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OBJECTIVE: Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals. DESIGN: In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months. RESULTS: A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high. CONCLUSION: A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm. TRIAL REGISTRATION NUMBER: NTR7477.
Assuntos
Pólipos do Colo , Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Humanos , Pólipos do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais/cirurgiaRESUMO
BACKGROUND: Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35â%-60â% in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. METHODS: In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. RESULTS: 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47â%] trained). Median T1 CRC size was 20âmm. Lesions were mainly located in the distal colorectum (66â%). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74â% vs. 62â%; mixed model analysis odds ratio [OR] 2.90, 95â%CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69â% vs. 56â%; OR 1.73, 95â%CI 1.03-2.91). CONCLUSION: Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.
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The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vírus da Influenza A/química , Animais , Anticorpos/química , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Cromatografia em Gel , Ensaio de Imunoadsorção Enzimática , Epitopos/química , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Humanos , Memória Imunológica , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Modelos Moleculares , Conformação Molecular , Especificidade da EspécieRESUMO
The pathogenicity of mycobacteria is closely associated with their ability to export virulence factors. For this purpose, mycobacteria possess different protein secretion systems, including the accessory Sec translocation pathway, SecA2. Although this pathway is associated with intracellular survival and virulence, the SecA2-dependent effector proteins remain largely undefined. In this work, we studied a Mycobacterium marinumâ secA2 mutant with an impaired capacity to initiate granuloma formation in zebrafish embryos. By comparing the proteomic profile of cell envelope fractions from the secA2 mutant with wild type M. marinum, we identified putative SecA2-dependent substrates. Immunoblotting procedures confirmed SecA2-dependent membrane localization for several of these proteins, including the virulence factor protein kinase G (PknG). Interestingly, phenotypical defects of the secA2 mutant are similar to those described for ΔpknG, including phagosomal maturation. Overexpression of PknG in the secA2 mutant restored its localization to the cell envelope. Importantly, PknG-overexpression also partially restored the virulence of the secA2 mutant, as indicated by enhanced infectivity in zebrafish embryos and restored inhibition of phagosomal maturation. These results suggest that SecA2-dependent membrane localization of PknG is an important determinant for M. marinum virulence.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mycobacterium marinum/metabolismo , Fatores de Virulência/metabolismo , Animais , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Immunoblotting , Mutagênese Insercional , Infecções por Mycobacterium/microbiologia , Mycobacterium marinum/patogenicidade , Especificidade por Substrato , Peixe-ZebraRESUMO
OBJECTIVE: Faecal immunochemical testing (FIT) is increasingly used in colorectal cancer (CRC) screening but has a less than perfect sensitivity. Combining risk stratification, based on established risk factors for advanced neoplasia, with the FIT result for allocating screenees to colonoscopy could increase the sensitivity and diagnostic yield of FIT-based screening. We explored the use of a risk prediction model in CRC screening. DESIGN: We collected data in the colonoscopy arm of the Colonoscopy or Colonography for Screening study, a multicentre screening trial. For this study 6600 randomly selected, asymptomatic men and women between 50 years and 75 years of age were invited to undergo colonoscopy. Screening participants were asked for one sample FIT (OC-sensor) and to complete a risk questionnaire prior to colonoscopy. Based on the questionnaire data and the FIT results, we developed a multivariable risk model with the following factors: total calcium intake, family history, age and FIT result. We evaluated goodness-of-fit, calibration and discrimination, and compared it with a model based on primary screening with FIT only. RESULTS: Of the 1426 screening participants, 1112 (78%) completed the questionnaire and FIT. Of these, 101 (9.1%) had advanced neoplasia. The risk based model significantly increased the goodness-of-fit compared with a model based on FIT only (p<0.001). Discrimination improved significantly with the risk-based model (area under the receiver operating characteristic (ROC) curve: from 0.69 to 0.76, (p=0.02)). Calibration was good (Hosmer-Lemeshow test; p=0.94). By offering colonoscopy to the 102 patients at highest risk, rather than to the 102 cases with a FIT result >50 ng/mL, 5 more cases of advanced neoplasia would be detected (net reclassification improvement 0.054, p=0.073). CONCLUSIONS: Adding risk based stratification increases the accuracy FIT-based CRC screening and could be used in preselection for colonoscopy in CRC screening programmes.
