An in silico study of the effects of cardiovascular aging on carotid flow waveforms and indexes in a virtual population.

Cardiovascular aging is strongly associated with increased risk of cardiovascular disease and mortality. Moreover, health and lifestyle factors may accelerate age-induced alterations, such as increased arterial stiffness and wall dilation, beyond chronological age, making the clinical assessment of cardiovascular aging an important prompt for preventative action. Carotid flow waveforms contain information about age-dependent cardiovascular properties, and their ease of measurement via noninvasive Doppler ultrasound (US) makes their analysis a promising tool for the routine assessment of cardiovascular aging. In this work, the impact of different aging processes on carotid waveform morphology and derived indexes is studied in silico, with the aim of establishing the clinical potential of a carotid US-based assessment of cardiovascular aging. One-dimensional (1-D) hemodynamic modeling was employed to generate an age-specific virtual population (VP) of N = 5,160 realistic carotid hemodynamic waveforms. The resulting VP was statistically validated against in vivo aging trends in waveforms and indexes from the literature, and simulated waveforms were studied in relation to age and underlying cardiovascular parameters. In our study, the carotid flow augmentation index (FAI) significantly increased with age (with a median increase of 50% from the youngest to the oldest age group) and was strongly correlated to local arterial stiffening (r = 0.94). The carotid pulsatility index (PI), which showed less pronounced age variation, was inversely correlated with the reflection coefficient at the carotid branching (r = -0.88) and directly correlated with carotid net forward wave energy (r = 0.90), corroborating previous literature where it was linked to increased risk of cerebrovascular damage in the elderly. There was a high correlation between corrected carotid flow time (ccFT) and cardiac output (CO) (r = 0.99), which was not affected by vascular age. This study highlights the potential of carotid waveforms as a valuable tool for the assessment of cardiovascular aging.NEW & NOTEWORTHY An age-specific virtual population was generated based on a 1-D model of the arterial circulation, including newly defined literature-based specific age variations in carotid vessel properties. Simulated carotid flow/velocity waveforms, indexes, and age trends were statistically validated against in vivo data from the literature. A comprehensive study of the impact of aging on carotid flow waveform morphology was performed, and the mechanisms influencing different carotid indexes were elucidated. Notably, flow augmentation index (FAI) was found to be a strong indicator of local carotid stiffness.

Suitable temperature indicator for adverse health impacts in sub-tropical cities: a case study in Hong Kong from 2010-2019.

Heat-health warning systems and services are important preventive actions for extreme heat, however, global evidence differs on which temperature indicator is more informative for heat-health outcomes. We comprehensively assessed temperature predictors on their summer associations with adverse health impacts in a high-density subtropical city. Maximum, mean, and minimum temperatures were examined on their associations with non-cancer mortality and hospital admissions in Hong Kong during summer seasons 2010-2019 using Generalized Additive Models and Distributed Lag Non-linear Models. In summary, mean and minimum temperatures were identified as strong indicators for mortality, with a relative risk(RR) and 95% confidence interval(CI) of 1.037 (1.006-1.069) and 1.055 (1.019-1.092), respectively, at 95th percentile vs. optimal temperature. Additionally, minimum temperatures captured the effects of hospital admissions, RR1.009 (95%CI: 1.000- 1.018). In stratified analyses, significant associations were found for older adults, female sex, and respiratory-related outcomes. For comparison, there was no association between maximum temperature and health outcomes. With climate change and projected increase of night-time warming, the findings from this comprehensive assessment method are useful to strengthen heat prevention strategies and enhance heat-health warning systems. Other locations could refer to this comprehensive method to evaluate their heat risk, especially in highly urbanized environments and subtropical cities.

Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms.

BACKGROUND: Autoimmunity has been reported in patients with severe coronavirus disease 2019 (COVID-19). We investigated whether anti-nuclear/extractable-nuclear antibodies (ANAs/ENAs) were present up to a year after infection, and if they were associated with the development of clinically relevant post-acute sequalae of COVID-19 (PASC) symptoms. METHODS: A rapid-assessment line immunoassay was used to measure circulating levels of ANAs/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6 and 12 months post-recovery. Patient-reported fatigue, cough and dyspnoea were recorded at each time point. Multivariable logistic regression model and receiver operating curves were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines. RESULTS: Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased between 3 and 12 months (from 3.99 to 1.55) with persistent positive titres associated with fatigue, dyspnoea and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, area under the curve (AUC) 0.86) and dyspnoea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and C-reactive protein predicted the elevated ANAs at 12 months. TNF-α, D-dimer and interleukin-1ß had the strongest association with symptoms at 12 months. Regression analysis showed that TNF-α predicted fatigue (ß=4.65, p=0.004) and general symptomaticity (ß=2.40, p=0.03) at 12 months. INTERPRETATION: Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.

