Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Helicobacter ; 27(2): e12876, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35150597

RESUMO

BACKGROUND: Antibiotic resistance emerges as a major issue for Helicobacter pylori (H. pylori) treatment. High-dose dual therapy has recently shown encouraging results in H. pylori eradication, but it has yet to be validated in this H. pylori highly infected area; it is also not known if this concept can be extended to antibiotics other than amoxicillin, and factors that affect the eradication. We investigate if rabeprazole plus amoxicillin or furazolidone regimens could be a first-line therapy for H. pylori eradication, and factors that affect the curing rate. METHODS: This is a single-center, prospective, open-label, randomized-controlled trial. Naive patients (n=292) were randomly treated with bismuth-containing quadruple therapy (BQT), rabeprazole plus amoxicillin (RADT), or furazolidone (RFDT) groups. RADT and FADT use three times daily regimens. H. pylori diagnosis and eradication were determined and confirmed by 13 C-urea breath test. RESULTS: In per-protocol (PP) analysis, H. pylori eradication rate was 91.2% in BQT group, 89.6% in RADT, and 51.0% in RFDT group. In intention-to-treat (ITT) analysis, infection was eradicated in 86.7% of patients in BQT group, 85.8% in RADT, and 48.1% in RFDT groups, respectively. Noninferiority was confirmed between BQT and RADT groups. The incidence of side effects in BQT group was significantly higher than that in RADT group. Successful eradication was associated with lower body surface area (BSA) and low body mass index (BMI) in BQT group. Smoking and high BSA index reduced H. pylori eradication rate in RADT group. CONCLUSIONS: Rabeprazole-amoxicillin dual therapy is equally effective to the bismuth-containing quadruple therapy for H. pylori eradication with fewer side effects and saves use of one antibiotic per each treatment. Successful eradication is also associated with low BSA and non-smoking condition, which deserves future stratified analysis for refinement and optimization.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Antibacterianos , Bismuto , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Humanos , Estudos Prospectivos , Rabeprazol/uso terapêutico , Resultado do Tratamento
2.
Helicobacter ; 26(3): e12793, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33675089

RESUMO

BACKGROUND: Two critical concerns during Helicobacter pylori (H. pylori) eradication are the successful eradication and recurrence. It is debatable whether whole family-based H. pylori treatment regimen might have any advantage over single-infected patient treatment approach in increasing eradication rate and reducing recurrence rate. We conduct systematic review and meta-analysis to compare the efficacy of these two treatment regimens in order to provide clinical practice a better option for H. pylori eradication. METHODS: Randomized controlled trials evaluating H. pylori eradication and recurrence in whole family-based treatment group (WFTG) versus single-infected patient treatment group (SPTG) were collected from published literature up to July 2020 from common databases. Pooled results were analyzed using either fixed-effect or random-effect model. Results were expressed as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 1751 relevant articles were identified, and 12 studies were eligible for analysis. Among them: (a) Eight articles including 1198 patients were selected to analyze H. pylori eradication rate, pooled result showed that eradication rate of WFTG was higher than that of SPTG (OR=2.93; 95% CI 1.68-5.13). Stratified analysis showed that H. pylori eradication rate in WFTG were higher over SPTG in children subgroup, but had no difference in spouse subgroup. (b) Six studies including 881 patients were analyzed for recurrence rate between the two groups, pooled analysis showed that the overall recurrence rate of WFTG was lower than that of SPTG (OR=0.3; 95% CI 0.19-0.48). Stratified analysis showed that the recurrence rate in WFTG was lower over SPTG at 6, 12, 18, and more than 24 months post-treatment subgroups. CONCLUSION: Whole family-based H. pylori treatment can partially increase eradication rate and reduce recurrence rate over single-infected patient treatment approach, the results provide clinical practice a novel notion for H. pylori eradication and infection prevention.


