Stage I-III colon cancer patients with tumor deposits behave similarly to stage IV patients. Cross-section analysis of 392 patients.

BACKGROUND AND OBJECTIVES: Tumor deposits (TDs) are associated with adverse prognostic factors and decreased survival in colorectal cancer. However, controversy exists regarding their definition, evaluation, and staging categories. This study aimed to determine the survival and recurrence impact of the TD in colon adenocarcinomas; and to determine if TD patients behave similarly to stage IV patients. METHODS: Cross-section study from 392 patients with colon adenocarcinoma from 2005 to 2012. We performed survival analysis and further stratified patients considering TD patients as a "stage IV-TD" to demonstrate if they behave similarly than stage IV patients. RESULTS: From 392 patients, 204 (52%) were men, the mean age was 57.4 ± 13.9 years and 11.5% of cases had TD. In a multivariate analysis, TD failed to predict mortality and recurrence. Considering cases with TD as stage IV-TD, their mean survival was similar to stage IV patients (69.3 and 64.6 months, respectively) and different to those in stage III (110.5 months), II (135.7 months), and I (114.9 months) (P < 0.001). CONCLUSIONS: TD failed to predict mortality and recurrence. Patients with TD in stage I-III shows similar mortality than stage IV patients; then, we suggest putting them into a substage IV category instead of the N1c category.

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.

BACKGROUND: Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases. METHODS: In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury. RESULTS: During the acute post-injury period (24 h-15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1(-/-) mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1(-/-) mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1(-/-) mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFß. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI. CONCLUSION: Collectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.

Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation.

Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1(-/-) mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115(+)Ly6C(-)CD11c(+) dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-γ and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-γ- and IL-17-producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35-55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.

Neurocognitive subtypes of schizophrenia.

OBJECTIVE: To empirically identify schizophrenia neurocognitive subtypes and establish their association with clinical characteristics. METHODS: Sustained attention, executive function, facial emotion recognition, verbal learning, and working memory tests were applied to 253 subjects with schizophrenia. We identified neurocognitive subtypes by a latent class analysis of the tests results. After, we made a search for the association of these subtypes with clinic characteristics. RESULTS: We identified four neurocognitive subtypes: 1) “Global cognitive deficit”, 2) “Memory and executive function deficit”, 3) “Memory and facial emotion recognition deficit,” and 4) “Without cognitive deficit.” In comparison with the subtype “without cognitive deficit,” we found that the “memory and executive function deficit subtype” and the “global cognitive deficit subtype” had a higher frequency of male, unemployed, severe impairment, and adherence to treatment participants. However, in the “global cognitive deficit subtype” the differences were higher and there was also a lower frequency of past major depressive episodes (OR 0.39; 95%CI: 0.16 to 0.97). The “memory and facial recognition deficit subtype” had a higher probability of severe impairment (OR 5.52; 95%CI: 1.89 to 16.14) and unemployed (OR 2.43; 95%CI: 1.06 to 5.55) participants, but also a lower probability of past depressive episodes (OR 0.21; 95%CI: 0.07 to 0.66). CONCLUSION: Our results suggest the existence of four neurocognitive subtypes in schizophrenia with a spectrum of dysfunction and severity. We found higher dysfunction in those with worse cognitive dysfunction, and higher affective psychopathology and less treatment adherence in those with less cognitive dysfunction.

Increased accumulation of regulatory granulocytic myeloid cells in mannose receptor C type 1-deficient mice correlates with protection in a mouse model of neurocysticercosis.

Neurocysticercosis (NCC) is a central nervous system (CNS) infection caused by the metacestode stage of the parasite Taenia solium. During NCC, the parasites release immunodominant glycan antigens in the CNS environment, invoking immune responses. The majority of the associated pathogenesis is attributed to the immune response against the parasites. Glycans from a number of pathogens, including helminths, act as pathogen-associated molecular pattern molecules (PAMPs), which are recognized by pattern recognition receptors (PRRs) known as C-type lectin receptors (CLRs). Using a mouse model of NCC by infection with the related parasite Mesocestoides corti, we have investigated the role of mannose receptor C type 1 (MRC1), a CLR which recognizes high-mannose-containing glycan antigens. Here we show that MRC1(-/-) mice exhibit increased survival times after infection compared with their wild-type (WT) counterparts. The decreased disease severity correlates with reduced levels of expression of markers implicated in NCC pathology, such as interleukin-1ß (IL-1ß), IL-6, CCL5, and matrix metalloproteinase 9 (MMP9), in addition to induction of an important repair marker, fibroblast growth factor 2 (FGF2). Furthermore, the immune cell subsets that infiltrate the brain of MRC1(-/-) mice are dramatically altered and characterized by reduced numbers of T cells and the accumulation of granulocytic cells with an immune phenotype resembling granulocytic myeloid-dependent suppressor cells (gMDSCs). The results suggest that MRC1 plays a critical role in myeloid plasticity, which in turn affects the adaptive immune response and immunopathogenesis during murine NCC.

Verbal working memory in individuals with schizophrenia and their first degree relatives: relationship with negative and disorganized symptoms.

OBJECTIVE: To determine whether there are differences in verbal working memory amongst subjects with schizophrenia, their first degree relatives and controls, and to evaluate the influence of symptoms on these differences, as an initial step to assess whether this cognitive function is an endophenotype. METHODS: We examined 197 cases with schizophrenia, 197 first degree relatives and 200 controls through psychiatric interviews and the Letters and Numbers Sequencing test (LNS). Performance was compared among the three groups adjusting for age, sex and education level. Adjustment for "negative symptoms" and "disorganization" was performed afterwards. RESULTS: Subjects with schizophrenia showed lower performance in the LNS than their first degree relatives and the healthy controls; the effect sizes were 0.75 and 1.18 respectively. There was a small difference between relatives and controls (effect size =0.38). These differences were significant after adjustment for negative and disorganized symptoms, but the effect sizes became smaller: 0.26 for relatives vs. subjects with schizophrenia, 0.56 for controls vs. subjects with schizophrenia and 0.33 for relatives vs. controls. Among individuals with schizophrenia, performance in the LNS was not associated with disorder duration, disease onset age, antipsychotics, history of depressive episodes or substance use disorders. CONCLUSION: Results suggest verbal working memory may be considered as an endophenotype in schizophrenia.

Identifying age- and sex-specific COVID-19 mortality trends over time in six countries.

OBJECTIVES: The COVID-19 pandemic is characterized by successive waves that each developed differently over time and through space. We aim to provide an in-depth analysis of the evolution of COVID-19 mortality during 2020 and 2021 in a selection of countries. METHODS: We focus on five European countries and the United States. Using standardized and age-specific mortality rates, we address variations in COVID-19 mortality within and between countries, and demographic characteristics and seasonality patterns. RESULTS: Our results highlight periods of acceleration and deceleration in the pace of COVID-19 mortality, with substantial differences across countries. Periods of stabilization were identified during summer (especially in 2020) among the European countries analyzed but not in the United States. The latter stands out as the study population with the highest COVID-19 mortality at young ages. In general, COVID-19 mortality is highest at old ages, particularly during winter. Compared with women, men have higher COVID-19 mortality rates at most ages and in most seasons. CONCLUSION: There is seasonality in COVID-19 mortality for both sexes at all ages, characterized by higher rates during winter. In 2021, the highest COVID-19 mortality rates continued to be observed at ages 75+, despite vaccinations having targeted those ages specifically.

Substance Use-Related Cognitive Decline in Families with Autosomal Dominant Alzheimer's Disease: A Cohort Study.

BACKGROUND: Cigarette smoking is a known risk factor for Alzheimer's disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. OBJECTIVE: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. METHODS: A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. RESULTS: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. CONCLUSION: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

[Description of a telehealth mental health programme in the framework of the COVID-19 pandemic in Colombia]. / Descripción de un programa de telesalud mental en el marco de la pandemia de COVID-19 en Colombia.

Background: A telehealth mental health programme was designed at the LivingLab of the Faculty of Medicine of the Universidad de Antioquia [University of Antioquia].Objectives: To describe the development and operation of the programme and evaluate the satisfaction of the patients treated during the COVID-19 pandemic in 2020 and 2021.Methods: Descriptive study that details the development of the programme. Data were extracted from medical records to describe the patients who were treated. A satisfaction scale was applied to a random sample and the data were summarised with descriptive statistics.Results: In March 2020 and August 2021, 10,229 patients were treated, with 20,276 treated by telepsychology and 4,164 by psychiatry, 1,808 by telepsychiatry and 2,356 by tele-expertise, with a total of 6,312 visits. The most frequent diagnoses were depressive (36.8%), anxiety (12.0%), and psychotic (10.7%) disorders. Respondents were satisfied to the point that more than 93% would recommend it to another person.Conclusions: The LivingLab telehealth mental health programme allowed for the care of patients with mental health problems and disorders in Antioquia during the first two years of the COVID-19 pandemic, and there was a high degree of satisfaction among the beneficiaries. Therefore it could be adopted in mental health care.

The demography of COVID-19 deaths database, a gateway to well-documented international data.

National authorities publish COVID-19 death counts, which are extensively re-circulated and compared; but data are generally poorly sourced and documented. Academics and stakeholders need tools to assess data quality and to track data-related discrepancies for comparability over time or across countries. "The Demography of COVID-19 Deaths" database aims at bridging this gap. It provides COVID-19 death counts along with associated documentation, which includes the exact data sources and points out issues of quality and coverage of the data. The database - launched in April 2020 and continuously updated - contains daily cumulative death counts attributable to COVID-19 broken down by sex and age, place and date of occurrence of the death. Data and metadata undergo quality control checks prior to online release. As of mid-December 2021, it covers 21 countries in Europe and beyond. It is open access at a bilingual (English and French) website with content intended for expert users and non-specialists ( https://dc-covid.site.ined.fr/en/ ; figshare: https://doi.org/10.6084/m9.figshare.c.5807027 ). Data and metadata are available for each country separately and pooled over all countries.

Barriers to Access to Palliative Care in Colombia: A Social Mapping Approach Involving Stakeholder Participation.

This study aimed to identify barriers to access to palliative care through a social mapping approach. In Colombia, the barriers to access to palliative care denote an enormous geographic disparity of resources and health needs, making it necessary to conduct community-based participatory research using an approach such as social mapping. A qualitative research design was used. Stakeholders from health insurance companies, regulatory authorities, regional health secretariats, health care professionals, patient and caregiver organizations, scientific societies, and medical journalists from 7 Colombian regions participated. It involved 3 stages. Stage 1: Semi-structured, audio-recorded interviews were conducted with 36 stakeholders and were subsequently transcribed and analyzed. Stage 2: An electronic survey was conducted to obtain feedback on the first outline of the map and the categories that emerged from stage 1. Stage 3: The nominal group technique was used to analyze and validate the barriers to access to palliative care included in the final map. The COREQ checklist was used. Twenty-seven barriers to access to palliative care related to limited availability of medications, stakeholders' poor knowledge of regulations, limited formal education in palliative care, few patients' support networks, patient care fragmentation, few specialized programs of palliative care, and mistaken beliefs about palliative care were identified. Stakeholders' diverse perspectives and opinions were crucial to understanding the development of palliative care in Colombia and its challenges. Better knowledge about palliative care can open opportunities to overcome the barriers identified in this study, directly impacting access to palliative care.

An Integrated View of Virus-Triggered Cellular Plasticity Using Boolean Networks.

Virus-related mortality and morbidity are due to cell/tissue damage caused by replicative pressure and resource exhaustion, e.g., HBV or HIV; exaggerated immune responses, e.g., SARS-CoV-2; and cancer, e.g., EBV or HPV. In this context, oncogenic and other types of viruses drive genetic and epigenetic changes that expand the tumorigenic program, including modifications to the ability of cancer cells to migrate. The best-characterized group of changes is collectively known as the epithelial-mesenchymal transition, or EMT. This is a complex phenomenon classically described using biochemistry, cell biology and genetics. However, these methods require enormous, often slow, efforts to identify and validate novel therapeutic targets. Systems biology can complement and accelerate discoveries in this field. One example of such an approach is Boolean networks, which make complex biological problems tractable by modeling data ("nodes") connected by logical operators. Here, we focus on virus-induced cellular plasticity and cell reprogramming in mammals, and how Boolean networks could provide novel insights into the ability of some viruses to trigger uncontrolled cell proliferation and EMT, two key hallmarks of cancer.

Evidence for a role of the NOS1AP (CAPON) gene in schizophrenia and its clinical dimensions: an association study in a South American population isolate.

BACKGROUND/AIMS: Recent studies have implicated a region on chromosome 1q21-23, including the NOS1AP gene, in susceptibility to schizophrenia. However, replication studies have been inconsistent, a fact that could partly relate to the marked psychopathological heterogeneity of schizophrenia. The aim of this study is to evaluate association of polymorphisms in the NOS1AP gene region to schizophrenia, in patients from a South American population isolate, and to assess if these variants are associated with specific clinical dimensions of the disorder. METHODS: We genotyped 24 densely spaced SNPs in the NOS1AP gene region in a schizophrenia trio sample. The transmission disequilibrium test (TDT) was applied to single marker and haplotype data. Association to clinical dimensions (identified by factor analysis) was evaluated using a quantitative transmission disequilibrium test (QTDT). RESULTS: We found significant association between eight SNPs in the NOS1AP gene region to schizophrenia (minimum p value = 0.004). The QTDT analysis of clinical dimensions revealed an association to a dimension consisting mainly of negative symptoms (minimum p value 0.001). CONCLUSIONS: Our findings are consistent with a role for NOS1AP in susceptibility to schizophrenia, especially for the 'negative syndrome' of the disorder.

Interobserver Variability in Assessing Pathologic Response to Preoperative Treatment in Rectal Cancer: Standardization of an Evaluation Method and Comparisons Between Published Scales.

BACKGROUND: Evaluating tumor response of rectal cancer to preoperative chemoradiotherapy (NCRT) has a prognostic value on overall survival; however, grading tumor response is a controversial issue due to lack of reproducibility and the lack of information about the standardization of the evaluation. METHODS: We performed this study to examine the variability between observers' assessment of the pathological responses to NCRT using a systematic quantitative grading system based on a percentage of tumor response against the proportion of residual tumor burden. As a secondary aim, we classified the tumor response according to six published systems to determine the correlation between the observers into each grading system. RESULTS: From 70 cases, the mean age was 60.6 ± 11.78 years, 36 (51.47%) patients were female, the pathological T stage was pT3 in 48.6% of cases, pT2 in 32.9%, pT1 in 11.4% and 7.1% in pT4, whereas 40% had lymph node metastasis. The median lymph node count was ten lymph nodes (range 6-43). Our method of tumor regression evaluation has a good intraclass correlation (ICC) value. From the scales compared regarding interobserver agreement, the Ryan's and Royal College of Pathologists showed fair agreement (but good ICC); the scales from Dworak, Becker, and Rizk showed substantial agreement (and good to excellent ICC values); and the scale from Rödel showed almost-perfect agreement. RESULTS: All the evaluated systems showed good interobserver agreement, but the best interobserver agreement was reached with the Rödel's scale.

The impact of violence on Venezuelan life expectancy and lifespan inequality.