Impact of Exposure to Diesel Exhaust on Inflammation Markers and Proteases in Former Smokers with Chronic Obstructive Pulmonary Disease: A Randomized, Double-blinded, Crossover Study.

Rationale: There is growing evidence that chronic obstructive pulmonary disease (COPD) can be caused and exacerbated by air pollution exposure. Objectives: To document the impact of short-term air pollution exposure on inflammation markers, proteases, and antiproteases in the lower airways of older adults with and without COPD. Methods: Thirty participants (10 ex-smokers with mild to moderate COPD and 20 healthy participants [9 ex-smokers and 11 never-smokers]), with an average age of 60 years, completed this double-blinded, controlled, human crossover exposure study. Each participant was exposed to filtered air (control) and diesel exhaust (DE), in washout-separated 2-hour periods, in a randomly assigned order. Bronchoscopy was performed 24 hours after exposure to collect lavage. Cell counts were performed on blood and airway samples. ELISAs were performed to measure acute inflammatory proteins, matrix proteinases, and antiproteases in the airway and blood samples. Measurements and Main Results: In former smokers with COPD, but not in the other participants, exposure to DE increased serum amyloid A (effect estimate, 1.67; 95% confidence interval [CI], 1.21-2.30; P = 0.04) and matrix metalloproteinase 10 (effect estimate, 2.61; 95% CI, 1.38-4.91; P = 0.04) in BAL. Circulating lymphocytes were increased after DE exposure (0.14 [95% CI, 0.05-0.24] cells × 109/L; P = 0.03), irrespective of COPD status. Conclusions: A controlled human crossover study of DE exposure reveals that former smokers with COPD may be susceptible to an inflammatory response compared with ex-smokers without COPD or never-smoking healthy control participants. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).

Acute air pollution exposure increases TET enzymes in human PBMCs.

BACKGROUND: Exposure to traffic-related air pollution is associated with increased morbidity and mortality. Negative health impact of diesel exhaust (DE) exposure may in part be mediated via epigenetic modulation. Ten-eleven translocation (TET) enzymes catalyze the active DNA demethylation process and play important roles in epigenetic regulation. OBJECTIVES: We sought to assess the expression of TET enzymes in human PBMCs and the differentiation of immune subsets in response to acute DE exposure at a range of concentrations. METHODS: Thirteen healthy participants were recruited for this randomized, double-blind, controlled human exposure study to DE. In this 4-arm crossover study, each participant was exposed for 4 hours to 3 different concentrations of DE (DE diluted to have particulate matter with a diameter of ≤2.5 micron concentration nominally set at 20, 50, and 150 µg/m3) and filtered air. Blood was collected at baseline and 4 and 24 hours after the exposure start time. The composition of PBMCs and their TET enzymes' expression were evaluated with flow cytometry. Cytokines in plasma were measured by electrochemiluminescence multiplex assays. RESULTS: DE exposure decreased the proportion of B cells, TH17 cells, and activated T cells in PBMCs. TET enzymes were upregulated in PBMCs, especially in TH1, TH2, and TH17 cells, at 4 hours following DE exposure. The expression of TET enzymes correlated with proinflammatory cytokine secretion in plasma. CONCLUSIONS: We demonstrated that acute DE exposure impacted peripheral blood leukocyte proportions and TET enzymes' expression in lymphocyte subsets at DE concentration of 50 µg/m3 and above. Our finding suggests that even a modest exposure to air pollution can impact the circulating immune cells via epigenetic modulation.

