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Aims: Muscle disorders are clinically and genetically heterogeneous. Investigations, including plasma creatine kinase, electromyography, and nerve conduction velocity studies are often nonspecific, whereas muscle biopsy might be limited by sampling bias and variable histopathology. Next-generation sequencing is now generally considered an important diagnostic tool for muscle disorders, with decreased costs and improved diagnostic yield. Inclusion of a large number of genes in the analysis might, however, generate a large number of ambiguous results and create unnecessary confusion for clinicians and patients. Methods: An ethnic Chinese patient presented at age 10 with tip-toe walking. Upon examination the patient had a waddling gait, a tight Achilles tendon with pes cavus . A muscle biopsy showed the presence of minicores with disruption of the myofibrillary network and Z-bands. Sequencing was performed using the Flexi-Myo panel, which provides coverage for 85 myopathic genes. Reporting of sequencing results was decided by the responsible chemical pathologists based on the available clinical and genetic information. Results: A previously identified heterozygous in-frame deletion was detected in MYH7 , which confirmed the diagnosis of Laing myopathy. No variants of uncertain significance required reporting. Conclusion: We describe the effectiveness of our Flexi-Myo panel approach for the diagnosis of muscle disorders, which confirmed diagnosis of Laing myopathy in what had been a clinically ambiguous presentation. This approach enables efficient genomic testing for muscle diseases in adults and children with satisfactory diagnostic yield and sufficient sensitivity, whereas avoiding the reporting of ambiguous results. Similar strategies might also be implemented for other groups of disorders.

Recurrent rhabdomyolysis is frequently ascribed to fatty acid ß-oxidation defects, mitochondrial respiratory chain disorders and glycogen storage-related diseases. In recent years, autosomal recessive LPIN1 mutations have been identified as a prevailing cause of severe rhabdomyolysis in children in Western countries. We report the first probable Hong Kong Chinese case of recurrent severe rhabdomyolysis in early childhood caused by LPIN1 variants. Compound heterozygous novel variants NM_145693.2(LPIN1):c.[1949_1967dupGTGTCACCACGCAGTACCA]; [2410G>C] (p.[Gly657Cysfs*12];[Asp804His]) were detected. The former variant was classified as likely pathogenic while the latter variant was classified as a variant of uncertain significance (VUS) based on the guideline published by the American College of Medical Genetics and Genomics (ACMG) in 2015. Although the genetic findings were inconclusive, the patient's presentation was compatible with LPIN1-related acute recurrent rhabdomyolysis, and the patient was treated as such. The early recognition, timely diagnosis and management of this condition are important to avoid fatal consequences. To our knowledge, there has been no previous report in the English-language literature of a child with Chinese ethnicity and LPIN1 -related acute recurrent rhabdomyolysis (MIM #268200).  Functional characterization of the novel variants detected in this study are warranted in future studies., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Yim SW et al.)

KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Introduction: Reference intervals (RIs) are essential tool for proper interpretation of results. There is a global trend towards implementing common RIs to avoid confusion and enhance patient management across different laboratories. However, local practices with respect to RIs lack harmonisation., Methods: We have conducted the first local survey regarding RIs for 14 general chemistry analytes in 10 chemical pathology laboratories that employ four different analytical platforms (Abbott Architect, Beckman Coulter AU, Roche Cobas, and Siemens Dimension EXL). Analytical bias was assessed by an inter-laboratory results comparison of external quality assurance programmes., Results: Sufficient inter-laboratory and inter-platform agreement regarding the 10 analytes (albumin, alanine aminotransferase, aspartate aminotransferase, chloride, gamma-glutamyl transferase, phosphate, potassium, sodium, total protein, and urea) were demonstrated. However, the RIs were heterogeneous across all laboratories, with percentage differences of the upper RI value of up to 47% for aspartate aminotransferase (absolute difference of 16 U/L), 29% for urea (1.8 mmol/L), and 18% for potassium (0.8 mmol/L). The percentage difference between lower RI values was up to 24% for urea (0.6 mmol/L), 22% for phosphate (0.16 mmol/L), and 8% for total protein (5 g/L). The coefficients of variation of the upper RI values of potassium and sodium were 1.2 times and 1.0 times of their corresponding between-subject biological variation, respectively, representing unnecessary variations that are overlooked and unchecked in current practice., Conclusions: We recommend the use of common RIs for general chemistry analytes in Hong Kong to prevent interpreter confusion, improve electronic data transfer, and unite laboratory practice. This is the first local study on this topic, and our data can lay the groundwork for increasing harmonisation of RIs across more laboratory tests., Competing Interests: All authors have disclosed no conflicts of interest.

