FECAL IMMUNOCHEMICAL TEST TO DETECT COLORECTAL NEOPLASIA IN LYNCH SYNDROME - A PROSPECTIVE MULTICENTER STUDY.

OBJECTIVES: Colonoscopy surveillance for Lynch syndrome is burdensome and post-colonoscopy colorectal cancers (CRCs) still occur. The non-invasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. METHODS: Prospective, multi-center observational study in which individuals with Lynch syndrome performed a quantitative FIT prior to high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 µg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AA] and advanced serrated lesions [ASL]) and non-advanced adenomas (NAA). RESULTS: Of the 217 included individuals (59% female, median age 51y), 4 had CRC, 5 AA, 4 ASL and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 µg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value (NPV) of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and NPV, specificity for advanced neoplasia optimized to 94% at threshold 4.1 µg/g. Per 100 FITs at threshold 4.1 µg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia. CONCLUSIONS: FIT at thresholds ≤ 4.1 µg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 out of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The multitarget faecal immunochemical test for improving stool-based colorectal cancer screening programmes: a Dutch population-based, paired-design, intervention study.

BACKGROUND: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening. METHODS: Individuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 µg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete. FINDINGS: Between March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening. INTERPRETATION: The higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening. FUNDING: Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.

Baby Date: a mobile application for teaching nursing care to newborns in primary care / Baby Date: aplicación móvil instructora de consulta de enfermería al recién nacido en atención básica / Baby Date: aplicación móvil instructora de consulta de enfermería al recién nacido en atención básica

Objective: to develop and validate a mobile application for teaching undergraduates about the first nursing visit to a newborn in primary care. Method: methodological study with an Instructional Design framework; content drawn up from scientific documents on caring for newborns and their families, supported by the results of an integrative review on the subject. The Integrated Development Environment Android Studio 4.0.1 tool and the IntelliJ IDEA platform were used to build the digital technology. Experts validated content and students evaluated navigability. Results: the final version of the mobile application contains 67 screens grouped into 12 sections with random access. The device is presented on the introductory screen; this is followed by content on the physical examination, neonatal screening, nutrition, oral health, the vaccination calendar, growth, development, danger signs, and accident prevention; at the end, there is a fact sheet and references. Audiovisual resources (texts, images, and videos) complement the application; experts presented a Content Validity Index (CVI) = 1.00; for nursing students all the items had a CVI = 1.00; only the item "layout and presentation" had a CVI = 0.95. Conclusion: the digital technology received a satisfactory evaluation from experts and students. It is innovative in child health care, with the potential to be used in the teaching-learning process of nursing students.

Objetivo: desarrollar y validar aplicación móvil para instrucción de estudiantes sobre la primera consulta de Enfermería al recién nacido en atención básica. Método: estudio metodológico con referencial Diseño Instruccional; contenido elaborado partiendo de documentos científicos sobre atención al recién nacido y su familia, respaldado en resultados de revisión integrativa del tema. Fueron utilizadas la herramienta Integrated Development Environment Android Studio 4.0.1 y la plataforma IntelliJ IDEA para construir la tecnología digital. Expertos validaron contenido, y estudiantes evaluaron navegabilidad. Resultados: la versión final de la aplicación móvil incluye 67 pantallas agrupadas en 12 secciones de acceso aleatorio. El dispositivo es presentado en la pantalla introductora, a continuación, se muestra contenido referente al examen físico, cribado neonatal, alimentación, salud bucal, calendario de vacunación, crecimiento, desarrollo, señales de riesgo, prevención de accidentes; al final, ficha técnica y referencias. Recursos audiovisuales (textos, imágenes y videos) complementan la aplicación; para expertos, Índice de Validez de Contenido (IVC)=1,00; y para estudiantes de Enfermería, todos los ítems presentaron IVC=1,00; solo el ítem " layout y presentación" obtuvo IVC=0,95. Conclusión: la tecnología digital fue evaluada satisfactoriamente por expertos y estudiantes; es innovadora en el área de salud del niño, con potencial uso en el proceso de enseñanza-aprendizaje de los estudiantes de Enfermería.