Peroxisome proliferator-activated receptor gamma gene variants modify human airway and systemic responses to indoor dibutyl phthalate exposure.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor gamma (PPAR-γ; gene: PPARG) and oxidative stress genes are associated with asthma risk. However, whether such variants modulate responses to dibutyl phthalate (DBP), a common plasticizer associated with increased asthma development, remains unknown. The purpose of this study is to investigate how SNPs in PPARG and oxidative stress genes, as represented by two separate genetic risk scores, modify the impact of DBP exposure on lung function and the airway and systemic response after an inhaled allergen challenge. METHODS: We conducted a double-blinded human crossover study with sixteen allergen-sensitized participants exposed for three hours to DBP and control air on distinct occasions separated by a 4-week washout. Each exposure was followed by an allergen inhalation challenge; subsequently, lung function was measured, and blood and bronchoalveolar lavage (BAL) were collected and analyzed for cell counts and allergen-specific immunoglobulin E (IgE). Genetic risk scores for PPAR-γ (P-GRS; weighted sum of PPARG SNPs rs10865710, rs709158, and rs3856806) and oxidative stress (OS-GRS; unweighted sum of 16 SNPs across multiple genes) were developed, and their ability to modify DBP effects were assessed using linear mixed-effects models. RESULTS: P-GRS and OS-GRS modified DBP effects on allergen-specific IgE in blood at 20 h (interaction effect [95% CI]: 1.43 [1.13 to 1.80], p = 0.005) and 3 h (0.99 [0.98 to 1], p = 0.03), respectively. P-GRS also modified DBP effects on Th2 cells in blood at 3 h (- 25.2 [- 47.7 to - 2.70], p = 0.03) and 20 h (- 39.1 [- 57.9 to - 20.3], p = 0.0005), and Th2 cells in BAL at 24 h (- 4.99 [- 8.97 to - 1.01], p = 0.02). An increasing P-GRS associated with reduced DBP effect on Th2 cells. Neither GRS significantly modified DBP effects on lung function parameters. CONCLUSIONS: PPAR-γ variants modulated several airway and systemic immune responses to the ubiquitous chemical plasticizer DBP. Our results suggest that PPAR-γ variants may play a greater role than those in oxidative stress-related genes in airway allergic responses to DBP. TRIAL REGISTRATION: This study reports results from The Phthalate-Allergen Immune Response Study that was registered on ClinicalTrials.gov with identification NCT02688478.

CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization.

Visits to the accident and emergency department in hot season of a city with subtropical climate: association with heat stress and related meteorological variables.

BACKGROUND: Literature reporting the association between heat stress defined by universal thermal climate index (UTCI) and emergency department visits is mainly conducted in Europe. This study aimed to investigate the association between heat stress, as defined by the UTCI, and visits to the accident and emergency department (AED) in Hong Kong, which represents a subtropical climate region. METHODS: A retrospective study involving 13,438,846 AED visits in the public sector from May 2000 to September 2016, excluding 2003 and 2009, was conducted in Hong Kong. Age-sex-specific ANCOVA models of daily AED rates on heat stress and prolonged heat stress, adjusting for air quality, prolonged poor air quality, typhoon, rainstorm, year, day of the week, public holiday, summer vacation, and fee charging, were used. RESULTS: On a day with strong heat stress (32.1 °C ≤ UTCI ≤ 38.0 °C), the AED visit rate (per 100,000) increased by 0.9 (95% CI: 0.5, 1.3) and 1.7 (95% CI: 1.3, 2.1) for females and males aged 19-64 and 4.1 (95% CI: 2.7, 5.4) and 4.1 (95% CI: 2.6, 5.6) for females and males aged ≥ 65, while keeping other variables constant. On a day with very strong heat stress (38.1 °C ≤ UTCI ≤ 46.0 °C), the corresponding rates increased by 0.6 (95% CI: 0.1, 1.2), 2.2 (95% CI: 1.7, 2.7), 4.9 (95% CI: 3.1, 6.7), and 4.7 (95% CI: 2.7, 6.6), respectively. The effect size of heat stress associated with AED visit rates was negligible among those aged ≤ 18. Heat stress showed the greatest effect size for males aged 19-64 among all subgroups. CONCLUSION: Biothermal condition from heat stress was associated with the health of the citizens in a city with a subtropical climate and reflected in the increase of daily AED visit. Public health recommendations have been made accordingly for the prevention of heat-related AED visits.

Myeloid differentiation factor 88 expression in eyelid specimens of rosacea.

