The rational modulation of autophagy sensitizes colorectal cancer cells to 5-fluouracil and oxaliplatin.

Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.

Gut mycobiota changes in liver diseases: A systematic review.

Intestinal fungi play an important role in the health-disease process. We observed that in liver diseases, fungal infections lead to high mortality. In this review, we were able to gather and evaluate the available scientific evidence on intestinal mycobiota and liver diseases. We searched PubMed and Embase, using a combination of several entry terms. Only studies in adults ≥ 18 years old with liver disease and published after 2010 were included. We observed that individuals with liver disease have an altered intestinal mycobioma, which accompanies the progression of these diseases. In cirrhotic patients, there are a high number of Candida sp. strains, especially Candida albicans. In early chronic liver disease, there is an increase in alpha diversity at the expense of Candida sp. and conversely, in advanced liver disease, there is a negative correlation between alpha diversity and model for end-stage liver disease score. On the other hand, patients with non-alcoholic fatty liver disease demonstrate greater diversity compared to controls. Our study concluded that the evidence on the subject is sparse, with few studies and a lack of standardization of outcome measures and reporting, and it was not possible to perform a meta-analysis capable of synthesizing relevant parameters of the human mycobiotic profile. However, certain fungal genera such as Candida play an important role in the context of liver disease and that adults with liver disease have a distinct gut mycobiotic profile from healthy controls.

In people with end-stage liver disease, there is a high mortality from fungal infections. In this context, the genus Candida plays an important role in the context of liver disease, and adults with liver disease have a distinct gut mycobiota profile from healthy controls.

Acute-on-chronic liver failure: A comparison of three different diagnostic criteria.

INTRODUCTION AND AIM: Different criteria are applied for the diagnosis of acute-on-chronic liver failure (ACLF). Our aim was to compare the performance of different ACLF diagnostic criteria for predicting mortality. MATERIALS AND METHODS: This was a prospective cohort study of adult cirrhotic patients admitted to a tertiary hospital for acute decompensation (AD) of cirrhosis. The evaluated outcome was mortality at 28 and 90 days, according to the different ACLF diagnostic criteria: Chronic Liver Failure Consortium (CLIF-C), Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD). Prognostic performance was evaluated using receiver operating characteristic (ROC) curves. RESULTS: 146 patients were included. 43 (29.5%) with ACLF according to CLIF-C definition, 14 (9.6%) with ACLF by AARC definition, and 6 (4.1%) by NACSELD definition. According to Kaplan-Meier survival analyses median survival of patients with ACLF by CLIF-C definition was 27.0 days, median survival of patients with ACLF by AARC definition was 27.0 days, and median survival of patients with ACLF by NACSELD definition was 4.0 days. The areas under the ROC curves for performance evaluation in predicting mortality at 28 days for CLIF-C, AARC and NACSELD criteria were, respectively, 0.710, 0.560 and 0.561 (p=0.002). Regarding 90-day mortality, the areas under the ROC curves were 0.760, 0.554 and 0.555 respectively (p<0.001). CONCLUSION: ACLF definition proposed by CLIF-C had better performance in predicting mortality at 28 and 90 days when compared to criteria proposed by AARC and NACSELD.

ALBI and PALBI: Novel Scores for Outcome Prediction of Cirrhotic Outpatients Awaiting Liver Transplantation.

Cirrhosis has four different stages that encompass mild stable compensated cirrhosis, stable cirrhosis with prior decompensation, acutely decompensated cirrhosis and acute-on-chronic liver failure. A worse ALBI score has been associated to an increased mortality in a recent study involving patients with stable cirrhosis and prior decompensation.

The prognostic impact of different stages of acute kidney injury in patients with decompensated cirrhosis: a prospective cohort study.

AIM: To assess the impact of the different stages of acute kidney injury (AKI) on the prognosis of patients hospitalized with decompensated cirrhosis. METHODS: This was a prospective cohort study of consecutive patients admitted in two tertiary hospitals in southern Brazil. Participants were considered eligible if they were admitted for acute decompensation of cirrhosis. The main exposure factor was the onset of AKI. AKI stages were defined according the European recommendations. The outcomes evaluated were survival time and death rates at 28 and 90 days from hospital admission. A χ2 test was used to compare mortality between groups. Kaplan-Meier survival analyses were undertaken assessing time to event as days from AKI diagnosis to death or liver transplant. RESULTS: Two hundred and five patients were included in the study, and 121 met the criteria for AKI. Patients with AKI 1b, AKI 2 and AKI 3 had higher 90-day mortality than patients without AKI (P = 0.008, P < 0.001 and P < 0.001, respectively). However, there was no difference in 90-day mortality when patients with AKI 1a were compared with those without AKI (P = 0.742). The mean survival of patients without AKI was higher than that of patients with AKI 1b (591.4 and 305.4 days, respectively, P = 0.015), while there was no significant difference between the mean survival of patients without AKI and that of patients with AKI 1a (591.4 and 373.6 days, respectively, P = 0.198). CONCLUSION: Only AKI ≥1b seems to substantially impact mortality of patients hospitalized for acute decompensation of cirrhosis.