Assuntos
Antibacterianos , Saúde da Família , Infecções por Helicobacter , Antibacterianos/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Int J Hyperthermia ; 37(1): 1260-1267, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33191810

RESUMO

AIM: The purpose of this study is to observe the volume change of prostate and laser-ablated lesions in the canine and to explore the mechanism and clinical significance through histopathology. MATERIALS AND METHODS: Transperineal laser ablation (TPLA) was performed under the guidance of transrectal ultrasound (TRUS) in eight canines. Two canines were sacrificed 1 day and 1 week after TPLA, respectively. The remaining six canines were sacrificed after finishing transrectal contrast-enhanced ultrasound (TR-CEUS) at three phases. RESULTS: The prostatic volumes immediately following TPLA and 1 week later were larger than before TPLA (20.1 ± 3.9 vs 17.1 ± 3.8 ml; 21.7 ± 3.6 vs 17.1 ± 3.8 ml, p < 0.05), but 1 month later, returned to the preoperative level (17.4 ± 3.2 ml). At three time points, the mean volumes of laser-ablated lesions at 3 W/600 J were 0.6 ± 0.2, 1.1 ± 0.4, and 1.7 ± 0.5 ml, respectively, while those of laser-ablated lesions at 3 W/1200 J were 1.2 ± 0.2, 1.6 ± 0.3, and 2.2 ± 0.5 ml, respectively. The mean volumes of laser-ablated lesions increased significantly over time after TPLA (p < 0.050). CONCLUSION: The prostate volume transient enlarges after TPLA, which prompts for clinical application that it should prolong appropriately the duration of urinary catheterization to avoid acute urinary retention. Many inflammatory cells were observed in the laser-ablated lesions and adjacent normal prostate parenchyma through histopathology. It is speculated that the inflammatory response is involved in the progression of tissue damage.


Assuntos
Terapia a Laser , Neoplasias da Próstata , Animais , Cães , Humanos , Lasers , Masculino , Próstata/diagnóstico por imagem , Próstata/cirurgia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Ultrassonografia
4.
Echocardiography ; 35(7): 991-998, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29676485

RESUMO

OBJECTIVE: The objective of this study was to evaluate the feasibility of online real time three-dimensional transesophageal echocardiography (RT3DTEE) in the measurement of left atrial appendage (LAA) orifice size. We also analyzed the correlation between LAA ejection fraction (EF) and its peak empty velocity (PEV). METHODS: There were 91 subjects enrolled in this study, with 46 patients with AF and 45 individuals with sinus rhythm (SR). RT3DTEE was performed by four methods including iSlice and iCrop online and QLAB software 3DQ and GI-3DQ off-line which were used to measure LAA orifice area, long diameter, short diameter, depth in the largest LAA, and number of LAA lobes. These LAA parameters achieved by the four methods were compared, respectively. GI-3DQ off-line was used to measure LAA end-diastolic and end-systolic volumes to calculate EF of LAA. Two-dimensional (2D) TEE was applied to measure PEV of LAA. The correlation between EF and PEV was analyzed. RESULTS: There were no significant differences in all LAA parameters between any two RT3DTEE methods (All P > .05). There was a significant and positive correlation between PEV and EF (r = .423, P = .000). There were statistical differences in LAA EF and PEV between patients with AF and SR individuals (0.38 ± 0.12 vs 0.61 ± 0.07, 35.7 ± 12.1 vs 49.5 ± 10.0 cm/s, P = .000). CONCLUSION: Using online RT3DTEE for measuring LAA orifice size is feasible, and online RT3DTEE is more convenient than offline RT3DTEE. EF is positively correlated with PEV. LAA function is significantly decreased in patients with AF.


Assuntos
Apêndice Atrial/diagnóstico por imagem , Fibrilação Atrial/diagnóstico , Função do Átrio Esquerdo/fisiologia , Sistemas Computacionais , Ecocardiografia Tridimensional/métodos , Ecocardiografia Transesofagiana/métodos , Sistemas On-Line , Adolescente , Adulto , Idoso , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/fisiopatologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
5.
J Gene Med ; 19(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28220983