PURPOSE: Rosacea is a common cause of ocular surface disease. Specific immunologic features have been implicated in its pathogenesis, including toll-like receptors, mitogen-associated kinase, and nuclear factor kappa-B. Myeolid differentiation factor 88 (MYD88) has been associated with these elements, suggesting a role for this protein in rosacea. This study was designed to compare the expression of MYD88 in the eyelids of patients with and without this disease. METHODS: Western blotting for MYD88 was performed in 14 control patients and 15 patients with rosacea. Bands were quantified and normalized to actin. Immunohistochemical staining for MYD88 was performed in a different cohort of 12 patients with rosacea and 12 controls, and positively-staining cells were counted across five consecutive 40x fields. Statistical analyses compared the differences between the two groups via a dedicated software package. RESULTS: On western blotting, the mean ratios of MYD88 to actin were 13.8 (standard deviation = 14.1) and 44.3 (standard deviation = 39.6) in control and rosacea patients, respectively (p = .002). On immunohistochemistry, the mean numbers of positively-staining cells were 12.1/40x field (standard deviation = 9.61/40x field) and 27.4/40x (standard deviation = 18.7/40x field) in control and rosacea patients, respectively (p = .0438). CONCLUSIONS: MYD88 is enriched in eyelid specimens of rosacea. This finding further implicates the innate immune system in the pathogenesis of rosacea, and is consistent with previous reports regarding the role of this protein in ocular surface disease and the previously-implicated cellular features of the disease. Inhibition of MYD88 may be a successful treatment strategy to manage rosacea.

Longitudinal association of built environment pattern with DXA-derived body fat in elderly Hong Kong Chinese: a latent profile analysis.

BACKGROUND: One major limitation of prior studies regarding the associations between built environment (BE) and obesity has been the use of anthropometric indices (e.g., body mass index [BMI]) for assessing obesity status, and there has been limited evidence of associations between BE and body fat. This study aimed to explore the longitudinal association between BE and body fat in a cohort of elderly Hong Kong Chinese and examine whether the BE-body fat associations differed by BMI categories. METHODS: Between 2001 and 2003, 3944 participants aged 65-98 years were recruited and followed for a mean of 6.4 years. BE characteristics were assessed via Geographic Information System. Body fat (%) at whole body and regional areas (trunk, limbs, android, and gynoid) were assessed by dual energy X-ray absorptiometry at baseline and three follow-ups. Latent profile analysis was used to derive BE class, and linear mixed-effects models were used to investigate the associations of BE class with changes in body fat. Stratified analyses by BMI categories were also conducted. RESULTS: Three BE classes were identified. Participants in Class 2 (characterized by greater open space and proportion of residential land use) had a slower increase in whole body fat (B = -0.403, 95% confidence interval [CI]: -0.780, -0.014) and limbs fat (-0.471, 95% CI: -0.870, -0.071) compared with participants in Class 1 (characterized by high proportion of commercial land use). There were significant interactions of BE class with BMI, and participants in Class 2 had a slower increase in whole body fat and regional fat compared with participants in Class 1 (B ranging from -0.987 [limbs] to -0.523 [gynoid]) among overweight and obese participants only. CONCLUSIONS: We found that those who resided in the areas characterized by greater open space and proportion of residential land use had a slower body fat increase.

Long-term association between urban air ventilation and mortality in Hong Kong.

While associations between population health outcomes and some urban design characteristics, such as green space, urban heat islands (UHI), and walkability, have been well studied, no prior studies have examined the association of urban air ventilation and health outcomes. This study used data from Hong Kong, a densely populated city, to explore the association between urban air ventilation and mortality during 2008-2014. Frontal area density (FAD), was used to measure urban ventilation, with higher FAD indicating poorer ventilation, due to structures blocking wind penetration. Negative binomial regression models were constructed to regress mortality counts for each 5-year age group, gender, and small area group, on small area level variables including green space density, population density and socioeconomic indicators. An interquartile range increase in FAD was significantly associated with a 10% (95% confidence interval (CI) 2%-19%, p = 0.019) increase in all-cause mortality and a 21% (95% CI: 2%-45%, p = 0.030) increase in asthma mortality, and non-significantly associated with a 9% (95% CI: 1%-19%, p = 0.073) in cardio-respiratory mortality. Better urban ventilation can help disperse vehicle-related pollutants and allow moderation of UHIs, and for a coastal city may allow moderation of cold temperatures. Urban planning should take ventilation into account. Further studies on urban ventilation and health outcomes from different settings are needed.

Association of green space with bone mineral density change and incident fracture in elderly Hong Kong Chinese: Mr. OS and Ms. OS study.