Introduction: With the development of transportation system and the economy, the rapidly increasing number of automobiles brings the associated problem of road traffic noise, especially in metropolitan and densely populated high-rise cities like Hong Kong. In Hong Kong, approximately one million people are affected by severe road traffic noise. Excessive noise exposure is hazardous to the health and wellbeing of people and therefore has drawn progressively more attention in Hong Kong. The Calculation of Road Traffic Noise (CRTN) has been adopted as the sole tool to evaluate road traffic noise in the form of descriptor L A10 . The accuracy and suitability of the CRTN method for predicting road traffic noise in Hong Kong were evaluated in this study by comparing the prediction results and measured traffic noise levels. The results show that the CRTN method was able to provide adequate predictions with correlation coefficients of 0.8032 and 0.7626 between the predicted and measured L A10 for 2007 and 2017 respectively. The predicted traffic noise levels on different floors of seven selected residential buildings in 2017 were compared with those predictions for the same buildings in 2007. The worsening traffic noise exposure in these residential buildings was analysed and some suggestions and counter-measures to alleviate the traffic noise problems are put forward. Since the situation of Hong Kong is an example of what may happen in other cities, the present longitudinal study of the road traffic noise in Hong Kong hopes to contribute to a better urban acoustic environment worldwide., Context: Excessive noise exposure is hazardous to the health and wellbeing of people and therefore has drawn progressively more attention in Hong Kong. The urban road traffic noise exposure of residential buildings in Hong Kong over the past decade has been analysed., Aims: This study aims to assess the road traffic noise exposure of residential buildings over the past decade., Settings and Design: Measurements of traffic noise levels at some selected residential buildings were first conducted in 2007, and then repeated at the same buildings in 2017., Material and Methods: The CRTN was adopted to predict the traffic noise levels based on the recorded traffic flow data., Results: The exposure of these buildings to road traffic noise is higher in 2017 than in 2007. The study illustrates that the deterioration of the urban acoustic environment may not be caused by an increased total number of vehicles, but that heavy vehicles are dominantly responsible for the increased traffic noise levels. Restriction of vehicle velocity for urban street canyons is useless for road traffic noise control., Conclusions: This study shows the deterioration of traffic noise levels is mainly due to the increased heavy vehicles instead of the increased total number of vehicles. The alleviation of traffic noise levels by velocity restriction may not be obvious for urban street canyons and may only work with a certain velocity range., Competing Interests: None

All real processes, be they chemical, mechanical or electrical, are thermodynamically irreversible and therefore suffer from thermodynamic losses. Here, we report the design and operation of a chemical reactor capable of approaching thermodynamically reversible operation. The reactor was employed for hydrogen production via the water-gas shift reaction, an important route to 'green' hydrogen. The reactor avoids mixing reactant gases by transferring oxygen from the (oxidizing) water stream to the (reducing) carbon monoxide stream via a solid-state oxygen reservoir consisting of a perovskite phase (La 0.6 Sr 0.4 FeO 3-δ ). This reservoir is able to remain close to equilibrium with the reacting gas streams because of its variable degree of non-stoichiometry and thus develops a 'chemical memory' that we employ to approach reversibility. We demonstrate this memory using operando, spatially resolved, real-time, high-resolution X-ray powder diffraction on a working reactor. The design leads to a reactor unconstrained by overall chemical equilibrium limitations, which can produce essentially pure hydrogen and carbon dioxide as separate product streams.

High-rise deep street canyons usually experience poor ventilation and large vehicular pollutant exposure to residents in near-road buildings. Investigations are still required to clarify the flow and dispersion mechanisms in deep street canyons and explore techniques to reduce such large pollutant exposure. By conducting computational fluid dynamics (CFD) simulations validated by wind tunnel data and scale-model outdoor field measurements, we investigate the integrated impacts of aspect ratios, first-floor and second-floor elevated building designs, viaduct settings, height variations and wind catchers on the flow, personal intake fraction (P_IF) of CO (carbon dioxide) and its spatial mean value 〈P_IF〉 in two-dimensional (2D) street canyons. Results show that cases with H/W = 5 experience two counter-rotating vortices, much poorer ventilation and 1-2 orders larger 〈P_IF〉 (43.6-120.8 ppm) than H/W = 1 and 3 (3.8-4.3 and 5.6-5.8 ppm). Moreover, in cases with H/W = 5 the height variation results in three vertically-aligned vortices and much weaker wind, subsequently produces greater 〈P_IF〉 (1402-2047 ppm). To reduce 〈P_IF〉 with H/W = 5, various urban designs are evaluated. The first-floor elevated building design creates more effective ventilation pathways than the second-floor elevated type does and reduces 〈P_IF〉 at H/W = 5 by five orders (1402 to ~0.01 ppm) or two orders (43.6 to ~0.1 ppm) in cases with or without the height variation. However, such reductions at H/W = 1 and 3 are only 76.8%-81.4% and 22.4%-36.2% respectively. Wind catchers destroy the multi-vortex flow pattern as H/W = 5, produce a contra-clockwise main vortex and reduce 〈P_IF〉 by 1-2 orders for cases with or without the height variation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population., Methods: This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing., Results: There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features., Conclusion: This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists., Competing Interests: All authors have disclosed no conflicts of interest.

Background: To evaluate the analytical performance of five commercial acetaminophen assays and select the best method for routine use., Methods: Imprecision, accuracy, linearity, and interferences of three enzymatic assays (Beckman Coulter AU Paracetamol, Abbott MULTIGENT Acetaminophen, and Sekisui Acetaminophen L3K) and two immunoassay-based assays (Beckman Coulter SYNCHRON ACTM (Acetaminophen) Reagent and Siemens SYVA Emit-tox Acetaminophen) were evaluated on a Beckman Coulter AU680 chemistry analyzer. Hook effect for immunoassay-based assays and recovery in ultrafiltrate for enzymatic methods were studied., Results: Within-run and between-run imprecision of the enzymatic assays ranged 0.26%-0.82% and 0.53%-2.86%, respectively, while that for the immunoassay-based methods ranged 0.96%-6.34% and 1.50%-11.33%, respectively. All assays except the SYNCHRON assay fell within the program analytical performance specifications (±20 µmol/L or 10%) for external quality assurance (EQA) samples, with the highest positive bias (31.7%) observed in the SYNCHRON assay. Icteric interference was demonstrated most significantly in the Abbott assay (up to 88 μmol/L positive bias in blank serum). The lipemic interference on the SYNCHRON was significant (up to 110% positive bias at level of 100 μmol/L). The immunoassay-based methods were less susceptible to hemolytic interference, while the Abbott and AU assays were more susceptible to N-acetylcysteine interference. Both immunoassay-based methods showed no hook effect up to 18 000 μmol/L. Ultrafiltration recoveries for enzymatic methods were satisfactory, ranging from 80.0% ± 5.1% to 89.5% ± 3.0%., Conclusions: Proportional bias was observed in the SYNCHRON assay, while the Siemens and Sekisui assays were minimally affected by bilirubin interferences., (© 2018 Wiley Periodicals, Inc.)

