Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice.

BACKGROUND: New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) privileges real-world data. As part of the ongoing HTA, this study aimed to evaluate the effectiveness of palbociclib with aromatase inhibitors (AI) and compare it with the efficacy reported in PALOMA-2. METHODS: A population-based retrospective exposure cohort study was conducted including all patients initiating treatment in Portugal with palbociclib under early access use and registered in the National Oncology Registry. The primary outcome was progression free survival (PFS). Secondary outcomes considered included time to palbociclib failure (TPF), overall survival (OS), time to next treatment (TTNT), and proportion of patients discontinuing treatment due to  adverse events (AEs). The Kaplan-Meier method was used and median, 1- and 2-year survival rates were computed, with two-sided 95% confidence intervals (95%CI). STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were used. RESULTS: There were 131 patients included. Median follow-up was 28.3 months (IQR: 22.7-35.2) and median duration of treatment was 17.5 months (IQR: 7.8-29.1). Median PFS was 19.5 months (95%CI 14.2-24.2), corresponding to a 1-year PFS rate of 67.9% (95%CI 59.2-75.2) and a 2-year PFS rate of 42.0% (95%CI 33.5-50.3). Sensitivity analysis showed median PFS would increase slightly when excluding those not initiating treatment with the recommended dose, raising to 19.8 months (95%CI 14.4-28.9). By considering only patients meeting PALOMA-2 criteria, we could observe a major difference in treatment outcomes, with a mean PFS of 28.8 months (95%CI 19.4-36.0). TPF was 19.8 months (95%CI 14.2-24.9). Median OS was not reached. Median TTNT was 22.5 months (95%CI 18.0-29.8). A total of 14 patients discontinued palbociclib because of AEs (10.7%). CONCLUSIONS: Data suggest palbociclib with AI to have an effectiveness of 28.8 months, when used in patients with overlapping characteristics to those used in PALOMA-2. However, when used outside of these eligibility criteria, namely in patients with less favorable prognosis (e.g., presence of visceral disease), the benefits are inferior, even though still favorable.

Mechanisms protecting host cells against bacterial pore-forming toxins.

Pore-forming toxins (PFTs) are key virulence determinants produced and secreted by a variety of human bacterial pathogens. They disrupt the plasma membrane (PM) by generating stable protein pores, which allow uncontrolled exchanges between the extracellular and intracellular milieus, dramatically disturbing cellular homeostasis. In recent years, many advances were made regarding the characterization of conserved repair mechanisms that allow eukaryotic cells to recover from mechanical disruption of the PM membrane. However, the specificities of the cell recovery pathways that protect host cells against PFT-induced damage remain remarkably elusive. During bacterial infections, the coordinated action of such cell recovery processes defines the outcome of infected cells and is, thus, critical for our understanding of bacterial pathogenesis. Here, we review the cellular pathways reported to be involved in the response to bacterial PFTs and discuss their impact in single-cell recovery and infection.

MouR controls the expression of the Listeria monocytogenes Agr system and mediates virulence.

The foodborne pathogen Listeria monocytogenes (Lm) causes invasive infection in susceptible animals and humans. To survive and proliferate within hosts, this facultative intracellular pathogen tightly coordinates the expression of a complex regulatory network that controls the expression of virulence factors. Here, we identified and characterized MouR, a novel virulence regulator of Lm. Through RNA-seq transcriptomic analysis, we determined the MouR regulon and demonstrated how MouR positively controls the expression of the Agr quorum sensing system (agrBDCA) of Lm. The MouR three-dimensional structure revealed a dimeric DNA-binding transcription factor belonging to the VanR class of the GntR superfamily of regulatory proteins. We also showed that by directly binding to the agr promoter region, MouR ultimately modulates chitinase activity and biofilm formation. Importantly, we demonstrated by in vitro cell invasion assays and in vivo mice infections the role of MouR in Lm virulence.

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins.

During infection, plasma membrane (PM) blebs protect host cells against bacterial pore-forming toxins (PFTs), but were also proposed to promote pathogen dissemination. However, the details and impact of blebbing regulation during infection remained unclear. Here, we identify the endoplasmic reticulum chaperone Gp96 as a novel regulator of PFT-induced blebbing. Gp96 interacts with non-muscle myosin heavy chain IIA (NMHCIIA) and controls its activity and remodelling, which is required for appropriate coordination of bleb formation and retraction. This mechanism involves NMHCIIA-Gp96 interaction and their recruitment to PM blebs and strongly resembles retraction of uropod-like structures from polarized migrating cells, a process that also promotes NMHCIIA-Gp96 association. Consistently, Gp96 and NMHCIIA not only protect the PM integrity from listeriolysin O (LLO) during infection by Listeria monocytogenes but also affect cytoskeletal organization and cell migration. Finally, we validate the association between Gp96 and NMHCIIA in vivo and show that Gp96 is required to protect hosts from LLO-dependent killing.

Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro-inflammatory cytokines such as IL-1ß and TNF-α, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Expression of these cytokines can be modulated by polymorphisms such as rs16944 and rs1800629, respectively, both of which have been associated with febrile seizures (FS) and MTLE-HS development. The human leukocyte antigen (HLA) system has also been implicated in diverse epileptic entities, suggesting a variable role of this system in epilepsy. Our aim was to analyse the association between immunogenetic factors and MTLE-HS development. For that rs16944 (-511 T>C, IL-1ß), rs1800629 (-308 G>A, TNF-α) polymorphisms and HLA-DRB1 locus were genotyped in a Portuguese Population. METHODS: We studied 196 MTLE-HS patients (108 females, 88 males, 44.7 ± 12.0 years, age of onset = 13.6 ± 10.3 years, 104 with FS antecedents) and 282 healthy controls in a case-control study. RESULTS: The frequency of rs16944 TT genotype was higher in MTLE-HS patients compared to controls (14.9% in MTLE-HS vs. 7.7% in controls, p = 0.021, OR [95% CI] = 2.20 [1.13-4.30]). This association was independent of FS antecedents. No association was observed between rs1800629 genotypes or HLA-DRB1 alleles and MTLE-HS susceptibility. Also, no correlation was observed between the studied polymorphisms and disease age of onset. CONCLUSION: The rs16944 TT genotype is associated with MTLE-HS development what may be explained by the higher IL-1ß levels produced by this genotype. High IL-1ß levels may have neurotoxic effects or imbalance neurotransmission leading to seizures.

Src-dependent tyrosine phosphorylation of non-muscle myosin heavy chain-IIA restricts Listeria monocytogenes cellular infection.

Bacterial pathogens often interfere with host tyrosine phosphorylation cascades to control host responses and cause infection. Given the role of tyrosine phosphorylation events in different human infections and our previous results showing the activation of the tyrosine kinase Src upon incubation of cells with Listeria monocytogenes, we searched for novel host proteins undergoing tyrosine phosphorylation upon L. monocytogenes infection. We identify the heavy chain of the non-muscle myosin IIA (NMHC-IIA) as being phosphorylated in a specific tyrosine residue in response to L. monocytogenes infection. We characterize this novel post-translational modification event and show that, upon L. monocytogenes infection, Src phosphorylates NMHC-IIA in a previously uncharacterized tyrosine residue (Tyr-158) located in its motor domain near the ATP-binding site. In addition, we found that other intracellular and extracellular bacterial pathogens trigger NMHC-IIA tyrosine phosphorylation. We demonstrate that NMHC-IIA limits intracellular levels of L. monocytogenes, and this is dependent on the phosphorylation of Tyr-158. Our data suggest a novel mechanism of regulation of NMHC-IIA activity relying on the phosphorylation of Tyr-158 by Src.

Health care factors associated with survival among women with breast cancer on hormone therapy in Rio de Janeiro, Brazil, 2004 - 2010.

Objectives To better understand the role that health care plays in breast cancer survival by investigating the effects that hormone therapy adherence and other select health care variables, adjusted for clinical and sociodemographic factors, had among a population of women in Rio de Janeiro, Brazil. Methods This was a longitudinal study based on secondary data of 5 861 women treated with hormone therapy (tamoxifen or aromatase inhibitors) at the National Cancer Institute of Brazil (INCA), from 1 January 2004 - 29 October 2010. Four different sources of data were integrated for analysis: INCA Pharmacy Sector Dispensation System; Hospital-based Cancer Registry; Integrated Hospital System and INCA Absolute System; and Mortality Information System. Analyses explored the effects of adherence to hormone therapy, disease care aspects, and sociodemographic, behavioral, and clinical variables, on the time of survival, using Kaplan-Meier and Cox proportional hazards models. Results The general survival rate was 94% in the first year after initiation of hormone therapy, and 71% in the fifth year. The Cox model indicated a higher hazard of death among women smokers, with more hospitalizations, more exams, and, among those who used, who used only aromatase inhibitors, as hormone therapy modality. The hazard was lower among women with a partner (stable relationship), a high school or college education a family history of cancer, and those who were treated by a mastologist, oncologist, and/or psychotherapist, who underwent surgery, and who adhered to hormone therapy. Conclusions The study indicated more vulnerable sub-groups and the aspects of care that provide best results, bringing new knowledge to improve assistance to this group of women.