Performance of the ISAAC questionnaire to establish the prevalence of asthma in adolescents: a population-based study.

BACKGROUND: The epidemiology of asthma has been investigated with questionnaires, such as the International Study of Asthma and Allergies in Childhood protocol. AIM: To investigate the performance of the questions of the International Study of Asthma and Allergies in Childhood questionnaire to diagnose asthma in adolescents. METHODS: This is a population-based cross-sectional study of adolescents in the Syndrome of Obesity and Risk Factors for Cardiovascular Disease study. The validity of the asthma symptoms of the International Study of Asthma and Allergies in Childhood protocol was assessed by calculating sensitivity, specificity, positive and negative posttest probabilities, and Youden's Index, taking as a gold standard the history of a medical diagnosis of asthma. Risk ratios (RRs) and 95% confidence intervals (CIs), adjusting for sex and age, were calculated using Cox regression model. RESULTS: In total, 575 adolescents were investigated. Overall, 28.7% reported a lifetime medical diagnosis of asthma, and 40.0% reported at least one episode of wheezing. Ever wheezing had the highest sensitivity (80.6%) for the diagnosis of asthma, compared with the other ISAAC questions. Adolescents who reported ever wheezing were about 8 times more likely (adjusted RR: 8.3; 95% CI: 4.9-14.2) to have ever had asthma, independent of age and sex. Symptoms within the last 12 months (wheezing, cough without cold or respiratory infection, sleep disturbed due to wheezing, wheezing due to exercise, speech limited due to wheezing) had specificity of 92.0% or higher. Dry cough at night without cold or respiratory infection was the strongest independent predictor of asthma (adjusted RR: 8.8; 95% CI: 6.1-12.7). CONCLUSIONS: Ever wheezing is the most sensitive indicator of the diagnosis of asthma but falsely identifies a portion of adolescents as asthmatic. Symptoms of asthma in the last 12 months, such as cough without cold or respiratory infection, are rarely positive in the absence of a lifetime asthma diagnosis. The combination of ever wheezing for screening and the presence of other symptoms within the past 12 months to confirm the diagnosis could be an effective strategy to identify the prevalence of asthma in communities.

Increasing rational use of cholinesterase inhibitors for Alzheimer's disease in Brazil: public health strategy combining guideline with peer-review of prescriptions.

OBJECTIVES: Since 2002, the treatment with cholinesterase inhibitors (CHEIs) for Alzheimer's disease (AD) has been paid for by the public health system of the Brazilian Ministry of Health for any patient that fulfills clinical criteria established by an evidence-based guideline developed and published by the Ministry. The aim of this study was to evaluate compliance of prescription patterns to the national guideline for use of CHEIs' in the southern Brazilian state of Rio Grande do Sul. METHODS: We created a regional expert-committee reference center to review all prescriptions of CHEIs and to send feedback to physicians whenever prescriptions without compliance to the guideline were noted. One thousand three hundred ninety-nine (1,399) CHEI prescriptions presented to the public health system from 2005 to 2007 were evaluated by an expert team of neurologists and psychiatrists. Clinical history, performance on mental status screening by Mini Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), laboratory results, and neuroimaging findings were evaluated in relation to the adherence to the national guideline's recommendations. If the prescription was rejected because of lack of adherence to the criteria of the guideline, a written response was sent by the expert committee to physicians concerning the request. RESULTS: The majority of the requests (n = 1,044; 75 percent) did not meet the AD guideline's criteria, either for diagnosis or for treatment, and were not granted. A diagnostic mistake was evident in 64.3 percent of cases. Findings of vascular or Parkinson's dementia or severe AD were the main reasons for rejection. Rivastigmine was the most prescribed cholinesterase inhibitor, used in 86 percent of cases. Of note was the reduction in the number of CHEIs prescriptions in the years following this intervention. CONCLUSIONS: The public health strategy of using expert-review of prescriptions and their compliance to national guideline revealed a low rate of rational use of CHEIs for dementia. Such a strategy is relevant for protecting patients from unproven medical interventions and for reducing waste of resources.

Randomized clinical trial of a phytotherapic compound containing Pimpinella anisum, Foeniculum vulgare, Sambucus nigra, and Cassia augustifolia for chronic constipation.

