Resting state networks of awake adolescent and adult squirrel monkeys using ultra-high field (9.4T) functional magnetic resonance imaging.

Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys (n=12 adolescents [6 male/6 female] ∼2.5 years and n=15 adults [7 male/8 female] ∼9.5 years) were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 Tesla scanner. Group level independent component (ICA) analysis (30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward, and cognitive processes were identified in both adolescent and adult monkeys. The reproducibility of these RSNs was evaluated across several ICA model orders. Adults showed a trend for greater connectivity compared to adolescent subjects in two of the networks of interest: (1) in the right occipital region with the OFC network and (2) in the left temporal cortex, bilateral occipital cortex, and cerebellum with the posterior cingulate network. However, when age was entered into the above model, this trend for significance was lost. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood.Significance Statement Functional magnetic resonance imaging procedures have revealed important information about how the brain is modified by experimental manipulations, disease states, and aging throughout the lifespan. Preclinical neuroimaging, especially in nonhuman primates, has become a frequently used means to answer targeted questions related to brain resting-state functional connectivity. The present study characterized resting state networks (RSNs) in adult and adolescent squirrel monkeys; twenty RSNs corresponding to networks representing a range of neural functions were identified. The RSNs identified here can be utilized in future studies examining the effects of experimental manipulations on brain connectivity in squirrel monkeys. These data also may be useful for comparative analysis with other primate species to provide an evolutionary perspective for understanding brain function and organization.

Brain and cortisol responses to smoking cues are linked in tobacco-smoking individuals.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Epidemiological profile, temporal analysis, and future projections of suicide cases in rural cities in the extreme south of Brazil.

The present study aimed to verify the time series (2000-2017) of death rates by suicide and its associated factors in 4 municipalities in the extreme south of Brazil. Data were obtained through the analysis of medical reports and police report bulletins at the Instituto Médico Legal, in the city of Rio Grande. The suicide rate in the Rio Grande region varied from 4 to 11 suicides per 100,000 inhabitants and it is estimated that by 2030 this rate could reach 16.5 suicides per 100,000 inhabitants. The rural cities of Santa Vitória do Palmar and Chuí present even higher suicide averages when compared to Rio Grande, the most populous city of the four. The death rate from suicide increased gradually in the period analyzed, with the prevalence rising among the youngest and the elderly population. A more comprehensive understanding of the influences of environmental issues on suicidal decisions constitutes an important action that needs to be taken, both because of regional vulnerabilities and the target population identified. Evidence indicates that knowledge of factors affecting individuals residing in this Brazilian region where increased suicide rates are recorded needs to be recognized as a priority.

Beneficial effects of mate-herb, Ilex paraguariensis St. Hil. against potassium dichromate-induced oxidative stress and nephrotoxicity.

Chimarrão is a typical beverage made from the infusion of dried and ground leaves and stems of Ilex paraguariensis (popularly known as Yerba mate or mate herb) which is widely consumed in parts of South America. The aim of this study was to examine the effects of the chimarrão against nephrotoxicity and oxidative stress induced by the potassium dichromate (PD) salt in male Wistar rats. The experiment lasted 17 days, and in the first 15 days animals ingested a chimarrão infusion or control drinking water and then submitted to an intraperitoneal injection (15 mg/kg) of PD (or saline solution) and euthanized after 48 hr at which time animals still received infusion or drinking water. Blood plasma and 24 hr-urine samples were collected to measure creatinine levels as an estimate of glomerular filtration rate (GFR). Concomitantly oxidative stress was determined in the kidneys as evidenced by levels of carbonyl groups, malondialdehyde (MDA) and antioxidant capacity against peroxyl radicals. Potassium dichromate induced oxidative stress in the kidneys and reduced GFR. Treatment with chimarrão during the 15 days prior to PD injection reduced PD salt-mediated oxidative stress. Further, treatment with post-injection chimarrão to PD-administered rats improved the GFR. Our findings support that the use of the chimarrão beverage may be considered as an important nephroprotective substance.

Oxidative damage in the Vesper mouse (Calomys laucha) exposed to a simulated oil spill-a multi-organ study.

Small wild mammals have been used to measure the damage caused by exposure to oil-contaminated soil, including deer mice. However, the study of toxic effects of crude oil using oxidative damage biomarkers in the wild rodent Calomys laucha (Vesper mouse) is absent. This investigation aimed to evaluate the effects of acute exposure to contaminated soil with different concentrations of crude oil (0, 1, 2, 4 and 8% w/w), simulating an accidental spill, using oxidative stress biomarkers in the liver, kidneys, lungs, testes, paw muscle, and lymphocytes of C. laucha. Animals exposed to the contaminated soil showed increases in lipid peroxidation and protein carbonylation at the highest exposure concentrations in most organ homogenates analyzed and also in blood cells, but responses to total antioxidant capacity were tissue-dependent. These results showed that acute exposure to oil-contaminated soil caused oxidative damage in C. laucha and indicate these small mammals may be susceptible to suffer the impacts of such contamination in its occurrence region, threatening the species' survival.

In silicostudy of the effects of cerebral circulation on source localization using a dynamical anatomical atlas of the human head.

Objective.This study focuses on the effects of dynamical vascular modeling on source localization errors in electroencephalography (EEG). Our aim of thisin silicostudy is to (a) find out the effects of cerebral circulation on the accuracy of EEG source localization estimates, and (b) evaluate its relevance with respect to measurement noise and interpatient variation.Approach.We employ a four-dimensional (3D + T) statistical atlas of the electrical properties of the human head with a cerebral circulation model to generate virtual patients with different cerebral circulatory conditions for EEG source localization analysis. As source reconstruction techniques, we use the linearly constraint minimum variance (LCMV) beamformer, standardized low-resolution brain electromagnetic tomography (sLORETA), and the dipole scan (DS).Main results.Results indicate that arterial blood flow affects source localization at different depths and with varying significance. The average flow rate plays an important role in source localization performance, while the pulsatility effects are very small. In cases where a personalized model of the head is available, blood circulation mismodeling causes localization errors, especially in the deep structures of the brain where the main cerebral arteries are located. When interpatient variations are considered, the results show differences up to 15 mm for sLORETA and LCMV beamformer and 10 mm for DS in the brainstem and entorhinal cortices regions. In regions far from the main arteries vessels, the discrepancies are smaller than 3 mm. When measurement noise is added and interpatient differences are considered in a deep dipolar source, the results indicate that the effects of conductivity mismatch are detectable even for moderate measurement noise. The signal-to-noise ratio limit for sLORETA and LCMV beamformer is 15 dB, while the limit is under 30 dB for DS.Significance.Localization of the brain activity via EEG constitutes an ill-posed inverse problem, where any modeling uncertainty, e.g. a slight amount of noise in the data or material parameter discrepancies, can lead to a significant deviation of the estimated activity, especially in the deep structures of the brain. Proper modeling of the conductivity distribution is necessary in order to obtain an appropriate source localization. In this study, we show that the conductivity of the deep brain structures is particularly impacted by blood flow-induced changes in conductivity because large arteries and veins access the brain through that region.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report.

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

Oxycodone self-administration and reinstatement in male and female squirrel monkeys: Effects of alternative reinforcer availability.

The use of non-drug alternative reinforcers has long been utilized as a component of therapeutic interventions for the management of substance use disorder; however, the conditions under which alternative reinforcers are most effective are not well characterized. This study evaluated the impact of varying the magnitude of an alternative reinforcer on oxycodone self-administration and reinstatement in male and female squirrel monkeys. Subjects (n=4/sex) were trained under concurrent second-order schedules of reinforcement for intravenous oxycodone (0.001-0.1mg/kg/inj) on one lever, and sweetened condensed milk (5, 10, 20, 30% in water) on another. Oxycodone-primed reinstatement was evaluated by administering 0.32mg/kg oxycodone prior to sessions in which saline was available on the drug-paired lever. During oxycodone self-administration sessions, milk availability decreased oxycodone self-administration and preference in a concentration-dependent manner; low milk concentrations were more effective at decreasing oxycodone’s reinforcing potency in males. During reinstatement tests, milk significantly attenuated oxycodone-primed responding in both males and females; low milk concentrations were more effective at decreasing the priming effects of oxycodone in females. That alternative reinforcers differentially impacted self-administration and reinstatement in a sex-dependent manner suggests that treatment strategies that utilize alternative reinforcers may be more effective in males or females depending on when they are implemented.

Resting state networks of awake adolescent and adult squirrel monkeys using ultra-high field (9.4T) functional magnetic resonance imaging.

Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys ( n =12 adolescents [6 male/6 female] ∼2.5 years and n =15 adults [7 male/8 female] ∼9.5 years) were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 Tesla scanner. Group level independent component (IC) analysis (30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward (e.g., basal ganglia), and cognitive processes were identified in both adolescent and adult monkeys. Significant age-related differences between the adult and adolescent subjects (adult > adolescent) were found in two networks of interest: (1) the right upper occipital region with an OFC IC and (2) the left temporal cortex, bilateral visual areas, and cerebellum with the cingulate IC. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood. Significance Statement: Functional magnetic resonance imaging procedures have revealed important information about how the brain is modified by experimental manipulations, disease states, and aging throughout the lifespan. Preclinical neuroimaging, especially in nonhuman primates, has become a frequently used means to answer targeted questions related to brain resting-state functional connectivity. The present study characterized resting state networks (RSNs) in adult and adolescent squirrel monkeys; twenty RSNs corresponding to networks representing a range of neural functions were identified. The RSNs identified here can be utilized in future studies examining the effects of experimental manipulations on brain connectivity in squirrel monkeys. These data also may be useful for comparative analysis with other primate species to provide an evolutionary perspective for understanding brain function and organization.

Better understanding the behavior of air pollutants at shutdown times - results of a short full lockdown.

Numerous studies have evaluated the effects of lockdowns during the COVID-19 pandemic, but most of them have concerned large cities and regions. This study aimed to evaluate the dynamics of air pollutants during and after the implementation of a short lockdown in the medium-sized city of Pelotas, Brazil, using hourly measurements of pollutants. The evaluation period included in this study was between August 9th and 12th, 2020. A machine learning model was used to investigate the expected behavior against what was observed during the study period. All pollutants presented a gradual reduction until a dynamic plateau established 48 hours after the start of the lockdown: NO2 (↓4%), O3 (↓34%), SO2 (↓24%), CO (↓48%), PM10 (↓82%) and PM2.5 (↓82%). At the end of the restriction measures, the PM10 and PM2.5 levels continued to decline beyond expectations. Our findings show that these measures can positively affect the air quality in medium-sized cities.

"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

2030 Agenda: discussion on Brazilian priorities facing air pollution and climate change challenges.

The advance of human activities in a disorderly way has accelerated in recent decades, intensifying the environmental impacts directly linked to these practices. The atmosphere, essential for the maintenance of life, is increasingly saturated with pollutants, offering risks to practically all the inhabitants of the planet, a process that, in addition to causing illness and early mortality, is related to serious financial losses (including in the production of goods), dangerous temperature increase and severe natural disasters. Although this perception is not recent, the global initiative to control the different mechanisms that trigger the commitment of biodiversity and irreversible climate changes arising from pollution is still very incipient, given that global initiatives on the subject emerged just over 50 years ago. Brazil is a territory that centralizes many of these discussions, as it still faces both political and economic obstacles in achieving a sustainable growth model as it was agreed through the United Nations 2030 Agenda. Even though there is little time left for the completion of these goals, much remains to be done, and despite the fulfillment of this deadline, the works will certainly need to be extended for much longer until an effective reorientation of consciousness occurs. Scientific researches and discussions are fundamental tools to the understanding of issues still little explored in this field.

Clinical Course, Genetic, and Immunohistochemical Characterization of Solid Pseudopapillary Tumor of the Pancreas (Frantz Tumors) in a Brazilian Cohort.

Frantz tumors or solid pseudopapillary pancreatic neoplasm (SPN) are rare exocrine neoplasms that carry a favorable prognosis; they represent up to 3% of all tumors located in the region of the pancreas and have specific age and gender predispositions. In recent years, the rising curve of diagnosis is entitled to the evolution and access of diagnostic imaging. In this paper, we have retrospectively reviewed and described the clinical course of 40 patients with SPN from three institutions in Brazil, who had their diagnosis between 2005 and 2020, and analyzed the clinicopathological, genetic, and surgical aspects of these individuals. In accordance with the literature, most patients were women, 60% with unspecified symptoms at diagnosis, with tumors mainly located in the body and tail of the pancreas, of whom 70% underwent a distal pancreatectomy with sparing splenectomy as a standard procedure, and none of the cases have experienced recurrence to date. Surgery still remains the mainstay of treatment given the low metastatic potential, but more conservative approaches as observed in this cohort are evolving to become the standard of care. Herein, we present an in-depth analysis of cases focusing on the latest literature and report some of the smallest tumor cases in the literature. To our knowledge, this is the first report evaluating germline genetic testing and presenting a case of detected Li-Fraumeni syndrome.

Gestational and Neonatal Outcomes in Cities in the Largest Coal Mining Region in Brazil.

Brazil has one of the largest mineral coal reserves in the world. More than 40% of this ore is in the Candiota Mine, in the extreme south of Brazil, which was previously identified as a hotspot of environmental pollution. In addition, an important part of Brazil's population suffers from socioeconomic vulnerability. Since there is no information on unfavorable gestational and neonatal outcomes associated with these problems, we conducted a cross-sectional study with 1950 mother-child binomials, aiming to evaluate the association between these outcomes and air pollution as well as socioeconomic, demographic and health variables in seven cities in the region. Of the total births, 11.6% were preterm and 9.5% of neonates had low birth weight (<2500 g). These conditions were also associated with skin color, previous abortions, birth type and prenatal care, as well as exposure to higher levels of coarse particulate matter (PM10) during the first trimester of pregnancy. Regarding air pollutants, although the daily limits for PM10 were exceeded on less than 5% of days, the annual average overtook the values proposed by WHO. Thus, we concluded that prematurity and low birth weight in this region are related to air pollution, and to socioeconomic variables and health care.

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis.

Neoadjuvant chemotherapy is considered a new treatment option for potentially resectable pancreatic cancer. However, data are not well established on overall survival and delaying surgery in resectable pancreatic cancer, as well as on those patients that ultimately cannot undergo surgery. We analyzed pancreatic cancer patients treated in a tertiary hospital from January 2016 to December 2020. Patients with resectable stage I and II pancreatic cancer were evaluated regarding surgery, neoadjuvant treatment, and other clinical demographics. The survival function was estimated using the Kaplan-Meier method, and the relationship between the variables of interest and the overall survival (OS) was assessed by adopting the proportional regression Cox models. A total of 216 patients were evaluated. 81 of them with resectable/borderline resectable disease and 135 with unresectable /metastatic disease at diagnosis. Median OS for stage I and II disease were 36 and 28 months, respectively. For resectable pancreatic cancer median OS was 28 months, for borderline resectable pancreatic cancer median OS was 11 months. Median OS for stage III (locally advanced) and stage IV (metastatic) were 10 and 7 months, respectively (p < 0.0001). Median OS of 9 months were obtained for patients with stage I and II that did not undergo surgery compared to 25 months in patients that underwent surgery in any time (p < 0.001). Comparing patients with localized disease, median OS for patients treated with upfront surgery was 28 months, compared to 15 months in patients treated with neoadjuvant approach (p = 0.04). Most patients that did not undergo surgery have decline of performance status or disease progression on neoadjuvant treatment. On multivariable analysis in pancreatic cancer stages I and II, including age, sex, borderline or resectable disease, CA 19-9, positive lymph nodes and neoadjuvant treatment, the surgery was the only factor associated with improved overall survival (p = 0.04). Upfront surgery should still be considered a standard of care approach for resectable pancreatic cancer. Biomarker driven studies and randomized trials with combination therapies are necessary to address neoadjuvant chemotherapy and delaying surgery in purely resectable pancreatic cancer.

EGFR-RAD51 fusion in lung adenocarcinoma with systemic and intracranial response to osimertinib: A case report and review of the literature.

Comprehensive next-generation sequencing panels are leading to detection of rare gene fusion events. EFGR-RAD51 fusion is a rare oncogenic finding and clinical data for management of this condition is scarce. We report a widely metastatic non-small cell lung cancer in a never-smoker young male patient with sustained near-complete systemic and intracranial response to osimertinib, a third-generation EGFR tyrosine-kinase inhibitor (TKI). We also review the available data of other TKIs in this scenario and underscore the role of comprehensive molecular testing for NSCLC.