Background: Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is a hereditary progressive neurodegenerative disease well documented among Caucasians, but such clinical data and genetic characterization is lacking among Asian populations., Patient and Methods: A 13-year-old Chinese girl presented for diagnostic evaluation with retinitis pigmentosa, generalised tonic-clonic seizure and cerebellar ataxia. Electron microscopy of whole blood and skin biopsy, and mutation analysis of CLN3 gene with genomic DNA and cDNA, were performed., Results: Electron microscopy showed vacuolated lymphocytes, and characteristic patterns in eccrine glands suggestive of neuronal ceroid lipofuscinosis. Sequencing of genomic DNA showed homozygous splice site variant NM_000086.2(CLN3):c.906+6T>G, and the pathogenicity of which was confirmed by cDNA sequencing to demonstrate the deletion of a transmembrane domain of the CLN3 protein. The mutant protein was predicted to adversely affect ligand binding of CLN3 as a lysosomal membrane protein., Conclusions: Here we report the first genetically confirmed CLN3 disease in Chinese, with a novel splice site variant with proposed pathogenetic mechanism relating gene and protein, and highlights the potential ethnic differences in the mutation spectrum. We wish to establish the importance of clinical awareness and laboratory diagnosis of CLN3 disease, especially in the promising age of gene therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An acceptable pedestrian level wind environment is essential to maintain an enjoyable outdoor space for city residents. Low wind velocity environment can lead to uncomfortable outdoor thermal experience in hot and humid summer, and it is unable to remove the pollutants out of city canyons. However, the average wind velocity at pedestrian level is significantly lowered by closely spaced tall buildings in modern megacities. To improve the low wind velocity environment at pedestrian level in high-density cities, a general framework and detailed guidelines are needed. This study is the first time to develop such a framework, and provide detailed guidelines for improving pedestrian level low wind velocity environment in high-density cities. Additionally, a detailed review and summarisation of evaluation criteria and improvement measures are presented in this paper, which provide additional options for urban planners. To investigate the performance of the framework, the Hong Kong Polytechnic University campus was utilised as a case study. Results showed that pedestrian level wind comfort was greatly improved with the developed framework. The outcomes of this study can assist city planners to improve the low wind velocity environment, and can help policy makers to establish sustainable urban planning policies., (© 2018 Elsevier Ltd. All rights reserved.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary stroke syndrome characterized by recurrent stroke and progressive cognitive impairment caused by NOTCH3 mutations. We report here the clinical and molecular findings of three unrelated Hong Kong Chinese families with CADASIL syndrome. Sanger sequencing of genomic DNA revealed a novel heterozygous variant NM_000435.2(NOTCH3):c.[5903_5904insATAA];[5903_5904=] NP_000426.2:p.(Asp1969 ∗ );(Asp1969=) and two previously reported heterozygous mutations NM_000435.2(NOTCH3):c.[328C>T];[328C=] NP_000426.2:p.[(Arg110Cys)];[(Arg110=)] and NM_000435.2(NOTCH3):c.[580T>A];[580T=] NP_000426.2:p.(Cys194Ser);(Cys194=) in the three families respectively. Molecular basis of CADASIL in these three patients were further established. Genetic analysis provides a reliable method for confirming the diagnosis of CADASIL and enables proper genetic counseling and cascade testing., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015., Methods: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy., Results: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in SCN5A (NM_198056.2:c.429del and c.2024-11T>A), two in MYBPC3 (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in LMNA (NM_170707.3:c.73C>A and c.1209_1213dup)., Conclusions: We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening.

Introduction: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM., Methods: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling., Results: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years., Conclusion: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Introduction: Pleural fluid adenosine deaminase level can be applied to rapidly detect tuberculous pleural effusion. We aimed to establish a local diagnostic cut-off value for pleural fluid adenosine deaminase to identify patients with tuberculous pleural effusion, and optimise its utility., Methods: We retrospectively reviewed the medical records of consecutive adults with pleural fluid adenosine deaminase level measured by the Diazyme commercial kit (Diazyme Laboratories, San Diego [CA], United States) during 1 January to 31 December 2011 in a cluster of public hospitals in Hong Kong. We considered its level alongside early (within 2 weeks) findings in pleural fluid and pleural biopsy, with and without applying Light's criteria in multiple scenarios. For each scenario, we used the receiver operating characteristic curve to identify a diagnostic cut-off value for pleural fluid adenosine deaminase, and estimated its positive and negative predictive values., Results: A total of 860 medical records were reviewed. Pleural effusion was caused by congestive heart failure, chronic renal failure, or hypoalbuminaemia caused by liver or kidney diseases in 246 (28.6%) patients, malignancy in 198 (23.0%), non-tuberculous infection in 168 (19.5%), tuberculous pleural effusion in 157 (18.3%), and miscellaneous causes in 91 (10.6%). All those with tuberculous pleural effusion had a pleural fluid adenosine deaminase level of ≤100 U/L. When analysis was restricted to 689 patients with pleural fluid adenosine deaminase level of ≤100 U/L and early negative findings for malignancy and non-tuberculous infection in pleural fluid, the positive predictive value was significantly increased and the negative predictive value non-significantly reduced. Using this approach, neither additionally restricting analysis to exudates by Light's criteria nor adding closed pleural biopsy would further enhance predictive values. As such, the diagnostic cut-off value for pleural fluid adenosine deaminase is 26.5 U/L, with a sensitivity of 87.3%, specificity of 93.2%, positive predictive value of 79.2%, negative predictive value of 96.1%, and accuracy of 91.9%. Sex, age, and co-morbidity did not significantly affect prediction of tuberculous pleural effusion using the cut-off value., Conclusion: We have established a diagnostic cut-off level for pleural fluid adenosine deaminase in the diagnosis of tuberculous pleural effusion by restricting analysis to a level of ≤100 U/L, and considering early pleural fluid findings for malignancy and non-tuberculous infection, but not Light's criteria.