BACKGROUND: A phytotherapic compound containing Pimpinella anisum L., Foeniculum vulgare Miller, Sambucus nigra L., and Cassia augustifolia is largely used in Brazil for the treatment of constipation. However, the laxative efficacy of the compound has never been tested in a randomized clinical trial. The aim of this study was to evaluate the efficacy and safety of the product. METHODS: This randomized, crossover, placebo-controlled, single-blinded trial included 20 patients presenting with chronic constipation according to the criteria of the American Association of Gastroenterology. The order of treatments was counterbalanced across subjects: half of the subjects received the phytotherapic compound for a 5-day period, whereas the other half received placebo for the same period. Both treatment periods were separated by a 9-day washout period followed by the reverse treatment for another 5-day period. The primary endpoint was colonic transit time (CTT), measured radiologically. Secondary endpoints included number of evacuations per day, perception of bowel function, adverse effects, and quality of life. RESULTS: Mean CTT assessed by X ray was 15.7 hours (95%CI 11.1-20.2) in the active treatment period and 42.3 hours (95%CI 33.5-51.1) during the placebo treatment (p < 0.001). Number of evacuations per day increased during the use of active tea; significant differences were observed as of the second day of treatment (p < 0.001). Patient perception of bowel function was improved (p < 0.01), but quality of life did not show significant differences among the study periods. Except for a small reduction in serum potassium levels during the active treatment, no significant differences were observed in terms of adverse effects throughout the study period. CONCLUSIONS: The findings of this randomized controlled trial allow to conclude that the phytotherapic compound assessed has laxative efficacy and is a safe alternative option for the treatment of constipation. TRIAL REGISTRATION: ClinicalTrial.gov NCT00872430.

Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives.

BACKGROUND: Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today's clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. SUMMARY: Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

Coronavirus disease 2019 population-based prevalence, risk factors, hospitalization, and fatality rates in southern Brazil.

OBJECTIVES: To assess population-based prevalence, risk factors, hospitalization, and infection fatality rates (IFR) associated with COVID-19. METHODS: We conducted two household surveys among the non-institutionalized adult population from May 30 to June 17, 2020, in Lajeado, an 84,000-inhabitant industrial city in southern Brazil. Primary outcome was prevalence of SARS-CoV-2 infection. Secondary outcomes were COVID-19-related hospitalizations and deaths occurring up to June 20, 2020. We summarized prevalence rates across surveys with meta-analysis. We assessed age-range IFR and hospitalization rate and regressed these rates over age strata using nonlinear (exponential) coefficients of determination (R2). RESULTS: Summarized overall prevalence was 3.40% (95% CI, 2.74-4.18), 34% lower in older adults ≥60 years. Prevalence was 14.3 and 5.4 times higher among household contacts and meat-precessing plant (MPP) workers, respectively. IFR ranged from 0.08% (0.06-0.11) to 4.63% (2.93-7.84) in individuals 20-39 years and ≥60 years, respectively. R2 for hospitalization rate and IFR over age were 0.98 and 0.93 (both p-values <0.0001), respectively. CONCLUSIONS: This is the first population-based study in Brazil to estimate COVID-19 prevalence, hospitalization, and fatality rates per age stratum. Rates were largely age-dependent. Household contacts and MPP workers are at higher risk of infection. Our findings are valuable for health-policy making and resource allocation to mitigate the pandemic.

Hypertension Management in Brazil: Usual Practice in Primary Care-A Meta-Analysis.

Knowing the usual clinical practice is relevant for evaluations in health care and economic policies of management of hypertension. This study aimed to describe the usual management of hypertension in the Brazilian primary healthcare system through a systematic review and meta-analysis. The search of population-based studies conducted in Brazil was undertaken using PubMed, EMBASE, and Brazilian databases. Eligible studies were those conducted in adults with hypertension (blood pressure (BP) ≥ 140/90 mmHg or using BP lowering drugs). Three datasets' data were analyzed: SESI study (in Brazilian workers); HIPERDIA (Brazilian Registration and Monitoring of Hypertensive and Diabetic Patients Program); and a population-based study. Meta-analysis has been performed using the fixed and random effect models. A total of 11 studies or data sets were included in the systematic review. Hypertensive individuals had, on average, 2.6 medical visits annually and 18.2% were on diuretics (n = 811 hypertensive patients) and 16.2% on ACE inhibitors (n = 1768 hypertensive patients). BP control rate ranged from 43.7 to 67.5%; 35.5% had measured total cholesterol and 36.5% determined fasting plasma glucose in the previous 12 months. Thiazide diuretics and ACE inhibitors were the most used BP lowering medications as single drugs, but the control rate of hypertension is insufficient.

Prevalence of hypertension among elderly persons in urban Brazil: a systematic review with meta-analysis.

BACKGROUND: The prevalence of hypertension among elderly persons has been assessed in several circumscribed studies scattered across Brazil, and no representative data about this exist for the whole country. In this meta-analysis with a systematic review of the literature, we provide a summary estimate of hypertension among elderly persons in Brazil and present the trend in prevalence of the condition from 1980 to 2010. METHODS: Population-based prevalence studies carried out between 1980 and 2010 were identified by two independent reviewers, without language restrictions, in electronic databases. For PubMed searches we used the following Mesh Terms: "Aged"[Majr] AND "Hypertension" AND "Prevalence" AND "Brazil." Elderly individuals were defined as being ≥ 60 or ≥ 65 years of age, depending on the cutoff age of the relevant study. Hypertension was defined as the use of antihypertensive medication or as a seated blood pressure ≥ 140/90mm Hg, in accord with the criteria of the Joint National Committee (JNC) on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure of the U.S. National Heart, Lung and Blood Institute. The prevalence of self-reported hypertension, assessed by household surveys and through telephone inquiries, was also evaluated. Prevalence estimates were calculated with a random-effects model. RESULTS: On the basis of the screening process, we selected 16 studies for meta-analysis, comprising 13,978 individuals. The prevalence of hypertension for the period from 1980 to 2010, according to the JNC criteria, was 68.0% (95% CI, 65.1%-69.4%). In the 2000s, the prevalence of hypertension according to the same criteria was 68.9% (95% CI, 64.1%-73.3%), whereas the self-reported prevalence based on household surveys was 49.0% (95% CI, 46.8%-51.2%) and the prevalence based on telephone surveys was 53.8% (95% CI, 44.8%-62.6%). CONCLUSIONS: The prevalence of hypertension is high among elderly persons in Brazil, and there is considerable underestimation of the prevalence of the disease through self-reported estimates.

Trends in prevalence of hypertension in Brazil: a systematic review with meta-analysis.

BACKGROUND: The prevalence of hypertension in emerging nations was scarcely described to date. In Brazil, many population-based surveys evaluated the prevalence in cities throughout the country. However, there is no population-based nationwide study of prevalence of hypertension. In this study, we estimated the prevalence of hypertension for the country and analyzed the trends for the last three decades. METHODS: Cross-sectional and cohort studies conducted from 1980 to 2010 were independently identified by two reviewers, without language restriction, in the PubMed, Embase, LILACS, and Scielo electronic databases. Unpublished studies were identified in the Brazilian electronic database of theses and in annals of Cardiology congresses and meetings. In total, 40 studies were selected, comprising 122,018 individuals. RESULTS: Summary estimates of prevalence by the former WHO criteria (BP≥160/95 mmHg) in the 1980's and 1990's were 23.6% (95% CI 17.3-31.4%) and 19.6% (16.4-23.3%) respectively. The prevalence of hypertension by the JNC criteria (BP≥140/90 mmHg) in the 1980's, 1990's and 2000's were 36.1% (95% CI 28.7-44.2%), 32.9% (29.9-36.0%), and 28.7% (26.2-31.4%), respectively (P<0.001). In the 2000's, the pooled prevalence estimates of self-reported hypertension on telephone inquiries was 20.6% (19.0-22.4%), and of self-reported hypertension in home surveys was 25.2% (23.3-27.2%). CONCLUSIONS: The prevalence of hypertension in Brazil seems to have diminished 6% in the last three decades, but it still is approximately 30%. Nationwide surveys by self-reporting by telephone interviews underestimate the real prevalence. Rates of blood pressure control decreased in the same period, corresponding currently to only one quarter of individuals with hypertension.

Cardiovascular risk attributable to diabetes in southern Brazil: a population-based cohort study.

OBJECTIVE: To analyze the effect of diabetes on general and cardiovascular disease (CVD) mortality and morbidity in southern Brazil. RESEARCH DESIGN AND METHODS: A population-based cohort study of 1,091 individuals was conducted. Diabetes was ascertained by medical history. The vital status of 982 individuals and the incidence of events were ascertained during another visit and through hospital records, death certificates, and verbal necropsy with relatives. RESULTS: The mean +/- SD age of participants was 43.1 +/- 17 years, and 55.7% were women. The prevalence of diabetes was 4.2%, and the mean follow-up time was 5.3 +/- 0.07 years. Mortality was 36.3% and 6.6% in participants with or without diabetes, respectively; the incidence of CVD was 20.8% and 3.0%, with an adjusted hazard ratio of 4.4 (95% CI 2.4-7.9). Diabetic population-attributable risk (PAR) for CVD mortality was 10.1% and 13.1% for total CVD. CONCLUSIONS: Diabetes is responsible for a large PAR for overall mortality and cardiovascular events in Brazil.