BACKGROUND: A large body of literature has reported positive effects of green space (GS) on various aspects of health and well-being, while no studies explore the role of GS in bone health. OBJECTIVES: The present study aimed to investigate the associations of GS with bone mineral density (BMD) change and incident fracture in a prospective cohort of elderly Hong Kong Chinese. METHODS: Between 2001 and 2003, 3944 participants aged 65 years and older at baseline were recruited. GS (%) within 300-m and 500-m buffers were calculated for each participant based on the Normalized Difference Vegetation Index. BMD at whole body, lumbar spine, total hip, and femoral neck were assessed by dual energy X-ray absorptiometry at baseline and 3 follow-ups. Incident fracture cases were ascertained from the electronic database of Hospital Authority of Hong Kong. Linear mixed-effects models and Cox proportional hazards models were used to investigate the associations of GS with changes in BMD and incident fracture, respectively. RESULTS: Greater GS within 300-m and 500-m buffers were associated with a slower increase in lumbar spine BMD over 14 years. After adjustment for potential confounders, ß and 95% confidence intervals (CIs) of change in BMD across Q2-Q4 (quartiles of GS measured in a 300-m, compared with Q1) were -6.42 (-12.3, -0.59), -7.78 (-13.6, -1.97), and -7.83 (-13.7, -2.00) mg/cm3, respectively. GS was also positively associated with non-spinal fracture and major osteoporotic fracture incidence risks. Multivariable-adjusted hazard ratios (95%CIs) were 1.40 (1.09, 1.79; P-trend = 0.036) for non-spinal fracture and 1.53 (1.13, 2.07; P-trend = 0.010) for major osteoporotic fracture (Q4 compared with Q1 of GS measured in a 300-m buffer). Positive GS-fracture associations were also found for GS within a 500-m buffer. CONCLUSIONS: We found that those who lived near higher GS levels had a slower increase in lumbar spine BMD and had higher incident fracture risk.

Socioeconomic status as an effect modifier of the association between built environment and mortality in elderly Hong Kong Chinese: A latent profile analysis.

BACKGROUND: Previous studies have focused on associations between individual built environment (BE) characteristics and mortality, and found the BE-mortality associations differed by socioeconomic status (SES). Different individual BE characteristics may have different impacts on health and thus could interact. Combinations of BE characteristics may be a better approach to explore the BE-mortality associations. OBJECTIVES: This study aimed to investigate the associations of BE pattern with mortality in a prospective cohort of elderly Hong Kong Chinese (Mr. OS and Ms. OS Study), and assess whether the BE-mortality association differed by SES. METHODS: Between 2001 and 2003, 3944 participants aged 65-98 years at baseline were included in the present analysis. BE characteristics were assessed via Geographic Information System. Data on all-cause and cause-specific mortality were obtained from the Hong Kong Government Death Registry. Latent profile analysis was used to derive BE class, and the Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Three BE classes were identified. During a total of 53276 person-years of follow-up, 1632 deaths were observed. There were no significant associations of BE class with all-cause and cause-specific mortality. However, we found the associations of BE class with all-cause mortality were modified by SES. In comparison with Class 3 (characterized by greater green space), HRs (95%CIs) were 0.72 (0.54, 0.97) for Class 1 (characterized by greater commercial land use) and 0.77 (0.64, 0.94) for Class 2 (characterized by greater residential land use) among low-SES participants. The associations were stronger among high-SES participants, with 0.55 (0.33, 0.89) for Class 1 and 0.68 (0.48, 0.97) for Class 2. In contrast, Class 2 (HR 1.18, 95%CI 1.01-1.39) had a higher mortality risk compared with Class 3 among middle-SES participants. CONCLUSIONS: Our findings provide new evidence on the role of SES as an effect modifier of BE pattern and mortality. BE pattern has a varied effect on mortality risk for different SES groups.

Comprehensive sexuality education in Hong Kong: study protocol for process and outcome evaluation.

