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Hypertension and diabetes mellitus (DM) are highly prevalent in low and middle-income countries (LMICs), and the proportion of patients with uncontrolled diseases is higher than in high-income countries. Innovative strategies are required to surpass barriers of low sources, distance and quality of health care. Our aim is to assess the uptake and effectiveness of the implementation of an integrated multidimensional strategy in the primary care setting, for the management of people with hypertension and diabetes mellitus in Brazil. This scale up implementation study called Control of Hypertension and diAbetes in MINas Gerais (CHArMING) Project has mixed-methods, and comprehends 4 steps: (1) needs assessment, including a standardized structured questionnaire and focus groups with health care practitioners; (2) baseline period, 3 months before the implementation of the intervention; (3) cluster randomized controlled trial (RCT) with a 12-months follow-up period; and (4) a qualitative study after the end of follow-up. The cluster RCT will randomize 35 centers to intervention (n = 18) or usual care (n = 17). Patients ≥18 years old, with diagnosis of hypertension and/or DM, of 5 Brazilian cities in a resource-constrained area will be enrolled. The intervention consists of a multifaceted strategy, with a multidisciplinary approach, including telehealth tools (decision support systems, short message service, telediagnosis), continued education with an approach to issues related to the care of people with hypertension and diabetes in primary care, including pharmacological and non-pharmacological treatment and behavioral change. The project has actions focused on professionals and patients. This study consists of a multidimensional strategy with multidisciplinary approach using digital health to improve the control of hypertension and/or DM in the primary health care setting. We expect to provide the basis for implementing an innovative management program for hypertension and DM in Brazil, aiming to reduce the present and future burden of these diseases in Brazil and other LMICs. This study was registered in ClinicalTrials.gov. (NCT05660928) [ABSTRACT FROM AUTHOR]

Purpose: To develop a mortality risk score for COVID-19 patients admitted to intensive care units (ICU), and to compare it with other existing scores., Materials and Methods: This retrospective observational study included consecutive adult patients with laboratory-confirmed COVID-19 admitted to ICUs of 18 hospitals from nine Brazilian cities, from September 2021 to July 2022. Potential predictors were selected based on the literature review. Generalized Additive Models were used to examine outcomes and predictors. LASSO regression was used to derive the mortality score., Results: From 558 patients, median age was 69 years (IQR 58-78), 56.3 % were men, 19.7 % required mechanical ventilation (MV), and 44.8 % died. The final model comprised six variables: age, pO 2 /FiO 2 , respiratory function (respiratory rate or if in MV), chronic obstructive pulmonary disease, and obesity. The AB 2 CO had an AUROC of 0.781 (95 % CI 0.744 to 0.819), good overall performance (Brier score = 0.191) and an excellent calibration (slope = 1.063, intercept = 0.015, p-value = 0.834). The model was compared with other scores and displayed better discrimination ability than the majority of them., Conclusions: The AB 2 CO score is a fast and easy tool to be used upon ICU admission., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest concerning the research, authorship, and/or publication and/or competing financial of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patients with chronic kidney disease (CKD), especially those on dialysis or who have received a kidney transplant (KT), are considered more vulnerable to severe COVID-19. This susceptibility is attributed to advanced age, a higher frequency of comorbidities, and the chronic immunosuppressed state, which may exacerbate their susceptibility to severe outcomes. Therefore, our study aimed to compare the clinical characteristics and outcomes of COVID-19 in KT patients with those on chronic dialysis and non-CKD patients in a propensity score-matched cohort study. This multicentric retrospective cohort included adult COVID-19 laboratory-confirmed patients admitted from March/2020 to July/2022, from 43 Brazilian hospitals. The primary outcome was in-hospital mortality. Propensity score analysis matched KT recipients with controls - patients on chronic dialysis and those without CKD (within 0.25 standard deviations of the logit of the propensity score) - according to age, sex, number of comorbidities, and admission year. This study included 555 patients: 163 KT, 146 on chronic dialysis, and 249 non-CKD patients (median age 57 years, 55.2% women). With regards to clinical outcomes, chronic dialysis patients had a higher prevalence of acute heart failure, compared to KT recipients, furthermore, both groups presented high in-hospital mortality, 34.0 and 28.1%, for KT and chronic dialysis patients, respectively. When comparing KT and non-CKD patients, the first group had a higher incidence of in-hospital dialysis (26.4% vs . 8.8%, p  < 0.001), septic shock (24.1% vs . 12.0%, p  = 0.002), and mortality (32.5% vs . 23.3%, p  = 0.039), in addition to longer time spent in the intensive care unit (ICU). In this study, chronic dialysis patients presented a higher prevalence of acute heart failure, compared to KT recipients, whereas KT patients had a higher frequency of complications than those without CKD, including septic shock, dialysis during hospitalization, and in-hospital mortality as well as longer time spent in the ICU., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Delfino-Pereira, Ventura, Pires, Ponce, Carmo, Carmo, Paiva, Schwarzbold, Gomes, Castro, Polanczyk, Cimini, Lima, Sousa, Bartolazzi, Vietta, Vianna, Chatkin, Ruschel, Kopittke, Castro, Carneiro, Reis and Marcolino.)

Background: Although dementia has emerged as an important risk factor for severe SARS-CoV-2 infection, results on COVID-19-related complications and mortality are not consistent. We examined the clinical presentations and outcomes of COVID-19 in a multicentre cohort of in-hospital patients, comparing those with and without dementia., Methods: This retrospective observational study comprises COVID-19 laboratory-confirmed patients aged ≥ 60 years admitted to 38 hospitals from 19 cities in Brazil. Data were obtained from electronic hospital records. A propensity score analysis was used to match patients with and without dementia (up to 3:1) according to age, sex, comorbidities, year, and hospital of admission. Our primary outcome was in-hospital mortality. We also assessed admission to the intensive care unit (ICU), invasive mechanical ventilation (IMV), kidney replacement therapy (KRT), sepsis, nosocomial infection, and thromboembolic events., Results: Among 1,556 patients included in the study, 405 (4.5%) had a diagnosis of dementia and 1,151 were matched controls. When compared to matched controls, patients with dementia had a lower frequency of dyspnoea, cough, myalgia, headache, ageusia, and anosmia; and higher frequency of fever and delirium. They also had a lower frequency of ICU admission (32.7% vs. 47.1%, p < 0.001) and shorter ICU length of stay (7 vs. 9 days, p < 0.026), and a lower frequency of sepsis (17% vs. 24%, p = 0.005), KRT (6.4% vs. 13%, p < 0.001), and IVM (4.6% vs. 9.8%, p = 0.002). There were no differences in hospital mortality between groups., Conclusion: Clinical manifestations of COVID-19 differ between older inpatients with and without dementia. We observed that dementia alone could not explain the higher short-term mortality following severe COVID-19. Therefore, clinicians should consider other risk factors such as acute morbidity severity and baseline frailty when evaluating the prognosis of older adults with dementia hospitalised with COVID-19., (© 2024. The Author(s).)

Background: Predicting the need for invasive mechanical ventilation (IMV) is important for the allocation of human and technological resources, improvement of surveillance, and use of effective therapeutic measures. This study aimed (i) to assess whether the ABC 2 -SPH score is able to predict the receipt of IMV in COVID-19 patients; (ii) to compare its performance with other existing scores; (iii) to perform score recalibration, and to assess whether recalibration improved prediction., Methods: Retrospective observational cohort, which included adult laboratory-confirmed COVID-19 patients admitted in 32 hospitals, from 14 Brazilian cities. This study was conducted in two stages: (i) for the assessment of the ABC 2 -SPH score and comparison with other available scores, patients hospitalized from July 31, 2020, to March 31, 2022, were included; (ii) for ABC 2 -SPH score recalibration and also comparison with other existing scores, patients admitted from January 1, 2021, to March 31, 2022, were enrolled. For both steps, the area under the receiving operator characteristic score (AUROC) was calculated for all scores, while a calibration plot was assessed only for the ABC 2 -SPH score. Comparisons between ABC 2 -SPH and the other scores followed the Delong Test recommendations. Logistic recalibration methods were used to improve results and adapt to the studied sample., Results: Overall, 9,350 patients were included in the study, the median age was 58.5 (IQR 47.0-69.0) years old, and 45.4% were women. Of those, 33.5% were admitted to the ICU, 25.2% received IMV, and 17.8% died. The ABC 2 -SPH score showed a significantly greater discriminatory capacity, than the CURB-65, STSS, and SUM scores, with potentialized results when we consider only patients younger than 80 years old (AUROC 0.714 [95% CI 0.698-0.731]). Thus, after the ABC 2 -SPH score recalibration, we observed improvements in calibration (slope = 1.135, intercept = 0.242) and overall performance (Brier score = 0.127)., Conclusion: The ABC 2 -SPHr risk score demonstrated a good performance to predict the need for mechanical ventilation in COVID-19 hospitalized patients under 80 years of age., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cimini, Delfino-Pereira, Pires, Ramos, Gomes, Jorge, Fagundes, Garcia, Pessoa, de Carvalho, Ponce, Rios, Anschau, Vigil, Bartolazzi, Grizende, Vietta, Goedert, Nascimento, Vianna, Vasconcelos, Alvarenga, Chatkin, Machado Rugolo, Ruschel, Zandoná, Menezes, Castro, Souza, Carneiro, Bicalho, Cunha, Sacioto, Lutkmeier, Oliveira, Andrade, Menezes, Ribeiro and Marcolino.)

Objectives: To analyze the clinical characteristics and outcomes of admitted patients with the hospital- versus community-manifested COVID-19 and to evaluate the risk factors related to mortality in the first population., Methods: This retrospective cohort included consecutive adult patients with COVID-19, hospitalized between March and September 2020. The demographic data, clinical characteristics, and outcomes were extracted from medical records. Patients with hospital-manifested COVID-19 (study group) and those with community-manifested COVID-19 (control group) were matched by the propensity score model. Logistic regression models were used to verify the risk factors for mortality in the study group., Results: Among 7,710 hospitalized patients who had COVID-19, 7.2% developed symptoms while admitted for other reasons. Patients with hospital-manifested COVID-19 had a higher prevalence of cancer (19.2% vs 10.8%) and alcoholism (8.8% vs 2.8%) than patients with community-manifested COVID-19 and also had a higher rate of intensive care unit requirement (45.1% vs 35.2%), sepsis (23.8% vs 14.5%), and death (35.8% vs 22.5%) (P <0.05 for all). The factors independently associated with increased mortality in the study group were increasing age, male sex, number of comorbidities, and cancer., Conclusion: Hospital-manifested COVID-19 was associated with increased mortality. Increasing age, male sex, number of comorbidities, and cancer were independent predictors of mortality among those with hospital-manifested COVID-19 disease., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the ABC 2 -SPH score in predicting COVID-19 in-hospital mortality, during intensive care unit (ICU) admission, and to compare its performance with other scores (SOFA, SAPS-3, NEWS2, 4C Mortality Score, SOARS, CURB-65, modified CHA2DS2-VASc, and a novel severity score)., Materials and Methods: Consecutive patients (≥ 18 years) with laboratory-confirmed COVID-19 admitted to ICUs of 25 hospitals, located in 17 Brazilian cities, from October 2020 to March 2022, were included. Overall performance of the scores was evaluated using the Brier score. ABC 2 -SPH was used as the reference score, and comparisons between ABC 2 -SPH and the other scores were performed by using the Bonferroni method of correction. The primary outcome was in-hospital mortality., Results: ABC 2 -SPH had an area under the curve of 0.716 (95% CI 0.693-0.738), significantly higher than CURB-65, SOFA, NEWS2, SOARS, and modified CHA2DS2-VASc scores. There was no statistically significant difference between ABC 2 -SPH and SAPS-3, 4C Mortality Score, and the novel severity score., Conclusion: ABC 2 -SPH was superior to other risk scores, but it still did not demonstrate an excellent predictive ability for mortality in critically ill COVID-19 patients. Our results indicate the need to develop a new score, for this subset of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nogueira, Nobre, Pires, Ramos, Ribeiro, Aguiar, Vigil, Gomes, Santos, Miranda, Durães, Costa, Schwarzbold, Gomes, Pessoa, Matos, Cimini, Carvalho, Ponce, Manenti, Cenci, Anschau, Costa, Nascimento, Bartolazzi, Grizende, Vianna, Nepomuceno, Ruschel, Zandoná, Castro, Souza, Carneiro, Bicalho, Vilaça, Bonardi, Oliveira, Lutkmeier, Francisco, Araújo, Delfino-Pereira and Marcolino.)

Background: Cardiovascular complications of COVID-19 are important aspects of the disease's pathogenesis and prognosis. Evidence on the prognostic role of troponin and myocardial injury in Latin American hospitalized COVID-19 patients is still scarce., Objectives: To evaluate myocardial injury as independent predictor of in-hospital mortality and invasive mechanical ventilation support in hospitalized patients, from the Brazilian COVID-19 Registry., Methods: This cohort study is a substudy of the Brazilian COVID-19 Registry, conducted in 31 Brazilian hospitals of 17 cities, March-September 2020. Primary outcomes included in-hospital mortality and invasive mechanical ventilation support. Models for the primary outcomes were estimated by Poisson regression with robust variance, with statistical significance of p<0.05., Results: Of 2,925 patients (median age of 60 years [48-71], 57.1% men), 27.3% presented myocardial injury. The proportion of patients with comorbidities was higher among patients with cardiac injury (median 2 [1-2] vs. 1 [0-2]). Patients with myocardial injury had higher median levels of brain natriuretic peptide, lactate dehydrogenase, creatine phosphokinase, N-terminal pro-brain natriuretic peptide, and C-reactive protein than patients without myocardial injury. As independent predictors, C-reactive protein and platelet counts were related to the risk of death, and neutrophils and platelet counts were related to the risk of invasive mechanical ventilation support. Patients with high troponin levels presented a higher risk of death (RR 2.03, 95% CI 1.60-2.58) and invasive mechanical ventilation support (RR 1.87, 95% CI 1.57-2.23), when compared to those with normal troponin levels., Conclusion: Cardiac injury was an independent predictor of in-hospital mortality and the need for invasive mechanical ventilation support in hospitalized COVID-19 patients.

Background: Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection and outcomes in the Brazilian population., Methods: This study is part of the Brazilian COVID-19 Registry, a multicentric cohort, including data from 37 hospitals. For the present analysis, patients were grouped according to the presence of reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) vs. clinically-diagnosed neurological manifestations (clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation) and matched with patients without neurological manifestations by age, sex, number of comorbidities, hospital of admission, and whether or not patients had underlying neurological disease., Results: From 6,635 hospitalized patients with COVID-19, 30.8% presented reported neurological manifestations, 10.3% were diagnosed with a neurological syndrome and 60.1% did not show any neurological manifestations. In patients with reported symptoms, the most common ones were headache (20.7%), ageusia (11.1%) and anosmia (8.0%). In patients with neurological syndromes, acute encephalopathy was the most common diagnosis (9.7%). In the matched analysis, patients with neurological syndromes presented more cases of septic shock (17.0 vs. 13.0%, p = 0.045), intensive care unit admission (45.3 vs. 38.9%, p = 0.023), and mortality (38.7 vs. 32.6%, p = 0.026; and 39.2 vs. 30.3%, p < 0.001) when compared to controls., Conclusion: COVID-19 in-hospital patients with clinically defined neurological syndromes presented a higher incidence of septic shock, ICU admission and death when compared to controls., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier B.V.)

Background: Clinical and experimental evidence indicates that olfactory stimulation modulates limbic seizures, either blocking or inducing ictal activity. Objective: We aim to evaluate the behavioral and electroencephalographic (EEGraphic) effects of dihydro-2,4,5-trimethylthiazoline (TMT) olfactory exposure on limbic seizures induced by amygdala rapid kindling (ARK). Materials and Methods: Wistar male rats (280-300 g) underwent stereotaxic surgery for electrode implantation in piriform cortex (PC), hippocampal formation (HIP), and amygdaloid complex (AMYG). Part of the animals was exposed to a saturated chamber with water or TMT, while others had ARK and olfactory exposure prior to the 21st stimulus. Behavioral responses were measured by traditional seizure severity scales (Racine and Pinel and Rovner) and/or by sequential analysis/neuroethology. The electrographic activity of epileptogenic limbic networks was quantified by the occurrence of the first and second EEG afterdischarges, comparing the 1st and 21st stimulus. The spectral analysis [Fast Fourier Transform (FFT)] of the first afterdischarge was performed at the 21st stimulus. Results: TMT olfactory exposure reduced the seizure severity in kindled rats, altering the displayed behavioral sequence. Moreover, TMT decreased the occurrence of first and second afterdischarges, at the 21st stimulus, and altered the spectral features. Conclusions: Both behavioral and EEGraphic evaluations indicated that TMT, a potent molecule with strong biological relevance, in fact, "predator odor," suppressed the epileptiform activity in limbic networks., (Copyright © 2020 Delfino-Pereira, Bertti-Dutra, Del Vecchio, de Oliveira, Medeiros, Cestari, Santos, Moraes, Rosa, Mendes and Garcia-Cairasco.)

We aimed to evaluate the chemical and behavioral effects of 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) after olfactory exposure and to verify their influence in the expression of acute audiogenic seizures in the Wistar Audiogenic Rat (WAR) strain. PROTOCOL 1: TMT gas chromatography was applied to define odor saturation in a chamber to different concentrations, time required for saturation and desaturation, and if saturation was homogeneous. Also, male Adult Wistar rats were exposed to saline (SAL) or to different TMT concentrations and their behaviors were evaluated (neuroethology). PROTOCOL 2: Male adult WARs were exposed for 15 s to SAL or TMT, followed by sound stimulation for 1 min or until tonic-clonic convulsion. Behavioral analysis included latencies (wild running and tonic-clonic convulsion), seizure severity indexes, and neuroethology. Gas chromatography established a saturation homogeneous to different concentrations of TMT, indicating that saturation and desaturation occurred in 30 min. TMT triggered fear-like or aversion-like reactions associated with reduction in motor activity and in grooming behavior, in the 2 highest concentrations. Pure TMT presented anticonvulsant properties, such as less-severe seizure phenotype, as well as a decrease in tonic-clonic convulsion expression. TMT elicited fear-like or aversion-like behaviors in Wistar and WAR and can be utilized in a quantifiable and controllable way. Our results suggested possible antagonism between "fear-related" or "aversion-related" and "seizure-related" networks., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Temporal lobe epilepsy is often accompanied by behavioral, electroencephalographic and autonomic abnormalities. Amygdala kindling has been used as an experimental model to study epileptogenesis. Although amygdala kindling has been extensively investigated in the context of its clinical relevance to the epilepsies, potential associated respiratory alterations are not well known. Here, our main objective was to better investigate the mechanisms involved in respiratory physiology impairment in the amygdala rapid kindling (ARK) model of epileptogenesis. Male Wistar rats with electrodes implanted into the amygdaloid complex were used. After recovery from surgery, the rats were subjected to electrical stimulation of basolateral amygdala for 2 consecutive days (10 stimuli/day). The ventilatory parameters were evaluated by whole body plethysmography. Thereafter, animals were also exposed to hypercapnia (7% CO 2 ) for 3 h to evaluate fos protein expression in several nuclei involved in respiratory control. We observed a significant reduction in ventilation during the ictal phase elicited by ARK. We also found that 10 days after ARK, baseline ventilation as well as the hypercapnia ventilatory response (7% CO 2 ) were reduced compared to control rats. The number of fos-immunoreactive neurons in the retrotrapezoid nucleus, raphe magnus and nucleus of the solitary tract were also reduced after ARK. Our results showed that ARK was able to impair breathing function, demonstrating a strong coupling between amygdala and the respiratory neurons in the brainstem, with potential impact in respiratory failures, frequently fatal, during or after epileptic seizures in chronic animal models and in patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Stress is recognized as an important issue in basic and clinical neuroscience research, based upon the founding historical studies by Walter Canon and Hans Selye in the past century, when the concept of stress emerged in a biological and adaptive perspective. A lot of research after that period has expanded the knowledge in the stress field. Since then, it was discovered that the response to stressful stimuli is elaborated and triggered by the, now known, stress system , which integrates a wide diversity of brain structures that, collectively, are able to detect events and interpret them as real or potential threats. However, different types of stressors engage different brain networks, requiring a fine-tuned functional neuroanatomical processing. This integration of information from the stressor itself may result in a rapid activation of the Sympathetic-Adreno-Medullar (SAM) axis and the Hypothalamus-Pituitary-Adrenal (HPA) axis, the two major components involved in the stress response. The complexity of the stress response is not restricted to neuroanatomy or to SAM and HPA axes mediators, but also diverge according to timing and duration of stressor exposure, as well as its short- and/or long-term consequences. The identification of neuronal circuits of stress, as well as their interaction with mediator molecules over time is critical, not only for understanding the physiological stress responses, but also to understand their implications on mental health.

The neuronal control of the immune system is fundamental to the development of new therapeutic strategies for inflammatory disorders. Recent studies reported that afferent vagal stimulation attenuates peripheral inflammation by activating specific sympathetic central and peripheral networks, but only few subcortical brain areas were investigated. In the present study, we report that afferent vagal stimulation also activates specific cortical areas, as the parietal and cingulate cortex. Since these cortical structures innervate sympathetic-related areas, we investigate whether electrical stimulation of parietal cortex can attenuate knee joint inflammation in non-anesthetized rats. Our results show that cortical stimulation in rats increased sympathetic activity and improved joint inflammatory parameters, such as local neutrophil infiltration and pro-inflammatory cytokine levels, without causing behavioral disturbance, brain epileptiform activity or neural damage. In addition, we superposed the areas activated by afferent vagal or cortical stimulation to map common central structures to depict a brain immunological homunculus that can allow novel therapeutic approaches against inflammatory joint diseases, such as rheumatoid arthritis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There are reports of patients whose epileptic seizures are prevented by means of olfactory stimulation. Similar findings were described in animal models of epilepsy, such as the electrical kindling of amygdala, where olfactory stimulation with toluene (TOL) suppressed seizures in most rats, even when the stimuli were 20% above the threshold to evoke seizures in already kindled animals. The Wistar Audiogenic Rat (WAR) strain is a model of tonic-clonic seizures induced by acute acoustic stimulation, although it also expresses limbic seizures when repeated acoustic stimulation occurs - a process known as audiogenic kindling (AK). The aim of this study was to evaluate whether or not the olfactory stimulation with TOL would interfere on the behavioral expression of brainstem (acute) and limbic (chronic) seizures in the WAR strain. For this, animals were exposed to TOL or saline (SAL) and subsequently exposed to acoustic stimulation in two conditions that generated: I) acute audiogenic seizures (only one acoustic stimulus, without previous seizure experience before of the odor test) and II) after AK (20 acoustic stimuli [2 daily] before of the protocol test). We observed a decrease in the seizure severity index of animals exposed only to TOL in both conditions, with TOL presented 20s before the acoustic stimulation in both protocols. These findings were confirmed by behavioral sequential analysis (neuroethology), which clearly indicated an exacerbation of clusters of specific behaviors such as exploration and grooming (self-cleaning), as well as significant decrease in the expression of brainstem and limbic seizures in response to TOL. Thus, these data demonstrate that TOL, a strong olfactory stimulus, has anticonvulsant properties, detected by the decrease of acute and AK seizures in WARs., (Copyright © 2017 Elsevier Inc. All rights reserved.)