Adherence to hormone therapy among women with breast cancer.

BACKGROUND: Despite the excellent results obtained with hormone therapy, the long treatment period and the side effects associated with its use make patient adherence difficult. Moreover, certain aspects of health care can mitigate or exacerbate non-adherence. This study aimed to identify the factors associated with adherence to hormone therapy for breast cancer, with the goal of contributing to the reformulation of the care process and to improvements in outcomes. METHOD: This was a retrospective longitudinal study based on secondary data. The study integrated and analyzed data from a cohort of 5,861 women with breast cancer who were identified in the databases of the Brazilian National Cancer Institute [Instituto Nacional de Câncer - INCA] and the Unified Health System [Sistema Único de Saúde - SUS]. All of the patients were treated at INCA, which dispenses free medication, and the follow-up period lasted from 01/01/2004 to 10/29/2010. The outcome of interest was hormone treatment adherence, which was defined as the possession of medication, and a logistic regression model was employed to identify the socio-demographic, behavioral, clinical, and health care variables that were independently associated with the variations in this outcome. RESULTS: The proportion of women who adhered to hormone therapy was 76.3%. The likelihood of adherence to hormone therapy increased with each additional year of age, as well as among women with a secondary or higher level education, those with a partner, those who underwent surgery, those who had more consultations with a breast specialist and clinical oncologist, and those who underwent psychotherapy; the effect for the latter increased with each additional consultation. Conversely, the likelihood of adherence was lower among patients at a non-curable stage, those who were alcohol drinkers, those who received chemotherapy, those who had undergone more tests and had more hospitalizations, and those who used tamoxifen and combined aromatase inhibitors. CONCLUSION: This study shows that approximately a quarter of the women with breast cancer did not adhere to hormone treatment, thus risking clinical responses below the expected standards. It also identifies the most vulnerable subgroups in the treatment process and the aspects of care that provide better results.

[Difficult situations and feelings in palliative oncology care]. / Situações difíceis e sentimentos no cuidado paliativo oncológico.

The act of caring for people in pain, shortness of breath, and imminent death on a daily basis can intensify difficult situations for health professionals. However, difficult situations are rarely discussed in the services and in the professional training process. This study aimed to analyze difficult situations and feelings that emerge from healthcare. This is a phenomenological and qualitative study based on 30 difficult situations of health professionals who work exclusively in palliative oncological care. The interviews were conducted from August to February 2020. The results show that the main difficulties were motivated by identification (when the professional recognizes similarities in the patient they are caring for), a bad death (with suffering), caring for young patients, the death of a mother with a small child, and when there was a divergence between what the professional proposed and the patient's choice. There was a relationship between types of difficult situations and professional category. The professionals expressed both unpleasant feelings (sadness, impotence, anguish, fear) and pleasant feelings (compassion, gratitude). The results show that the concealment of the dying process throughout the societies' development turned it into a taboo, causing distress even in those who work in palliative care. They also show an important subjective dimension of care, usually neglected, which generates suffering, but also resignification. To properly provide care, health professionals must find meaning in the work, made possible by the modification of the their internal mindset via experience, which generates transformation, new meaning, and knowledge from praxis.