BACKGROUND: Hong Kong lacks comprehensive school-based sexuality education. Recent public health concerns have brought the inadequacies of sex education in Hong Kong to the forefront. The aim of the proposed study is to develop and evaluate the effectiveness of a comprehensive school-based sexuality education program in Hong Kong. METHODS: The proposed study is a prospective longitudinal study implemented in six secondary schools in Hong Kong over two academic years. The study adopts an ecological approach providing informational workshops for students, teachers and school management, social workers and guidance counsellors and parents. Study outcomes will be evaluated through pre- and post-tests. RESULTS: Key outcomes of interest among students include sexual health knowledge, awareness of values motivating healthy sexual decisions, understanding and efficacy of sexual communication and intention to use contraception. Among school employees and parents key outcomes include self-efficacy to engage in sexual health discussions with students/children, sexual health knowledge and awareness of Hong Kong community sexual health resources. CONCLUSIONS: The proposed study will result in the development of a tested school-based culturally relevant comprehensive sexual health education program. Ultimately, this program aims to not only empower adolescents and their trusted adults in building a supportive environment for sexual health promotion but also construct a learning network to generate longitudinal evidence for the effectiveness of comprehensive sexuality education in improving sexual health outcomes. The program has the potential for expansion through widespread adoption in Hong Kong schools to benefit more adolescents and reduce the medical and societal burdens related to crisis pregnancy, sexually transmitted infections and sexual abuse.

Cytotoxic T-Lymphocyte-Associated Protein-4 and Lymphocyte Activation Gene-3 Expression in Orbitally-Invasive Versus Nodular Basal Cell Carcinoma.

PURPOSE: To compare the expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and lymphocyte activation gene-3 (LAG-3) in nodular and orbitally-invasive forms of basal cell carcinoma (BCC). METHODS: Immunohistochemical staining for CTLA-4 and LAG-3 was performed on the pathology specimens of BCC from orbital exenteration and nodular forms. The numbers of positively-staining cells/×40 field were counted across 5 consecutive fields of each specimen and statistical analysis was performed to calculate the difference in expression between the 2 groups. RESULTS: Nine cases of orbitally-invasive BCC and 6 cases of nodular BCC were studied. The mean numbers of CTLA-4-positively staining cells were 11.51 cells/×40 field (median = 6.60 cells/×40 field, range = 0.4-31.8 cells/×40 field) in invasive BCC and 0.90 cells/×40 field (median = 0.60 cells/×40 field, range = 0.0-2.8 cells/×40 field) in nodular specimens. The difference between the 2 groups was statistically significant (p = 0.0030). The mean number of LAG-3-positively staining cells was 0.58 cells/×40 field (median = 0.0, range = 0.0-2.8 cells/×40 field) in invasive BCC and 3.13 cells/×40 field (median = 0.0, range = 0.0-18.18 cells/×40 field). There was no significant difference in LAG-3 positivity between tumor groups (p = 0.5564). CONCLUSIONS: CTLA-4 expression was enriched in orbitally invasive BCC compared with nodular forms of BCC, whereas LAG-3 expression did not differ between these entities. CTLA-4 mediated immune suppression may facilitate the development of orbitally invasive BCC. Treatment strategies that use existing medications to target CTLA-4 may decrease the requirement for orbital exenteration and provide enhanced survival outcomes.

Particle depletion of diesel exhaust restores allergen-induced lung-protective surfactant protein D in human lungs.

RATIONALE: Exposure to air pollution is linked with increased asthma morbidity and mortality. To understand pathological processes linking air pollution and allergen exposures to asthma pathophysiology, we investigated the effect of coexposure to diesel exhaust (DE) and aeroallergen on immune regulatory proteins in human airways. METHODS: Fourteen allergen-sensitised participants completed this randomised, double-blinded, cross-over, controlled exposure study. Each participant underwent four exposures (allergen-alone exposure, DE and allergen coexposure, particle-depleted DE (PDDE) and allergen coexposure, and sham exposure) on different order-randomised dates, each separated by a 4-week washout. Serum and bronchoalveolar lavage (BAL) were assayed for pattern recognition molecules, cytokines, chemokines and inflammatory mediators. RESULTS: In human airways, allergen-alone exposure led to accumulation of surfactant protein D (SPD; p=0.02). Coexposure to allergen and DE did not elicit the same increase of SPD as did allergen alone; diesel particulate reduction restored allergen-induced SPD accumulation. Soluble receptor for advanced glycation end products was higher with particle reduction than without it. In the systemic circulation, there was a transient increase in SPD and club cell protein 16 (CC16) 4 hours after allergen alone. CC16 was augmented by PDDE, but not DE. % eosinophils in BAL (p<0.005), eotaxin-3 (p<0.0001), interleukin 5 (IL-5; p<0.0001) and thymus and activation regulated chemokine (p=0.0001) were each increased in BAL by allergen. IL-5, SPD and % eosinophils in BAL were correlated with decreased FEV1. CONCLUSION: Short-term coexposure to aeroallergen and DE alters immune regulatory proteins in lungs; surfactant levels are dependent on particle depletion. TRIAL REGISTRATION NUMBER: NCT02017431.

