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Objectives To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. Methods We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. Results We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. Conclusion Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.

Steven Truong,1,* Nam Quang Tran,2,3,* Phat Tung Ma,2,3 Chi Khanh Hoang,3 Bao Hoang Le,3 Thang Dinh,3 Luong Tran,3 Thang Viet Tran,2,3 Linh Hoang Gia Le,4 Hoang Anh Vu,4 Thao Phuong Mai,5 Minh Duc Do4 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; 2Department of Endocrinology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam; 3Department of Endocrinology, University Medical Center, Ho Chi Minh City, Vietnam; 4Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam; 5Department of Physiology-Pathophysiology-Immunology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam*These authors contributed equally to this workCorrespondence: Minh Duc DoCenter for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, 217 Hong Bang, District 5, Ho Chi Minh City, 700000, Vietnam, Tel +84 932999989, Email ducminh@ump.edu.vnPurpose: Genetic factors play an important role in the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). However, few genetic association studies related to these disorders have been performed with Vietnamese subjects. In this study, the potential associations of ADIPOQ single nucleotide polymorphisms (SNPs) with T2DM and MetS in a Kinh Vietnamese population were investigated.Patients and Methods: A study with 768 subjects was conducted to examine the associations of four ADIPOQ SNPs (rs266729, rs1501299, rs3774261, and rs822393) primarily with T2DM and secondarily with MetS. The TaqMan SNP genotyping assay was used to determine genotypes from subjects’ DNA samples.Results: After statistical adjustment for age, sex, and body mass index, the ADIPOQ SNP rs266729 was found to be associated with increased risk of T2DM under multiple inheritance models: codominant (OR = 2.30, 95% CI = 1.16– 4.58), recessive (OR = 2.17, 95% CI = 1.11– 4.26), and log-additive (OR = 1.32, 95% CI = 1.02– 1.70). However, rs1501299, rs3774261, and rs822393 were not associated with risk for T2DM. Additionally, rs266729, rs3774261, and rs822393 were statistically associated with MetS, while rs1501299 was not. Haplotype analysis showed a strong linkage disequilibrium between the SNP pairs rs266729/rs822393 and rs1501299/rs3774261, and the haplotype rs266729(G)/rs822393(T) was not statistically associated with MetS.Conclusion: The results show that rs266729 is a lead candidate SNP associated with increased risk of developing T2DM and MetS in a Kinh Vietnamese population, while rs3774261 is associated with MetS only. Further functional characterization is needed to uncover the mechanism underlying the potential genotype–phenotype associations.Keywords: genetic association, Kinh Vietnamese, metabolic syndrome, type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a genetically influenced disease, but few studies have been performed to investigate the genetic basis of T2DM in Vietnamese subjects. Thus, the potential associations of KCNJ11 and ABCC8 single nucleotide polymorphisms (SNPs) with T2DM were investigated in a Kinh Vietnamese population. A cross-sectional study consisting of 404 subjects including 202 T2DM cases and 202 non-T2DM controls was designed to examine the potential associations of 4 KCNJ11 and ABCC8 SNPs (rs5219, rs2285676, rs1799859, and rs757110) with T2DM. Genotypes were identified based on restriction fragment length polymorphism and tetra-primer amplification refractory mutation system polymerase chain reaction. After statistically adjusting for age, sex, and BMI, rs5219 was found to be associated with an increased risk of T2DM under 2 inheritance models: codominant (OR = 2.15, 95% confidence intervals [CI] = 1.09-4.22) and recessive (OR = 2.08, 95%CI = 1.09-3.94). On the other hand, rs2285676, rs1799859, and rs757110 were not associated with an increased risk of T2DM. Haplotype analysis elucidated a strong linkage disequilibrium between the 3 SNPs, rs5219, rs2285676, and rs757110. The haplotype rs5219(A)/rs2285676(T)/rs757110(G) was associated with an increased risk of T2DM (OR = 1.42, 95%CI = 1.01-1.99). The results show that rs5219 is a lead candidate SNP associated with an increased risk of developing T2DM in the Kinh Vietnamese population. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