O ato de cuidar cotidianamente de pessoas com dor, falta de ar e em morte iminente pode potencializar situações difíceis para profissionais da área. Contudo, raramente são discutidas nos serviços e no processo de formação profissional. Objetivou-se, então, analisar situações difíceis e sentimentos que emergem do cuidado de saúde. Esta é uma pesquisa de perspectiva fenomenológica e qualitativa, baseada em 30 situações difíceis de profissionais de saúde que atuam exclusivamente no cuidado paliativo oncológico. As entrevistas foram realizadas de agosto de 2019 a fevereiro de 2020. Os resultados mostram que as principais dificuldades foram motivadas pela identificação (quando o profissional vê semelhança com o paciente que cuida), morte ruim (com sofrimento), quando o paciente era jovem, morte de mãe com filho pequeno e quando havia divergência entre o proposto pelo profissional e a recusa do paciente. Percebeu-se relação entre tipos de situações difíceis e categoria profissional. Os profissionais expressaram tanto sentimentos desagradáveis (tristeza, impotência, angústia, medo) quanto agradáveis (compaixão, gratidão). Os resultados mostram que o ocultamento do processo de morrer ao longo do desenvolvimento civilizatório transformou-o em tabu, angustiante inclusive para quem trabalha com cuidados paliativos. Contribuem, também, para mostrar uma importante dimensão subjetiva do cuidado, geralmente negligenciada, que gera sofrimento, mas também ressignificação. Para que alguém cumpra seu propósito, é necessário encontrar sentido no trabalho, possibilitado pela modificação do estado interno do profissional pela experiência, que gera transformação e novo significado e saber a partir da práxis.

El acto de atender diariamente a personas con dolor, dificultad para respirar y muerte inminente puede potenciar situaciones difíciles para los profesionales del área. Sin embargo, casi nunca se discuten en los servicios y en el proceso de formación profesional. El objetivo fue analizar situaciones difíciles y sentimientos que emergen del cuidado de la salud. Investigación de perspectiva fenomenológica y cualitativa, basada en 30 situaciones difíciles de profesionales de la salud que actúan exclusivamente en el cuidado paliativo oncológico. Las entrevistas se realizaron entre agosto y febrero de 2020. Los resultados enseñan que las principales dificultades se motivaron por la identificación (cuando el profesional ve similitud con el paciente que atiende), mala muerte (con sufrimiento), cuando el paciente era joven, muerte de una madre con hijo pequeño y cuando hubo discrepancia entre lo propuesto por el profesional y el rechazo del paciente. Se observó una relación entre tipos de situaciones difíciles y categoría profesional. Los profesionales expresaron tanto sentimientos desagradables (tristeza, impotencia, angustia, miedo) como agradables (compasión, gratitud). Los resultados indican que ocultar el proceso de morir a lo largo del desarrollo de la civilización lo convirtió en un tabú e, incluso, es angustiante para las personas que trabajan con cuidados paliativos. También contribuye a mostrar una importante dimensión subjetiva del cuidado, generalmente ignorada, que genera sufrimiento, pero también resignificación. Para que cumpla con su propósito es necesario encontrar sentido en el trabajo, posibilitado por la modificación del estado interno del profesional a través de la experiencia, generando transformación y un nuevo significado y conocimiento a partir de la praxis.

Transition of human γ-tubulin ring complex into a closed conformation during microtubule nucleation.

Microtubules are essential for intracellular organization and chromosome segregation. They are nucleated by the γ-tubulin ring complex (γTuRC). However, isolated vertebrate γTuRC adopts an open conformation that deviates from the microtubule structure, raising the question of the nucleation mechanism. In this study, we determined cryo-electron microscopy structures of human γTuRC bound to a nascent microtubule. Structural changes of the complex into a closed conformation ensure that γTuRC templates the 13-protofilament microtubules that exist in human cells. Closure is mediated by a latch that interacts with incorporating tubulin, making it part of the closing mechanism. Further rearrangements involve all γTuRC subunits and the removal of the actin-containing luminal bridge. Our proposed mechanism of microtubule nucleation by human γTuRC relies on large-scale structural changes that are likely the target of regulation in cells.

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules.

During mitosis, microtubules in the spindle turn over continuously. At spindle poles, where microtubule minus ends are concentrated, microtubule nucleation and depolymerization, the latter required for poleward microtubule flux, happen side by side. How these seemingly antagonistic processes of nucleation and depolymerization are coordinated is not understood. Here, we reconstitute this coordination in vitro combining different pole-localized activities. We find that the spindle pole-localized kinesin-13 KIF2A is a microtubule minus-end depolymerase, in contrast to its paralog MCAK. Due to its asymmetric activity, KIF2A still allows microtubule nucleation from the γ-tubulin ring complex (γTuRC), which serves as a protective cap shielding the minus end against KIF2A binding. Efficient γTuRC uncapping requires the combined action of KIF2A and a microtubule severing enzyme, leading to treadmilling of the uncapped microtubule driven by KIF2A. Together, these results provide insight into the molecular mechanisms by which a minimal protein module coordinates microtubule nucleation and depolymerization at spindle poles consistent with their role in poleward microtubule flux.