This study examines the influence of building envelope features on interunit dispersion around multi-story buildings, when the presence of an upstream interfering building is also considered. Validated CFD methods in the steady-state RANS framework are employed. In general, the reentry ratios of pollutant from a source unit to adjacent units are mostly in the order of 0.1%, but there are still many cases being in the order of 1%. The influence of envelope features is dependent strongly on the interaction between local wind direction and envelope feature. In a downward dominated near-facade flow field, the presence of vertical envelope features forms dispersion channels to intensify the unidirectional spread. Horizontal envelope features help induce the dilution of pollutant to the main stream and weakens largely the vertical interunit dispersion. The large influences caused by the presence of envelope features extend the existing understanding of interunit dispersion based on flat-facade buildings., (© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018.)

Owing to the void space at lower heights, lift-up buildings have high building permeability at ground level and subsequently improve the air circulation in congested urban areas. Despite this advantage, the lift-up design has been sparsely adopted for buildings in urban areas partly because of the lack of understanding of the combined effects of building dimensions and lift-up design on the surrounding pedestrian level wind (PLW) field. Therefore, this study aims to investigate the influence of lift-up buildings with different aspect ratios (height/width) on the surrounding PLW field and pedestrian wind comfort level. Five lift-up buildings with aspect ratios 4:1 to 0.5:1 were tested in a boundary layer wind tunnel and results were compared with those of five buildings with similar dimensions but without lift-up design. The results reveal a strong dependence of the maximum wind speed in lift-up areas with building height, which results subsequently a small area of acceptable wind conditions near tall and slender lift-up buildings. Lift-up designs adopted for short and wide buildings produce larger areas of pedestrian wind comfort. The central cores modified with corner modifications are effective in increasing the pedestrian wind comfort in the lift-up area of tall and slender buildings., (© 2017 Elsevier Ltd. All rights reserved.)

Occupational noise is unavoidably produced from dental equipment, building facilities, and human voices in the dental environment. The purpose of this study was to investigate the effect of occupational noise exposure on the dental professionals' health condition. The psychoacoustics approach noise exposure assessment followed by the health risk assessment was carried on at the paediatric dentistry clinic and the dental laboratory in the Prince Philip Dental Hospital of Hong Kong. The A-weighted equivalent sound level, total loudness, and sharpness values were statistically significantly higher for the noise at the laboratory than that at the clinic. The degree of perceived influences and sharpness of noise were found to have the impacts on the dental professionals' working performance and health. Moreover, the risk of having a bad hearing state would a have 26% and 31% higher chance for a unit increment of the short-term and long-term impact scores, respectively. The dental professionals with the service length more than 10 years and the daily working hours of more than eight showed the highest risk to their hearing state. The worse the hearing state was, the worse the health state was found for the dental professionals. Also, the risk of dissatisfaction would be increased by 4.41 and 1.22 times for those who worked at the laboratory and a unit increment of the long-term impact score. The constructed health risk mode with the scientific and statistical evidence is hence important for the future noise management of environmental improvement., Competing Interests: The authors declare no conflict of interest.

A combined approach based on finite element method and genetic algorithm (FEM-GA) is proposed for optimizing the natural frequencies of plate structures. This approach can identify the optimal boundary conditions so that the plate's natural frequencies can be adjusted simultaneously to their corresponding target values. In this approach, the natural frequencies of plates with arbitrary boundary conditions are calculated by FEM, while GA is employed for searching the optimal solutions of the multiple-objective optimization problem. The FEM is validated by comparing with previous results. The proposed approach is illustrated by numerical examples. The results demonstrate the effectiveness of this approach.

Modern megacities are teeming with closely-spaced tall buildings, which limit air circulation at the pedestrian level. The resultant lack of air circulation creates poorly ventilated areas with accumulated air pollutants and thermal discomfort in the summer. To improve air circulation at the pedestrian level, buildings may be designed to have a 'lift-up' shape, in which the main structure is supported by a central core, columns or shear walls. However, a lack of knowledge on the influence of the 'lift-up' design on the surrounding wind environment limits the use of 'lift-up' buildings. This study aims to investigate the influence of 'lift-up' buildings and their dimensions on the pedestrian-level wind environments using wind tunnel tests. A parametric study was undertaken by using 9 'lift-up' building models with different core heights and widths. The results were compared with the surrounding wind environment of a control building with similar dimensions. The results reveal that the 'lift-up' core height is the most influential parameter and governs the area and magnitude of high and low wind speed zones around such buildings. Based on wind tunnel test results and a selected comfort criterion, appropriate core dimensions could be selected to have acceptable wind conditions near lift-up buildings., (© 2017 Elsevier Ltd. All rights reserved.)

The acoustic performance of the ducted Helmholtz resonator (HR) system is analyzed theoretically and numerically. The periodic HR array could provide a wider noise attenuation band due to the coupling of the Bragg reflection and the HR's resonance. However, the transmission loss achieved by a periodic HR array is mainly dependent on the number of HRs, which restricted by the available space in the longitudinal direction of the duct. The full distance along the longitudinal direction of the duct for HR's installation is sometimes unavailable in practical applications. Only several pieces of the duct may be available for the installation. It is therefore that this paper concentrates on the acoustic performance of a HR array consisting of several periodic parts. The transfer matrix method and the Bragg theory are used to investigate wave propagation in the duct. The theoretical prediction results show good agreement with the Finite Element Method (FEM) simulation results. The present study provides a practical way in noise control application of ventilation ductwork system by utilizing the advantage of periodicity with the limitation of available completed installation length for HRs.