Assuntos
Colonoscopia , Neoplasias Colorretais/diagnóstico , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Fezes/química , Idoso , Neoplasias Colorretais/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Medição de Risco , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1â2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M. tuberculosis orthologue, disruption of M. marinum mptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1â2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M. marinum mptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatis mptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity.
Assuntos
Lipopolissacarídeos/metabolismo , Mycobacterium marinum/imunologia , Mycobacterium marinum/patogenicidade , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/metabolismo , Animais , Carga Bacteriana , Imunidade Inata , Lipopolissacarídeos/química , Manose/química , Infecções por Mycobacterium não Tuberculosas/imunologia , Mycobacterium marinum/genética , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/genética , Tuberculose/imunologia , Peixe-Zebra/imunologia , Peixe-Zebra/microbiologiaRESUMO
BACKGROUND AND STUDY AIMS: Serrated polyps of the large intestine comprise a heterogeneous group of lesions with distinct histological and malignant features. The aim of the study was to estimate the prevalence of serrated polyp subtypes in a cohort of individuals undergoing screening colonoscopy, and to identify associations between the detection of serrated polyp subtypes and advanced neoplasia. PATIENTS AND METHODS: Data on serrated polyps, adenomas, and cancers were collected from participants of a randomized screening trial that compared colonoscopy with computed tomography colonography. Only data from participants in the colonoscopy arm were used. Logistic regression analyses were performed to identify associations between patients' age, sex, and prevalence of the different types of serrated polyps and to identify associations between the detection of these polyps and advanced neoplasia (defined as an adenoma ≥â10âmm, villous component, high grade dysplasia or colorectal cancer). RESULTS: A total of 1426 screen-naïve individuals (51â% male) with a median age of 60 years (IQR 55â-â65) were included. The prevalence of hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) was 23.8â%, 4.8â%, and 0.1â%, respectively. SSA/Ps comprised 7.3â% of all polyps. No differences based on age or sex were observed in the prevalence of SSA/Ps. Proximal and large (≥â10âmm) hyperplastic polyps, as well as proximal and large (≥â10âmm) SSA/Ps, were associated with synchronous advanced neoplasia. CONCLUSIONS: Serrated polyps, including SSA/Ps, were frequently encountered in routine screening colonoscopies. Large and proximal hyperplastic polyps, as well large and proximal SSA/Ps, were associated with advanced neoplasia.
Assuntos
Adenoma/epidemiologia , Carcinoma/epidemiologia , Pólipos do Colo/epidemiologia , Pólipos do Colo/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Adenoma/diagnóstico , Idoso , Carcinoma/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Feminino , Humanos , Hiperplasia/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , PrevalênciaRESUMO
Differences in the risk of a false negative or a false positive fecal immunochemical test (FIT) across subgroups may affect optimal screening strategies. We evaluate whether subgroups are at increased risk of a false positive or a false negative FIT result, whether such variability in risk is related to differences in FIT sensitivity and specificity or to differences in prior CRC risk. Randomly selected, asymptomatic individuals were invited to undergo colonoscopy. Participants were asked to undergo one sample FIT and to complete a risk questionnaire. We identified patient characteristics associated with a false negative and false positive FIT results using logistic regression. We focused on statistically significant differences as well as on variables influencing the false positive or negative risk for which the odds ratio exceeded 1.25. Of the 1,426 screening participants, 1,112 (78%) completed FIT and the questionnaire; 101 (9.1%) had advanced neoplasia. 102 Individuals were FIT positive, 65 (64%) had a false negative FIT result and 66 (65%) a false positive FIT result. Participants at higher age and smokers had a significantly higher risk of a false negative FIT result. Males were at increased risk of a false positive result, so were smokers and regular NSAID users. FIT sensitivity was lower in females. Specificity was lower for males, smokers and regular NSAID users. FIT sensitivity was lower in women. FIT specificity was lower in males, smokers and regular NSAID users. Our results can be used for further evidence based individualization of screening strategies.