BACKGROUND: Venezuela is one of the most violent countries in the world. According to the United Nations, homicide rates in the country increased from 32.9 to 61.9 per 100 000 people between 2000 and 2014. This upsurge coincided with a slowdown in life expectancy improvements. We estimate mortality trends and quantify the impact of violence-related deaths and other causes of death on life expectancy and lifespan inequality in Venezuela. METHODS: Life tables were computed with corrected age-specific mortality rates from 1996 to 2013. From these, changes in life expectancy and lifespan inequality were decomposed by age and cause of death using a continuous-change model. Lifespan inequality, or variation in age at death, is measured by the standard deviation of the age-at-death distribution. RESULTS: From 1996 to 2013 in Venezuela, female life expectancy rose 3.57 [95% confidence interval (CI): 3.08-4.09] years [from 75.79 (75.98-76.10) to 79.36 (78.97-79.68)], and lifespan inequality fell 1.03 (-2.96 to 1.26) years [from 18.44 (18.01-19.00) to 17.41 (17.30-18.27)]. Male life expectancy increased 1.64 (1.09-2.25) years [from 69.36 (68.89-59.70) to 71.00 (70.53-71.39)], but lifespan inequality increased 0.95 (-0.80 to 2.89) years [from 20.70 (20.24-21.08) to 21.65 (21.34-22.12)]. If violence-related death rates had not risen over this period, male life expectancy would have increased an additional 1.55 years, and lifespan inequality would have declined slightly (-0.31 years). CONCLUSIONS: As increases in violence-related deaths among young men (ages 15-39) have slowed gains in male life expectancy and increased lifespan inequality, Venezuelan males face more uncertainty about their age at death. There is an urgent need for more accurate mortality estimates in Venezuela.

Trends in infant mortality in Venezuela between 1985 and 2016: a systematic analysis of demographic data.

BACKGROUND: Between the 1950s and 2000, Venezuela showed one of the most substantial improvements in infant mortality rates in Latin America. However, the recent economic crisis alongside an increase in infectious and parasitic diseases might be reversing previous patterns. Because no official updated mortality statistics have been published since 2013, the effect of these recent events has been difficult to assess accurately. We therefore aimed to estimate infant mortality rate trends and report the effect of the crisis. METHODS: We estimated infant mortality rates using direct methods (ie, death counts from Venezuelan Ministry of Health via yearbooks and notifiable diseases bulletins, and birth records published by the UN Economic Commission for Latin America and the Caribbean and the Venezuelan National Institute of Statistics) and indirect methods (using census data and a Living Conditions Survey ENCOVI 2016). We shaped yearly estimations using a semiparametric regression model, specifically a P-Spline model with a cubic thin plate base. The primary objective was to estimate infant mortality rate trends from 1985 to 2016. FINDINGS: Around 2009, the long-term decline in infant mortality rate stopped, and a new pattern of increase was observed. The infant mortality rate reached 21·1 deaths per 1000 livebirths (90% CI -17·8 to 24·3) in 2016, almost 1·4 times the rate of 2008 (15·0, -14·0 to 16·1). This increase represents a huge setback on previous achievements in reducing infant mortality. INTERPRETATION: Our conservative estimation indicates that Venezuela is in the throes of a humanitarian crisis. The increase in infant mortality rate in 2016 compared with 2008 takes the country back to the level observed at the end of the 1990s, wiping out 18 years of expected progress, and leaves the Venezuelan Government far from achieving the target of nine deaths per 1000 livebirths stated in the UN Millennium Development Goals. FUNDING: None.

WITHDRAWN: Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer's Disease.

Ahead of Print article withdrawn by publisher.

Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer's Disease.

BACKGROUND: There are forms of Alzheimer's disease (AD) that have an autosomal dominant inheritance pattern; one of them is caused by the E280A mutation in the gene that codes for Presenilin-1 (PSEN1). Studying families of people with this mutation allows the evaluation of characteristics of the subjects before cognitive decline begins. OBJECTIVE: To determine whether having the mutation E280A in PSEN1 increases the risk of presenting mental disorders in adults under 30 years old who are in the preclinical stage of AD and may be eligible for primary prevention studies of AD. METHODS: A psychiatric evaluation was made to 120 people belonging to families with a history of early onset AD. Of these, 62 carried the E280A mutation in PSEN1. The occurrence of mental disorders between carriers and non-carriers of the mutation was compared. RESULTS: No statistically significant differences were found in the frequency of any mental disorder between the group of carriers and non-carriers of the mutation (Hazard Ratio: 0.80, 95% CI 0.49 to 1.31); nor were differences observed when evaluating specific disorders. CONCLUSION: The E280A mutation does not increase the risk of mental disorders before the age of 30 in the relatives of people affected by familial AD. Studies with larger sample sizes are required to assess the risk of low incidence mental disorders.