RESUMO

BACKGROUND: Little information is available regarding the penetrance of 1q21.1 copy number variants (CNVs). In the present study, we explored the clinical significance of 1q21.1 microdeletion or microduplication. METHODS: In four families, chromosome karyotype was analyzed using G-banding karyotype analysis technology. CNVs were detected using array-comparative genomic hybridization (aCGH) and then a quantitative polymerase chain reaction (qPCR) was used to validate candidate CNVs. Sequence signature in the breakpoint region was analyzed using University of California Santa Cruz (UCSC) databases. RESULTS: Except for karyotype 45, XX, der (13, 14) (q10, q10) in the mother (I2) of family 2, the karyotype was normal in all other members of the four families. In the mother (I2) and fetus (II2) of family 1, in newborn (II1) of family 2 and in fetus (II1) of family 3, there was 1.22-Mb heterozygous microdeletion in the chromosome 1q21.1q21.2 region. The child (II1) of family 4 had a 1.46-Mb heterozygous microduplication in the chromosome 1q21.1q21.2 region. The results of the qPCR were consistent with that of aCGH. There was large number of low copy repeats (LCRs) in the breakpoint region found by analysis of the UCSC database, and multiple LCRs were matched with sequences in the chromosome 1 short-arm region. CONCLUSIONS: 1q21.1 microdeletion and microduplication exhibit a variety of clinical manifestations and the specificity of their clinical features is not high. The penetrance of the distal 1q21.1 microdeletion may be affected by other factors in the present study. In summary, we report the discovery of a new distal 1q21.1 microduplication, which enriches the CNV spectrum in the 1q21.1 region and is conducive to prenatal genetic counseling.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Duplicação Cromossômica , Estudos de Associação Genética , Megalencefalia/diagnóstico , Megalencefalia/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Hibridização Genômica Comparativa , Análise Citogenética , Variações do Número de Cópias de DNA , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Linhagem , Penetrância , Ultrassonografia Pré-Natal , Adulto Jovem
6.
J Ultrasound Med ; 33(12): 2125-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25425368

RESUMO

OBJECTIVES: To explore the application of instantaneous wave intensity for early diagnosis of systemic lupus erythematosus (SLE)-induced atherosclerosis, we observed carotid elasticity by instantaneous wave intensity in premenopausal women with SLE. METHODS: The study included 3 groups (each group with 30 participants): SLE1 (course of disease <5 years), SLE2 (course of disease ≥5 years) and healthy control. Carotid parameters, including instantaneous acceleration wave intensity, instantaneous deceleration wave intensity, negative area, stiffness constant, wave intensity pulse wave velocity, stiffness constant pulse wave velocity, pressure strain elastic modulus, arterial compliance, augmentation index, and intima-media thickness, were measured. RESULTS: Compared with the control group, the instantaneous deceleration wave intensity, stiffness constant, pressure strain elastic modulus, wave intensity pulse wave velocity, and stiffness constant pulse wave velocity were significantly increased but the arterial compliance was significantly decreased in the SLE1 and SLE2 groups (all P ≤ .01). The instantaneous acceleration wave intensity, augmentation index, and negative area tended to increase in all 3 groups, but there were no statistical differences among the groups. The instantaneous deceleration wave intensity, stiffness constant, pressure strain elastic modulus, wave intensity pulse wave velocity, and stiffness constant pulse wave velocity were significantly higher in the SLE2 group than the SLE1 group, but the arterial compliance was significantly lower in the SLE2 group than the SLE1 group (all P ≤ .01). CONCLUSIONS: Instantaneous wave intensity can be used to evaluate carotid elasticity in the patients with SLE, which is important for early prevention and treatment of cardiovascular disease.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/fisiopatologia , Técnicas de Imagem por Elasticidade/métodos , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/fisiopatologia , Adolescente , Adulto , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Diagnóstico Precoce , Módulo de Elasticidade , Feminino , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Rigidez Vascular , Adulto Jovem
7.
Medicine (Baltimore) ; 97(33): e11643, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113455

RESUMO

The aim of this study was to explore the effects of nonvalvular atrial fibrillation (NVAF) on the structure and function of mitral valve and analyze independent risk factors of moderate to severe mitral regurgitation (MR) by quantitative measurement of mitral parameters using real-time 3-dimensional transesophageal echocardiography.This study included 30 subjects with sinus rhythm group, and 65 patients with NVAF. The 65 patients with NVAF were divided into 35 with paroxysmal atrial fibrillation group and 30 with persistent atrial fibrillation. According to MR degree, the patients with NVAF were again divided into no or mild MR group (n = 44) and moderate to severe MR group (n = 21).There were significant differences in anterolateral-to-posteromedial diameter (DAlPm), anterior-to-posterior diameter, 3-dimensional circumference (C3D), 2-dimensional area (A2D), mitral leaflet surface area in late systolic phase, the index of mitral valve coaptation and left atrial internal diameter (LAID) between different cardiac rhythm groups (all P < .05). The DAlPm, C3D, A2D, nonplanar angle (θNPA), and LAID were greater but the mitral valve coaptation index was smaller in the moderate to severe MR group than in the no or mild MR group (all P < .05). Logistic regression analysis indicated that DAlPm and LAID were independent risk factors of moderate to severe MR in the patients with NVAF (OR > 1, P < .05).DAlPm and LAID are independent risk factors of moderate to severe MR in the patients with NVAF. NVAF can change the structure and function of mitral valve, which leads to MR.


Assuntos
Fibrilação Atrial/complicações , Ecocardiografia Tridimensional/métodos , Ecocardiografia Transesofagiana/métodos , Átrios do Coração/diagnóstico por imagem , Insuficiência da Valva Mitral/fisiopatologia , Valva Mitral/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Feminino , Átrios do Coração/anatomia & histologia , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/anatomia & histologia , Valva Mitral/fisiopatologia , Fatores de Risco
8.
Medicine (Baltimore) ; 97(48): e13307, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508919

RESUMO

The prognosis of right heart enlargement varies according to different etiologies. The purpose of this study was to investigate the characteristics of echocardiogram, surgical treatment, chromosome and prognosis for fetal right heart enlargement.The foetal echocardiogram was performed on 3987 pregnant women, and then 88 fetuses with right heart enlargement were identified. The data about prenatal and postnatal echocardiograms, postnatal cardiac surgical treatment, karyotype analysis and autopsy after induced labor were analyzed in the 88 fetuses.Except the 1111 cases that had loss of follow-up, 2876 cases had complete data. Among the 2876 cases, right heart enlargement was identified in 88 fetuses. Of the 88 fetuses, 15 had total atrioventricular septal defect (unbalanced type: right ventricular dominance), 15 Ebstein's anomaly, 18 fallot tetrad, 14 double outlet right ventricle, 13 total anomalous pulmonary venous drainage, and 13 premature closure of ductus arteriosus. Chromosomal abnormality was found in 12 cases.There are many etiological factors causing right heart enlargement. The prognosis is better in the fetuses with single heart malformation than in the fetuses who have extracardiac malformation or/and chromosomal abnormality besides heart malformation. Fetal echocardiography combined with karyotype analysis can provide important bases for evaluating the prognosis of fetuses with right heart enlargement.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Ecocardiografia , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/genética , Ultrassonografia Pré-Natal , Adolescente , Adulto , Aberrações Cromossômicas , Feminino , Seguimentos , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia , Humanos , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/cirurgia , Cariótipo , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
9.
Oncotarget ; 8(63): 106976-106988, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29291004

RESUMO

BACKGROUND: Tetralogy of Fallot is the most common cyanotic congenital heart disease. However, its pathogenesis remains to be clarified. The purpose of this study was to identify the genetic variants in Tetralogy of Fallot by whole exome sequencing. METHODS: Whole exome sequencing was performed among eight small families with Tetralogy of Fallot. Differential single nucleotide polymorphisms and small InDels were found by alignment within families and between families and then were verified by Sanger sequencing. Tetralogy of Fallot-related genes were determined by analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases. RESULTS: A total of sixteen differential single nucleotide polymorphisms loci and eight differential small InDels were discovered. The sixteen differential single nucleotide polymorphisms loci were located on Chr 1, 2, 4, 5, 11, 12, 15, 22 and X. Among the sixteen single nucleotide polymorphisms loci, six has not been reported. The eight differential small InDels were located on Chr 2, 4, 9, 12, 17, 19 and X, whereas of the eight differential small InDels, two has not been reported. Analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases revealed that PEX5, NACA, ATXN2, CELA1, PCDHB4 and CTBP1 were associated with Tetralogy of Fallot. CONCLUSIONS: Our findings identify PEX5, NACA, ATXN2, CELA1, PCDHB4 and CTBP1 mutations as underlying genetic causes of isolated tetralogy of Fallot.

