ABSTRACT
La falta de información sobre el uso de la tecnología en niños con trastorno del espectro autista (TEA) de diferentes perfiles puede dificultar que docentes y alumnos se estén beneficiando del apoyo tecnológico más eficaz y ajustado a sus necesidades. El objetivo de esta revisión fue analizar y sintetizar la evidencia científica sobre la eficacia de los recursos tecnológicos en la mejora de la comprensión emocional de estudiantes con TEA con perfiles de alto y bajo funcionamiento. Para ello se realizó una revisión sistemática de las publicaciones científicas indexadas en algunas de las bases de datos de mayor relevancia siguiendo los criterios establecidos en la declaración PRISMA. En total se analizaron 38 artículos que cumplieron con los criterios de inclusión preestablecidos. Los resultados muestran la importancia de diseñar sistemas versátiles que puedan personalizarse y adaptarse en tiempo real y en contextos naturales con un enfoque claramente inclusivo. Pero también sugieren que la tecnología puede no ser una herramienta de intervención complementaria adecuada para todos los niños con TEA. Lo que subraya la necesidad de ensayos adicionales bien controlados sobre las características que permitan identificar qué estudiantes podrían o no beneficiarse de diferentes modalidades de tecnología. (AU)
The lack of information on the use of technology in children with autism spectrum disorder (ASD) of different profiles can make it difficult for teachers and students to benefit from the most effective technology support tailored to their needs. The aim of this review was to analyze and synthesize scientific evidence on the effectiveness of technological resources in improving the emotional understanding of students with high and low functioning ASD profiles. A systematic review of the scientific publications indexed in some of the most relevant databases was carried out following the criteria established in the PRISMA declaration. A total of 38 articles that met the pre-established inclusion criteria were analyzed. The results show the importance of designing versatile systems that can be customized and adapted in real time and in natural contexts with a clearly inclusive approach. But they also suggest that technology may not be an appropriate complementary intervention tool for all children with ASD. This underlines the need for additional well-controlled tests on the characteristics that would allow identifying which students might or might not benefit from different technology modalities. (AU)
Subject(s)
Humans , Child, Preschool , Child , Adolescent , Educational Technology , Autism Spectrum Disorder , Autistic DisorderABSTRACT
La falta de información sobre el uso de la tecnología en niños con trastorno del espectro autista (TEA) de diferentes perfiles puede dificultar que docentes y alumnos se estén beneficiando del apoyo tecnológico más eficaz y ajustado a sus necesidades. El objetivo de esta revisión fue analizar y sintetizar la evidencia científica sobre la eficacia de los recursos tecnológicos en la mejora de la comprensión emocional de estudiantes con TEA con perfiles de alto y bajo funcionamiento. Para ello se realizó una revisión sistemática de las publicaciones científicas indexadas en algunas de las bases de datos de mayor relevancia siguiendo los criterios establecidos en la declaración PRISMA. En total se analizaron 38 artículos que cumplieron con los criterios de inclusión preestablecidos. Los resultados muestran la importancia de diseñar sistemas versátiles que puedan personalizarse y adaptarse en tiempo real y en contextos naturales con un enfoque claramente inclusivo. Pero también sugieren que la tecnología puede no ser una herramienta de intervención complementaria adecuada para todos los niños con TEA. Lo que subraya la necesidad de ensayos adicionales bien controlados sobre las características que permitan identificar qué estudiantes podrían o no beneficiarse de diferentes modalidades de tecnología. (AU)
The lack of information on the use of technology in children with autism spectrum disorder (ASD) of different profiles can make it difficult for teachers and students to benefit from the most effective technology support tailored to their needs. The aim of this review was to analyze and synthesize scientific evidence on the effectiveness of technological resources in improving the emotional understanding of students with high and low functioning ASD profiles. A systematic review of the scientific publications indexed in some of the most relevant databases was carried out following the criteria established in the PRISMA declaration. A total of 38 articles that met the pre-established inclusion criteria were analyzed. The results show the importance of designing versatile systems that can be customized and adapted in real time and in natural contexts with a clearly inclusive approach. But they also suggest that technology may not be an appropriate complementary intervention tool for all children with ASD. This underlines the need for additional well-controlled tests on the characteristics that would allow identifying which students might or might not benefit from different technology modalities. (AU)
Subject(s)
Humans , Child, Preschool , Child , Adolescent , Educational Technology , Autism Spectrum Disorder , Autistic DisorderABSTRACT
In case of suspicion of a T1 colorectal tumor, the tumor should not be biopsied but removed completely (so-called en-bloc resection). With more recent endoscopic techniques, T1 colorectal tumors can be more often radical resected. If at least one of the following four characteristics is present, there is a high-risk T1 colorectal tumor and it is recommended to consider surgical resection with adequate lymphadenectomy; poor differentiation, presence of (lymphatic) angioinvasion, high-grade tumor budding (grade 2-3) and a positive resection margin (where the malignant cells approach the cut edge to 0.1mm). The risk of recurrent disease after endoscopic resection of a high-risk T1 colorectal tumor without additional surgery is not well known. Scheduled surgery for bowel cancer at an early stage is associated with the same risk of a serious complication and/or death as scheduled surgery at a more advanced stage.
Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/surgery , Colorectal Neoplasms/pathology , Neoplasm Staging , Lymph Node Excision , Neoplasm Recurrence, LocalABSTRACT
Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.
Subject(s)
Colorectal Neoplasms , DNA Mismatch Repair , Microsatellite Instability , Humans , Colorectal Neoplasms/genetics , DNA Mismatch Repair/genetics , DNA-Binding Proteins/genetics , Mutation , MutS Homolog 3 Protein/genetics , Mutation Rate , Frameshift Mutation/geneticsABSTRACT
Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage. We investigated the relationship between APOE genotypes and fertility in EFAD mice, a transgenic mouse model expressing h-APOE. We show that APOE4 transgenic mice had the highest level of reproductive performance, followed by APOE3 and APOE2. Intriguingly, APOE3 pregnancies had more fetal resorptions and reduced fetal weights relative to APOE4 pregnancies. In conclusion, APOE genotypes impact fertility and pregnancy outcomes in female mice, in concordance with findings in human populations. These mouse models may help elucidate how h-APOE4 promotes reproductive fitness at the cost of AD in later life.
Subject(s)
Alzheimer Disease , Apolipoproteins E , Disease Models, Animal , Fertility , Mice, Transgenic , Animals , Alzheimer Disease/genetics , Female , Mice , Fertility/genetics , Humans , Apolipoproteins E/genetics , Apolipoprotein E4/genetics , Polymorphism, Genetic , Pregnancy , Genotype , Apolipoprotein E3/genetics , AllelesABSTRACT
Deciphering the evolutionary forces controlling insecticide resistance in malaria vectors remains a prerequisite to designing molecular tools to detect and assess resistance impact on control tools. Here, we demonstrate that a 4.3kb transposon-containing structural variation is associated with pyrethroid resistance in central/eastern African populations of the malaria vector Anopheles funestus. In this study, we analysed Pooled template sequencing data and direct sequencing to identify an insertion of 4.3kb containing a putative retro-transposon in the intergenic region of two P450s CYP6P5-CYP6P9b in mosquitoes of the malaria vector Anopheles funestus from Uganda. We then designed a PCR assay to track its spread temporally and regionally and decipher its role in insecticide resistance. The insertion originates in or near Uganda in East Africa, where it is fixed and has spread to high frequencies in the Central African nation of Cameroon but is still at low frequency in West Africa and absent in Southern Africa. A marked and rapid selection was observed with the 4.3kb-SV frequency increasing from 3% in 2014 to 98% in 2021 in Cameroon. A strong association was established between this SV and pyrethroid resistance in field populations and is reducing pyrethroid-only nets' efficacy. Genetic crosses and qRT-PCR revealed that this SV enhances the expression of CYP6P9a/b but not CYP6P5. Within this structural variant (SV), we identified putative binding sites for transcription factors associated with the regulation of detoxification genes. An inverse correlation was observed between the 4.3kb SV and malaria parasite infection, indicating that mosquitoes lacking the 4.3kb SV were more frequently infected compared to those possessing it. Our findings highlight the underexplored role and rapid spread of SVs in the evolution of insecticide resistance and provide additional tools for molecular surveillance of insecticide resistance.
ABSTRACT
BACKGROUND: Healthcare providers' attitudes and beliefs can influence how patients with persistent musculoskeletal pain are treated. A biopsychosocial approach is more effective than a purely biomedical approach. Ensuring healthcare professionals have appropriate pain science education (PSE) is essential for successful treatment outcomes. OBJECTIVE: To validate the Spanish version of the Knowledge and Attitudes of Pain (KNAP-SP) questionnaire among Spanish physiotherapists and students and analyze its psychometric properties. METHODS: From May to October 2022, two independent teams adapted the KNAP questionnaire from English to both European and Hispanic-Spanish. A cross-sectional validation study was conducted with 517 physiotherapists examining internal consistency (Cronbach's alpha), structural validity (exploratory factor analysis), and construct validity (hypothesis testing). Longitudinal analyses assessed test-retest reliability (intraclass correlation coefficient [ICC2,1; n = 63]) and responsiveness following a PSE intervention using Receiver Operating Characteristic (ROC) curve analysis and hypothesis testing (n = 70). RESULTS: The KNAP-SP showed strong internal consistency [overall α coefficient = 0.86; domain 1 (α = 0.82); domain 2 (α = 0.70)], explaining 32.3% of the variance. Construct validity was supported by 75% of the hypotheses. Test-retest reliability was high (ICC2,1 = 0.84). KNAP-SP's responsiveness was confirmed by ROC analysis (area under the curve [AUC] = 0.87 [95% CI: 0.79-0.96, p-value <.01]) and accepting 75% of prior hypotheses. The minimal clinically important change was 6.96 points. No floor or ceiling effects were detected. CONCLUSIONS: The KNAP-SP, with robust psychometric properties and successful adaptation and validation, is a valuable tool for assessing pain knowledge and attitudes among Spanish-speaking physiotherapists.
ABSTRACT
Quantitative assessment of skin mechanical properties can play a pivotal role in diagnosing and tracking various dermatological conditions. Myoton is a promising tool that rapidly and noninvasively measures five skin biomechanical parameters. Accurate interpretation of these parameters requires systematic in vitro testing with easy-to-fabricate, cost-effective skin-mimicking phantoms with controllable properties. In this study, we assessed the ability of phantoms made with 5% and 10% gelatin crosslinked with microbial transglutaminase (mTG) to mimic the human skin for Myoton measurements. We discovered that each of the five Myoton parameters displayed moderate to high correlations with shear elastic modulus of the phantoms. Furthermore, Myoton effectively tracked changes in the mechanical properties of these models over time. Additionally, we designed bilayer phantoms incorporating both dermis and subcutaneous tissue-mimicking layers. Myoton successfully distinguished changes in the mechanical properties of the bilayer phantoms due to the introduction of a stiff 2 mm top layer. We also found that 5% mTG-gelatin phantoms mimic Myoton measurements from healthy subjects and 10% phantoms mimic patients with sclerotic chronic graft-versus-host disease (cGVHD). Therefore, multi-layered mTG-gelatin models for skin and soft tissues can serve as standardized testbeds to study different sclerotic skin conditions in a systematic manner.
ABSTRACT
Carbohydrate recognition is essential for numerous biological processes and is governed by various factors within the supramolecular environment of the cell. Photoswitchable glycoconjugates have proven as valuable tools for the investigation and modulation of carbohydrate recognition as they allow to control the relative orientation of sugar ligands by light. We have synthesized a biantennary glycocluster in which two glycoazobenzene antennas are conjugated to the 3- and 6-position of a scaffold glycoside. Orthogonal isomerization of the photoswitchable units was made possible by the different conjugation of the azobenzene moieties via an oxygen and a sulfur atom, respectively, and the ortho-fluorination of one of the azobenzene units. This design enabled a switching cycle comprising the EE, EZ and the ZZ isomer. This is the first example of an orthogonally photoswitchable glycocluster. The full analysis of its photochromic properties included the investigation of the isolated glycoazobenzene antennas allowing the comparison of the intra- versus the intermolecular orthogonal photoswitching. The kinetics of the thermal relaxation were analyzed in detail. A molecular dynamics study shows that indeed, the relative orientation of the glycoantennas and the distances between the terminal sugar ligands significantly vary depending on the isomeric state, as intended.
ABSTRACT
Over the past several decades, there have been many epidemiology studies on talc and cancer published in the scientific literature, and several reviews and meta-analyses of talc and respiratory, female reproductive, and stomach cancers, specifically. To help provide a resource for the evaluation of talc as a potential human carcinogen, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the association between talc exposure (by various routes) and cancers (of various types). We identified 30 cohort, 35 case-control, and 12 pooled studies that evaluated occupational, medicinal, and personal-care product talc exposure and cancers of the respiratory system, the female reproductive tract, the gastrointestinal tract, the urinary system, the lymphohematopoietic system, the prostate, male genital organs, and the central nervous system, as well as skin, eye, bone, connective tissue, peritoneal, and breast cancers. We tabulated study characteristics, quality, and results in a systematic manner, and evaluated all cancer types for which studies of at least three unique populations were available in a narrative review. We focused on study quality aspects most likely to impact the interpretation of results. We found that only one study, of medicinal talc use, evaluated direct exposure measurements for any individuals, though some used semi-quantitative exposure metrics, and few studies adequately assessed potential confounders. The only consistent associations were with ovarian cancer in case-control studies and these associations were likely impacted by recall and potentially other biases. This systematic review indicates that epidemiology studies do not support a causal association between occupational, medicinal, or personal talc exposure and any cancer in humans.
Subject(s)
Neoplasms , Talc , Talc/toxicity , Humans , Neoplasms/epidemiology , Neoplasms/chemically induced , Female , Occupational Exposure , Male , Carcinogens/toxicityABSTRACT
Introduction and importance: The spinal accessory nerve is at risk when performing neck dissections for head and neck cancers. Injury to this nerve can result in shoulder syndrome, which can be challenging to manage. Various nerve repair or grafting methods are available to prevent this condition. A safe, simple, and cost-effective option is the ansa cervicalis to spinal accessory transposition graft. Case presentation: A 60-year-old Afro-Trinidadian female presented to the Outpatient clinic for evaluation of a scalp lesion and a large neck mass for a duration of one year. Preoperative tissue biopsies confirmed she had squamous cell cancer with metastatic spread to the cervical nodes. The patient underwent surgical excision of the scalp lesion and left neck dissection with the sacrifice of the sternocleidomastoid and the left spinal accessory nerve due to tumour involvement. During the procedure, the ansa cervicalis was successfully joined to the distal remainder of the spinal accessory nerve. After the surgery, the patient fully recovered and achieved a good quality of life during the 24-month follow-up. Clinical discussion: This is the first reported case of using the ansa cervicalis to reinnervate the trapezius muscle through the spinal accessory nerve. This procedure aims to prevent pain, muscle wasting, and adhesive capsulitis. A quality-of-life questionnaire and adequate range of motion proved the success of this procedure, demonstrating that this option provides practical, functional, and aesthetic benefits for patients. Conclusion: The ansa cervicalis to spinal accessory transposition nerve graft is a valuable option for reinnervation. This case report highlights the effectiveness of this single-stage procedure in preventing shoulder syndrome.
ABSTRACT
AIMS: To evaluate different cardiovascular magnetic resonance (CMR) parameters for the differentiation of light chain amyloidosis (AL) and transthyretin-related amyloidosis (ATTR). METHODS AND RESULTS: In total, 75 patients, 53 with cardiac amyloidosis (20 patients with AL (66±12 years, 14 males [70%]) and 33 patients with ATTR (78±5 years, 28 males [88%])) were retrospectively analyzed regarding CMR parameters such as T1 and T2 mapping, extracellular volume (ECV), and late gadolinium enhancement (LGE) distribution patterns, and myocardial strain, and compared to a control cohort with other causes of left ventricular hypertrophy (LVH; 22 patients (53±16 years, 17 males [85%])). One way-ANOVA and receiver operating characteristic analysis were used for statistical analysis. ECV was the single best parameter to differentiate between cardiac amyloidosis and controls (area under the curve [AUC]: 0.97, 95% confidence intervals [CI]: 0.89-0.99, p<.0001, cutoff: >30%). T2 mapping was the best single parameter to differentiate between AL and ATTR amyloidosis (AL: 63±4 ms, ATTR: 58±2 ms, p<.001, AUC: 0.86, 95% CI: 0.74-0.94, cutoff: >61 ms). Subendocardial LGE was predominantly observed in AL patients (10/20 [50%] vs. 5/33 [15%]; p=.002). Transmural LGE was predominantly observed in ATTR patients (23/33 [70%] vs. 2/20 [10%]; p<.001). The diagnostic performance of T2 mapping to differentiate between AL and ATTR amyloidosis was further increased with the inclusion of LGE patterns (AUC: 0.96, 95% CI: 0.86-0.99]; p=.05). CONCLUSION: ECV differentiates cardiac amyloidosis from other causes of LVH. T2 mapping combined with LGE differentiates AL from ATTR amyloidosis with high accuracy on a patient level.
ABSTRACT
The activity concentration of 3H in water samples collected from places unaffected by nuclear activities or for human consumption can be very low. In these cases, determination procedures must achieve a Minimum Detectable Activity (MDA) low enough to ensure that 3H is accurately determined. In this paper, we present a method that uses a new Liquid Scintillation Spectrometer (LSC in what follows): the Quantulus GCT 6220. Furthermore, a new liquid scintillation cocktail, the ProSafe LT+, has been tested for 3H measurement, showing to be a good option for the determination of low levels of this radionuclide. The MDAs achieved are low enough to enable the measurement of very low levels of 3H in recent environmental water. The results obtained using a Quantulus GCT 6220 and Prosafe LT + are compared to those obtained with a Quantulus 1220 and Prosafe HC + as liquid scintillation cocktail.
Subject(s)
Radiation Monitoring , Scintillation Counting , Tritium , Water Pollutants, Radioactive , Scintillation Counting/methods , Scintillation Counting/instrumentation , Water Pollutants, Radioactive/analysis , Radiation Monitoring/methods , Radiation Monitoring/instrumentation , Tritium/analysisABSTRACT
Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aß42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aß in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aß in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aß pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aß pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aß pathology, APOE impacts the response to E2 supplementation post-menopause.
Subject(s)
Apolipoprotein E3 , Apolipoprotein E4 , Estradiol , Ovariectomy , Animals , Female , Humans , Mice , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Apolipoprotein E3/genetics , Apolipoprotein E3/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Behavior, Animal/drug effects , Disease Models, Animal , Estradiol/pharmacology , Mice, TransgenicABSTRACT
BACKGROUND: The epidemiology of colorectal cancer (CRC) has changed rapidly over the years. The aim of this study was to assess the trends in incidence, treatment, and relative survival (RS) of patients diagnosed with CRC in the Netherlands between 2000 and 2021. PATIENTS AND METHODS: 2 75667 patients diagnosed with CRC between 2000 and 2021 were included from the Netherlands Cancer Registry. Analyses were stratified for disease extent (localised: T1-3N0M0; regional: T4N0M0/T1-4N1-2M0; distant: T1-4N0-2M1) and localisation (colon; rectum). Trends were assessed with joinpoint regression. RESULTS: CRC incidence increased until the mid-2010s but decreased strongly thereafter to rates comparable with the early 2000s. Amongst other trend changes, local excision rates increased for patients with localised colon (2021: 13.6 %) and rectal cancer (2021: 34.9 %). Moreover, primary tumour resection became less common in patients with distant colon (2000-2021: 60.9-12.5 %) or rectal cancer (2000-2021: 47.8-6.9 %), while local treatment of metastases rates increased. Five-year RS improved continuously for localised and regional colon (97.7 % and 72.0 % in 2017, respectively) and rectal cancer (95.2 % and 76.3 % in 2017, respectively). The rate of anti-cancer treatments decreased in distant colon (2010-2021: 80.3 % to 67.2 %; p < 0.001) and rectal cancer (2011-2021: 86.0 % to 77.0 %; p < 0.001). The improvement of five-year RS stagnated for distant colon (2010-2017: 11.2 % to 11.9 %; average percentage of change [APC]: 2.1, 95 % confidence interval [CI]: -7.6, 4.7) and rectal cancer (2009-2017: 12.7 % to 15.6 %; APC: 1.4, 95 % CI: -19.1, 5.5). CONCLUSIONS: Major changes in the incidence and treatment of CRC between 2000 and 2021 were identified and quantified. Five-year RS increased continuously for patients with localised and regional CRC, but stagnated for patients with distant CRC, likely caused by decreased rates of anti-cancer treatment in this group.
Subject(s)
Colorectal Neoplasms , Registries , Humans , Netherlands/epidemiology , Male , Female , Incidence , Colorectal Neoplasms/mortality , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/therapy , Colorectal Neoplasms/pathology , Aged , Middle Aged , Registries/statistics & numerical data , Aged, 80 and over , Adult , Survival RateABSTRACT
Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated â¼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.
Subject(s)
Alzheimer Disease , Genetic Predisposition to Disease , tau Proteins , Humans , Alzheimer Disease/genetics , Male , Female , Aged , tau Proteins/cerebrospinal fluid , tau Proteins/genetics , Genetic Predisposition to Disease/genetics , Disease Progression , Biomarkers/cerebrospinal fluid , Aged, 80 and over , Apolipoproteins E/genetics , Positron-Emission Tomography , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Middle Aged , Cohort StudiesABSTRACT
1: ESGE recommends cold snare polypectomy (CSP), to include a clear margin of normal tissue (1-2âmm) surrounding the polyp, for the removal of diminutive polyps (≤â5âmm).Strong recommendation, high quality of evidence. 2: ESGE recommends against the use of cold biopsy forceps excision because of its high rate of incomplete resection.Strong recommendation, moderate quality of evidence. 3: ESGE recommends CSP, to include a clear margin of normal tissue (1-2âmm) surrounding the polyp, for the removal of small polyps (6-9âmm).Strong recommendation, high quality of evidence. 4: ESGE recommends hot snare polypectomy for the removal of nonpedunculated adenomatous polyps of 10-19âmm in size.Strong recommendation, high quality of evidence. 5: ESGE recommends conventional (diathermy-based) endoscopic mucosal resection (EMR) for large (≥â20âmm) nonpedunculated adenomatous polyps (LNPCPs).Strong recommendation, high quality of evidence. 6: ESGE suggests that underwater EMR can be considered an alternative to conventional hot EMR for the treatment of adenomatous LNPCPs.Weak recommendation, moderate quality of evidence. 7: Endoscopic submucosal dissection (ESD) may also be suggested as an alternative for removal of LNPCPs of ≥â20âmm in selected cases and in high-volume centers.Weak recommendation, low quality evidence. 8: ESGE recommends that, after piecemeal EMR of LNPCPs by hot snare, the resection margins should be treated by thermal ablation using snare-tip soft coagulation to prevent adenoma recurrence.Strong recommendation, high quality of evidence. 9: ESGE recommends (piecemeal) cold snare polypectomy or cold EMR for SSLs of all sizes without suspected dysplasia.Strong recommendation, moderate quality of evidence. 10: ESGE recommends prophylactic endoscopic clip closure of the mucosal defect after EMR of LNPCPs in the right colon to reduce to reduce the risk of delayed bleeding.Strong recommendation, high quality of evidence. 11: ESGE recommends that en bloc resection techniques, such as en bloc EMR, ESD, endoscopic intermuscular dissection, endoscopic full-thickness resection, or surgery should be the techniques of choice in cases with suspected superficial invasive carcinoma, which otherwise cannot be removed en bloc by standard polypectomy or EMR.Strong recommendation, moderate quality of evidence.