Calcitonin Gene-Related Peptide in Blind, Painful Eyes.

PURPOSE: To determine if calcitonin gene-related peptide (CGRP) is overexpressed in blind, painful eyes. METHODS: This was a retrospective cross-sectional randomized control study conducted at a tertiary level hospital. Eight specimens of eyes enucleated by a single surgeon were included in the study. The control group patients underwent exenteration for cutaneous malignancy without intraocular involvement, while the case group was enucleated for management of blind, painful eye. Each eye was stained using immunohistochemistry for the expression of CGRP. Expression of CGRP was examined by counting the number of cells staining positive for CGRP in 5 consecutive ×40 fields in the choroid, iris, and cornea of each specimen. RESULTS: The mean number of cells staining positively for CGRP in the choroid of blind, painful eye group was 45.5 (26.3) versus 5.5 (7.7) in nonpainful enucleated eyes. This difference was found to be statistically significant (p = 0.016). Comparison of iris and cornea did not reach statistical significance. Expression of CGRP was compared using a paired t test. CONCLUSIONS: This study demonstrates that CGRP is overexpressed in the choroid of enucleated blind, painful eyes. Modulation of this protein may represent a meaningful, nonsurgical therapeutic strategy to addressing the blind, painful eye.

Assessing spatial variability of extreme hot weather conditions in Hong Kong: A land use regression approach.

The number of extreme hot weather events have considerably increased in Hong Kong in the recent decades. The complex urban context of Hong Kong leads to a significant intra-urban spatial variability in climate. Under such circumstance, a spatial understanding of extreme hot weather condition is urgently needed for heat risk prevention and public health actions. In this study, the extreme hot weather events of Hong Kong were quantified and measured using two indicators - very hot day hours (VHDHs) and hot night hours (HNHs) which were counted based on the summertime hourly-resolved air temperature data from a total of 40 weather stations (WSs) from 2011 to 2015. Using the VHDHs and HNHs at the locations of the 40 WSs as the outcome variables, land use regression (LUR) models are developed to achieve a spatial understanding of the extreme hot weather conditions in Hong Kong. Land surface morphology was quantified as the predictor variables in LUR modelling. A total of 167 predictor variables were considered in the model development process based on a stepwise multiple linear regression (MLR). The performance of resultant LUR models was evaluated via cross validation. VHDHs and HNHs were mapped at the community level for Hong Kong. The mapping results illustrate a significant spatial variation in the extreme hot weather conditions of Hong Kong in both the daytime and nighttime, which indicates that the spatial variation of land use configurations must be considered in the risk assessment and corresponding public health management associated with the extreme hot weather.

Dynamic response of pedestrian thermal comfort under outdoor transient conditions.

Outdoor thermal comfort studies have proved that urban design has a great influence on pedestrians' thermal comfort and that its assessment helps one to understand the quality and usage of the pedestrian environment. However, the majority of outdoor thermal comfort studies perceive pedestrian thermal comfort as "static". The dynamic multiple uses of urban spaces and the highly inhomogeneous urban morphology in high-density cities of the tropics are seldom considered, which leads to a lack of understanding about how pedestrians respond to the changes of the outdoor environment. This study contributes to the understanding of the dynamic thermal comfort using a longitudinal survey that was conducted to obtain information about how thermal sensation changes throughout the walking route and how it is affected by micro-meteorological conditions and the urban geometry. The large variations in micro-meteorological conditions throughout the walking routes are predominantly influenced by the urban geometry. Additionally, the spatial pattern of thermal sensation varies based on the weather conditions, emphasizing the need to account for such variations in the assessment of pedestrian thermal comfort. The results also show that thermal sensation was associated with participants' short-term thermal experience (2-3 min) and that the urban geometry plays an important role in the time-lag effect of meteorological variables on thermal sensation. The findings of this study contribute to improving urban geometry design in order to mitigate the thermal discomfort and create a better pedestrian environment in high-density cities.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).