Late onset Pompe disease is a rare inherited metabolic disease with diverse clinical manifestation. However, there is a lack of local data in Hong Kong. We aimed at performing an in-depth review of natural history of all patients in Hong Kong. Eleven patients were diagnosed to have the disease in Hong Kong from 2000 to 2013. All case records were reviewed and face-to-face interviews were conducted to complete a questionnaire regarding the clinical manifestation and diagnosis of the disease. The estimated birth incidence was 1/300,000. The age of diagnosis ranged from 9 to 44 years; all patients were ethnic Chinese. The median ages of first symptoms and first medical attention were 20.5(6-44) and 29(9-44) years respectively. The most common initial complaint was decreased exercise tolerance. Two patients' first complaint was difficulty with getting up from lying position and failure to perform sit up. The mean time from first medical attention to diagnosis was 1.3 years but one patient was diagnosed 8 years later. Half of the patients sought medical attention due to progressive shortness of breath and all of them developed type 2 respiratory failure requiring ventilator support during the first admission. Two patients became chair-bound and seven patients required assisted ventilation. Late onset Pompe disease tends to have an earlier and more aggressive clinical presentation in Chinese and lower birth incidence was found in Hong Kong., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong., Methods: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array., Results: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort)., Conclusions: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

This paper presents a theoretical study of the dispersion characteristics of sound wave propagation in a periodic ducted Helmholtz resonator (HR) system. The predicted result fits well with a numerical simulation using a finite element method. This study indicates that for the same system, no matter how many HRs are connected or what the periodic distance is, the area under average transmission loss T L¯ curves is always the same. The broader the noise attenuation band, the lower the peak attenuation amplitude. A noise control zone compromising the attenuation bandwidth or peak amplitude is proposed for noise control optimization.

Previous studies regarding interunit dispersion used Reynolds-averaged Navier-Stokes (RANS) models and thus obtained only mean dispersion routes and re-entry ratios. Given that the envelope flow around a building is highly fluctuating, mean values could be insufficient to describe interunit dispersion. This study investigates the wind-induced interunit dispersion around multistory buildings using the large eddy simulation (LES) method. This is the first time interunit dispersion has been investigated transiently using a LES model. The quality of the selected LES model is seriously assured through both experimental validation and sensitivity analyses. Two aspects are paid special attention: (i) comparison of dispersion routes with those provided by previous RANS simulations and (ii) comparison of timescales with those of natural ventilation and the survival times of pathogens. The LES results reveal larger dispersion scopes than the RANS results. Such larger scopes could be caused by the fluctuating and stochastic nature of envelope flows, which, however, is canceled out by the inherent Reynolds-averaged treatment of RANS models. The timescales of interunit dispersion are comparable with those of natural ventilation. They are much shorter than the survival time of most pathogens under ordinary physical environments, indicating that interunit dispersion is a valid route for disease transmission., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders with a high degree of heritability, but the genetic basis is exceedingly heterogeneous. Microdeletions of chromosome 15q24 have been demonstrated to be recurrent genomic alterations in ASD patients. Of interest, neuronal migration genes are of particular relevance to the pathogenesis of ASD. NEO1 is located in 15q24 and encodes for neogenin, a membrane receptor involved in cortical interneuron migration and axon guidance. We postulated that the ASD patient has one copy of the NEO1 gene deleted and the other copy disrupted by intragenic mutation., Results: We identify genetic changes in both alleles of NEO1 in two individuals from a cohort of 66 Han Chinese patients with ASD. In one patient, we detected a hemizygous 1.97-Mb deletion at 15q23q24.1 encompassing the NEO1 gene, a missense variant in NEO1, c.3388C>T (p.Arg1130Cys), and a duplication, c.2204-14_2204-2dup, in the acceptor splice site of intron 14 of NEO1. Furthermore, we identified a second patient was a compound heterozygote for NEO1. A novel missense variant in NEO1, c.302G>A (p.Arg101His), in addition to c.3388C>T and c.2204-14_2204-2dup was detected in the second patient. The c.3388C>T is a single nucleotide polymorphism with allele frequency of 0.045 in Han Chinese individuals. In silico and functional analyses indicated that p.Arg1130Cys, located at the nuclear localization signal (NLS) domain of neogenin led to defective nuclear translocation of neogenin., Conclusions: The hemizygous 15q deletion unmasks the recessive functional polymorphism in NEO1 which plays a pivotal role in cortical interneuron development. Our study provides the first evidence linking NEO1 with ASD in humans., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Many buildings in urban areas are more or less naturally ventilated. A good understanding of the current status and issues of indoor environmental quality (IEQ) in naturally ventilated urban buildings and the association with urban microclimate is fundamental for improving their IEQ. This paper reviews past studies on (a) the microclimate in urban street canyons, (b) the potential influence of such microclimate on IEQ of nearby naturally ventilated buildings, and (c) the real-life IEQ status in these buildings. The review focuses mainly on studies conducted by on-site measurements. The microclimate in urban street canyons is characterized by low wind speed, high surface temperature difference, high pollutant concentration, and high noise level. Insufficient ventilation rates and excessive penetration of outdoor pollutants are two key risks involved in naturally ventilated urban buildings. Existing knowledge suggests that reasonable urban planning and careful building envelope design are the primary methods to ensure acceptable IEQ and maximize the utilization of natural ventilation. However, quantitative studies of both microclimate in street canyons and IEQ in buildings are still highly insufficient in many aspects, which make cross comparison and influencing factors analysis currently impossible. Based on the limitations of previous studies and the current issues of naturally ventilated urban buildings, suggestions are made for future studies to better understand and improve IEQ in naturally ventilated urban buildings., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Despite the prevalent use of Drosophila as a model in studies of nutrition, the effects of fundamental food properties, such as pH, on animal health and behavior are not well known., Objectives: We examined the effect of food pH on adult Drosophila lifespan, feeding behavior, and microbiota composition and tested the hypothesis that pH-mediated changes in palatability and total consumption are required for modulating longevity., Methods: We measured the effect of buffered food (pH 5, 7, or 9) on male gustatory responses (proboscis extension), total food intake, and male and female lifespan. The effect of food pH on germfree male lifespan was also assessed. Changes in fly-associated microbial composition as a result of food pH were determined by 16S ribosomal RNA gene sequencing. Male gustatory responses, total consumption, and male and female longevity were additionally measured in the taste-defective Pox neuro (Poxn) mutant and its transgenic rescue control., Results: An acidic diet increased Drosophila gustatory responses (40-230%) and food intake (5-50%) and extended survival (10-160% longer median lifespan) compared with flies on either neutral or alkaline pH food. Alkaline food pH shifted the composition of fly-associated bacteria and resulted in greater lifespan extension (260% longer median survival) after microbes were eliminated compared with flies on an acidic (50%) or neutral (130%) diet. However, germfree flies lived longer on an acidic diet (5-20% longer median lifespan) compared with those on either neutral or alkaline pH food. Gustatory responses, total consumption, and longevity were unaffected by food pH in Poxn mutant flies., Conclusions: Food pH can directly influence palatability and feeding behavior and affect parameters such as microbial growth to ultimately affect Drosophila lifespan. Fundamental food properties altered by dietary or drug interventions may therefore contribute to changes in animal physiology, metabolism, and survival., (© 2015 American Society for Nutrition.)

Governments all over the world have enacted environmental noise directives and noise control ordinances/acts to protect tranquility in residential areas. However, there is a lack of literature on the evaluation of whether the Acceptable Noise Levels (ANLs) stipulated in the directive/ordinance/act are actually achievable. The study aimed at measuring outdoor environmental noise levels in Hong Kong and identifying whether the measured noise levels are lower than the stipulated ANLs at 20 categories of residential areas. Data were gathered from a territory-wide noise survey. Outdoor noise measurements were conducted at 203 residential premises in urban areas, low-density residential areas, rural areas, and other areas. In total, 366 daytime hourly Leq outdoor noise levels, 362 nighttime hourly Leq outdoor noise levels, and 20 sets of daily, that is, 24 L(eq,1-)h outdoor noise levels were recorded. The mean daytime L(eq,1-h) values ranged 54.4-70.8 dBA, while the mean nighttime L(eq,1-h) values ranged 52.6-67.9 dBA. When the measured noise levels were compared with the stipulated ANLs, only three out of the 20 categories of areas had outdoor noise levels below ANLs during daytime. All other areas (and all areas during nighttime) were found to have outdoor noise levels at or above ANLs.

Identification of germline mutation in patients with apparently sporadic pheochromocytomas and paragangliomas is crucial. Clinical indicators, which include young age, bilateral or multifocal, extra-adrenal, malignant, or recurrent tumors, predict the likelihood of harboring germline mutation in Caucasian subjects. However, data on the prevalence of germline mutation, as well as the applicability of these clinical indicators in Chinese, are lacking. We conducted a cross-sectional study at a single endocrine tertiary referral center in Hong Kong. Subjects with pheochromocytomas and paragangliomas were evaluated for the presence of germline mutations involving 10 susceptibility genes, which included NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, TMEM 127, MAX, and FH genes. Clinical indicators were assessed for their association with the presence of germline mutations. Germline mutations, 2 being novel, were found in 24.4% of the 41 Chinese subjects recruited and 11.4% among those with apparently sporadic presentation. The increasing number of the afore-mentioned clinical indicators significantly correlated with the likelihood of harboring germline mutation in one of the 10 susceptibility genes. (r=0.757, p=0.026). The presence of 2 or more clinical indicators should prompt genetic testing for germline mutations in Chinese subjects. In conclusion, our study confirmed that a significant proportion of Chinese subjects with apparently sporadic pheochromocytoma and paraganglioma harbored germline mutations and these clinical indicators identified from Caucasians series were also applicable in Chinese subjects. This information will be of clinical relevance in the design of appropriate genetic screening strategies in Chinese populations., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Clinical diagnosis of POLG-related disorders can be challenging because the phenotypic spectrums are heterogeneous which can mimic different types of mitochondrial disorders., Case: We report a case of POLG-related disorder in an 18y Chinese girl who had been diagnosed as MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) for the past 8y. She first presented at 10y with sudden onset of headache, repeated focal seizures and visual loss, complicated with residual sensory and motor neuropathy, ophthalmoparesis and cortical blindness. MRI brain showed extensive cytotoxic edema and ischemia in bilateral parietal-occipital lobes. Mutation analysis for common point mutations in the mitochondrial DNA and muscle biopsy was negative. She was referred to us for mitochondrial whole genome analysis. However, no pathogenic variants can be determined. We initiated further genetic analysis for POLG which confirmed compound heterozygous mutations NM_002693.2:c.925C>T (p.Arg309Cys) and a novel mutation c.2244G>T (p.Trp748Cys). Both were determined to be pathogenic using in silico analysis., Conclusions: The novel mutation contributes to the expanding spectrum of disease-causing mutations. A definitive diagnosis can benefit our patient and also the relatives by avoiding sodium valproate induced liver toxicity in POLG patients and also the heterozygotes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: The recent declaration of Ebola virus disease as epidemic by the World Health Organization indicates urgency for affected countries and their laboratories to evaluate and provide treatment to patients potentially infected by the Ebola virus. A heat inactivation procedure involving treating specimens at 60°C for 60 minutes has been suggested for inactivation of the Ebola virus. This study aimed at evaluating the effect of plasma heating on common biochemical tests., Design: Comparative experimental study., Setting: A regional chemical pathology laboratory in Hong Kong., Methods: Forty consecutive plasma specimens for general chemistry analytes on Beckman Coulter AU5822 and another 40 plasma specimens for troponin I analysis on Access 2 Immunoassay System were obtained, anonymised, and divided into two aliquots. One aliquot was analysed directly and the other was analysed after heating at 60°C for 60 minutes., Results: A total of 20 chemical pathology tests were evaluated. Nine tests (sodium, potassium, chloride, urea, creatinine, total calcium, phosphate, total protein, and glucose) were not significantly affected by the heat inactivation procedure and remained clinically interpretable. Results for magnesium (15% mean increase), albumin (41% mean increase), bilirubin (8% mean decrease), amylase (27% mean decrease), and troponin I (76% mean decrease) were still interpretable using regression estimation with proportional bias. However, all enzymes studied except amylase (alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, creatine kinase, and lactate dehydrogenase) were inactivated to a significant degree. Their Pearson r or Spearman rho values ranged from no significant correlation (P≥0.05) to 0.767, and most normality was rejected., Conclusion: Heat inactivation results in no significant change in electrolytes, glucose, and renal function tests, but causes a significant bias for many analytes. Recognition of the relationship between pre- and post-heat inactivation specimens allows clinical interpretation of affected values and contributes to patient care. For safety and diagnostic accuracy, we recommend use of a point-of-care device for blood gases, electrolytes, troponin, and liver and renal function tests within a class 2 or above biosafety cabinet with level 3 or above biosafety laboratory practice.