Objetivo: desenvolver e validar aplicativo móvel para o ensino de graduandos sobre a primeira consulta de Enfermagem ao recém-nascido na atenção básica. Método: estudo metodológico com referencial Design Instrucional; conteúdo elaborado a partir de documentos científicos acerca do cuidado ao recém-nascido e sua família, apoiado em resultados de revisão integrativa sobre o tema. A ferramenta Integrated Development Environment Android Studio 4.0.1 e a plataforma IntelliJ IDEA foram utilizadas para a construção da tecnologia digital. Experts validaram conteúdo e alunos avaliaram navegabilidade. Resultados: a versão final do aplicativo móvel contém 67 telas agrupadas em 12 seções com acesso aleatório. O dispositivo é apresentado na tela introdutória; na sequência, tem-se conteúdo referente ao exame físico, triagem neonatal, alimentação, saúde bucal, calendário vacinal, crescimento, desenvolvimento, sinais de perigo, prevenção de acidentes; ao final, ficha técnica e referências. Recursos audiovisuais (textos, imagens e vídeos) complementam o aplicativo; para experts Índice de Validade de Conteúdo (IVC)=1,00; para estudantes de Enfermagem, todos os itens apresentaram IVC=1,00; somente o item " layout e apresentação" obteve IVC=0,95. Conclusão: a tecnologia digital obteve avaliação satisfatória entre experts e estudantes; é inovadora para a área da saúde da criança, com potencial para uso no processo de ensino-aprendizagem dos estudantes de Enfermagem.

Índice de massa corporal e desfechos clínicos: um estudo retrospectivo durante a pandemia de Covid-19 / Body mass index and clinical outcomes: a retrospective study in Covid-19 / Índice de masa corporal y resultado clínico: un estudio retrospectivo durante la pandemia de Covid-19

A COVID-19 é uma doença respiratória aguda provocada pela infecção do vírus SARS-CoV-2, que pode causar uma grave insuficiência respiratória hipoxêmica, complicações e mortes, principalmente na população com condições crônicas de saúde. Os mecanismos pelos quais a obesidade pode aumentar a gravidade da COVID-19 incluem mecanismos físicos, inflamação crônica e uma função imunológica prejudicada. Além disso, o índice de massa corporal elevado é um fator de risco para várias condições médicas que têm sido sugeridas para aumentar o risco de gravidade da COVID-19. Objetivo: analisar a associação entre o índice de massa corporal e desfechos clínicos dos casos confirmados de COVID-19. Metodologia: Estudo transversal, com coleta de dados de prontuários, conduzido de março de 2020 a dezembro 2021. Foram analisados os registros de prontuários, exames bioquímicos e de imagem de pacientes internados com COVID-19 em três hospitais da cidade de Francisco Beltrão (PR). As variáveis analisadas foram o diagnóstico nutricional, idade, sexo, necessidade de internação em UTI, comorbidades, dias de hospitalização, complicações, exames laboratoriais e desfecho. Os critérios para inclusão no estudo foram, pacientes hospitalizados com diagnóstico para COVID-19, com presença de diagnóstico nutricional relatado. Resultados: No ano de 2020 foram analisados 292 prontuários e no ano de 2021 foram 860 prontuários. Destes, somente 413 possuíam diagnóstico nutricional, sendo assim incluídos no presente estudo. Foram classificados como peso normal 78 (18,9%), com sobrepeso 153 (37%)e como obeso 182 (44,1%) participantes. A maior prevalência de obesidade foi encontrada no sexo feminino (52,5%), portadores de diabetes (27,6%), pacientes com estado geral comprometido (67,9%), que apresentaram complicações pulmonares (54,5%) e arritmias (23%). A média de idade encontrada em pacientes com obesidade foi mais jovem (55,54) em comparação com os classificados com sobrepeso (59,08) e normal (62,51). Observou-se que quanto maior o IMC menor foram os valores encontrados para idade (rho = -0,190), leucócitos (rho = -0,109), ureia (rho = -0,145) e D-dímero (rho = -0,155). Conclusão: Este estudo fornece evidências de que o sobrepeso e/ou obesidade então associadas a um pior quadro clínico durante a internação dos pacientes com COVID-19. Em relação a frequência de óbito, não houve diferença estatística em relação ao diagnóstico nutricional.