Assuntos
Técnicas de Laboratório Clínico/normas , Fezes/química , Sangue Oculto , Técnicas de Laboratório Clínico/métodos , Colonoscopia/métodos , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Projetos Piloto , Risco , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Insufficient detection of proximal serrated polyps (PSP) might explain the occurrence of a proportion of interval carcinomas in colonoscopy surveillance programs. OBJECTIVE: To compare PSP detection among endoscopists and to identify patient-related and endoscopist-related factors associated with PSP detection. DESIGN: Prospective study in unselected patients. SETTING: Colonoscopy screening program for colorectal cancer at two academic medical centers. PATIENTS: Asymptomatic consecutive screening participants (aged 50-75 years). INTERVENTION: Colonoscopies were performed by 5 experienced endoscopists. All detected polyps were removed. Multiple colonoscopy quality indicators were prospectively recorded. MAIN OUTCOME MEASUREMENTS: We compared PSP detection among endoscopists by calculating odds ratios (OR) with logistic regression analysis. Logistic regression also was used to identify patient features and colonoscopy factors associated with PSP detection. RESULTS: A total of 1354 patients underwent a complete screening colonoscopy: 1635 polyps were detected, of which 707 (43%) were adenomas and 685 (42%) were serrated polyps, including 215 PSPs. In 167 patients (12%) 1 or more PSPs were detected. The PSP detection rate differed significantly among endoscopists, ranging from 6% to 22% (P < .001). Longer withdrawal time (OR 1.12; 95% confidence interval, 1.10-1.16) was significantly associated with better PSP detection, whereas patient age, sex, and quality of bowel preparation were not. LIMITATIONS: Limited number of highly experienced endoscopists. CONCLUSION: The PSP detection rate differs among endoscopists. Longer withdrawal times are associated with better PSP detection, but patient features are not. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR1888.).
Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Idoso , Colonoscopia/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVE: CT-colonography has been suggested to be less burdensome for primary colorectal cancer (CRC) screening than colonoscopy. To compare the expected and perceived burden of both in a randomised trial. DESIGN: 8844 Dutch citizens aged 50-74 years were randomly invited for CRC screening with colonoscopy (n=5924) or CT-colonography (n=2920). Colonoscopy was performed after full colon lavage, or CT-colonography after limited bowel preparation (non-cathartic). All invitees were asked to complete the expected burden questionnaire before the procedure. All participants were invited to complete the perceived burden questionnaire 14 days later. Mean scores were calculated on 5-point scales. RESULTS: Expected burden: 2111 (36%) colonoscopy and 1199 (41%) CT-colonography invitees completed the expected burden questionnaire. Colonoscopy invitees expected the bowel preparation and screening procedure to be more burdensome than CT-colonography invitees: mean scores 3.0±1.1 vs 2.3±0.9 (p<0.001) and 3.1±1.1 vs 2.2±0.9 (p<0.001). Perceived burden: 1009/1276 (79%) colonoscopy and 801/982 (82%) CT-colonography participants completed the perceived burden questionnaire. The full screening procedure was reported as more burdensome in CT-colonography than in colonoscopy: 1.8±0.9 vs 2.0±0.9 (p<0.001). Drinking the bowel preparation resulted in a higher burden score in colonoscopy (3.0±1.3 vs 1.7±1.0, p<0.001) while related bowel movements were scored more burdensome in CT-colonography (2.0±1.0 vs 2.2±1.1, p<0.001). Most participants would probably or definitely take part in a next screening round: 96% for colonoscopy and 93% for CT-colonography (p=0.99). CONCLUSION: In a CRC screening programme, colonoscopy invitees expected the screening procedure and bowel preparation to be more burdensome than CT-colonography invitees. In participants, CT-colonography was scored as more burdensome than colonoscopy. Intended participation in a next screening round was comparable.
Assuntos
Colonografia Tomográfica Computadorizada/métodos , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Programas de Rastreamento/métodos , Idoso , Ansiedade/epidemiologia , Catárticos/administração & dosagem , Neoplasias Colorretais/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Medição da Dor , Satisfação do Paciente/estatística & dados numéricos , Medição de Risco , Estatísticas não Paramétricas , Inquéritos e Questionários , Irrigação Terapêutica/métodosRESUMO
OBJECTIVE: Conventional colonoscopy (CC) is considered the reference standard for detection of colorectal neoplasia, but it can still miss a substantial number of adenomas. The use of a transparent plastic cap may improve colonic visualisation. Cap-assisted colonoscopy (CAC) was compared with CC for adenoma detection. Secondary outcomes were caecal intubation time, caecal intubation rate and the degree of discomfort of colonoscopy. DESIGN: This is a parallel, randomised, controlled trial at two centres. Asymptomatic participants (aged 50-75 years) in a primary colonoscopy screening programme were consecutively invited. Consenting subjects were 1:1 randomised to either CAC or CC. All colonoscopies were performed by experienced endoscopists (≥ 1000 colonoscopies) who were trained in CAC. Colonoscopy quality indicators were prospectively recorded. RESULTS: A total of 1380 participants were randomly allocated to CC (N=694) or CAC (N=686). Caecal intubation rate was comparable in the two groups (98% vs 99%; p=0.29). Caecal intubation time was significantly lower in the CAC group: 7.7 ± 5.0 min with CAC vs 8.9 ± 6.2 min with CC (p<0.001) (values mean ± SD). Adenoma detection rates of all endoscopists were ≥ 20%. The proportion of subjects with at least one adenoma was similar in the two groups (28% vs 28%; RR 0.98; 95% CI 0.82 to 1.16), as well as the mean number of adenomas per subject (0.49 ± 1.05 vs 0.50 ± 1.03; p=0.91). Detection of small size, flat and proximally located adenomas was comparable. CAC participants had lower Gloucester Comfort Scores during colonoscopy (2.2 ± 1.0 vs 2.0 ± 1.0; p=0.03). CONCLUSION: CAC does not improve adenoma detection, but does reduce caecal intubation time by more than 1 min and does lessen the degree of discomfort during colonoscopy.
Assuntos
Adenoma/diagnóstico , Neoplasias do Colo/diagnóstico , Colonoscopia/instrumentação , Idoso , Colonoscopia/métodos , Colonoscopia/normas , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente/estatística & dados numéricos , Indicadores de Qualidade em Assistência à Saúde , Fatores de TempoRESUMO
BACKGROUND: Screening for colorectal cancer is widely recommended, but the preferred strategy remains unidentified. We aimed to compare participation and diagnostic yield between screening with colonoscopy and with non-cathartic CT colonography. METHODS: Members of the general population, aged 50-75 years, and living in the regions of Amsterdam or Rotterdam, identified via the registries of the regional municipal administration, were randomly allocated (2:1) to be invited for primary screening for colorectal cancer by colonoscopy or by CT colonography. Randomisation was done per household with a minimisation algorithm based on age, sex, and socioeconomic status. Invitations were sent between June 8, 2009, and Aug 16, 2010. Participants assigned to CT colonography who were found to have one or more large lesions (≥10 mm) were offered colonoscopy; those with 6-9 mm lesions were offered surveillance CT colonography. The primary outcome was the participation rate, defined as number of invitees undergoing the examination relative to the total number of invitees. Diagnostic yield was calculated as number of participants with advanced neoplasia relative to the total number of invitees. Invitees and screening centre employees were not masked to allocation. This trial is registered in the Dutch trial register, number NTR1829. FINDINGS: 1276 (22%) of 5924 colonoscopy invitees participated, compared with 982 (34%) of 2920 CT colonography invitees (relative risk [RR] 1·56, 95% CI 1·46-1·68; p<0·0001). Of the participants in the colonoscopy group, 111 (9%) had advanced neoplasia of whom seven (<1%) had a carcinoma. Of CT colonography participants, 84 (9%) were offered colonoscopy, of whom 60 (6%) had advanced neoplasia of whom five (<1%) had a carcinoma; 82 (8%) were offered surveillance. The diagnostic yield for all advanced neoplasia was 8·7 per 100 participants for colonoscopy versus 6·1 per 100 for CT colonography (RR 1·46, 95% CI 1·06-2·03; p=0·02) and 1·9 per 100 invitees for colonoscopy and 2·1 per 100 invitees for CT colonography (RR 0·91, 0·66-2·03; p=0·56). The diagnostic yield for advanced neoplasia of 10 mm or more was 1·5 per 100 invitees for colonoscopy and 2·0 per 100 invitees for CT colonography, respectively (RR 0·74, 95% CI 0·53-1·03; p=0·07). Serious adverse events related to the screening procedure were post-polypectomy bleedings: two in the colonoscopy group and three in the CT colonography group. INTERPRETATION: Participation in colorectal cancer screening with CT colonography was significantly better than with colonoscopy, but colonoscopy identified significantly more advanced neoplasia per 100 participants than did CT colonography. The diagnostic yield for advanced neoplasia per 100 invitees was similar for both strategies, indicating that both techniques can be used for population-based screening for colorectal cancer. Other factors such as cost-effectiveness and perceived burden should be taken into account when deciding which technique is preferable. FUNDING: Netherlands Organisation for Health Research and Development, Centre for Translational Molecular Medicine, and the Nuts Ohra Foundation.
Assuntos
Adenoma/diagnóstico , Colonografia Tomográfica Computadorizada , Colonoscopia , Neoplasias Colorretais/diagnóstico , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Programas de Rastreamento/métodos , Aceitação pelo Paciente de Cuidados de Saúde , Adenoma/diagnóstico por imagem , Adenoma/patologia , Idoso , Colonografia Tomográfica Computadorizada/efeitos adversos , Colonoscopia/efeitos adversos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Valor Preditivo dos Testes , Prognóstico , Carga TumoralRESUMO
OBJECTIVES: We compared reported reasons for participation and nonparticipation in colorectal cancer (CRC) screening between colonoscopy and computed tomographic (CT) colonography in a randomized controlled trial. METHODS: We randomly invited 8,844 people for screening by colonoscopy or CT colonography. On a questionnaire, invitees indicated reasons for participation or nonparticipation and indicated the most decisive reason. RESULTS: The most frequently cited reasons to accept screening were early detection of precursor lesions and CRC, and contribution to science. The most frequently cited reasons to decline were the unpleasantness of the examination, the inconvenience of the preparation, a lack of symptoms, and "no time/too much effort." Among colonoscopy nonparticipants, elderly invitees cited inconvenience less often, and absence of symptoms more often, than did the group overall. The reason reported most frequently as the most decisive reason not to participate was the unpleasantness of the examination among colonoscopy nonparticipants, and "no time/too much effort" and lack of symptoms among CT colonography nonparticipants. CONCLUSIONS: In light of these results, future screening programs could tailor the information provided to invitees.
Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias do Colo/prevenção & controle , Colonografia Tomográfica Computadorizada , Colonoscopia , Detecção Precoce de Câncer/métodos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Distribuição por Idade , Fatores Etários , Idoso , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/epidemiologia , Colonografia Tomográfica Computadorizada/estatística & dados numéricos , Colonoscopia/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos de Amostragem , Distribuição por Sexo , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Lipoarabinomannan (LAM) is a major glycolipid in the mycobacterial cell envelope. LAM consists of a mannosylphosphatidylinositol (MPI) anchor, a mannan core and a branched arabinan domain. The termini of the arabinan branches can become substituted with one to three α(1â2)-linked mannosyl residues, the mannose cap, producing ManLAM. ManLAM has been associated with a range of different immunomodulatory properties of Mycobacterium tuberculosis during infection of the host. In some of these effects, the presence of the mannose cap on ManLAM appears to be crucial for its activity. So far, in the biosynthesis of the mannose cap on ManLAM, two enzymes have been reported to be involved: a mannosyltransferase that adds the first mannosyl residue of the mannose caps to the arabinan domain of LAM, and another mannosyltransferase that elongates the mannose cap up to three mannosyl residues. Here, we report that a third gene is involved, MMAR_2380, which is the Mycobacterium marinum orthologue of Rv1565c. MMAR_2380 encodes a predicted transmembrane acyltransferase. In M. marinum ΔMMAR_2380, the LAM arabinan domain is still intact, but the mutant LAM lacks the mannose cap. Additional effects of mutation of MMAR_2380 on LAM were observed: a higher degree of branching of both the arabinan domain and the mannan core, and a decreased incorporation of [1,2-(14)C]acetate into the acyl chains in mutant LAM as compared with the wild-type form. This latter effect was also observed for related lipoglycans, i.e. lipomannan (LM) and phosphatidylinositol mannosides (PIMs). Furthermore, the mutant strain showed increased aggregation in liquid cultures as compared with the wild-type strain. All phenotypic traits of M. marinum ΔMMAR_2380, the deficiency in the mannose cap on LAM and changes at the cell surface, could be reversed by complementing the mutant strain with MMAR_2380. Strikingly, membrane preparations of the mutant strain still showed enzymic activity for the arabinan mannose-capping mannosyltransferase similar to that of the wild-type strain. Although the exact function of MMAR_2380 remains unknown, we show that the protein is essential for the presence of a mannose cap on LAM.
Assuntos
Aciltransferases/metabolismo , Lipopolissacarídeos/biossíntese , Manose/biossíntese , Mycobacterium marinum/enzimologia , Acilação , Aciltransferases/genética , Genes Bacterianos , Teste de Complementação Genética , Lipopolissacarídeos/química , Manose/química , Manosiltransferases/metabolismo , Mutação , Mycobacterium marinum/genéticaRESUMO
BACKGROUND: Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives. METHODS AND DESIGN: 7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods. DISCUSSION: This study will provide further evidence to enable decision making in population screening for colorectal cancer. TRIAL REGISTRATION: Dutch trial register: NTR1829.
Assuntos
Colonografia Tomográfica Computadorizada , Colonoscopia , Neoplasias Colorretais/diagnóstico , Programas de Rastreamento/métodos , Idoso , Colonografia Tomográfica Computadorizada/efeitos adversos , Colonografia Tomográfica Computadorizada/economia , Colonografia Tomográfica Computadorizada/estatística & dados numéricos , Colonoscopia/efeitos adversos , Colonoscopia/economia , Colonoscopia/estatística & dados numéricos , Participação da Comunidade , Análise Custo-Benefício , Humanos , Pessoa de Meia-Idade , Países Baixos , Encaminhamento e Consulta , Fatores de RiscoRESUMO
OBJECTIVES: Traumatic perforations of the eardrum are generally treated conservatively as they tend to heal spontaneously. Retraction pockets of the eardrum, leading to atelectasis of the middle ear and often ultimately though unpredictably, to cholesteatoma formation, are treated in a variety of ways including complex grafting procedures. On the premise that a surgically resected retraction pocket is in essence a traumatic perforation, we examined the results of spontaneous healing of the resected retraction pocket. METHODS: Retrospective case note study. PATIENTS: A group of 86 ears in 62 patients who had undergone simple excision of the atrophic segment of the eardrum and who had no grafting procedure of the resultant defect, were followed at 6 days, 6-7 weeks and then every 6 months to determine the incidence of spontaneous healing of the eardrum. Audiograms were taken preoperatively, at 7 weeks and between 7 and 15 months postoperative. RESULTS: 94.2% of the eardrums (81 out of 86 ears) healed spontaneously without any form of grafting within 7 weeks. Air bone gap showed improvement in 53 patients. Only one of the four ears that failed to achieve closure had postoperative ear discharge. There were no other complications. In 17 ears (19.8%) there was a recurrence of the atelectasis. CONCLUSION: Excision of retraction pockets in pediatric ear atelectasis, in principle does not require grafting, as the great majority will heal spontaneously. The spontaneous healing in this study is comparable to reported studies of spontaneous healing of traumatic perforations. Irrespective of the size of the atrophic part of the membrane, recurrence rates for the atelectasis after simple excision is similar to that described in other studies. Retraction pockets may be excised and allowed to heal without risk to the hearing.
Assuntos
Otopatias/fisiopatologia , Orelha Média/fisiopatologia , Perfuração da Membrana Timpânica/fisiopatologia , Perfuração da Membrana Timpânica/cirurgia , Cicatrização/fisiologia , Adolescente , Limiar Auditivo/fisiologia , Condução Óssea/fisiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Ventilação da Orelha Média , Recidiva , Estudos Retrospectivos , Perfuração da Membrana Timpânica/patologiaRESUMO
Aggregation of the hyperphosphorylated protein tau into neurofibrillary tangles and neuropil threads is a hallmark of Alzheimer disease (AD). Identification and characterization of the epitopes recognized by anti-tau antibodies might shed light on the molecular mechanisms of AD pathogenesis. Here we report on the biochemical and structural characterization of a tau-specific monoclonal antibody CBTAU-24.1, which was isolated from the human memory B cell repertoire. Immunohistochemical staining with CBTAU-24.1 specifically detects pathological tau structures in AD brain samples. The crystal structure of CBTAU-24.1 Fab with a phosphorylated tau peptide revealed recognition of a unique epitope (Ser235-Leu243) in the tau proline-rich domain. Interestingly, the antibody can bind tau regardless of phosphorylation state of its epitope region and also recognizes both monomeric and paired helical filament tau irrespective of phosphorylation status. This human anti-tau antibody and its unique epitope may aid in development of diagnostics and/or therapeutic AD strategies.
Assuntos
Doença de Alzheimer/diagnóstico , Anticorpos Monoclonais/metabolismo , Epitopos de Linfócito B/metabolismo , Proteínas tau/química , Doença de Alzheimer/metabolismo , Anticorpos Monoclonais/química , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Epitopos de Linfócito B/química , Células HEK293 , Humanos , Modelos Moleculares , Fosforilação , Conformação Proteica , Proteínas tau/metabolismoRESUMO
Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.
Assuntos
Linfócitos B/metabolismo , Imunoglobulina G/farmacologia , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Proteínas tau/imunologia , Proteínas tau/metabolismo , Adolescente , Adulto , Idoso , Especificidade de Anticorpos , Linfócitos B/efeitos dos fármacos , Cristalização , Relação Dose-Resposta a Droga , Feminino , Humanos , Epitopos Imunodominantes/metabolismo , Masculino , Microglia/metabolismo , Microscopia de Força Atômica , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Agregados Proteicos , Adulto JovemRESUMO
BACKGROUND: Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders. OBJECTIVE: The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN). METHODS: Participants (age 50-75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated. RESULTS: In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56-66) and 49% female (median age 60 years; IQR 55-65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%-25% and 35%-22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs. CONCLUSION: More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men).
RESUMO
Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies. We used a panel of anti-stem and anti-head influenza A and B monoclonal antibodies with identical human IgG1 Fc domains and investigated their ability to mediate ADCC-associated FcγRIIIa activation. Antibodies which do not interfere with sialic acid binding of HA can mediate FcγRIIIa activation. However, the FcγRIIIa activation was inhibited when a mutant HA, unable to bind sialic acids, was used. Antibodies which block sialic acid receptor interactions of HA interfered with FcγRIIIa activation. The inhibition of FcγRIIIa activation by HA head-binding and sialic acid receptor-blocking antibodies was confirmed in plasma samples of H5N1 vaccinated human subjects. Together, these results suggest that in addition to Fc-FcγR binding, interactions between HA and sialic acids on immune cells are required for optimal Fc-mediated effector functions by anti-HA antibodies.