Background: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min., Case: An 11-month-old Chinese boy had dual molecular diagnoses, β-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of β-ureidopropionic acid and β-ureidoisobutyric acid, the two disease-specific markers for β-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2., Conclusions: The differentiation between Dravet syndrome and β-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine β-ureidoisobutyric and β-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of β-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of β-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); β-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: It is well known that enzymatic assays for acetaminophen are positively interfered by bilirubin. The effect on acetaminophen not only depends on the concentration of bilirubin but also on that of acetaminophen. We demonstrated a negative interference instead of a positive one in a commonly used routine analyzer and investigated the recovery of acetaminophen in an enzymatic assay by a bi-variate regression., Methods: Commercially available blank serum specimens were spiked with acetaminophen and bilirubin at various concentrations, and were analyzed in the Beckman Coulter AU5822 analyzer. The specimens were run in duplicates. The results were then analyzed by least-square analysis and was built into a bi-variate quadratic model., Results: The recovery of acetaminophen in this experiment ranged from 38.9% to 100% throughout a range of 23 μmol/L to 2052 μmol/L (for acetaminophen) and 19 μmol/L to 570 μmol/L (for bilirubin). A contour map, as well as a bi-variate equation was established, describing the relationship between acetaminophen recovery, acetaminophen concentration, and bilirubin concentration., Conclusion: It was shown that the degree of bilirubin interference in a commercially available acetaminophen assay is dependent on both bilirubin and acetaminophen concentrations. There was a decrease in the apparent acetaminophen concentration by an average of 30% at a bilirubin concentration of 420 μmol/L in the Beckman Coulter AU5822 analyzer. The complex relationship can be modeled by mathematical means. This allows the laboratory staff to estimate the recovery of acetaminophen when bilirubin level is concurrently measured., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Beta-ketothiolase deficiency is a rare inborn errors of metabolism (IEM) affecting the catabolism of isoleucine, characterized by severe ketoacidosis in children of 6 to 24months old. A prompt diagnosis is of paramount importance as the metabolic decompensation can be effectively reverted by glucose infusion and health outcomes are improved on a protein-restricted diet. Currently, majority of the laboratory diagnosis were made based on mass-spectrometry and molecular genetics while little is mentioned on the advancement of nuclear magnetic resonance (NMR) spectroscopy for the diagnosis of this condition., Case: We report a case of beta-ketothiolase deficiency in a 1-y-old Chinese boy who presented with repeated vomiting, impaired consciousness and severe ketoacidosis. NMR urinalysis detected excessive amount of butanone (a disease specific marker of beta-ketothiolase deficiency), tiglylglycine, (intermediate of isoleucine catabolism) and ketones. Diagnosis of beta-ketothiolase deficiency was further established by molecular genetic studies of ACAT1 gene of the proband., Conclusions: This case illustrated that NMR-based urinalysis is complementary to organic acid analysis for diagnosis of beta-ketothiolase deficiency. The operation of NMR is simple and fast; sample preparation is a two-step procedure while the NMR acquisition is automatic and usually takes <15min. We envisage that NMR analysis will become more available in clinical laboratories and will play an important role in acute pediatric care., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Alpha-dystroglycanopathies are a group of diseases due to reduced glycosylation of alpha-dystroglycan, which commonly result from mutations in POMT1, POMT2, and POMGnT1. Patients with alpha-dystroglycanopathies present with muscular, cerebral, and ocular involvements with differing severities. We reported a boy who presented with muscular dystrophy, developmental delay, and non-specific white matter lesions. Mutation analysis of POMT1 was performed and revealed two novel mutations, a substitution mutation (c.176T>G) and a duplication mutation (c.2059dupC) which results in premature termination of translation. In-silico prediction in five different platforms concurred that the substitution is damaging, and functional studies by immunofluorescence revealed lack of staining in the carbohydrate moiety of alpha-dystroglycan, confirming the molecular findings in a functional manner. In conclusion, we reported the first case of genetically confirmed alpha-dystroglycanopathy due to mutations in POMT1 in Chinese., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Pseudohypoparathyroidism is a rare genetic disorder characterised by end-organ resistance to parathyroid hormone due to a defect of the guanine nucleotide-binding protein alpha that simulates activity of the polypeptide 1 (GNAS) gene. Patients with type 1a pseudohypoparathyroidism display different features of Albright's hereditary osteodystrophy as well as multi-hormone resistance. We describe a Chinese woman and her son, who presented with different symptoms of pseudohypoparathyroidism and clinically manifested different degree of Albright's hereditary osteodystrophy. Genetic study detected a mutation [NM&#95;000516.4(GNAS):c682C>T (p.Arg228Cys)] in the GNAS gene.

Objectives: To evaluate the cost-benefit of implementing an expanded newborn screening programme for hyperphenylalaninemias due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency in Hong Kong., Setting: Regional public hospitals in Hong Kong providing care for cases of inborn errors of metabolism., Methods: Implementational and operational costs of a new expanded mass spectrometry-based newborn screening programme were estimated. Data on various medical expenditures for the mild and severe phenotypic subtypes were gathered from a case cohort diagnosed with PTPS deficiency from 2001 to 2009. Local incidence from a previously published study was used., Results: Implementation and operational costs of an expanded newborn screening programme in Hong Kong were estimated at HKD 10,473,848 (USD 1,342,801) annually. Assuming a birthrate of 50,000 per year and an incidence of 1 in 29,542 live births, the medical costs and adjusted loss of workforce per year would be HKD 20,773,207 (USD 2,663,232). Overall the annual savings from implementing the programme would be HKD 9,632,750 (USD 1,234,968)., Conclusions: Our estimates show that implementation of an expanded newborn screening programme in Hong Kong is cost-effective, with a significant annual saving for public expenditure., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.

The accurate prediction of pressure losses across in-duct fittings is of significance in relation to the accurate sizing and good energy efficiency of air-delivery systems. Current design guides provide design methods and data for the prediction of pressure losses only for a single and isolated fitting. This study presents an investigation of pressure losses across multiple interactive in-duct fittings in a ventilation duct. A laboratory measurement of pressure losses across one fitting and multiple fittings in a ventilation duct is carried out. The pressure loss across multiple interactive fittings is lower than that across multiple similar individual fittings, while the percentage decrease is dependent on the configuration and combination of the fittings. This implies that the pressure loss across multiple closely mounted fittings calculated by summing the pressure losses across individual fittings, as provided in the ASHRAE handbook and the CIBSE guide, is overpredicted. The numerical prediction of the pressure losses across multiple fittings using the large-eddy simulation (LES) model shows good agreement with the measured data, suggesting that this model is a useful tool in ductwork design and can help to save experimental resources and improve experimental accuracy and reliability.

Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.

Background: Recent studies presented a contradictory approach for the investigation of pediatric patients with an isolated increase in alanine transaminase. While classical teaching advised for a thorough investigation, recent studies suggested the yield on further investigation was low and thus not necessary. Yet the approach to the same clinical problem may need to be different due to variable disease prevalence rates among different ethnic populations. For the population with a higher prevalence rate of genetic liver diseases like Wilson's disease, an abnormal liver function may be the first presenting feature for some patients., Methods: We reviewed 10 Chinese children with Wilson's disease who were diagnosed at a presymptomatic stage because of an isolated persistent elevation of alanine transaminase., Results: All 10 patients did not have overt symptoms of liver impairment or neurological deficit. They were picked up incidentally with an abnormal liver function test. All patients were started on treatment shortly after diagnosis, and they remained well and symptom-free on the latest follow-up., Conclusions: This case series illustrated that an isolated persistent elevation of alanine transaminase is an important clue to the early diagnosis of pre-symptomatic Wilson's disease. It is particularly relevant in the Asian population where the disease is more prevalent.

Compared with the buoyancy-dominated upward spread, the interunit dispersion of pollutants in wind-dominated conditions is expected to be more complex and multiple. The aim of this study is to investigate the wind-induced airflow and interunit pollutant dispersion in typical multistory residential buildings using computational fluid dynamics. The mathematical model used is the nonstandard k-ε model incorporated with a two-layer near-wall modification, which is validated against experiments of previous investigators. Using tracer gas technique, the reentry of exhaust air from each distinct unit to other units on the same building, under different practical conditions, is quantified, and then, the possible dispersion routes are revealed. The units on the floor immediately below the source on the windward side, and vertically above it on the leeward side, where the reentry ratios are up to 4.8% and 14.9%, respectively, should be included on the high-infection list. It is also found that the presence of balconies results in a more turbulent near-wall flow field, which in turn significantly changes the reentry characteristics. Comparison of the dispersion characteristics of the slab-like building and the more complicated building in cross (#) floorplan concludes that distinctive infectious control measures should be implemented in these two types of buildings., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC&#95;012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

Background: PCR-based technology is indispensable for genetic diagnosis. On the other hand, allele dropout is one significant cause of genotyping errors. Most allele dropout mechanisms are related to annealing failure caused by single nucleotide variant (SNV) situated inside the primer sequences. Here, we demonstrate a novel allele dropout mechanism caused by a non-primer-binding-site SNV., Methods: We demonstrate that the apparent homozygosity of NM&#95;000137.1(FAH):c.1035&#95;1037del was caused by allele dropout., Results: The non-primer-binding-site SNV causes a strong secondary hairpin structure formation of the PCR products and leads to amplification failure. SNV check of the primer sequences per se during primer design is not adequate to avoid allele dropout., Conclusions: The next-generation primer design software should analyze the secondary structure of primers and template sequence taking SNV in both sequences into account in order to avoid genotyping errors., (Copyright © 2013 Elsevier B.V. All rights reserved.)