COVID-19 is an acute respiratory disease caused by SARS-CoV-2 virus infection, which can cause severe hypoxemic respiratory failure, complications, and deaths, especially in the population with chronic health conditions. The mechanisms by which obesity may increase the severity of COVID-19 include physical mechanisms, chronic inflammation, and impaired immune function. In addition, high body mass index is a risk factor for several medical conditions that have been suggested to increase the risk of COVID-19 severity. Objective: to analyze the association between body mass index and clinical outcomes of confirmed cases of COVID-19. Methodology: Cross-sectional study, with data collection from medical records, conducted from March 2020 to December 2021. The records of medical records, biochemical and imaging tests of patients hospitalized with COVID-19 in three hospitals in the city of Francisco Beltrão (PR) were analyzed. The variables analyzed were nutritional diagnosis, age, gender, need for ICU admission, comorbidities, days of hospitalization, complications, laboratory tests and outcome. The inclusion criteria for the study were, hospitalized patients with diagnosis for COVID-19, with presence of nutritional diagnosis reported. Results: In the year 2020, 292 medical records were analyzed and in the year 2021 there were 860 medical records. Of these, only 413 had nutritional diagnosis, thus being included in this study. Were classified as normal weight 78 (18.9%), overweight 153 (37%), and obese 182 (44.1%) participants. The highest prevalence of obesity was found in females (52.5%), patients with diabetes (27.6%), patients with impaired general condition (67.9%), who presented pulmonary complications (54.5%) and arrhythmias (23%). The mean age found in obese patients was younger (55.54) compared to those classified as overweight (59.08) and normal (62.51). It was observed that the higher the BMI the lower were the values found for age (rho = -0.190), leukocytes (rho = -0.109), urea (rho = -0.145) and D-dimer (rho = -0.155). Conclusion: This study provides evidence that overweight and/or obesity then associated with a worse clinical picture during hospitalization of patients with COVID-19. Regarding the frequency of death, there was no statistical difference in relation to nutritional diagnosis.

COVID-19 es una enfermedad respiratoria aguda causada por la infección por el virus SARS-CoV-2, que puede provocar insuficiencia respiratoria hipoxémica grave, complicaciones y muertes, especialmente en poblaciones con enfermedades crónicas. Los mecanismos por los cuales la obesidad puede aumentar la gravedad de la COVID-19 incluyen mecanismos físicos, inflamación crónica y función inmune deteriorada. Además, un índice de masa corporal alto es un factor de riesgo para varias afecciones médicas que, según se ha sugerido, aumentan el riesgo de gravedad del COVID-19. Objetivo: analizar la asociación entre el índice de masa corporal y los resultados clínicos de casos confirmados de COVID-19. Metodología: Estudio transversal, con recolección de datos de historias clínicas, realizado de marzo de 2020 a diciembre de 2021. Se analizaron historias clínicas, exámenes bioquímicos y de imagen de pacientes hospitalizados con COVID-19 en tres hospitales de la ciudad de Francisco Beltrão (PR). Las variables analizadas fueron diagnóstico nutricional, edad, sexo, necesidad de ingreso a UCI, comorbilidades, días de internación, complicaciones, exámenes de laboratorio y evolución. Los criterios de inclusión en el estudio fueron pacientes hospitalizados con diagnóstico de COVID-19, con presencia de diagnóstico nutricional informado. Resultados: En 2020 se analizaron 292 historias clínicas y en 2021 se analizaron 860 historias clínicas. De ellos, sólo 413 tenían diagnóstico nutricional, por lo que fueron incluidos en el presente estudio. 78 (18,9%) participantes fueron clasificados como normopeso, 153 (37%) como sobrepeso y 182 (44,1%) como obesidad. La mayor prevalencia de obesidad se encontró en el sexo femenino (52,5%), pacientes con diabetes (27,6%), pacientes con estado general comprometido (67,9%), quienes presentaron complicaciones pulmonares (54,5%) y arritmias (23%). La edad promedio encontrada en los pacientes con obesidad fue menor (55,54) en comparación con los clasificados como con sobrepeso (59,08) y normales (62,51). Se observó que a mayor IMC, menores son los valores encontrados para edad (rho = -0,190), leucocitos (rho = -0,109), urea (rho = -0,145) y dímero D (rho = -0,155). Conclusión: Este estudio proporciona evidencia de que el sobrepeso y/u obesidad se asocia con una peor condición clínica durante la hospitalización de pacientes con COVID-19. En cuanto a la frecuencia de muerte, no hubo diferencia estadística en relación al diagnóstico nutricional.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