10.
Medicine (Baltimore) ; 95(49): e5552, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27930557

RESUMO

To explore the underlying pathogenesis and provide references for genetic counseling and prenatal gene diagnosis, we analyzed the chromosome karyotypes and genome-wide copy number variations (CNVs) in 86 patients with tetralogy of Fallot (TOF) by G-banding karyotype analysis and array-comparative genomic hybridization (aCGH), respectively. And then quantitative polymerase chain reaction was used to validate these candidate CNVs. Based on their different properties, CNVs were categorized into benign CNVs, suspiciously pathogenic CNVs, and indefinite CNVs. Data analysis was based on public databases such as UCSC, DECIPHER, DGV, ISCA, and OMIM.The karyotype was normal in all the 86 patients with TOF. CNVs were detected in 11 patients by aCGH and quantitative polymerase chain reaction. Patient no. 0001, 0010, and 0029 had 2.52-Mb deletion in the chromosome 22q11.21 region; patient no. 0008 had both 595- and 428-kb duplications, respectively, in 12p12.3p12.2 and 14q23.2q23.3 regions; patient no. 0009 had 1.46-Mb duplication in the 1q21.1q21.2 region; patient no. 0016 had 513-kb duplication in the 1q42.13 region; patient no. 0024 had 292-kb duplication in the 16q11.2 region; patient no. 0026 had 270-kb duplication in the 16q24.1 region; patient no. 0028 had 222-kb deletion in the 7q31.1 region; patient no. 0033 had 1.73-Mb duplication in the 17q12 region; and patient no. 0061 had 5.79-Mb deletion in the 1p36.33p36.31 region.aCGH can accurately detect CNVs in the patients with TOF. This is conducive to genetic counseling and prenatal diagnosis for TOF and provides a new clue and theoretical basis for exploring the pathogenesis of congenital heart disease.


Assuntos
Hibridização Genômica Comparativa , Tetralogia de Fallot/genética , Adolescente , Adulto , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Primers do DNA , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase , Adulto Jovem
11.
J Matern Fetal Neonatal Med ; 29(3): 493-503, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25731651

RESUMO

OBJECTIVE: To provide a basis for evaluating the prognosis of small left heart system development in fetuses, we analyzed its related factors. METHODS: The fetal echocardiogram was performed in 3859 pregnant women, and then small left heart system development was identified in 69 fetuses. The data of prenatal and postnatal echocardiograms, postnatal cardiac surgical treatment, chromosome and autopsy after induced labor were analyzed in the 69 fetuses. RESULTS: Except 1320 cases losing follow-up, 2539 cases had complete data. Among the 2539 cases, small left heart system development was identified in 69 fetuses. Of the 69 fetuses, 12 had hypoplastic left heart syndrome, 20 premature closure of foramen ovale, 13 total anomalous pulmonary venous drainage, 2 common pulmonary vein lumen atresia, 21 aortic coarctation or interruption and 1 right pulmonary hypoplasia. Among the 69 fetuses, chromosome abnormality was found in 7. CONCLUSION: There are many etiological factors causing small left heart system development. The prognosis is poor in the fetuses with hypoplastic left heart syndrome, common pulmonary vein lumen atresia, pulmonary hypoplasia, other malformations or/and chromosome abnormality. Fetal echocardiography combined with chromosome examination can provide important bases for making diagnosis and evaluating the prognosis regarding small left heart system development.


Assuntos
Doenças Fetais/etiologia , Cardiopatias Congênitas/etiologia , Adolescente , Adulto , Ecocardiografia , Feminino , Doenças Fetais/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Cariótipo , Pessoa de Meia-Idade , Gravidez , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Ultrassonografia Pré-Natal , Adulto Jovem
12.
J Chem Phys ; 125(10): 104502, 2006 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-16999536

RESUMO

The structural organization, the number of hydrogen bonds (H bond), and the self- and mutual diffusion coefficients of ethanol-water mixtures were studied by molecular dynamics simulation. It was found that both the numbers of H bonds per water and per ethanol decrease as the mole fraction of ethanol increases. The composition dependences and the relationships between the self- and the mutual diffusion coefficients were further discussed. The self-diffusion coefficient of water has a large drop as the concentration of ethanol increases from 0 to 0.3 and then it nearly keeps constant, while that of ethanol has a minimum around ethanol mole fraction of 0.5. The mutual diffusion coefficient could be divided into two parts, the kinematic factor and the thermodynamic factor. Both the kinematic and thermodynamic factors for ethanol-water mixtures were calculated. It was found that the change trend of mutual diffusion coefficients with the composition is mainly dependent on the thermodynamic factors.

SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa