Clinical profile of early- and late-onset colorectal cancer patients in a referral medical center in Medellín, Colombia: A comparative analysis / Perfil clínico de pacientes con cáncer colorrectal de aparición temprana y tardía en un centro médico de referencia en Medellín, Colombia: Un análisis comparativo

Introduction. Incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) in individuals aged < 50 years, is rising worldwide. Despite the increasing international scientific production on EOCRC, research is limited in Colombia. The objective of this study was to characterize the clinical features of adults with EOCRC and late-onset CRC (LOCRC, CRC in individuals aged ≥ 50 years). Methods. An observational, retrospective, cross-sectional study was conducted with CRC patients ≥ 18 years old at one medical center in Medellín, Colombia. Clinical and pathological data were retrieved from the Institutional Cancer Registry. Two analysis groups were established: EOCRC and LOCRC. The Chi-Square test was applied to compare the variables of interest between both groups. Results. The sample included 1,202 patients, 53.5% were female (N=643) and the median age was 65 years (interquartile range: 55-73). EOCRC represented 15.9% (N=192). LOCRC tended to have more history of cardiometabolic diseases and smoking (p<0.001) than EOCRC. CRC family history was proportionally more frequent in EOCRC (7.3% vs 3.8%; p=0.028) than in LOCRC. Right-sided tumors were more common in LOCRC (30.4% vs 21.9%; p=0.041) and left-sided tumors in EOCRC (30.7% vs 23.2%; p=0.041). Only one patient had inflammatory bowel disease history. Conclusion. EOCRC is clinically distinct from LOCRC regarding pathological and toxicological history as well as tumor location. Our findings provide valuable insights for enhancing clinical decision-making, particularly in relation to age at onset in Colombian CRC patients.

Introducción. La incidencia de cáncer colorrectal (CCR) de aparición temprana (CCR-ATem), definido como CCR en individuos menores de 50 años, está aumentando en todo el mundo. A pesar del incremento en la producción científica internacional sobre CCR-ATem, la investigación es limitada en Colombia. El objetivo de este estudio fue caracterizar clínicamente los adultos con CCR-ATem y CCR de aparición tardía (CCR-ATar, CCR en individuos ≥ 50 años). Métodos. Estudio observacional, retrospectivo, transversal, en el que se incluyeron los pacientes adultos con CCR atendidos en un centro médico de Medellín, Colombia. Los datos se obtuvieron del Registro Institucional de Cáncer. Se establecieron dos grupos de análisis: CCR-ATem y CCR-ATar. Se aplicó la prueba de Chi cuadrado para comparar las variables de interés entre ambos grupos. Resultados. La muestra incluyó 1.202 pacientes, 53,5 % fueron mujeres (N=643), y la mediana de edad fue de 65 años (rango intercuartil: 55-73). CCR-ATem representó el 15,9 % (N=192). CCR-ATar tuvo más casos de enfermedades cardiometabólicas y tabaquismo (p<0,001). El antecedente familiar de CCR fue proporcionalmente más frecuente en CCR-ATem (7,3 % vs. 3,8 %; p=0,028). Los tumores del colon derecho fueron más frecuentes en CCR-ATar (30,4 % vs. 21,9 %; p=0,041) y los del colon izquierdo en CCR-ATem (30,7 % vs. 23,2 %; p=0,041). Solo un paciente tuvo antecedente de enfermedad inflamatoria intestinal. Conclusión. CCR-ATem es clínicamente distinto de CCR-ATar con respecto a antecedentes patológicos y toxicológicos, y localización tumoral. Nuestros hallazgos proporcionan información útil para mejorar la toma de decisiones clínicas, particularmente en relación con la edad de inicio en pacientes colombianos con CCR.

Clinical and pathological differences between early- and late-onset colorectal cancer and determinants of one-year all-cause mortality among advanced-stage patients: a retrospective cohort study in Medellín, Colombia.

OBJECTIVE: To identify the differences between early- (EOCRC) and late-onset colorectal cancer (LOCRC), and to evaluate the determinants of one-year all-cause mortality among advanced-stage patients. METHODS: A retrospective cohort study was carried out. CRC patients ≥ 18 years old were included. Chi-Square test was applied to compare both groups. Uni- and multivariate regressions were performed to evaluate the determinants of one-year all-cause mortality in all advanced-stage patients regardless of age of onset. RESULTS: A total of 416 patients were enrolled; 53.1 % were female. Ninety cases (21.6 %) had EOCRC and 326 (78.4 %) had LOCRC. EOCRC cases were predominantly sporadic (88.9 %). Histology of carcinoma other than adenocarcinoma (p= 0.044) and rectum tumors (p= 0.039) were more prevalent in EOCRC. LOCRC patients were more likely to have smoking history (p < 0.001) and right colon tumors (p = 0.039). Alcohol consumption history (odds ratio [OR]: 3.375, 95 %CI: 1.022-11.150) and stage IV (OR: 12.632, 95 %CI: 3.506-45.513) were associated with higher one-year all-cause mortality among advanced-stage patients, the opposite was noted with left colon tumors (OR: 0.045, 95 %CI: 0.003-0.588). CONCLUSION: EOCRC was predominantly sporadic and had more cases of uncommon histological subtypes and rectal tumors. LOCRC was characterized by a higher prevalence of smoking history. Multivariate regression revealed an association between higher one-year all-cause mortality and alcohol consumption history and stage IV in advanced-stage patients. CRC exhibited differences based on age of onset. The evaluated factors associated with CRC mortality provide valuable insights for healthcare professionals, emphasizing the importance of adequate clinical assessment and early CRC diagnosis.

Hidden neuraxial pathology in idiopathic scoliosis: original research / Patologia neuroaxial oculta na escoliose idiopática: pesquisa original / Patología neuroaxial oculta en la escoliosis idiopática: investigación original

ABSTRACT Objective: To evaluate the prevalence of hidden neuraxial pathology (NAP) revealed in idiopathic scoliosis (IS) in neurologically normal patients. Methods: We selected 401 patients with IS who visited our clinic. We identified patterns of NAP and its frequency. In addition to the main part of the study, we assessed the reliability of Magnetic Resonance Imaging (MRI) measuring of the pedicles to plan screw width and trajectory. Results: Among the 401 patients, 53 (13%) presented NAP. The proportion of males in this group was higher (42% vs. 21%, p=0.004), the age of onset of the deformity was lower (8.9±3.77 vs. 9.9±3.93 years old, p=0.045), the left-sided thoracic curve was more frequent (21% vs. 8%, p=0.016), thoracic kyphosis was more pronounced (p=0.070), and the percentage of revision surgeries for deformity progression or non-fusion was higher (13% vs. 5%, p=0.147). Conclusions: The spine MRI should be performed in the early stages of IS, as in some cases of NAP (Chiari, tethered spinal cord), there is the possibility of an early neurosurgical operation that will prevent the development of scoliosis. The main signs of hidden NAP in IS are early-onset IS, IS with left-sided thoracic curve, male gender, and thoracic kyphosis > 40°Cobb. Level of Evidence II; Retrospective Study.

Resumo: Objetivo: Avaliar a prevalência das patologias neuroaxiais ocultas (PNO) reveladas na escoliose idiopática (EI) em pacientes neurologicamente normais. Métodos: Foram selecionados 401 pacientes com EI que visitaram nossa clínica. Identificamos padrões de PNO e sua frequência. Além disso, avaliamos a confiabilidade da medição por ressonância magnética (RM) dos pedículos para planejar a largura e a trajetória do parafuso. Resultados: Entre os 401 pacientes, 53 (13%) apresentaram PNO. A proporção de homens neste grupo foi maior (42% contra 21%, p=0,004), a idade de início da deformidade foi menor (8,9±3,77 contra 9,9±3,93 anos, p=0,045), a curva torácica do lado esquerdo foi mais frequente (21% contra 8%, p=0,016), a cifose torácica foi mais pronunciada (p=0,070) e a porcentagem de cirurgias de revisão para progressão da deformidade ou não fusão foi maior (13% contra 5%, p=0,147). Conclusões: A ressonância magnética da coluna deve ser realizada nos estágios iniciais da EI, pois em alguns casos de PNO (Chiari, medula espinhal amarrada) existe a possibilidade de uma operação neurocirúrgica precoce que impedirá o desenvolvimento de escoliose. Os principais sinais de PNO oculta na EI são: EI de início precoce, EI com curvatura torácica à esquerda, sexo masculino e cifose torácica > 40°Cobb. Nível de Evidência II; Estudo Retrospectivo.

Resumen: Objetivo: Evaluar la prevalencia de las patologías neuroaxiales ocultas (PNO) reveladas en la escoliosis idiopática (EI) en pacientes neurológicamente normales. Métodos: Se seleccionaron 401 pacientes con EI que visitaron nuestra clínica. Se identificaron patrones de PNO y su frecuencia. Además, evaluamos la fiabilidad de la medición por resonancia magnética (RM) de los pedículos para planificar la anchura y la trayectoria del tornillo. Resultados: Entre los 401 pacientes, 53 (13%) presentaron PNO. La proporción de hombres en este grupo fue mayor (42% vs 21%, p=0,004), la edad de aparición de la deformidad fue menor (8,9±3,77 vs 9,9±3,93 años edad, p=0,045), la curva torácica del lado izquierdo se encontró con más frecuencia (21 % frente a 8 %, p=0,016), la cifosis torácica fue más pronunciada (p=0,070) y el porcentaje de cirugías de revisión por progresión de la deformidad o falta de fusión fue mayor (13% vs 5%, p=0,147). Conclusiones: La resonancia magnética de la columna debe realizarse en las primeras etapas de la EI, ya que en algunos casos de PNO (Chiari, médula anclada) existe la posibilidad de una operación neuroquirúrgica temprana que prevendrá el desarrollo de la escoliosis. Los principales signos de PNO oculta en EI son: EI de inicio temprano, EI con curvatura torácica izquierda, sexo masculino y cifosis torácica > 40°Cobb. Nivel de Evidencia II; Estudio Retrospectivo.

Potential Modifying Effect of the APOEε4 Allele on Age of Onset and Clinical Manifestations in Patients with Early-Onset Alzheimer's Disease with and without a Pathogenic Variant in PSEN1 in a Sample of the Mexican Population.

In Alzheimer's disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and exhibiting symptoms prior to the age of 65 are typically classified as early onset (EOAD) cases. Notably, the apolipoprotein E (APOE) ε4 allele represents the most extensively studied genetic risk factor associated with AD. We clinically characterized and genotyped the APOEε4 allele from 101 individuals with a diagnosis of EOAD, and 69 of them were affected carriers of the autosomal dominant fully penetrant PSEN1 variant c.1292C>A (rs63750083, A431E) (PSEN1+ group), while there were 32 patients in which the genetic cause was unknown (PSEN1- group). We found a correlation between the AoO and the APOEε4 allele; patients carrying at least one APOEε4 allele showed delays, in AoO in patients in the PSEN1+ and PSEN1- groups, of 3.9 (p = 0.001) and 8.6 years (p = 0.012), respectively. The PSEN1+ group presented higher frequencies of gait disorders compared to PSEN1- group, and apraxia was more frequent with PSEN1+/APOE4+ than in the rest of the subgroup. This study shows what appears to be an inverse effect of APOEε4 in EOAD patients, as it delays AoO and modifies clinical manifestations.

Barriers to methamphetamine treatment seeking in residential centers in Aguascalientes, Mexico.

Introduction: In the Aguascalientes, most people who seek treatment go to non-governmental residential centers, and about half request treatment for meth use. Although some barriers to treatment seeking among these users are known, few studies have been conducted with the Mexican population, specifically with users of residential centers. The aim of this study was to explore the main barriers reported by these patients, the relationship between reported barriers and meth use, as well as identify possible user profiles based on the barriers and the pattern of consumption. Methods: We designed a brief survey that evaluated sociodemographic data, consumption pattern, help-seeking for consumption and use of services, barriers in the search for services, depression, and suicide attempts. Here, we report the results of barriers and consumption patterns. The study sample consisted of 865 individuals receiving treatment for meth use in 23 certified residential centers. Results: Patients reported an average of 2.12 barriers, the main ones being not considering the services useful for them (41.6%), not considering it important to attend (35%), and not finding time to attend the consultation (29.8%). We found a statistically significant relationship, although weak, between the number of barriers reported by participants and the age of onset of meth use, dangerous perception of meth use, attempts to quit, and the number of problems associated with use. We used a cluster analysis that was performed using the k-means machine learning algorithm, which revealed two clusters. The first was formed by patients who started using meth at a young age which has more problems associated with meth use and more barriers in seeking services, while the other was formed by patients who started at an older age which have fewer problems and fewer barriers. We found statistical differences between groups, where it was found that young group reported consuming more substances, more problems associated, and more barriers in seeking services. Discussions: This study revealed the main barriers to seeking treatment among patients in residential centers and found that the age of onset of meth use is a risk factor for presenting more barriers and more problems associated with consumption.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Acid Suppression and Antibiotics Administered during Infancy Are Associated with Celiac Disease.

OBJECTIVE: To investigate why certain at-risk individuals develop celiac disease (CD), we examined the association of proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RAs), and antibiotic prescriptions in the first 6 months of life with an early childhood diagnosis of CD. STUDY DESIGN: A retrospective cohort study was performed using the Military Healthcare System database. Children with a birth record from October 1, 2001, to September 30, 2013, were identified. Outpatient prescription records were queried for antibiotic, PPI, and H2RA prescriptions in the first 6 months of life. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of developing CD based on medication exposure. International Classification of Diseases, Ninth Revision, Clinical Modification codes identified children with an outpatient visit for CD. RESULTS: There were 968 524 children who met the inclusion criteria with 1704 cases of CD in this group. The median follow-up for the cohort was approximately 4.5 years. PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD. CONCLUSIONS: There is an increased risk of developing CD if antibiotics, PPIs and H2RAs are prescribed in the first 6 months of life. Our study highlights modifiable factors, such as medication stewardship, that may change the childhood risk of CD.

Age of onset and alcohol and cannabis use disorders among Mexican American young adults: Robust substance-specific effects of early use as a risk factor.

We investigated the substance-specific and cross-substance risk associated with early onset (before age 15) of drunkenness and cannabis use in the subsequent development of alcohol (AUD) and cannabis use disorder (CUD) in Mexican American young adults. Survival analyses employed Cox proportional hazards models for AUD and CUD, separately. In cross-risk analyses, we modeled estimates for those participants reporting lifetime use of both substances. Early onset of drunkenness and early onset of cannabis use were associated with shorter time to AUD and CUD, respectively, even after accounting for psychiatric disorders. While there were no cross-risk associations, adjusting for psychiatric disorders and early onset cannabis use attenuated the association of early drunkenness with AUD.

Drugs age-of-onset as a signal of later post-traumatic stress disorder: Bayesian analysis of a census protocol.

Individuals with PTSD have an increased risk of drug use disorders. Conversely, we aim to evaluate how early onset of alcohol, tobacco and psychoactive drugs use are associated with PTSD later in life. 2,193 brazilian young adults completed modularized assessments: The Trauma History Questionnaire, Post-Traumatic Stress Disorder Checklist-Civilian Version (PCL-C, transformed to PCL-5 through a crosswalk procedure), the Barratt Impulsivity Scale; and a survey on drug use with self-report questions about first use, current use, frequency, quantity, and interpersonal consequences. Bayesian inference and multivariate regression models were used to examine the effects on the risk of PTSD, considering different assumptions of information flow. Raw and unbiased (multivariate) estimates consistently revealed that earlier age of onset of alcohol and tobacco use increased risk for PTSD (Odds-ratios between 2.39 and 3.19 (Alcohol) and 1.82 to 2.05 (Tobacco). Among those who had PTSD (310), 10.3% (32) were very precocious at the onset age (12 to 18 years) of alcohol consumption (No-PTSD: 89 out 1883, 4.7%). Data supports a model in which age of onset effects are partially mediated by the number of trauma exposures. Early intoxication might suggest vulnerability for qualifying trauma events, or it may increase chances of exposure. Also, PTSD may be more likely to occur among trauma-exposed individuals with early intoxicating experiences due to alcohol or drug self-administration. The last possibility resonates with the idea that early intoxication might disrupt adolescent brain development, with a subsequent reduction in resilience when qualifying trauma events occur.

High risk for psychiatric disorders in bipolar offspring. A four years prospective study / Riesgo elevado de trastornos psiquiátricos en hijos de padres con trastorno bipolar. Estudio prospectivo de cuatro años de duración

ABSTRACT Bipolar disorder (BD) has a large hereditary component. It is a disorder that begins in early adulthood, but about which it has been described a premorbid period preceding the onset of BD. During this herald expression psychiatric disorders and symptoms, such as depressive, manic, psychotic, anxious and others, may appear. Objective: To determine the psychopathological profile of a Bipolar Offspring (BO) group compared with the Community Control Offspring (CCO) group, and its evolution over time, including subthreshold symptoms and mental disorders. Methods: We conducted an observational mixed cohort study, with a prospective design. We included subjects from six to 30 years of age, from the region of Antioquia, Colombia. A total of 131 subjects from the risk group BO and 150 subjects from the CCO group were evaluated through validated psychiatric diagnostic interviews (K-SADS-PL and DIGS) at baseline and at 4 years follow up. All interviews were carried out by a staff blind to parent diagnoses. Follow-up assessment were complete in 72% of the offspring. Forty-two subjects were excluded as they surpassed the age of 30 years, and only 46 subjects were not followed (change of address or did not consent to participate). Results: Compared with the CCO group, the BO group had a higher frequency of affective disorder, psychotic disorder, externalizing disorders and use of the psychoactive substances during both assessments at time 1 and 2. The magnitude of the differences between the groups increased when they reach time 2. The BO group had a greater risk for presenting subthreshold symptoms and definitive psychiatric disorders, such as affective disorders, psychotic disorders and externalizing disorders. In addition, the BO group had a younger age of onset for psychoactive substances consumption. Conclusion: During the follow-up period, the BO group had a higher risk of presenting mental disorders compared with the CCO group. The most relevant symptoms and disorders that could precede the onset of BD were depressive, bipolar not otherwise specified, psychotic and substance use.

RESUMEN El trastorno bipolar (TB) tiene un gran componente hereditario. Es un trastorno que comienza en la edad adulta temprana, pero acerca del cual se ha descrito un período premórbido que precede al inicio de TB. Durante esta expresión heraldo, pueden aparecer trastornos y síntomas psiquiátricos, como depresivos, maníacos, psicóticos, ansiosos y otros. Objetivo: Determinar el perfil psicopatológico de un grupo de hijos de padres con TB (BO) en comparación con el grupo de hijos de padres control de la misma comunidad (CCO), y su evolución en el tiempo. Los síntomas subumbrales y los trastornos mentales serán incluidos. Métodos: Nosotros llevamos a cabo un estudio observacional mixto de cohorte, con diseño prospectivo. Incluimos sujetos de seis a 30 anos de edad, de la región de Antioquia, Colombia. Un total de 131 sujetos del grupo de riesgo BO y 150 sujetos del grupo CCO fueron evaluados a través de entrevistas de diagnóstico psiquiátricas validadas (K-SADS-PL y DIGS), al inicio yalos4anos de seguimiento. Todas las entrevistas se llevaron a cabo por personal ciego a los diagnósticos de los padres. La evaluación de seguimiento se completó en el 72% de la descendencia. Cuarenta y dos sujetos fueron excluidos ya que superaron la edad de 30 anos, y solo 46 sujetos no fueron seguidos (cambio de dirección o no dieron su consentimiento para participar). Resultados: En comparación con el grupo CCO, el grupo BO tuvo una mayor frecuencia de trastorno afectivo, el trastorno psicótico, los trastornos de externalización y el uso de las sustancias psicoactivas durante ambas evaluaciones en los tiempos 1 y 2. La magnitud de las diferencias entre los grupos aumentó cuando alcanzaron el tiempo 2. El grupo BO tuvo un mayor riesgo de presentar síntomas subumbrales y trastornos psiquiátricos definitivos, tales como trastornos afectivos, trastornos psicóticos y trastornos de externalización. Además, el grupo BO tuvo una edad de comienzo más baja para el consumo de sustancias psicoactivas. Conclusión: Durante el período de seguimiento, el grupo BO tuvo un mayor riesgo de presentar trastornos mentales en comparación con el grupo CCO. Los síntomas y trastornos más importantes que preceden al inicio del TB fueron: depresivo, bipolar no especificado de otra manera, psicóticos y el uso de sustancias.

High risk for psychiatric disorders in bipolar offspring. A four years prospective study.

Bipolar disorder (BD) has a large hereditary component. It is a disorder that begins in early adulthood, but about which it has been described a premorbid period preceding the onset of BD. During this herald expression psychiatric disorders and symptoms, such as depressive, manic, psychotic, anxious and others, may appear. OBJECTIVE: To determine the psychopathological profile of a Bipolar Offspring (BO) group compared with the Community Control Offspring (CCO) group, and its evolution over time, including subthreshold symptoms and mental disorders. METHODS: We conducted an observational mixed cohort study, with a prospective design. We included subjects from six to 30 years of age, from the region of Antioquia, Colombia. A total of 131 subjects from the risk group BO and 150 subjects from the CCO group were evaluated through validated psychiatric diagnostic interviews (K-SADS-PL and DIGS) at baseline and at 4 years follow up. All interviews were carried out by a staff blind to parent diagnoses. Follow-up assessment were complete in 72% of the offspring. Forty-two subjects were excluded as they surpassed the age of 30 years, and only 46 subjects were not followed (change of address or did not consent to participate). RESULTS: Compared with the CCO group, the BO group had a higher frequency of affective disorder, psychotic disorder, externalizing disorders and use of the psychoactive substances during both assessments at time 1 and 2. The magnitude of the differences between the groups increased when they reach time 2. The BO group had a greater risk for presenting subthreshold symptoms and definitive psychiatric disorders, such as affective disorders, psychotic disorders and externalizing disorders. In addition, the BO group had a younger age of onset for psychoactive substances consumption. CONCLUSION: During the follow-up period, the BO group had a higher risk of presenting mental disorders compared with the CCO group. The most relevant symptoms and disorders that could precede the onset of BD were depressive, bipolar not otherwise specified, psychotic and substance use.

A Comprehensive Machine Learning Framework for the Exact Prediction of the Age of Onset in Familial and Sporadic Alzheimer's Disease.

Machine learning (ML) algorithms are widely used to develop predictive frameworks. Accurate prediction of Alzheimer's disease (AD) age of onset (ADAOO) is crucial to investigate potential treatments, follow-up, and therapeutic interventions. Although genetic and non-genetic factors affecting ADAOO were elucidated by other research groups and ours, the comprehensive and sequential application of ML to provide an exact estimation of the actual ADAOO, instead of a high-confidence-interval ADAOO that may fall, remains to be explored. Here, we assessed the performance of ML algorithms for predicting ADAOO using two AD cohorts with early-onset familial AD and with late-onset sporadic AD, combining genetic and demographic variables. Performance of ML algorithms was assessed using the root mean squared error (RMSE), the R-squared (R2), and the mean absolute error (MAE) with a 10-fold cross-validation procedure. For predicting ADAOO in familial AD, boosting-based ML algorithms performed the best. In the sporadic cohort, boosting-based ML algorithms performed best in the training data set, while regularization methods best performed for unseen data. ML algorithms represent a feasible alternative to accurately predict ADAOO with little human intervention. Future studies may include predicting the speed of cognitive decline in our cohorts using ML.

Factors associated with crack-cocaine early initiation: a Brazilian multicenter study.

BACKGROUND: Crack-cocaine dependence is a serious public health issue, related to several psychiatric and psychosocial problems. Crack-cocaine users are usually embedded in a context of great social vulnerability, often associated with violence, poverty, family conflict and easy and early access to alcohol, tobacco and other drugs. METHODS: This cross-sectional study enrolled a consecutive sample of 577 patients admitted to 20 therapeutic communities located in Southern Brazil, between September 2012 and September 2013. A structured interview assessed life-time exposure to risk and protective factors for drug use, such as parental monitoring in childhood, deviant behaviors and peer pressure. RESULTS: Presence of family conflict (p = 0.002), maltreatment (p = 0.016), and deviant behavior prior to age 15 in a bivariate analysis predicted an earlier age of crack-cocaine initiation, whereas adolescents experiencing parental monitoring during adolescence started use later (p < 0.001). In the multivariate model, perceptions related to ease of access of illicit drugs (marijuana: p = 0.028, 95% CI = - 3.81, - 0.22; crack-cocaine: p < 0.001, 95% CI = - 7.40, - 4.90), and deviant behavior (threatening someone with a gun: p = 0.028, 95% CI = - 2.57, - 0.14) remained independent predictors of early age of crack-cocaine initiation. CONCLUSIONS: Early onset of crack-cocaine use seems to be associated with exposure to family conflict, easy access to drugs and deviant behavior. Treatment and preventive programs should take these factors into account when designing and implementing community interventions.

Clinical, Pathological and Molecular Characteristics of Chilean Patients with Early-, Intermediate- and Late-Onset Colorectal Cancer.

Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years; EOCRC), intermediate- (51-69 years; IOCRC), and late-onset (≥70 years; LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan-Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.

Body Mass Index Is Significantly Associated With Disease Severity in Spinocerebellar Ataxia Type 2 Patients.

BACKGROUND: Spinocerebellar ataxia type 2 is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Although weight loss has been associated with disease progression in several neurodegenerative conditions, it has been barely assessed in patients with spinocerebellar ataxia type 2. OBJECTIVE: The objective of this study was to test whether body mass index is altered in patients with spinocerebellar ataxia type 2 with varying expansion sizes from early to late disease stages. METHODS: A cross-sectional case-control study was performed, which included 222 clinically and molecularly diagnosed patients and 214 sex- and age-matched healthy individuals. ATXN2 genotypes and sex were considered as risk factors. Clinical outcomes included the body mass index, age at onset, disease duration, Scale for the Assessment and Rating of Ataxia score, disease stage, dysphagia, and progression rate. Multiple linear regression models were generated. RESULTS: Body mass index was significantly decreased in male patients, but not in female patients, relative to control subjects. In addition to sex, body mass index was significantly associated with age at onset and progression rate. Conversely, body mass index, along with repeat length in ATXN2 expanded alleles and disease duration, was associated with Scale for the Assessment and Rating of Ataxia score. In addition, body mass index, along with the age at onset and the repeat length in ATXN2 normal and expanded alleles, has a significant influence on progression rate. CONCLUSIONS: Body mass index might be a useful biomarker of disease severity, particularly in male patients with spinocerebellar ataxia type 2 in the context of nutritional interventions or clinical trials assessing the efficacy of promising new drugs. © 2021 International Parkinson and Movement Disorder Society.

Rigidez arterial, hipertensão arterial e idade: associação com declínio do desempenho cognitivo após 4 anos de seguimento em participantes do ELSA-Brasil / Arterial stiffness, arterial hypertension and age: association with decline in cognitive performance after 4 years of follow-up in ELSA-Brasil participants

Nas últimas décadas, um número crescente de evidências destacou a importante contribuição dos fatores de risco vasculares para o declínio cognitivo acelerado e demências, incluindo a doença de Alzheimer. Apesar dos grandes progressos nesse campo de estudo, as evidências sobre o papel da rigidez arterial e da hipertensão na cognição não é conclusivo. O objetivo desta tese foi verificar se a rigidez arterial, a idade e a hipertensão arterial sistêmica estão associadas à diminuição do desempenho em testes de função cognitiva em adultos de meia idade e idosos após cerca de quatro anos de seguimento. Foram utilizados dados da linha de base (onda 1: 2008-2010) e do primeiro acompanhamento (onda 2: 2012-2014) do Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). No primeiro artigo, utilizando modelos lineares de efeitos mistos, foi investigado se a rigidez aórtica, medida pela velocidade da onda de pulso carotídeo-femoral (VOP-cf) e a idade na linha de base, estariam associados ao declínio no desempenho cognitivo avaliado por três testes cognitivos (Teste de Memória, Teste de Fluência Verbal Fonêmica e Semântica e Teste de Trilhas B), aplicados nas duas visitas da coorte. Encontramos que a rigidez aórtica foi associada de forma independente da pressão arterial sistólica e da idade ao declínio mais rápido em duas habilidades cognitivas, memória e fluência. Entretanto, o declínio no Teste de Memória foi restrito aos participantes com altos valores de VOP-cf na linha de base. A idade também foi associada ao declínio mais rápido no desempenho de todos os testes cognitivo avaliados entre as ondas. No entanto, apenas os participantes mais velhos apresentaram uma trajetória de desempenho descendente nos Testes de Memória e Trilha B. No segundo artigo, por meio de regressão linear de efeitos mistos, foi investigado se a exposição à hipertensão arterial sistêmica (HAS) e a pré-hipertensão estariam associados ao declínio no desempenho do escore cognitivo global (avaliado pelo fator g) e em Teste de Memória, Fluência Verbal Fonêmica e Semântica e Trilhas B, todos analisados como escores padronizados. Também foi investigado se a HAS diagnosticada na meia idade, o tempo de exposição a HAS e o status de tratamento e de controle da HAS na linha de base da coorte estariam associados ao declínio cognitivo mais acelerado entre visita. Encontramos que tanto a exposições à HAS quanto à Pré-HAS na linha de base foram associadas ao declínio no desempenho cognitivo, avaliado pelo escore cognitivo global (fator g). A HAS também foi associada à redução nos escores padronizados dos Testes de Memória e Fluência Verbal, enquanto a Pré-HAS permaneceu longitudinalmente associada apenas à redução no escore padronizado do Teste de Fluência Verbal. Não encontramos evidências de que a exposição à HAS na meia idade estivesse associada ao declínio cognitivo, somente a exposição à HAS na idade mais velha permaneceu associada a redução do escore cognitivo global e do Teste de Memória. Também não identificamos que maior tempo de exposição à HAS estivessem associadas ao declínio cognitivo relacionado à idade. O status de tratamento da HAS não foi associado a alterações nos escores padronizados dos testes cognitivos avaliado, mas a HAS não controlada quando comparada a controlada foi associada ao declínio mais acelerado no escore cognitivo global e no Teste de Memória. Nenhuma das variáveis de HAS analisadas foram associadas a alterações nos escores padronizados do Teste de trilhas B. O aumento da rigidez aórtica, a exposição à HAS, a pré-HAS e a HAS de início tardio foram associadas à uma pior trajetória longitudinal no desempenho cognitivo global e em diferentes habilidades cognitivas. Embora a magnitude dos efeitos seja pequena, é notável detectar o impacto direto desses fatores no declínio cognitivo relacionado à idade, uma vez que, avaliamos uma população altamente instruída e com idade relativamente jovem em um curto intervalo de tempo. Os resultados reforçam a importância de estudar a função cognitiva na meia-idade, com vistas a identificar precocemente indivíduos em maior risco de declínio, assim como, fatores de risco que podem potencialmente acelerar o processo de envelhecimento cognitivo e impactar negativamente na função cognitiva ao longo do tempo.

In recent decades, increasing evidence has highlighted the critical contribution of vascular risk factors to the risk of accelerated cognitive decline and dementia, including Alzheimer's disease. Despite significant progress in this field of study, how to reduce the role of arterial stiffness and hypertension in cognition is not conclusive. This thesis aimed to verify whether arterial stiffness, age, and systemic arterial hypertension are associated with decreased performance on cognitive function tests in middle-aged and elderly adults after approximately four years of follow-up. We used data from baseline (wave 1: 2008-2010), and the first follow - up (wave 2: 2012-2014) Study of Adult Health Longitudinal (ELSA-Brazil). In the first paper, using mixed effects linear models, we investigated whether aortic stiffness, measured by carotid-femoral pulse wave velocity (cf-PWV) and age at baseline, were associated with the decline in three cognitive tests (Memory Test, Phonemic and Semantic Verbal Fluency Test, and Trail B Test), applied at both cohort visits. We found that aortic stiffness was independently associated with systolic blood pressure and age with the fastest decline in two cognitive skills, memory and fluency. However, the decrease in the Memory Test was restricted to participants with high baseline cf-PWV values. Age was also associated with the faster decline in the performance of all cognitive tests evaluated between waves. Still, only older participants showed a downward performance trajectory on Memory and Trail B tests. In the second paper, using mixed effects linear regression was investigated whether exposure to hypertension and prehypertension would be associated with the decline in the performance global cognitive score (assessed by the g factor) and Memory, Verbal Fluency Phonemic and Semantics and Trail B Tests. It was also investigated whether hypertension diagnosed in middle age, the time of exposure to hypertension and the treatment and control status of hypertension at the baseline of the cohort were associated with more accelerated cognitive decline between visits. We found that exposure to hypertension and prehypertension at baseline were associated with a decrease in cognitive performance assessed by the global cognitive score (g factor). Hypertension was also associated with a reduction in the standardized Memory and Verbal Fluency tests scores, whereas prehypertension remained longitudinally associated only with a decrease in the standardized Verbal Fluency Test score. We found no evidence that exposure to hypertension in middle age was associated with cognitive decline; only exposure to hypertension in older age remained associated with a reduction in the global cognitive score and the Memory Test. We also did not identify that longer exposure to hypertension was associated with age-related cognitive decline. The treatment status of hypertension was not associated with changes in the standardized scores of the assessed cognitive tests, but uncontrolled hypertension when compared to controlled hypertension was associated with the more accelerated decline in the global cognitive score and the Memory Test. None of the hypertension variables analyzed were associated with changes in the standardized scores of the Trail B test. The increase in aortic stiffness, exposure to hypertension, prehypertension and late-onset hypertension were associated with a worse longitudinal trajectory in global cognitive performance at different cognitive abilities. Although the magnitude of the effects is small, it is noteworthy to detect the direct impact of these factors on age-related cognitive decline, since we evaluated a highly educated and relatively young age population over a short time. The results reinforce the importance of studying cognitive function in middle-aged, in order to identify early individuals at higher risk of decline, as well as risk factors that can potentially accelerate the cognitive aging process and negatively impact cognitive function over time.

High Risk for Psychiatric Disorders in Bipolar Offspring. A Four Years Prospective Study.

Bipolar disorder (BD) has a large hereditary component. It is a disorder that begins in early adulthood, but about which it has been described a premorbid period preceding the onset of BD. During this herald expression psychiatric disorders and symptoms, such as depressive, manic, psychotic, anxious and others, may appear. OBJECTIVE: To determine the psychopathological profile of a Bipolar Offspring (BO) group compared with the Community Control Offspring (CCO) group, and its evolution over time, including subthreshold symptoms and mental disorders. METHODS: We conducted an observational mixed cohort study, with a prospective design. We included subjects from six to 30 years of age, from the region of Antioquia, Colombia. A total of 131 subjects from the risk group BO and 150 subjects from the CCO group were evaluated through validated psychiatric diagnostic interviews (K-SADS-PL and DIGS) at baseline and at 4 years follow up. All interviews were carried out by a staff blind to parent diagnoses. Follow-up assessment were complete in 72% of the offspring. Forty-two subjects were excluded as they surpassed the age of 30 years, and only 46 subjects were not followed (change of address or did not consent to participate). RESULTS: Compared with the CCO group, the BO group had a higher frequency of affective disorder, psychotic disorder, externalizing disorders and use of the psychoactive substances during both assessments at time 1 and 2. The magnitude of the differences between the groups increased when they reach time 2. The BO group had a greater risk for presenting subthreshold symptoms and definitive psychiatric disorders, such as affective disorders, psychotic disorders and externalizing disorders. In addition, the BO group had a younger age of onset for psychoactive substances consumption. CONCLUSION: During the follow-up period, the BO group had a higher risk of presenting mental disorders compared with the CCO group. The most relevant symptoms and disorders that could precede the onset of BD were depressive, bipolar not otherwise specified, psychotic and substance use.

Familial Alzheimer's Disease and Recessive Modifiers.

Alzheimer's disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD.