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Brainstem astrocytes are important for CO 2 / H + chemoreception. Lateral Hypothalamus/Perifornicial Area (LH/PFA) neurons have an excitatory effect on the ventilatory response to CO 2 , however the role of the astrocytes is unknown. We hypothesized that LH/PFA astrocytes play an excitatory role in the hypercapnic ventilatory response in a sleep-wake and light-dark cycles-dependent manner. We manipulated the activity of astrocytes in the LH/PFA of male Wistar rats through microinjection of Fluorocitrate (Fct), which selectively affects astrocytes, inducing the exocytosis of gliotransmitters. We investigated the effects of intra-LH/PFA Fct microinjection on resting breathing and ventilatory responses to hypercapnia and hypoxia during wakefulness and NREM sleep, in the light and dark phases. Fct increased ventilation during hypercapnia but not during room air or hypoxia. The hypercapnic chemoreflex was increased exclusively during the dark-active phase during both, wakefulness and NREM sleep, indicating that LH/PFA astrocytes play an excitatory role in hypercapnic ventilatory response in a light-dark cycle-dependent manner., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell's invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure., (© 2023. The Author(s).)

This investigation aimed to assess the physiological parameters and quality of milk and fresh cheeses produced by cows that were housed in paddocks, either with or without shade, and supplemented with a phytogenic additive. Sixteen crossbred cows were allocated in a 4 × 4 Latin square design, dividing them into paddocks with or without shade, and providing or not providing a phytogenic additive in their feed. This resulted in a total of four treatment groups and sixteen experimental plots, each containing four animals, over four periods of 21 days. Various parameters were examined, including haematology, rectal and skin temperature, respiratory rate, milk yield and composition, serum parameters, and cheese yield and quality. It is worth noting that the temperature and humidity, as measured by a black globe thermometer, did not display significant variations between the different environments and exhibited minimal fluctuations throughout the day. Additionally, the supplementation of the phytogenic additive led to a reduction in haematocrit levels ( p = 0.011). Furthermore, the analysis showed that whey obtained from cheese production had a higher fat content when cows were without access to shade ( p = 0.005). Notably, there was an interaction between factors in relation to the total dry extract content, which was lower when cows had access to shade and received the additive ( p = 0.010). In summary, the provision of a phytogenic additive and the presence or absence of shade did not bring about significant changes in milk production and quality or in the yield and quality of fresh cheese.

Congenital heart disease (CHD) is the leading cause of death from malformations in the first year of life and carries a significant burden to the family when the diagnosis is made in the prenatal period. We recognize the significance of family counseling following a fetal CHD diagnosis. However, we have observed that most research focuses on assessing the emotional state of family members rather than examining the counseling process itself. The objective of this study was to identify and summarize the findings in the literature on family counseling in cases of diagnosis of CHD during pregnancy, demonstrating gaps and suggesting future research on this topic. Eight databases were searched to review the literature on family counseling in cases of CHD diagnosis during pregnancy. A systematic search was conducted from September to October 2022. The descriptors were "congenital heart disease", "fetal heart", and "family counseling". The inclusion criteria were studies on counseling family members who received a diagnosis of CHD in the fetus (family counseling was defined as any health professional who advises mothers and fathers on the diagnosis of CHD during the gestational period), how the news is expressed to family members (including an explanation of CHD and questions about management and prognosis), empirical and qualitative studies, quantitative studies, no publication deadline, and any language. Out of the initial search of 3719 reports, 21 articles were included. Most were cross-sectional (11) and qualitative (9) studies, and all were from developed countries. The findings in the literature address the difficulties in effectively conducting family counseling, the strengths of family counseling to be effective, opportunities to generate effective counseling, and the main challenges in family counseling.

Artificial Intelligence (AI) is increasingly influential across various sectors, including healthcare, with the potential to revolutionize clinical practice. However, risks associated with AI adoption in medicine have also been identified. Despite the general understanding that AI will impact healthcare, studies that assess the perceptions of medical doctors about AI use in medicine are still scarce. We set out to survey the medical doctors licensed to practice medicine in Portugal about the impact, advantages, and disadvantages of AI adoption in clinical practice. We designed an observational, descriptive, cross-sectional study with a quantitative approach and developed an online survey which addressed the following aspects: impact on healthcare quality of the extraction and processing of health data via AI; delegation of clinical procedures on AI tools; perception of the impact of AI in clinical practice; perceived advantages of using AI in clinical practice; perceived disadvantages of using AI in clinical practice and predisposition to adopt AI in professional activity. Our sample was also subject to demographic, professional and digital use and proficiency characterization. We obtained 1013 valid, fully answered questionnaires (sample representativeness of 99%, confidence level (p< 0.01), for the total universe of medical doctors licensed to practice in Portugal). Our results reveal that, in general terms, the medical community surveyed is optimistic about AI use in medicine and are predisposed to adopt it while still aware of some disadvantages and challenges to AI use in healthcare. Most medical doctors surveyed are also convinced that AI should be part of medical formation. These findings contribute to facilitating the professional integration of AI in medical practice in Portugal, aiding the seamless integration of AI into clinical workflows by leveraging its perceived strengths according to healthcare professionals. This study identifies challenges such as gaps in medical curricula, which hinder the adoption of AI applications due to inadequate digital health training. Due to high professional integration in the healthcare sector, particularly within the European Union, our results are also relevant for other jurisdictions and across diverse healthcare systems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pedro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Cognitive impairment is common after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, associations between post-hospital discharge risk factors and cognitive trajectories have not been explored., Methods: A total of 1105 adults (mean age ± SD 64.9 ± 9.9 years, 44% women, 63% White) with severe coronavirus disease 2019 (COVID-19) were evaluated for cognitive function 1 year after hospital discharge. Scores from cognitive tests were harmonized, and clusters of cognitive impairment were defined using sequential analysis., Results: Three groups of cognitive trajectories were observed during the follow-up: no cognitive impairment, initial short-term cognitive impairment, and long-term cognitive impairment. Predictors of cognitive decline after COVID-19 were older age (β = -0.013, 95% CI = -0.023;-0.003), female sex (β = -0.230, 95% CI = -0.413;-0.047), previous dementia diagnosis or substantial memory complaints (β = -0.606, 95% CI = -0.877;-0.335), frailty before hospitalization (β = -0.191, 95% CI = -0.264;-0.119), higher platelet count (β = -0.101, 95% CI = -0.185;-0.018), and delirium (β = -0.483, 95% CI = -0.724;-0.244). Post-discharge predictors included hospital readmissions and frailty., Discussion: Cognitive impairment was common and the patterns of cognitive trajectories depended on sociodemographic, in-hospital, and post-hospitalization predictors., Highlights: Cognitive impairment after coronavirus disease 2019 (COVID-19) hospital discharge was associated with higher age, less education, delirium during hospitalization, a higher number of hospitalizations post discharge, and frailty before and after hospitalization. Frequent cognitive evaluations for 12-month post-COVID-19 hospitalization showed three possible cognitive trajectories: no cognitive impairment, initial short-term impairment, and long-term impairment. This study highlights the importance of frequent cognitive testing to determine patterns of COVID-19 cognitive impairment, given the high frequency of incident cognitive impairment 1 year after hospitalization., (© 2023 the Alzheimer's Association.)

Heart failure is a prevalent condition and a frequent cause of hospital readmissions and poor quality of life. Teleconsultation support from cardiologists to primary care physicians managing patients with heart failure may improve care, but the effect on patient-relevant outcomes is unclear. We aim to evaluate whether collaboration through a novel teleconsultation platform in the Brazilian Heart Insufficiency with Telemedicine (BRAHIT) project, tested on a previous feasibility study, can improve patient-relevant outcomes. We will conduct a parallel-group, two-arm, cluster-randomised superiority trial with a 1:1 allocation ratio, with primary care practices from Rio de Janeiro as clusters. Physicians from the intervention group practices will receive teleconsultation support from a cardiologist to assist patients discharged from hospitals after admission for heart failure. In contrast, physicians from the control group practices will perform usual care. We will include 10 patients per each of the 80 enrolled practices (n = 800). The primary outcome will be a composite of mortality and hospital admissions after six months. Secondary outcomes will be adverse events, symptoms frequency, quality of life, and primary care physicians' compliance with treatment guidelines. We hypothesise that teleconsulting support will improve patient outcomes.

Rationale: Recent reports suggest that patients with severe coronavirus disease (COVID-19) often experience long-term consequences of the infection. However, studies on intensive care unit (ICU) survivors are underrepresented. Objectives: We aimed to explore 12-month clinical outcomes after critical COVID-19, describing the longitudinal progress of disabilities, frailty status, frequency of cognitive impairment, and clinical events (rehospitalization, institutionalization, and falls). Methods: We performed a prospective cohort study of survivors of COVID-19 ICU admissions in Sao Paulo, Brazil. We assessed patients every 3 months for 1 year after hospital discharge and obtained information on 15 activities of daily living (basic, instrumental, and mobility activities), frailty, cognition, and clinical events. Results: We included 428 patients (mean age of 64 yr, 61% required invasive mechanical ventilation during ICU stay). The number of disabilities peaked at 3 months compared with the pre-COVID-19 period (mean difference, 2.46; 99% confidence interval, 1.94-2.99) and then decreased at 12 months (mean difference, 0.67; 99% confidence interval, 0.28-1.07). At 12-month follow-up, 12% of patients were frail, but half of them presented frailty only after COVID-19. The prevalence of cognitive symptoms was 17% at 3 months and progressively decreased to 12.1% ( P  = 0.012 for trend) at the end of 1 year. Clinical events occurred in all assessments. Conclusions: Although a higher burden of disabilities and cognitive symptoms occurred 3 months after hospital discharge of critical COVID-19 survivors, a significant improvement occurred during the 1-year follow-up. However, one-third of the patients remained in worse conditions than their pre-COVID-19 status.

Objectives: We investigated functional trajectories after severe COVID-19 and estimated their associations with adverse outcomes (falls, rehospitalizations, institutionalization, or death), cognition and post COVID-19 condition within 1-year of hospital discharge., Design: Prospective cohort study., Setting: A large academic medical center in Sao Paulo, Brazil., Participants: Survivors of COVID-19 admissions to an intensive care unit., Interventions: None., Measurements: We evaluated participants' disability status before hospital admission and three, six, nine, and twelve months after discharge using 15 activities of daily living. During follow-up, cognition and post COVID-19 condition (defined as persistent symptoms with duration ≥2 months) were assessed. A latent class growth analysis was performed to investigate functional trajectories after discharge., Results: We included 422 participants (median age 63 years, 13.5% were frail before COVID-19). Four distinct functional trajectories could be identified: "minimal disability trajectory" (37.4% of participants), "mild disability trajectory" (37.9%), "moderate disability trajectory" (16.8%), and "severe disability trajectory" (7.8%). Compared with minimal disability trajectory, the odds ratios (95% confidence interval) for 1-year adverse outcomes were 2.28 (1.38-3.76) for minor disability trajectory; 4.21 (2.10-8.42) for moderate disability trajectory; and 4.16 (1.51-11.46) for severe disability trajectory, even after adjustments. The occurrence of post COVID-19 condition was 67.5% and associated with functional trajectories (p=0.004). Cognition was also associated with functional trajectories., Conclusion: Severe COVID-19 survivors can experience diverse functional trajectories, with those presenting higher levels of disability at increased risk for long-term adverse outcomes. Further investigations are essential to confirm our findings and assess the effectiveness of rehabilitation interventions, aiming to improve health outcomes in those who survived severe COVID-19 and other causes of sepsis., Competing Interests: The authors have no conflict of interest to declare or disclosure.

Orexinergic (OX) neurons in the lateral hypothalamus (LH), perifornical area (PFA) and dorsomedial hypothalamus (DMH) play a role in the hypercapnic ventilatory response, presumably through direct inputs to central pattern generator sites and/or through interactions with other chemosensitive regions. OX neurons can produce and release orexins, excitatory neuropeptides involved in many functions, including physiological responses to changes in CO 2 /pH. Thus, in the present study, we tested the hypothesis that different nuclei (LH, PFA and DMH) where the orexinergic neurons are located, show distinct activation by CO 2 during the light-dark cycle phases. For this purpose, we evaluated the Fos and OXA expression by immunohistochemistry to identify neurons that co-localize Fos + OXA in the LH, LPeF, MPeF and DMH in the light-inactive and dark-active phase in Wistar rats subjected to 3 h of normocapnia or hypercapnia (7% CO 2 ). Quantitative analyses of immunoreactive neurons show that hypercapnia caused an increase in the number of neurons expressing Fos in the LH, LPeF, MPeF and DMH in the light and dark phases. In addition, the number of Fos + OXA neurons increased in the LPeF and DMH independently of the phases of the diurnal cycle; whereas in the MPeF, this increase was observed exclusively in the light phase. Thus, we suggest that OX neurons are selectively activated by hypercapnia throughout the diurnal cycle, reinforcing the differential role of nuclei in the hypothalamus during central chemosensitivity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: As the pandemic advances, the interest in the long-lasting consequences of COVID-19 increases. However, a few studies have explored patient-centered outcomes in critical care survivors. We aimed to investigate frailty and disability transitions in COVID-19 patients admitted to ICUs., Design: Prospective cohort study., Setting: University hospital in Sao Paulo., Patients: Survivors of COVID-19 ICU admissions., Interventions: None., Measurements and Main Results: We assessed frailty using the Clinical Frailty Scale (CFS). We also evaluated 15 basic, instrumental, and mobility activities. Baseline frailty and disability were defined by clinical conditions 2-4 weeks before COVID-19, and post-COVID-19 was characterized 90 days (day 90) after hospital discharge. We used alluvial flow diagrams to visualize transitions in frailty status, Venn diagrams to describe the overlap between frailty and disabilities in activities of daily living, and linear mixed models to explore the occurrence of new disabilities following critical care in COVID-19. We included 428 participants with a mean age of 64 years, 57% males, and a median Simplified Acute Physiology Score-3 score of 59. Overall, 14% were frail at baseline. We found that 124/394 participants (31%) were frail at day 90, 70% of whom were previously non-frail. The number of disabilities also increased (mean difference, 2.46; 95% CI, 2.06-2.86), mainly in participants who were non-frail before COVID-19. Higher pre-COVID-19 CFS scores were independently associated with new-onset disabilities. At day 90, 135 patients (34%) were either frail or disabled., Conclusions: Frailty and disability were more frequent 90 days after hospital discharge compared with baseline in COVID-19 patients admitted to the ICU. Our results show that most COVID-19 critical care survivors transition to poorer health status, highlighting the importance of long-term medical follow-up for this population., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Few studies have explored the effect of frailty on the long-term survival of COVID-19 patients after ICU admission. Furthermore, the Clinical Frailty Scale (CFS) validity in critical care patients remains debated. We investigated the association between frailty and 6-month survival in critically ill COVID-19 patients. We also explored whether ICU resource utilization varied according to frailty status and examined the concurrent validity of the CFS in this setting., Design: Ancillary study of a longitudinal prospective cohort., Setting: University hospital in São Paulo., Patients: Patients with severe COVID-19 admitted to ICU., Interventions: None., Measurements and Main Results: We assessed baseline frailty using the CFS (1-9; frail ≥ 5) and used validated procedures to compute a Frailty Index (0-1; frail > 0.25). We used Cox models to estimate associations of frailty status with 6-month survival after ICU admission and area under the receiver operating characteristic curves (AUCs) to estimate CFS's accuracy in identifying frailty according to Frailty Index. We included 1,028 patients (mean age, 66 yr; male, 61%). Overall, 224 (22%) patients were frail (CFS ≥ 5), and 608 (59%) died over the 6-month follow-up. Frailty was independently associated with lower 6-month survival and further stratified mortality in patients with similar age and Sequential Organ Failure Assessment scores. We additionally verified that the CFS was highly accurate in identifying frailty as defined by the Frailty Index (AUC, 0.91; 95% CI, 0.89-0.93). Although treatment modalities did not diverge according to frailty status, higher CFS scores were associated with withholding organ support due to refractory organ failure., Conclusions: One in five COVID-19 patients admitted to the ICU was frail. CFS scores greater than or equal to 5 were associated with lower long-term survival and decisions on withholding further escalation of invasive support for multiple organ failure in the ICU. Clinicians should consider frailty alongside sociodemographic and clinical measures to have a fuller picture of COVID-19 prognosis in critical care., Competing Interests: Dr. Aliberti is supported by a scholarship from Hospital das Clinicas, University of São Paulo Medical School, with funds donated by NUBANK under the #HCCOMVIDA scheme. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Menopausal transition is a physiological process encompassing hormonal and body changes that impact women's health and life quality. This period may be characterized by the Stages of Reproductive Aging Workshop (STRAW + 10) criteria using menstrual patterns. Use of the STRAW + 10 is uncertain in HIV infection. We aimed to characterize menopausal transition in women with HIV (WWH) using the STRAW + 10 criteria, hormonal measures and menopause symptoms., Methods: We performed a cross-sectional study, nested to the HIV-Infected Women's Cohort, in Rio de Janeiro, Brazil. Eligible women included those aged 30 years or older, without clinical or surgical menopause, hormonal contraception, replacement therapy and ovarian disorders. We conducted face-to-face interviews and collected blood samples for follicle stimulating hormone (FSH) and estradiol measures., Results: We enrolled 328 WWH (28.3% of women in the cohort). The distribution of age, hormonal levels and reported symptoms per each STRAW + 10 stage was consistent with the expected distribution in the menopausal transition. Age and FSH significantly increased and estradiol decreased from stage -2 (7 + days of menstrual delay) to stage +2 (8 + years of amenorrhea)., Conclusions: The present results support use of the STRAW + 10 to characterize the menopausal transition of WWH with good clinical and immunological control.

Background: Frailty screening using the Clinical Frailty Scale (CFS) has been proposed to guide resource allocation in acute care settings during the pandemic. However, the association between frailty and coronavirus disease 2019 (COVID-19) prognosis remains unclear., Objectives: To investigate the association between frailty and mortality over 6 months in middle-aged and older patients hospitalized with COVID-19 and the association between acute morbidity severity and mortality across frailty strata., Design: Observational cohort study., Setting: Large academic medical center in Brazil., Participants: A total of 1830 patients aged ≥50 years hospitalized with COVID-19 (March-July 2020)., Measurements: We screened baseline frailty using the CFS (1-9) and classified patients as fit to managing well (1-3), vulnerable (4), mildly (5), moderately (6), or severely frail to terminally ill (7-9). We also computed a frailty index (0-1; frail >0.25), a well-known frailty measure. We used Cox proportional hazards models to estimate the association between frailty and time to death within 30 days and 6 months of admission. We also examined whether frailty identified different mortality risk levels within strata of similar age and acute morbidity as measured by the Sequential Organ Failure Assessment (SOFA) score., Results: Median age was 66 years, 58% were male, and 27% were frail to some degree. Compared with fit-to-managing-well patients, the adjusted hazard ratios (95% confidence interval [CI]) for 30-day and 6-month mortality were, respectively, 1.4 (1.1-1.7) and 1.4 (1.1-1.7) for vulnerable patients; 1.5 (1.1-1.9) and 1.5 (1.1-1.8) for mild frailty; 1.8 (1.4-2.3) and 1.9 (1.5-2.4) for moderate frailty; and 2.1 (1.6-2.7) and 2.3 (1.8-2.9) for severe frailty to terminally ill. The CFS achieved outstanding accuracy to identify frailty compared with the Frailty Index (area under the curve = 0.94; 95% CI = 0.93-0.95) and predicted different mortality risks within age and acute morbidity groups., Conclusions: Our results encourage the use of frailty, alongside measures of acute morbidity, to guide clinicians in prognostication and resource allocation in hospitalized patients with COVID-19., (© 2021 The American Geriatrics Society.)

Background: Although frailty has been associated with atypical manifestations of infections, little is known about COVID-19 presentations in hospitalized frail patients. We aimed to investigate the association between age, frailty, and clinical characteristics of COVID-19 in hospitalized middle-aged and older adults., Method: Longitudinal observational study comprising 711 patients aged ≥50 years consecutively admitted to a university hospital dedicated to COVID-19 severe cases, between March and May 2020. We reviewed electronic medical records to collect data on demographics, comorbidities, COVID-19 signs/symptoms, and laboratory findings on admission. We defined frailty using the Clinical Frailty Scale (CFS = 1-9; frail ≥5). We also documented in-hospital mortality. We used logistic regressions to explore associations between age, frailty, and COVID-19 signs/symptoms; and between typical symptoms (fever, cough, dyspnea) and mortality., Results: Participants had a mean age of 66 ± 11 years, and 43% were female. Overall, 25% were frail, and 37% died. The most common COVID-19 presentations were dyspnea (79%), cough (74%), and fever (62%), but patients aged ≥65 years were less likely to have a co-occurrence of typical symptoms, both in the absence (OR = 0.56; 95% CI = 0.39-0.79) and in the presence of frailty (OR = 0.52; 95% CI = 0.34-0.81). In contrast, older age and frailty were associated with unspecific presentations, including functional decline, acute mental change, and hypotension. After adjusting for age, sex, and frailty, reporting fever was associated with lower odds of mortality (OR = 0.70; 95% CI = 0.50-0.97)., Conclusions: Atypical COVID-19 presentations are common in frail and older hospitalized patients. Providers should be aware of unspecific disease manifestations during the management and follow-up of this population., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although coronavirus disease 2019 (COVID-19) disproportionally affects older adults, the use of conventional triage tools in acute care settings ignores the key aspects of vulnerability., Objective: This study aimed to determine the usefulness of adding a rapid vulnerability screening to an illness acuity tool to predict mortality in hospitalised COVID-19 patients., Design: Cohort study., Setting: Large university hospital dedicated to providing COVID-19 care., Participants: Participants included are 1,428 consecutive inpatients aged ≥50 years., Methods: Vulnerability was assessed using the modified version of PRO-AGE score (0-7; higher = worse), a validated and easy-to-administer tool that rates physical impairment, recent hospitalisation, acute mental change, weight loss and fatigue. The baseline covariates included age, sex, Charlson comorbidity score and the National Early Warning Score (NEWS), a well-known illness acuity tool. Our outcome was time-to-death within 60 days of admission., Results: The patients had a median age of 66 years, and 58% were male. The incidence of 60-day mortality ranged from 22% to 69% across the quartiles of modified PRO-AGE. In adjusted analysis, compared with modified PRO-AGE scores 0-1 ('lowest quartile'), the hazard ratios (95% confidence interval) for 60-day mortality for modified PRO-AGE scores 2-3, 4 and 5-7 were 1.4 (1.1-1.9), 2.0 (1.5-2.7) and 2.8 (2.1-3.8), respectively. The modified PRO-AGE predicted different mortality risk levels within each stratum of NEWS and improved the discrimination of mortality prediction models., Conclusions: Adding vulnerability to illness acuity improved accuracy of predicting mortality in hospitalised COVID-19 patients. Combining tools such as PRO-AGE and NEWS may help stratify the risk of mortality from COVID-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cervical cancer (CC) is a common preventable and curable disease that may lead to death. Our aim was to describe the patterns of time trends in CC mortality rates among women in Brazil from 1980 to 2017, and identify the influence of age, period and birth cohort (APC) stratified by region (North NR, Northeast NER, Southeast SER, South SR, Center-Western region CWR)., Methods: We performed a time-series analysis using secondary data bases. Crude (MR) and WHO age-standardized CC mortality rates (aMR) were estimated per 100,000 women. We evaluated time trends using permutation joinpoint regression models (JP) and APC models to estimate the effect of APC on MR., Results: The JP analysis showed a temporal decrease in all regions, except the NR, which had an annual percentage increase of 0.44 (95%CI 0.2 - 0.7). MR in the NR was 2 to 4 times higher than in the other regions. We observed steady increases in MR with age in the NR and NER. A plateau after age 40 was observed in SER, SR, and CWR. The NR and NER MR ratio stabilized around the year 2000. Birth cohort effect showed decreasing MR ratio from 1900 to 1970 for all regions, except the NR, which showed increasing MR rate from older to more recent cohorts., Conclusion: We showed relevant differences in cervical MR by region, which may reflect inequality in access to primary and secondary prevention as well as treatment, particularly in the NR., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To analyze characteristics, enrollments and completion rates of healthcare professionals enrolled in Self-Instructional Online Courses of the Home Health Care Multicentre Qualification Program, developed by the Ministry of Health and the Universidade Aberta do SUS (UNASUS), and its relationship with Home Health Care Teams implementation., Methods: Data were extracted from the Self-Instructional Online Courses' UNASUS enrollment platform database (2012-2018), cross-referenced with the Health Facilities' National Database and compared to Home Care General Coordination team's database. Main outcomes were completion rates and number of courses enrollments, analyzed by sex, age, region, location, profession, workplace, health teams and course type., Results: Men applied to courses slightly more than women and completion rates were higher (37.1 vs 30.5, p < 0.001); there was a small decline in completion rates by age groups (from 32.8% in 18-29 yr to 31.1% in 46-50 yr age group, p < 0.001) and a rise in course enrollment number, probably related to progressively "digital native" generations. Self-Instructional Online Courses were attended in all Brazilian states and reached all municipality sizes, with completion rates rising from 29.9% in the North to 37.3 in the South; 30-hour courses were completed by almost twice as many professionals as 45-hour and 60-hour courses, suggesting that modularity may improve completion rates. State distribution and national coverage suggest adequate range and coincidence between enrollment and Home Health Care Teams distribution., Conclusions: Regional aspects influence professional interaction with courses; the feminization of health professions and women's lower completion rates suggest the need for a deeper gender perspective in health facilities and training services. Self- Instructional Online Courses for Home Health Care were an important outreach strategy, with professional's doubts answered more contextually.

The Lateral Hypothalamus/Perifornical Area (LH/PFA) has been shown to be involved with the hypercapnic ventilatory response, in a state-dependent manner. We have demonstrated that purinergic signaling through ATP in the LH/PFA has an excitatory effect in ventilatory response to CO 2 in awake rats in the dark phase of the diurnal cycle, but it is unknown whether the ATP metabolite adenosine, acting in the LH/PFA, modulates the ventilatory responses to hypercapnia. Here, we studied the effects of the microdialysis of adenosine (A1/A2 adenosine receptors agonist; 17 mM) and an A1 receptor antagonist (DPCPX; 0.1 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO 2 during the light and the dark phases of the diurnal cycle. The microdialysis of adenosine and DPCPX caused no change in the CO 2 ventilatory responses of rats during wakefulness or NREM sleep in either the dark or light period. Our data suggest that adenosine in the LH/PFA does not contribute to the hypercapnic ventilatory response in conscious rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been shown that the lateral hypothalamus/perifornical area (LH/PFA) exerts an important role on arousal-state variations of the central chemoreflex, but the mechanisms that underlie LH/PFA chemoreception are poorly understood. Here we asked whether glutamate inputs on metabotropic receptors in the LH/PFA modulate the hypercapnic ventilatory response. We studied the effects of microinjection of a glutamate metabotropic receptor (mGluR) antagonist ((+)-α-Methyl-4-carboxyphenylglycine; MCPG; 100 mM) and a selective Group II/III mGluR antagonist ((2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; LY341495; 5 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO 2 , during wakefulness and sleep, in the dark and light periods of the diurnal cycle. Microinjection of MCPG and LY341495 increased the hypercapnic ventilatory response in both the light and the dark period during wakefulness, but not during sleep, (p < 0.001). Our data suggest that glutamate, acting on Group II/III metabotropic receptors in the LH/PFA, exerts an inhibitory modulation of the hypercapnic ventilatory response in awake rats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO 2 /H + -dependent drive to breathe., Abstract: The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO 2 /H + responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [α,β-methylene ATP (α,β-meATP), 10 mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1 mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO 2 . In the dark (active) phase, but not in the light, microdialysis of α,β-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P < 0.001). PPADS caused no change in CO 2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Background: Air quality affects us all and is a rapidly growing concern in the 21st century. We spend the majority of our lives indoors and can be exposed to a number of pollutants smaller than 2.5 microns (particulate matter, PM 2.5 ) resulting in detrimental health effects. Indoor air quality sensors have the potential to provide people with the information they need to understand their risk and take steps to reduce their exposure. One such sensor is the Speck sensor developed at the Community Robotics, Education and Technology Empowerment Lab at Carnegie Mellon University. This sensor provides users with continuous real-time and historical PM 2.5 information, a Web-based platform where people can track their PM 2.5 levels over time and learn about ways to reduce their exposure, and a venue (blog post) for the user community to exchange information. Little is known about how the use of such monitors affects people's knowledge, attitudes, and behaviors with respect to indoor air pollution., Objective: The aim of this study was to assess whether using the sensor changes what people know and do about indoor air pollution., Methods: We conducted 2 studies. In the first study, we recruited 276 Pittsburgh residents online and through local branches of the Carnegie Library of Pittsburgh, where the Speck sensor was made available by the researchers in the library catalog. Participants completed a 10- to 15-min survey on air pollution knowledge (its health impact, sources, and mitigation options), perceptions of indoor air quality, confidence in mitigation, current behaviors toward air quality, and personal empowerment and creativity in the spring and summer of 2016. In our second study, we surveyed 26 Pittsburgh residents in summer 2016 who checked out the Speck sensor for 3 weeks on the same measures assessed in the first study, with additional questions about the perception and use of the sensor. Follow-up interviews were conducted with a subset of those who used the Speck sensor., Results: A series of paired t tests found participants were significantly more knowledgeable (t 25 =-2.61, P=.02), reported having significantly better indoor air quality (t 25 =-5.20, P<.001), and felt more confident about knowing how to mitigate their risk (t 25 =-1.87, P=.07) after using the Speck sensor than before. McNemar test showed participants tended to take more action to reduce indoor air pollution after using the sensor (χ 2 25 =2.7, P=.10). Qualitative analysis suggested possible ripple effects of use, including encouraging family and friends to learn about indoor air pollution., Conclusions: Providing people with low- or no-cost portable indoor air quality monitors, with a supporting Web-based platform that offers information about how to reduce risk, can help people better express perceptions and adopt behaviors commensurate with the risks they face. Thus, thoughtfully designed and deployed personal sensing devices can help empower people to take steps to reduce their risk., (©Gabrielle Wong-Parodi, M Beatrice Dias, Michael Taylor. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 08.03.2018.)

Introduction: Heparin resistance is the failure of unusually high doses of heparin to achieve a target activated clotting time (ACT). We present the case of a 47-year-old female patient, ASA 2, who was diagnosed with a neuroendocrine retroperitoneal tumor with thrombus in the left renal vein, inferior vena cava and right atrium. General and cardiothoracic surgeons collaborated to remove the tumor under cardiopulmonary bypass. Heparin resistance was considered and treated with 1000 UI of antithrombin III concentrate. The authors review the mechanisms and management of this entity.

Background: Matrix metalloproteinases (MMPs) are responsible for the breakdown of the extracellular matrix and play an important role in the inflammatory processes of pleural exudates. The imbalance between MMPs and their inhibitors (TIMPs) is present in various pathological processes., Objective: To evaluate the profile of MMPs and TIMPs in pleural effusions of different etiologies correlated with inflammatory markers., Methods: The patients with pleural effusion due to tuberculosis (TB), cancer (CA) or transudate were prospectively evaluated. Pleural fluid was submitted to cytological, biochemical, cytokines, MMP, and TIMP analysis. Statistical analysis was performed using ANOVA and Spearman's correlation, and p < 0.05 was considered significant., Results: One hundred and fourteen patients were enrolled, 80 exudates (41 TB and 39 CA) and 34 transudates. The levels of MMP-8 and MMP-9 were higher in exudates compared to transudates. The level of MMP-8 was significantly higher in TB than in CA. TIMP-1 levels were higher in exudates. IL-6, VEGF, and TGF-β 1 showed differences between exudates and transudates. However, IL-6 level was higher in TB than in CA. We found a significant correlation between MMPs and TIMPs with inflammation markers. MMP-1 was correlated with LDH levels. MMP-8 was correlated with LDH, total cell count, neutrophils, and ADA as well as MMP-1 levels. MMP-9 was correlated with IL-6, TGF-β 1 , and VEGF. TIMP-1 was correlated with MMP-9 and IL-6., Conclusions: MMPs and TIMPs are expressed in pleural fluid of different etiologies and correlate with inflammatory mediators. MMPs may be useful in determining the cause of fluid, but more studies are needed to determine the spectrum of diseases associated with the various isoforms of MMPS and TIMPs.

The orexins are hypothalamic neuropeptides involved in an array of functions such as regulation of sleep/wake states and chemoreception to CO2/pH. The locus coeruleus (LC) is a chemosensitive site and expresses an extensive population of orexin receptor 1 (OX1R). We tested the hypothesis that OX1Rs located in the LC participate in the ventilatory response to hypercapnia in a vigilance state and diurnal cycle-dependent manner. For this, we performed unilateral injections of SB-334867 (OX1R antagonist, 5 mM) into the LC of male Wistar rats and evaluated the ventilatory response to 7 % CO2 during wakefulness and sleep in the dark and light phases of the diurnal cycle. Hypercapnia induced an increase in ventilation (V E) in all groups compared to normocapnic values. However, during the dark phase, but not in the light phase, SB-334867 injection promoted an attenuation of the hypercapnic chemoreflex during wakefulness (V E: vehicle, 1502.6 ± 100 mL kg(-1) min(-1) vs SB-334867, 1200.3 ± 70.0 mL kg(-1) min(-1)) but not during sleep (V E: vehicle, 1383.0 ± 113.9 vs SB-334687, 1287.6 ± 92.1 mL kg(-1) min(-1)), due to changes in tidal volume (V T). We suggest that projections of orexin-containing neurons to the LC contribute, via OX1Rs, to the hypercapnic chemoreflex during wakefulness in the dark phase.

Recent reports have suggested that orexins, also known as hypocretins, play an important role in the modulation of respiratory control in mammals, but there are no data available describing the role of the orexinergic system in the peripheral and central chemoreception of non-mammalian vertebrates. Therefore, the present study was designed to examine the localization of orexin-immunoreactive neurons in the brain of toads (Rhinella schneideri) and to investigate the contribution of orexin receptor-1 (OX1R) to the hypoxic and hypercarbic ventilatory responses of these animals during light and dark phases. Our results demonstrated that the orexinergic neurons of R. schneideri are located in the suprachiasmatic nucleus of the diencephalon. Additionally, the intracerebroventricular injection of SB-334867 (OX1R selective antagonist) attenuated the ventilatory response to hypercarbia during the dark phase by acting on tidal volume and breathing frequency, while during the light phase, SB-334867 attenuated the ventilatory response to hypoxia by acting on tidal volume only. We conclude that in the toad R. schneideri, orexinergic neurons are located in the suprachiasmatic nucleus and that OX1R contributes to hypercarbic and hypoxic chemoreflexes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In female rats, a single injection of estradiol valerate (EV) results in effects that are similar to those observed in women with polycystic ovary syndrome (PCOS). We hypothesized that EV-induced PCOS affects breathing control based on evidence showing an influence of sex hormones on ventilation. To test this hypothesis, we studied the effects of EV treatment on the ventilation of female rats in air, in 7% CO2 and in 7% O2, at 30, 45 and 60 days after EV injection. The group examined 30 days after EV treatment showed a 61% reduction in the hypercapnic ventilatory response compared to the control group. Basal ventilation, hypoxic ventilatory response, and body temperature were not affected. These results, suggest that the hormonal changes observed in PCOS may result in a temporary inhibition of the central chemoreflex but do not influence basal ventilation or the hypoxic peripheral chemoreflex., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Burkholderia cepacia complex (BCC) has been described as a cause of nosocomial outbreaks. We describe an outbreak of and identify risk factors for nosocomial BCC infections associated with intrinsically contaminated mannitol 3% solution., Methods: Urinary and bloodstream infection caused by BCC were identified in hospitalized patients who underwent urologic surgery and received intraoperative irrigation of 3% mannitol solution in February 2009. The investigation included retrospective chart review, case control study, procedural review, and culture of mannitol solution., Results: Seven BCC infections were identified. BCC isolates were recovered from blood and/or urine from patients and lots of mannitol in use during the outbreak period. Mannitol solution was produced by a compounding pharmacy. Receipt of larger volumes of contaminated solution was identified as a significant risk factor for infection (odds ratio, 1.5; P value < .05). BCC was also cultured in lots of mannitol in use in other hospitals., Conclusion: Manipulated mannitol solution is a potential source of infection. Contamination with paraben-degrading organisms can occur at the time of manufacture. Our findings suggest that contamination of mannitol at a compounding pharmacy occurred. Prompt communication to other hospitals and implementation of infection control measures were effective in avoiding further cases of infection., (Copyright © 2013 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Background and Study Aims: Although hand hygiene is the most important measure in preventing infection transmission in healthcare settings, adherence to recommendations among healthcare workers is low. We implemented and assessed the impact of a World Health Organization-recommended educational intervention to improve hand hygiene adherence at the endoscopy unit of a Brazilian tertiary hospital., Patients and Methods: Hand hygiene adherence and techniques used by healthcare workers of the endoscopy unit in the course of their duties were observed unobtrusively by four nurses from the infection control unit. Data were collected at every opportunity for hand hygiene. Evaluations were carried out before and 1 and 10 months after an educational intervention. The intervention consisted of task-orientated training sessions, with live demonstrations of the multitude of opportunities for hand hygiene and the appropriate techniques. In addition to assessing hand hygiene practices, we also evaluated staff knowledge through standardized questionnaires administered before and after the education intervention. Adherence was defined as hand hygiene/disinfection at an opportunity for hand hygiene., Results: Adherence improved from 21.4 % before the intervention to 63.3 % 1 month and 73.5 % 10 months after the educational intervention. Correct answers to the questionnaire were 82.1 % on pre-intervention test and 85.7 % on post-intervention test., Conclusion: Hand hygiene rates were low before the education intervention and improved significantly after it. Against expectations, adherence to hand hygiene practices had increased further at 10 months after the intervention, reinforcing the intervention's positive impact., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: Central chemoreceptors are important to detect changes of CO2/H(+), and the Locus coeruleus (LC) is one of the many putative central chemoreceptor sites. Here, we studied the contribution of LC glutamatergic receptors on ventilatory, cardiovascular and thermal responses to hypercapnia., Methods: To this end, we determined pulmonary ventilation (V(E)), body temperatures (T(b)), mean arterial pressure (MAP) and heart rate (HR) of male Wistar rats before and after unilateral microinjection of kynurenic acid (KY, an ionotropic glutamate receptor antagonist, 10 nmol/0.1 μL) or α-methyl-4-carboxyphenylglycine (MCPG, a metabotropic glutamate receptor antagonist, 10 nmol/0.1 μL) into the LC, followed by 60 min of air breathing or hypercapnia exposure (7% CO2)., Results: Ventilatory response to hypercapnia was higher in animals treated with KY intra-LC (1918.7 ± 275.4) compared with the control group (1057.8 ± 213.9, P < 0.01). However, the MCPG treatment within the LC had no effect on the hypercapnia-induced hyperpnea. The cardiovascular and thermal controls were not affected by hypercapnia or by the injection of KY and MCPG in the LC., Conclusion: These data suggest that glutamate acting on ionotropic, but not metabotropic, receptors in the LC exerts an inhibitory modulation of hypercapnia-induced hyperpnea., (Acta Physiologica © 2013 Scandinavian Physiological Society.)

The medullary raphe (MR) is a putative central chemoreceptor site, contributing to hypercapnic respiratory responses elicited by changes in brain PCO2/pH. Purinergic mechanisms in the central nervous system appear to contribute to central chemosensitivity. To further explore the role of P2 receptors within the rostral and caudal MR in relation to respiratory control in room air and hypercapnic conditions, we performed microinjections of PPADS, a non-selective P2X antagonist, in conscious rats. Microinjections of PPADS into the rostral or caudal MR produced no changes in the respiratory frequency, tidal volume and ventilation in room air condition. The ventilatory response to hypercapnia was attenuated after microinjection of PPADS into the rostral but not in the caudal MR when compared to the control group (vehicle microinjection). These data suggest that P2X receptors in the rostral MR contribute to the ventilatory response to CO2, but do not participate in the tonic maintenance of ventilation under room air condition in conscious rats., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Central mechanisms of coupling between respiratory and sympathetic systems are essential for the entrainment between the enhanced respiratory drive and sympathoexcitation in response to hypoxia. However, the brainstem nuclei and neuronal network involved in these respiratory-sympathetic interactions remain unclear. Here, we evaluated whether the increase in expiratory activity and expiratory-modulated sympathoexcitation produced by the peripheral chemoreflex activation involves the retrotrapezoid nucleus/parafacial respiratory region (RTN/pFRG). Using decerebrated arterially perfused in situ rat preparations (60-80 g), we recorded the activities of thoracic sympathetic (tSN), phrenic (PN), and abdominal nerves (AbN) as well as the extracellular activity of RTN/pFRG expiratory neurons, and reflex responses to chemoreflex activation were evaluated before and after inactivation of the RTN/pFRG region with muscimol (1 mM). In the RTN/pFRG, we identified late-expiratory (late-E) neurons (n = 5) that were silent at resting but fired coincidently with the emergence of late-E bursts in AbN after peripheral chemoreceptor activation. Bilateral muscimol microinjections into the RTN/pFRG region (n = 6) significantly reduced basal PN frequency, mean AbN activity, and the amplitude of respiratory modulation of tSN (P < 0.05). With respect to peripheral chemoreflex responses, muscimol microinjections in the RTN/pFRG enhanced the PN inspiratory response, abolished the evoked late-E activity of AbN, but did not alter either the magnitude or pattern of the tSN reflex response. These findings indicate that the RTN/pFRG region is critically involved in the processing of the active expiratory response but not of the expiratory-modulated sympathetic response to peripheral chemoreflex activation of rat in situ preparations.

Aim: It has been suggested that the medullary raphe (MR) plays a key role in the physiological responses to hypoxia. As opioid μ-receptors have been found in the MR, we studied the putative role of opioid μ-receptors in the rostral MR (rMR) region on ventilation in normal and 7% hypoxic conditions., Methods: We measured pulmonary ventilation (VE) and the body temperatures (Tb) of male Wistar rats before and after the selective opioid μ-receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, cyclic, 0.1 μg per 0.1 μL) was microinjected into the rMR during normoxia or after 60 min of hypoxia., Results: The animals treated with intra-rMR CTAP exhibited an attenuation of the ventilatory response to hypoxia (430 ± 86 mL kg(-1) min(-1)) compared with the control group (790 ± 82 mL kg(-1) min(-1) ) (P < 0.05). No differences in the Tb were observed between groups during hypoxia., Conclusion: These data suggest that opioids acting on μ-receptors in the rMR exert an excitatory modulation of hyperventilation induced by hypoxia., (© 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.)

Serotonergic (5-HT) neurons in the nucleus raphe obscurus (ROb) are involved in the respiratory control network. However, it is not known whether ROb 5-HT neurons play a role in the functional interdependence between central and peripheral chemoreceptors. Therefore, we investigated the role of ROb 5-HT neurons in the ventilatory responses to CO₂ and their putative involvement in the central-peripheral CO₂ chemoreceptor interaction in unanaesthetised rats. We used a chemical lesion specific for 5-HT neurons (anti-SERT-SAP) of the ROb in animals with the carotid body (CB) intact or removed (CBR). Pulmonary ventilation (V (E)), body temperature and the arterial blood gases were measured before, during and after a hypercapnic challenge (7% CO₂). The lesion of ROb 5-HT neurons alone (CB intact) or the lesion of 5-HT neurons of ROb+CBR did not affect baseline V (E) during normocapnic condition. Killing ROb 5-HT neurons (CB intact) significantly decreased the ventilatory response to hypercapnia (p < 0.05). The reduction in CO₂ sensitivity was approximately 15%. When ROb 5-HT neurons lesion was combined with CBR (anti-SERT-SAP+CBR), the V (E) response to hypercapnia was further decreased (-31.2%) compared to the control group. The attenuation of CO₂ sensitivity was approximately 30%, and it was more pronounced than the sum of the individual effects of central (ROb lesion; -12.3%) or peripheral (CBR; -5.5%) treatments. Our data indicate that ROb 5-HT neurons play an important role in the CO₂ drive to breathing and may act as an important element in the central-peripheral chemoreception interaction to CO₂ responsiveness.

We describe the effect of influenza-like illness (ILI) during the outbreak of pandemic (H1N1) 2009 on health care worker (HCW) absenteeism and compare the effectiveness and cost of 2 sick leave policies for HCWs with suspected influenza. We assessed initial 2-day sick leaves plus reassessment until the HCW was asymptomatic (2-day + reassessment policy), and initial 7-day sick leaves (7-day policy). Sick leaves peaked in August 2009: 3% of the workforce received leave for ILI. Costs during May-October reached R$798,051.87 (≈US $443,362). The 7-day policy led to a higher monthly rate of sick leave days per 100 HCWs than did the 2-day + reassessment policy (8.72 vs. 3.47 days/100 HCWs; p<0.0001) and resulted in higher costs (US $609 vs. US $1,128 per HCW on leave). ILI affected HCW absenteeism. The 7-day policy was more costly and not more effective in preventing transmission to patients than the 2-day + reassessment policy.

As national health systems seek to apply breast cancer screening recommendations to an entire population of women (within target age ranges for which there is evidence that screening reduces mortality), the volume of screening tests and resulting diagnostic investigations arising from abnormal test results-and the cost associated with them-will grow dramatically. Population-based early detection (screening) programs will need information systems and management tools to help these programs. This report describes Brazil's highly decentralized health care system and then describes in greater detail how the development and implementation of an information system for Brazil's nationwide breast cancer early detection program was carried out with input from various stakeholders. Challenges encountered in the implementation are shared. Preliminary findings from the first 1.5 million mammograms are presented to demonstrate the kind of provocative management information such a system can yield in a relatively short period of time. The potential of such information systems for improving efficiency, efficacy and cost-effectiveness of early detection programs is emphasized., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

It has been suggested that the medullary raphe (MR) plays a key role in the physiological responses to hypoxia and hypercapnia. We assessed the role of ionotropic glutamate receptors in the rostral MR (rMR) in the respiratory responses to hypoxia and hypercapnia by measuring pulmonary ventilation (V.(E)) and body temperature (Tb) of male Wistar rats before and after microinjecting Kynurenic acid (KY, an ionotropic glutamate receptors antagonist, 0.1mM) into the rMR followed by 60 min of hypoxia (7% O₂) or hypercapnia exposure (7% CO₂). Compared to the control group, the ventilatory response to hypoxia was attenuated in animals treated with KY intra-rMR, however the ventilatory response to hypercapnia increased significantly. No differences in Tb among groups were observed during hypoxia or hypercapnia. These data suggest that the glutamate acting on ionotropic receptors in the rMR exerts an excitatory modulation on hyperventilation induced by hypoxia but an inhibitory modulation on the hypercapnia-induced hyperpnea., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

A bibliometric analysis of the Bacillus anthracis and Ebola virus archival literature was conducted to determine whether negative consequences of the Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism" (USA PATRIOT) Act and the 2002 Bioterrorism Preparedness Act on US select agent research could be discerned. Indicators of the health of the field, such as number of papers published per year, number of researchers authoring papers, and influx rate of new authors, indicated an overall stimulus to the field after 2002. As measured by interorganizational coauthorships, both B. anthracis and Ebola virus research networks expanded after 2002 in terms of the number of organizations and the degree of collaboration. Coauthorship between US and non US scientists also grew for Ebola virus but contracted for the subset of B. anthracis research that did not involve possession of viable, virulent bacteria. Some non-US institutions were dropped, and collaborations with others intensified. Contrary to expectations, research did not become centralized around a few gatekeeper institutions. Two negative effects were detected. There was an increased turnover rate of authors in the select agent community that was not observed in the control organism (Klebsiella pneumoniae) research community. However, the most striking effect observed was not associated with individual authors or institutions; it was a loss of efficiency, with an approximate 2- to 5-fold increase in the cost of doing select agent research as measured by the number of research papers published per millions of US research dollars awarded.

The objective of this study was to describe a pseudo-outbreak of C. difficile in a hospital, following a change in the method used to detect the toxin. In February 2002, there were two cases of CDAD and in March 7 occurred, coinciding with a change of the test (from detection of toxin A to toxin A/B). An outbreak was suspected. Active surveillance and education of staff were started. A CDAD case was defined as a patient with acute onset of diarrhea (> or = three episodes of liquid stools) and a positive stool test. They were classified as hospital or community-acquired. Stool samples were also collected for C. difficile culture and isolates were typed using AP-PCR. From March 2002 through December 2003 there were 138 cases of CDAD: 70% were hospital-acquired and among the 30% with CDAD present on admission, most (81%) came directly from the community (50% had no history of hospitalization). Fifty-two percent of hospital-acquired CDAD and 94% of cases on admission had already used antibiotics. The incidence of CDAD in hospitalized patients during surveillance was 3.3 per 1000 patient-admissions. The incidence of CDAD present on admission was 6.1/1000 patients. Sixteen isolates were typed and presented 13 different profiles. In conclusion, the CDAD increase in our study occurred due to change in diagnostic methods and not due to an outbreak, as suspected initially. The incidence in hospitalized patients was much lower than in reported outbreaks. There were 13 molecular types suggesting that an outbreak did not occur. CDAD was largely community-acquired.

It has been shown that orexin plays an important role in the hypercapnic chemoreflex during wakefulness, and OX(1)Rs in the retrotrapezoid nucleus (RTN) participate in this mechanism. We hypothesized that OX(1)R in the rostral medullary raphe (MR) also contributes to the hypercapnic chemoreflex. We studied the effects on ventilation in air and in 7% CO(2) of focal antagonism of OX(1)R in the rostral MR by microdialysis of SB-334867 in rats during wakefulness and NREM sleep, under dark and light periods. During wakefulness in the dark period, but not in the light period, SB-334867 caused a 16% reduction of the hyperventilation induced by 7% CO(2) compared with vehicle. There was no significant effect in sleep. The basal ventilation, body temperature and V(O2) were not affected. No effect was observed in a separate group of animals which had the microdialysis probe misplaced (peri-raphe). We conclude that OX(1)R in the rostral medullary raphe contribute to the hypercapnic chemoreflex in wakefulness, during the dark period in rats., (Copyright 2009 Elsevier B.V. All rights reserved.)

Recent data from transgenic mice suggest that orexin plays an important role in the ventilatory response to CO(2) during wakefulness. We hypothesized that orexin receptor-1 (OX(1)R) in the retrotrapezoid nucleus (RTN) contributes to chemoreception. In unanaesthetized rats, we measured ventilation using a whole-body plethysmograph, together with EEG and EMG. We dialysed the vehicle and then SB-334867 (OX(1)R antagonist) into the RTN to focally inhibit OX(1)R and studied the effects of both treatments on breathing in air and in 7% CO(2). During wakefulness, SB-334867 caused a 30% reduction of the hyperventilation induced by 7% CO(2) (mean +/- S.E.M., 135 +/- 10 ml (100 g)(-1) min(-1)) compared with vehicle (182 +/- 10 ml (100 g)(-1) min(-1)) (P < 0.01). This effect was due to both decreased tidal volume and breathing frequency. There was a much smaller, though significant, effect in sleep (9% reduction). Neither basal ventilation nor oxygen consumption was affected. The number and duration of apnoeas were similar between control and treatment periods. No effect was observed in a separate group of animals who had the microdialysis probe misplaced (peri-RTN). We conclude that projections of orexin-containing neurons to the RTN contribute, via OX(1)Rs in the region, to the hypercapnic chemoreflex control during wakefulness and to a lesser extent, non-rapid eye movement sleep.

The purpose of the present study was to investigate antitumour and anti-inflammatory activities of flavonoids isolated from Byrsonima crassa, Davilla elliptica and Mouriri pusa. The antitumour activity was measured by the MTT assay in murine mammary tumour cells (LM2) and the IC50 values of the flavonoids tested ranged from (31.5 +/- 2.97) to (203.1 +/- 5.9) microg/ml. The flavonoids 1 (myricetin-3-O-alpha-L-rhamnopyranoside) and 3 (quercetin-3-O-galactopyranoside) from D. elliptica were the most active ones against the tumour cells. The same samples were tested to determine the inhibition of the release of nitric oxide (NO) and of the tumour necrosis factor-alpha (TNF-alpha) in murine macrophages by the Griess and ELISA sandwich assay, respectively. Almost all the samples showed inhibitory activity to the release of NO but not of TNF-alpha. Of all substances tested, flavonoids 2 (quercetin) and 6 (myricetin) may show promising activity in the treatment of murine breast cancer by immunomodulatory and antiproliferative activities.