortality and hospitalization for broad categories of disease were greater in those 65 years and older than in the all-ages group and were consistent with other studies. The biggest health impacts were seen at the extremes of the age range. The three measures employed for influenza activity based on virologic data-one based on a proportion and the other two using frequencies of positive influenza isolates-were found to produce consistent health impact estimates, in terms of statistical significance. In general, we found that adjustment for influenza activity in air pollution health effect estimations took account of relatively small confounding effects. However, we conclude that it is worthwhile to make the adjustment in a sensitivity analysis and to obtain the best possible range of effect estimates from the data, especially for respiratory hospitalization. Interestingly, interaction effects were found between influenza activity and air pollution in the estimated risks for hospitalization for RD, particularly for 03. These results could be explained in terms of the detrimental effects of both influenza viruses and air pollutants, which may be synergistic or competing with each other, though the mechanism is still unknown. The results deserve further study and the attention of both public health policy makers and virologists in considering prevention strategies. IMPLICATIONS In Hong Kong, where air pollution may pose more of a health threat than in North American and Western European cities, the effects of air pollution also interact with influenza and with residence in socially deprived areas, potentially leading to additional harm. Asian governments should be aware of the combined risks to the health of the population when considering environmental protection and management in the context of economic, urban, and infrastructure development. This is the first study in Asia to examine the interactions between air pollution, influenza, and social deprivation from an epidemiologic perspective. The biologic mechanisms are still unclear, and further research is needed.

Background: Influenza has been associated with a heavy burden of mortality. In tropical or subtropical regions where influenza viruses circulate in the community most of the year, it is possible that there are seasonal variations in the effects of influenza on mortality, because of periodic changes in environment and host factors as well as the frequent emergence of new antigenically drifted virus strains. In this paper we explored this seasonal effect of influenza., Methods: A time-varying coefficient Poisson regression model was fitted to the weekly numbers of mortality of Hong Kong from 1996 to 2002. Excess risks associated with influenza were calculated to assess the seasonal effects of influenza., Results: We demonstrated that the effects of influenza were higher in winter and late spring/early summer than other seasons. The two-peak pattern of seasonal effects of influenza was found for cardio-respiratory disease and sub-categories pneumonia and influenza, chronic obstructive pulmonary disease, cerebrovascular diseases and ischemic heart disease as well as for all-cause deaths., Conclusion: The results provide insight into the possibility that seasonal factors may have impact on virulence of influenza besides their effects on virus transmission. The results warrant further studies into the mechanisms behind the seasonal effect of influenza.

Background: Both influenza viruses and air pollutants have been well documented as major hazards to human health, but few epidemiologic studies have assessed effect modification of influenza on health effects of ambient air pollutants., Objectives: We aimed to assess modifying effects of influenza on health effects of ambient air pollutants., Methods: We applied Poisson regression to daily numbers of hospitalizations and mortality to develop core models after adjustment for potential time-varying confounding variables. We assessed modification of influenza by adding variables for concentrations of single ambient air pollutants and proportions of influenza-positive specimens (influenza intensity) and their cross-product terms., Results: We found significant effect modification of influenza (p < 0.05) for effects of ozone. When influenza intensity is assumed to increase from 0% to 10%, the excess risks per 10-microg/m(3) increase in concentration of O(3) increased 0.24% and 0.40% for hospitalization of respiratory disease in the all-ages group and >or= 65 year age group, respectively; 0.46% for hospitalization of acute respiratory disease in the all-ages group; and 0.40% for hospitalization of chronic obstructive pulmonary disease in the >or= 65 group. The estimated increases in the excess risks for mortality of respiratory disease and chronic obstructive pulmonary disease in the all-ages group were 0.59% and 1.05%, respectively. We found no significant modification of influenza on effects of other pollutants in most disease outcomes under study., Conclusions: Influenza activity could be an effect modifier for the health effects of air pollutants particularly for O(3) and should be considered in the studies for short-term effects of air pollutants on health.

The causal interpretation of reported associations between daily air pollution and daily admissions requires consideration of residual confounding, correlation between pollutants, and effect modification. If results obtained in Hong Kong and London--which differ in climate, lifestyle, and many other respects--were similar, a causal association would be supported. We used identical statistical methods for the analysis in each city. Associations between daily admissions and pollutant levels were estimated using Poisson regression. Nonparametric smoothing methods were used to model seasonality and the nonlinear dependence of admissions on temperature, humidity, and influenza admissions. For respiratory admissions (> or = 65 years of age), significant positive associations were observed with particulate matter < 10 microm in aerodynamic diameter (PM(10), nitrogen dioxide, sulfur dioxide, and ozone in both cities. These associations tended to be stronger at shorter lags in Hong Kong and at longer lags in London. Associations were stronger in the cool season in Hong Kong and in the warm season in London, periods during which levels of humidity are at their lowest in each city. For cardiac admissions (all ages) in both cities, significant positive associations were observed for PM(10), NO(2), and SO(2) with similar lag patterns. Associations tended to be stronger in the cool season. The associations with NO(2) and SO(2) were the most robust in two-pollutant models. Patterns of association for pollutants with ischemic heart disease were similar in the two cities. The associations between O(3) and cardiac admissions were negative in London but positive in Hong Kong. We conclude that air pollution has remarkably similar associations with daily cardiorespiratory admissions in both cities, in spite of considerable differences between cities in social, lifestyle, and environmental factors. The results strengthen the argument that air pollution causes detrimental short-term health effects.