Risk Prediction of Metachronous Colorectal Cancer from Molecular Features of Adenomas: A Nested Case-Control Study.

Current morphologic features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy-number profiles were determined, by low-coverage whole-genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (OR) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex.CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline [OR, 1.14; 95% confidence interval CI), 1.03-1.26; P = 0.012], advanced adenomas (OR, 2.46; 95% CI, 1.50-4.01; P < 0.001) and with the presence of ≥3 DNA copy-number losses (OR, 1.90; 95% CI. 1.02-3.54; P = 0.043).Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. SIGNIFICANCE: Identifying new biomarkers may improve prediction of me-CRC for individuals with adenomas and optimize surveillance intervals to reduce risk of colorectal cancer and reduce oversurveillance of patients with low risk of colorectal cancer. Use of DNA CNAs alone does not improve prediction of me-CRC. Further research to improve risk classification is required.

Gestational hypertension as a factor associated with chronic kidney disease: the importance of obstetric history of women undergoing hemodialysis / Hipertensão gestacional como fator associado à doença renal crônica: a importância do histórico obstétrico de mulheres submetidas à hemodiálise

ABSTRACT Introduction: Pregnancy-related complications may impact women's reproductive cycle and health through their lives. The objective of this study was to evaluate the sociodemographic, clinical, and obstetric history of women undergoing hemodialysis. Methods: We performed a cross-sectional study in a specialized health facility with four hemodialysis units. Sociodemographic characteristics, clinical and personal history, obstetric and perinatal results of women with pregnancies before hemodialysis were evaluated. Prevalence, bivariate, and logistic regression analyses were performed. Results: We included 208 (87.76%) women. Hypertension was the main cause of chronic kidney disease (CKD) (128 women). Rates of adverse perinatal outcomes, including prematurity, low birth weight, miscarriage, fetal death, and neonatal death, were 19.3%, 14.5%, 25.5%, 12.1%, and 5.3%, respectively. Hypertensive syndromes during pregnancy occurred in 37.0% of women, with 12.5% reporting preeclampsia and 1.4% reporting eclampsia. Up to 1 year after birth, 45.2% of women reported hypertension. Hemodialysis due to hypertension was associated with a history of hypertension during pregnancy (OR 2.33, CI 1.27 - 4.24), gestational hypertension (2.41, CI 3.30 - 4.45), and hypertension up to one year after birth (OR 1.98, CI 1.11 - 3.51). Logistic regression showed that gestational hypertension was independently associated with CKD due to hypertension (aOR 2.76, CI 1.45 - 5.24). Conclusion: Women undergoing hemodialysis due to hypertension were more likely to have gestational hypertension or hypertension up to one year after birth. To delay end-stage renal disease, it is necessary to identify women at risk of kidney failure according to their reproductive history.

RESUMO Introdução: Complicações relacionadas à gestação podem afetar o ciclo reprodutivo e a saúde das mulheres ao longo de suas vidas. Este estudo visou avaliar histórico sociodemográfico, clínico e obstétrico de mulheres em hemodiálise. Métodos: Realizamos estudo transversal em unidade de saúde especializada com quatro unidades de hemodiálise. Avaliou-se características sociodemográficas, histórico clínico e pessoal, resultados obstétricos e perinatais de mulheres com gestações anteriores à hemodiálise. Foram realizadas análises de prevalência, bivariadas e regressão logística. Resultados: Incluímos 208 (87,76%) mulheres. Hipertensão foi a principal causa de doença renal crônica (DRC) (128 mulheres). Taxas de desfechos perinatais adversos, incluindo prematuridade, baixo peso ao nascer, aborto espontâneo, óbito fetal e neonatal, foram de 19,3%, 14,5%, 25,5%, 12,1% e 5,3%, respectivamente. Síndromes hipertensivas durante a gestação ocorreram em 37,0% das mulheres, com 12,5% relatando pré-eclâmpsia e 1,4% relatando eclampsia. Até 1 ano após o parto, 45,2% das mulheres relataram hipertensão. Hemodiálise devido à hipertensão foi associada ao histórico de hipertensão na gestação (OR 2,33; IC 1,27 - 4,24), hipertensão gestacional (2,41; IC 3,30 - 4,45), e hipertensão até um ano após o parto (OR 1,98; IC 1,11 - 3,51). A regressão logística mostrou que hipertensão gestacional foi independentemente associada à DRC devido à hipertensão (ORa 2,76; IC 1,45 - 5,24). Conclusão: Mulheres submetidas à hemodiálise por hipertensão foram mais propensas a apresentar hipertensão gestacional ou hipertensão até um ano após o parto. Para retardar a doença renal em estágio terminal, deve-se identificar mulheres em risco de insuficiência renal de acordo com sua história reprodutiva.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Functional disability and associated factors in older adults seen at a primary health care unit / Incapacidade funcional e fatores associados em idosos atendidos na atenção primária

OBJECTIVES: To assess functional disability and associated factors in older patients cared for at a large Brazilian urban area. METHODS: This is a cross-sectional study performed at a primary health care unit in the city of São Paulo, Brazil. Participants were selected via probabilistic sampling of 400 older individuals. We used a sociodemographic and health questionnaire along with instruments for assessing fear of falling (FES-I), cognitive function (MMSE), and depression symptoms (GDS-15). For dependent variables, we used instruments for assessing basic activities (BADL; Katz) and instrumental activities of daily living (IADL; Lawton). Factors associated with functional disability were analyzed via logistic regression models. RESULTS: The mean age of participants was 75.23 (SD = 8.53); 63.20% were female, 27.00% were dependent in BADL and 39.25%, in IADL. Older individuals with better cognitive function and who had not been hospitalized in the previous year were less prone to functional disabilities. Factors such as older age, more depression symptoms, and greater fear of falling were more linked to disabilities in BADL. Factors such as older age, female sex, and greater fear of falling were more linked to disabilities in IADL. CONCLUSIONS: The prevalence of disability in BADL and IADL in the studied sample was high. Modifiable and non-modifiable factors were associated with functional disability. These results may help primary health care professionals understand the risk factors for functional disability in the older population

OBJETIVOS: Avaliar a incapacidade funcional e fatores associados em pacientes idosos atendidos em um grande centro urbano brasileiro. METODOLOGIA: Estudo transversal realizado em uma Unidade Básica de Saúde na cidade de São Paulo, Brasil. A seleção dos participantes foi por meio de amostragem probabilística de 400 indivíduos idosos. Foi utilizado um questionário sociodemográfico, de saúde e instrumentos para avaliar medo de queda (FES-I), status cognitivo (MEEM) e sintomas depressivos (GDS-15). Para as variáveis dependentes, utilizou-se os instrumentos para avaliar as atividades básicas (ABVD; Katz) e atividades instrumentais de vida diária (Lawton; AIVD). Os fatores associados à incapacidade funcional foram analisados por meio de modelos de regressão logística. RESULTADOS: A média de idade dos participantes foi de 75,23 (DP = 8,53), 63,20% eram do sexo feminino, 27,00% eram dependentes para ABVD e 39,25% para as AIVD. Indivíduos idosos com melhor status cognitivo e que não estiveram internados no último ano eram menos propensos às incapacidades funcionais. Fatores como ter mais idade, mais sintomas depressivos e mais medo de queda eram mais propensos às incapacidades das ABVD. Fatores como ter mais idade, ser do sexo feminino e mais medo de queda foram mais propensos às incapacidades das AIVD. CONCLUSÕES: A prevalência de incapacidade para ABVD e AIVD na amostra estudada foi alta. Fatores modificáveis e não modificáveis foram associados à incapacidade funcional. Esses resultados podem ajudar os profissionais da atenção primária à saúde a entenderem os fatores de risco de incapacidade funcional na população mais velha

Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas.

BACKGROUND: For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. AIM: To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)]. METHODS: FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs). RESULTS: Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039). CONCLUSION: Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs.

In Vitro and In Vivo Biological Activity of Ruthenium 1,10-Phenanthroline-5,6-dione Arene Complexes.

Ruthenium(II) arene complexes exhibit promising chemotherapeutic properties. In this study, the effect of the counter anion in Ru(II) complexes was evaluated by analyzing the biological effect of two Ru(II) p-cymene derivatives with the 1,10-phenanthroline-5,6-dione ligand of general-formula [(η6-arene)Ru(L)Cl][X] X = CF3SO3 (JHOR10) and PF6 (JHOR11). The biological activity of JHOR10 and JHOR11 was examined in the ovarian carcinoma cell line A2780, colorectal carcinoma cell line HCT116, doxorubicin-resistant HCT116 (HCT116-Dox) and in normal human dermal fibroblasts. Both complexes JHOR10 and JHOR11 displayed an antiproliferative effect on A2780 and HCT116 cell lines, and low cytotoxicity in fibroblasts. Interestingly, JHOR11 also showed antiproliferative activity in the HCT116-Dox cancer cell line, while JHOR10 was inactive. Studies in A2780 cells showed that JHOR11 induced the production of reactive oxygen species (ROS) that trigger autophagy and cellular senescence, but no apoptosis induction. Further analysis showed that JHOR11 presented no tumorigenicity, with no effect in the cellular mobility, as evaluated by thye wound scratch assay, and no anti- or pro-angiogenic effect, as evaluated by the ex-ovo chorioallantoic membrane (CAM) assay. Importantly, JHOR11 presented no toxicity in chicken and zebrafish embryos and reduced in vivo the proliferation of HCT116 injected into zebrafish embryos. These results show that these are suitable complexes for clinical applications with improved tumor cell cytotoxicity and low toxicity, and that counter-anion alteration might be a viable clinical strategy for improving chemotherapy outcomes in multidrug-resistant (MDR) tumors.

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors.

BACKGROUND: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC). METHODS: Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629). RESULTS: MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)). CONCLUSIONS: MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors.

Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy.

BACKGROUND: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. METHODS: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 µg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). RESULTS: Overall, the optimal surveillance strategy was annual FIT (47 µg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 µg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 µg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). CONCLUSIONS: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. IMPACT: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Guidance for setting international standards on reporting longitudinal adherence to stool-based colorectal cancer screening.

Longitudinal adherence to colorectal cancer (CRC) screening is reported using different summarizing measures, which hampers international comparison. We provide evidence to guide recommendations on which longitudinal adherence measure to report. Using adherence data over four stool-based CRC screening rounds in three countries, we calculated six summarizing adherence measures; adherence over all rounds, adherence per round, rescreening, full programme adherence (yes/no), regularity (never/inconsistent/consistent screenees) and number of times participated. For each measure, we calculated the accuracy in capturing the observed adherence patterns. Using the ASCCA model, we predicted screening effectiveness when using summarizing measures as model input versus the observed adherence patterns. Adherence over all rounds in the Italian, Spanish and Dutch cohorts was 64.9%, 42.8% and 61.5%, respectively, and the proportion of consistent screenees was 50.9%, 26.3% and 45.7%. Number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as simulating the observed adherence patterns of Italy, Spain and the Netherlands (mortality reductions: 24.4%, 16.9% and 23.5%). Adherence over all rounds and adherence per round were least accurate. Screening effectiveness was overestimated when using adherence over all rounds (mortality reductions: 26.8%, 19.4% and 25.7%) and adherence per round (mortality reductions: 26.8%, 19.5% and 25.9%). To conclude, number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as using the observed adherence patterns. However they require longitudinal data. To facilitate international comparison of CRC screening programme performance, consensus on an accurate adherence measure to report should be reached.

Overexpression of the miR-17-92 cluster in colorectal adenoma organoids causes a carcinoma-like gene expression signature.

Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma. The miR-17-92 cluster was overexpressed in human colorectal adenoma organoids without 13q gain and downstream effects on mRNA expression were investigated, along with functional consequences in vitro and in vivo. Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, tumor-associated characteristics, such as increased proliferation rate, were not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth. In conclusion, this study showed that miR-17-92 expression contributes to 13q gain-associated adenoma-to-carcinoma progression, however, this is insufficient to cause malignancy.

A progressive three-state model to estimate time to cancer: a likelihood-based approach.

BACKGROUND: To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly infer this time in a progressive three-state disease model using surveillance data. METHODS: Sixteen models were specified, with and without covariates. Parameters of the parametric time-to-event distributions from the adenoma-free state (AF) to AA and from AA to CRC were estimated simultaneously, by maximizing the likelihood function. Model performance was assessed via simulation. The methodology was applied to a random sample of 878 individuals from a Norwegian adenoma cohort. RESULTS: Estimates of the parameters of the time distributions are consistent and the 95% confidence intervals (CIs) have good coverage. For the Norwegian sample (AF: 78%, AA: 20%, CRC: 2%), a Weibull model for both transition times was selected as the final model based on information criteria. The mean time among those who have made the transition to CRC since AA onset within 50 years was estimated to be 4.80 years (95% CI: 0; 7.61). The 5-year and 10-year cumulative incidence of CRC from AA was 13.8% (95% CI: 7.8%;23.8%) and 15.4% (95% CI: 8.2%;34.0%), respectively. CONCLUSIONS: The time-dependent risk from AA to CRC is crucial to explain differences in the outcomes of microsimulation models used for the optimization of CRC prevention. Our method allows for improving models by the inclusion of data-driven time distributions.

Lessons From a Systematic Literature Search on Diagnostic DNA Methylation Biomarkers for Colorectal Cancer: How to Increase Research Value and Decrease Research Waste?

OBJECTIVES: To improve colorectal cancer (CRC) survival and lower incidence rates, colonoscopy and/or fecal immunochemical test screening are widely implemented. Although candidate DNA methylation biomarkers have been published to improve or complement the fecal immunochemical test, clinical translation is limited. We describe technical and methodological problems encountered after a systematic literature search and provide recommendations to increase (clinical) value and decrease research waste in biomarker research. In addition, we present current evidence for diagnostic CRC DNA methylation biomarkers. METHODS: A systematic literature search identified 331 diagnostic DNA methylation marker studies published before November 2020 in PubMed, EMBASE, Cochrane Library, and Google Scholar. For 136 bodily fluid studies, extended data extraction was performed. STARD criteria and level of evidence were registered to assess reporting quality and strength for clinical translation. RESULTS: Our systematic literature search revealed multiple issues that hamper the development of DNA methylation biomarkers for CRC diagnosis, including methodological and technical heterogeneity and lack of validation or clinical translation. For example, clinical translation and independent validation were limited, with 100 of 434 markers (23%) studied in bodily fluids, 3 of 434 markers (0.7%) translated into clinical tests, and independent validation for 92 of 411 tissue markers (22%) and 59 of 100 bodily fluids markers (59%). DISCUSSION: This systematic literature search revealed that major requirements to develop clinically relevant diagnostic CRC DNA methylation markers are often lacking. To avoid the resulting research waste, clinical needs, intended biomarker use, and independent validation should be better considered before study design. In addition, improved reporting quality would facilitate meta-analysis, thereby increasing the level of evidence and enabling clinical translation.

SCID and Other Inborn Errors of Immunity with Low TRECs - the Brazilian Experience.

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.