Background: The prevalence of diabetes mellitus in Vietnam is relatively low compared to other Asian countries, but it is accelerating with the economic and cultural transition. This study aimed to estimate the current prevalence and clinical profile of undiagnosed diabetes mellitus in a tertiary hospital in the south of Vietnam. Methods: A cross-sectional investigation was conducted to recruit 1, 250 participants, who were at least 18 year-old and randomly sampled from Cho Ray Hospital, Ho Chi Minh City, Vietnam. Fasting plasma glucose concentration and HbA1c were measured for each individual. The American Diabetes Association criteria were used to diagnose diabetes. Demographic data and other clinical characteristics of diabetes were also documented, including age, sex, residence, educational status, weight, height, waist and hip circumferences, blood pressure, familial history of diabetes, and lipid profile. Results: The prevalence of undiagnosed diabetes mellitus was 7.5% in the population studied. Age, waist circumference, waist-hip ratio, body mass index, and hypertension, as well as dyslipidaemia were well-correlated with the diabetes rate. Conclusion: The prevalence of undiagnosed diabetes mellitus is increasing far more than expected. Newly diagnosed diabetic patients usually presented with multiple comorbidities, including overweight/ obesity, hypertension, and dyslipidaemia.

Carbon fiber reinforced plastic (CFRP) fuselage and wing panels are being increasingly adopted for aircraft to reduce the aircraft weight, resulting in a reduction in fuel consumption and pollutant emission. CFRP panels are commonly manufactured on flexible manufacturing systems to maximize profit. However, the flexibility of the systems is gained at the cost of manufacturing accuracy, and a workpiece localization process, for finding six rigid transformation parameters, should be introduced in the manufacturing process for compensating for the inevitable workpiece location error. For symmetric workpieces, such as cylindrical fuselage panels, some of the transformation parameters are free, and therefore, multiple localization solutions exist, which are geometrically identical but result in different machining conditions. This paper proposes a multistep workpiece localization method with automated symmetry identification for determining the symmetry of symmetric CFRP panels and finding an optimal solution from numerous solutions. For a symmetric workpiece, the symmetry information, comprising the symmetry type and change-of-basis matrix, is extracted using slippage analysis with an infinitesimal transformation assumption. The extracted information is then used to separately construct nonsymmetric and symmetric transformation matrices for initial localization and final adjustment steps. In the initial localization, a nonsymmetric transformation is determined to minimize the workpiece’s profile error, and in the final adjustment, a symmetric transformation is identified to minimize the compensation (i.e., six rigid transformation parameters) without changing the minimum profile error. The proposed method was verified by conducting four case studies, and it showed high practical applicability.

Introduction: Germline mutations in predisposing genes have been found in 30-40% of pheochromocytoma/paraganglioma patients. Screening for inherited genetic mutations provide clinicians with mutation-positive patient management strategies in addition to identifying family members at risk of disease. However, genetic testing for pheochromocytoma has not been performed widely in Vietnam. Methods: Seven patients diagnosed with pheochromocytoma in Vietnam underwent germline genetic testing in known pheochromocytoma-associated genes by direct sequencing. When a germline mutation was identified the first-degree relatives were counseled and offered genetic testing for the inherited mutation. Results: Mutations were found in five of seven cases and all mutations were in RET proto-oncogene codon 634 indicating a high risk of developing aggressive medullary thyroid cancer and in some cases leading to prophylactic thyroidectomy as recommended. Conclusions: Genetic testing plays an essential role in the clinical management of pheochromocytoma patients. Genetic results have significantly changed the clinical approach in these patients and identified ‘at risk’ family members.

International audience; We have previously shown that ultrasonography can detect hyperechogenic crystal deposits in the kidney medulla of patients with gout. In this cross-sectional study we investigated the frequency and clinical correlates of hyperechogenic kidney medulla in 502 consecutive primary consultants for gout (ACR/EULAR criteria) at the Vien Gut medical center in Ho Chi Minh City, Vietnam. None of these patients received urate-lowering drugs. Kidney medulla echogenicity on B-mode ultrasonography was compared to that of the kidney cortex. Overall, 36% patients showed a hyperechoic pattern of Malpighi pyramids. On univariate analysis, the pattern was significantly associated with age, estimated gout duration, steroid-dependency, clinical tophi, urate arthropathy, double contour thickness at the scanned joints, coronary heart disease, arterial hypertension, hyperuricemia, proteinuria, leukocyturia, and decreased estimated glomerular filtration rate. On multivariable analysis, the hyperechoic pattern was associated with estimated disease duration, clinical tophi, urate arthropathy, double contour thickness and decreased estimated glomerular filtration rate. No hyperechoic pattern was observed in 515 consecutive consultants without gout. Thus, hyperechoic kidney medulla was frequently demonstrated in Vietnamese patients with tophaceous gout and associated with features of tubulointerstitial nephritis. This finding revives the hypothesis of microcrystalline nephropathy of gout, predominantly seen in untreated gouty patients, which could be an important target for urate-lowering therapy.

This study proposes an augmented reality (AR)-assisted workpiece-localization technique for rod-type flexible fixtures used in automotive and aerospace industries, for machining thin-walled components. The machining accuracy of a component depends considerably on the profile error and envelopment condition of the blank workpiece. An AR virtual reference of the component is created in the image space using a pinhole camera with a lens distortion model that visually assists the rough placement of the workpiece at the desired location. The fine workpiece-localization process is formulated as a nonlinear optimization problem to minimize the profile error. The problem is subjected to a point-in-polygon constraint in the image space to guarantee the envelopment requirement. The proposed method is validated using an aircraft body panel. It uses only the measurement data acquired from the upper surface of the panel and the AR reference and is a more flexible and accurate solution than the locating-pin method.

Genetic factors play an important role in the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). However, few genetic association studies related to these disorders have been performed with Vietnamese subjects. In this study, the potential associations ofA study with 768 subjects was conducted to examine the associations of fourAfter statistical adjustment for age, sex, and body mass index, theThe results show that rs266729 is a lead candidate SNP associated with increased risk of developing T2DM and MetS in a Kinh Vietnamese population, while rs3774261 is associated with MetS only. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

Truong S,Tran NQ,Ma PT, et al. Diabetes Metab Syndr Obes. 2022;15:307–319. The authors have advised that the funding statement on page 316 is incorrect. The text “This work was supported by the MIT UROP Program’s Peter J. Eloranta Research Fellowship and the National Foundation for Science & Technology Development (NAFOSTED), grant number 108.01-2019.319. We thank Christine Mendonca and the Joslin Diabetes Center DRC Core for their assistance in genotyping samples” should read “This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 108.01-2019.319 and the MIT UROP Program’s Peter J. Eloranta Research Fellowship. We thank Christine Mendonca and the Joslin Diabetes Center DRC Core for their assistance in genotyping samples”. Read the original article

Health monitoring systems play a key role inside smart factories. To enhance the real-time capability and reliability of health monitoring systems, we propose a fully automatic method for machine diagnosis. Firstly, acquired vibration signals are converted into high-resolution images by wavelet packet spectral subtraction. Next, a trained convolutional neural network (CNN) automatically extracts important features and determines the current health of the machine. The performance of the proposed method is demonstrated by employing a diagnosis problem of a bearing system. The result shows an outstanding classification accuracy of 99.64 % even with a small amount of training data (5 % of the data).

Colorectal cancer (CRC) is one of the most common cancer globally. Understanding the genetic characteristics of CRC is essential for appropriate treatment and genetic counseling.The genetic profile of CRC tumor tissues was identified using next-generation sequencing of 17 target genes (MLH1, MSH2, MSH6, PMS2, EPCAM, APC, SMAD4, BMPR1A, MUTYH, STK11, PTEN, TP53, ATM, CDH1, CHEK2, POLE, and POLD1) in a cohort of 101 Vietnamese patients diagnosed with young-onset CRC. Corresponding germline genetic alterations of determined somatic mutations were subsequently confirmed from patients' blood samples.Somatic mutations were determined in 96 out of 101 CRC patients. Two-thirds of the tumors harbored more than two mutations, and the most prevalent mutated genes were TP53 and APC. Among confirmed germline mutations, 10 pathogenic mutations and 11 variants of unknown significance were identified.Given the burden of CRC and the gradually reducing cost of genetic testing, multigene panel screening can benefit young-onset CRC patients as well as their relatives.

Introduction Genetic mutations of PROC and PROS1 are well-known risk factors for deep venous thrombosis (DVT) in the Asian population. However, the genetic profile of Vietnamese patients with DVT remains elusive. This study aimed to investigate the spectrum of genetic mutations of these two genes in Vietnamese patients diagnosed with idiopathic DVT. Materials and methods A total of 50 Vietnamese patients diagnosed with idiopathic DVT were recruited in this study. The entire coding regions of the protein C and protein S genes were amplified and directly sequenced to determine genetic alterations. Results Four and six genetic mutations were detected in protein C and protein S genes, respectively, in 24 Vietnamese DVT patients. PROC c.565C > T (p.R189W) was the most common mutation found in 13 out of 50 patients, while the mutations of PROS1 comprised three missense and three nonsense variants which diffuse along the gene. Conclusions This study shows that mutations of protein C and protein S genes are prevalent in Vietnamese patients diagnosed with idiopathic DVT, and PROC c.565C > T (p.R189W) was the most common genetic alteration.

Objective The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. Methods All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8–40.1], P P P 150 mg (OR 316 [101–122], P P 2 (OR 100 [32–353], P P = 0.004), and HLA-B*58:01 carriage (OR 147 [45–746], P n = 74), risk factors were eGFR 2 (OR 4.9 [1.61–14.6], P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2–3777], P = 0.01), and asymptomatic hyperuricemia (OR 27 [2–3777], P = 0.01). Conclusion This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.

Development of landslide predictive models with strong prediction power has become a major focus of many researchers. This study describes the first application of the Hyperpipes (HP) algorithm for the development of the five novel ensemble models that combine the HP algorithm and the AdaBoost (AB), Bagging (B), Dagging, Decorate, and Real AdaBoost (RAB) ensemble techniques for mapping the spatial variability of landslide susceptibility in the Nam Dan commune, Ha Giang province, Vietnam. Information on 76 historical landslides and ten geo-environmental factors (slope degree, slope aspect, elevation, topographic wetness index, curvature, weathering crust, geology, river density, fault density, and distance from roads) were used for the construction of the training and validation datasets that are the prerequisites for building and testing the proposed models. Using different performance metrics (i.e., the area under the receiver operating characteristic curve (AUC), negative predictive value, positive predictive value, accuracy, sensitivity, specificity, root mean square error, and Kappa), we verified the proficiency of all five ensemble learning techniques in increasing the fitness and predictive powers of the base HP model. Based on the AUC values derived from the models, the ensemble ABHP model that yielded an AUC value of 0.922 was identified as the most efficient model for mapping the landslide susceptibility in the Nam Dan commune, followed by RABHP (AUC = 0.919), BHP (AUC = 0.909), Dagging-HP (AUC = 0.897), Decorate-HP (AUC = 0.865), and the single HP model (AUC = 0.856), respectively. The novel ensemble models proposed for the Nam Dan commune and the resultant susceptibility maps can aid land-use planners in the development of efficient mitigation strategies in response to destructive landslides. Validerad;2020;Nivå 2;2020-06-15 (alebob)

Pemphigus is a rare, devastating, bullous autoimmune disease that damages the skin and mucous membranes, and has high morbidity and mortality. Studies have shown associations of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with human leukocyte antigen (HLA) class II polymorphisms.This study examined the frequency of Major Histocompatibility Complex, Class II, DR Beta 1, a Protein Coding gene (HLA-DRB1) and Major Histocompatibility Complex, Class II, DQ Beta 1 (HLA-DQB1) alleles in Vietnamese PV and PF patients, and the association of these polymorphisms with pemphigus subtypes and disease severity.The study enrolled 31 unrelated Vietnamese who underwent HLA typing using Sanger sequencing.HLA-DRB1∗14:54 was the most frequent allele in both PV (20.5%) and PF (33.3%) patients. The percentage of HLA-DQB1∗03:02 was significantly higher in PF than PV patients, while the percentage of HLA-DQB1∗05:03 was approximately 10 times higher in PV patients. Pemphigus patients who have the HLA-DRB1∗04 alleles are more likely to have mild or moderate disease.The HLA-DRB1 and DQB1 alleles may influence susceptibility to pemphigus subtypes, with DQB1∗05:03 being specific for PV and DQB1∗03:02 for PF. Our findings suggest that the DRB1∗04 alleles are likely to be associated with mild and moderate disease.

Flexible fixtures are finding widespread use in manufacturing processes of thin-walled components in the automotive and aerospace industries. Owing to its reconfigurability, a flexible fixture can take different layouts depending on the workpiece geometry and location. By finding the appropriate workpiece location, the deformation of workpieces under machining forces and their own weights can be reduced, hence increasing the quality of the final products. In this paper, we introduce a novel method for optimum workpiece positioning in rod type flexible fixtures for thin-walled components. First, the geometry of the workpiece is extracted from its CAD model. Second, a geometry-based method is proposed to find the optimal location of the workpiece relative to the fixture system. A composition of homogeneous transformations is performed to maximize the workpiece support capacity, initially place the workpiece in the fixture region, and maximize the number of active fixture elements (fixels). Third, the result is verified and visualized in a fixture verification module. An aircraft body panel is employed as an example to test the performance of the proposed method. Finally, conclusions and future studies are discussed.

This study is based on the studying, designing and manufacturing of eddy current probes for industry applications. The main tasks of this study include: + Describes the overview and classification of eddy current probes (which can be classified into three categories based on the mode of operation: absolute eddy current probe, differential eddy current probe and reflect eddy current probe). + Describes the three methods of probe designing and manufacturing (including experimental, analytical and numerical designs). + Describes the designing and manufacturing of eddy current probes for industry applications, which based on experimental and analytical methods. Based on this study, we have successfully manufactured some current probes (including absolute eddy current probe, differential eddy current probe and reflect eddy current probe) for surface and tube inspections.

Background Allopurinol (ALLO) exposes to mild (M) and severe (S) cutaneous adverse reactions (CARs). SCARS have been associated with HLA*B58 01 with various strength of across ethnicities. Little is known about ALLO tolerance in Vietnam (VN). Objectives The aim of this ongoing prospective study was to investigate risk factors, including HLA*B-58 01, for MCARs and SCARs in the predominant Kinh ethnicity of VN Methods All included patients were Kinh Vietnamese. SCARs were recruited at Ho Chi Minh City hospitals, MCARs from the same departments and from the Vien Gut clinic at HCMC (specialised in gout care), and tolerant gouty patients (no skin reaction after at least 3 months from the last increment in ALLO dose) at the Vien Gut clinic. Clinical data were prospectively collected and HLA*B-58 01 typing used the PG5801 DNA detection kit (Pharmigene-Taiwan). Fisher exact test for categorical variables and Kruskal/Wilkonson test for quantitative variables were used for statistics. Results 10 patients experienced a non-fatal SCAR. Toxic necrotic epidermolysis, Stevens-Johnson syndrome and mixed syndrome were diagnosed in 1, 8 and 1 patients respectively. 54 patients stopped ALLO because of MCAR.112 ALLO tolerant patients were recruited. Table 1 shows the main features of interest in the 3 groups. The Odds ratio of HLA*B-58 01 positive patients to develop SCARs was calculated at 171.2 (95% CI: 20; 7889) Conclusions HLA*B-58 01 was significantly associated with SCARs to ALLO in the VN Kinh population. Other known factors but not high ALLO dose were also associated. The only association with MCARs was lack of ALLO titration. Acknowledgements ART Viggo Disclosure of Interest None declared

This tool deals with a procedure for landslide susceptibility mapping at a regional scale. It is applied to the upper Lo River catchment in Vietnam, where data on spatial distribution of historic landslides and environmental factors are available, although they are limited. The available data include an inventory map and six landslide factor maps related to elevation, slope gradient, drainage density, fault density, types of weathering crust, and types of land cover. The Analytical Hierarchy Process method is used together with expert knowledge to define the weights of each factor and each factor class in order to determine the relative importance of the six landslide factors and their classes within the landslide susceptibility analysis. The Weighted Linear Combination method is used to assign the above-defined weights to all factor maps in raster format in order to compute the landslide susceptibility. As the approach is able to integrate expert knowledge in the weighting of the input factors, the actual study shows that the combination of Analytical Hierarchy Process and Weighted Linear Combination methods is suitable for landslide susceptibility mapping in large mountainous areas at medium scales, particularly for areas lacking detailed input data.

The literature contains limited information on variations in the factors of safety (FOS) of riverbank stability associated with river water level (RWL) fluctuations. This paper analyses a case study on the portion of the Red River flowing through Hanoi using the finite element method and extending the mechanics of saturated and unsaturated soils to understand how the riverbank’s FOS varies with RWL fluctuations. The results show that hydrostatic force is one of the key parameters influencing the FOS when the soil’s hydraulic conductivity is less than 10 −6 m/s. However, the pore-water pressure and rate of RWL change are the key parameters influencing the FOS when the hydraulic conductivity is greater than 10 −6 m/s. The study also indicates that a surcharge of 50 kPa or higher significantly weakens the riverbank stability and influences the FOS when the RWL rises. The construction of residential or other structures without taking special protection measures within 50 m of the lateral riverbank should be avoided for safety reasons.

Landslides, as one of the major natural hazards, account each year for enormous property damage in terms of both direct and indirect costs. Mountain roads where probability of land sliding is the highest, causes hurdles not only in the traffic flow but generate various traffic problems in the form of congestion, high accidents rate and waste of time. This paper introduces an agent-based model for modeling and simulation of the effects of landslide on the circulation of transports on mountain roads. This model is applied to the National Road N°6 of Vietnam to visualize and analyze the effects of landslide on the road when it occurs. This model could help us to improve and optimally organize of landslide warning and rescue system on the road.