Src-Dependent NM2A Tyrosine Phosphorylation Regulates Actomyosin Remodeling.

Non-muscle myosin 2A (NM2A) is a key cytoskeletal enzyme that, along with actin, assembles into actomyosin filaments inside cells. NM2A is fundamental for cell adhesion and motility, playing important functions in different stages of development and during the progression of viral and bacterial infections. Phosphorylation events regulate the activity and the cellular localization of NM2A. We previously identified the tyrosine phosphorylation of residue 158 (pTyr158) in the motor domain of the NM2A heavy chain. This phosphorylation can be promoted by Listeria monocytogenes infection of epithelial cells and is dependent on Src kinase; however, its molecular role is unknown. Here, we show that the status of pTyr158 defines cytoskeletal organization, affects the assembly/disassembly of focal adhesions, and interferes with cell migration. Cells overexpressing a non-phosphorylatable NM2A variant or expressing reduced levels of Src kinase display increased stress fibers and larger focal adhesions, suggesting an altered contraction status consistent with the increased NM2A activity that we also observed. We propose NM2A pTyr158 as a novel layer of regulation of actomyosin cytoskeleton organization.

Unhoused people: stigma, prejudice, and health care strategies. / População em situação de rua: estigmas, preconceitos e estratégias de cuidado em saúde.

Historical, social representations about stigma and prejudice related to unhoused people cause psychological distress, feeling of shame, and withdrawal from family and social relationships. This paper aimed to understand how unhoused people and health professionals perceive, reproduce, elaborate, and address the representations produced by their social conditions. This qualitative research employed participant observation, interviews with 24 unhoused people, and a focus group with professionals from the services providing care to the unhoused people. The study was conducted in Rio de Janeiro, Brazil, where crack use is very prevalent. An analysis was performed using the phenomenological narrative method. Stereotyping conjures the self-image of an unworthy, unwanted person, which justifies daily discrimination and, above all, the loss of the most critical condition of all beings, namely, their human condition, besides legitimizing the lack of care and violence against them. Deepening the relationship between prejudice and discrimination in the context of vulnerable populations and health services can assist therapeutic projects that promote the reduction of psychological distress, better care, and social recognition of citizenship of the unhoused people.

Representações sociais históricas sobre estigma e preconceito relacionado à População em Situação de Rua (PSR) provocam sofrimento psíquico, sentimento de vergonha, afastamento das relações familiares e sociais. Esse artigo objetivou entender como a PSR e os profissionais de saúde percebem, reproduzem, elaboram e lidam as representações produzidas por suas condições sociais. Pesquisa qualitativa, que envolve Observação Participante; Entrevistas com 24 PSR e Grupo Focal com profissionais dos serviços que prestam cuidado à PSR. O estudo foi realizado no município do Rio de Janeiro em local onde o uso do crack tem prevalência importante. Análise foi realizada pelo método da narrativa fenomenológica. O estereótipo provoca uma autoimagem de pessoa indigna, indesejada, que justifica discriminações cotidianas e, sobretudo, a perda da condição mais importante de todos os seres: sua condição humana, além de legitimar desassistência e violência contra elas. Aprofundar as relações entre preconceitos e discriminações em contexto de população vulnerável e serviços de saúde, pode auxiliar projetos terapêuticos que promovam diminuição do sofrimento psíquico, melhor assistência e reconhecimento social de cidadania da PSR.

Real-world effectiveness of palbociclib plus fulvestrant in advanced breast cancer: Results from a population-based cohort study.

BACKGROUND: Real-world (RW) data may provide valuable information on the effectiveness and safety of medicines, which is particularly relevant for clinicians, patients and third-party payers. Evidence on the effectiveness of palbociclib plus fulvestrant is scarce, which highlights the need of additional studies. The aim of this study was to evaluate the effectiveness of palbociclib plus fulvestrant in advanced breast cancer (ABC). MATERIALS AND METHODS: We conducted a population-based retrospective cohort study and cases of interest were identified through the Portuguese National Cancer Registry database and additional data sources. Patients aged≥18 years, diagnosed with ABC and exposed to palbociclib plus fulvestrant between May 31, 2017 and March 31, 2019 were included. Patients were followed-up until death or cut-off date (February 28, 2021). Primary outcome was rw-progression-free survival (rwPFS). Secondary outcomes were rw-overall survival (rwOS), rw-time to palbociclib failure (rwTPF) and rw-time to next treatment (rwTTNT). RESULTS: A total of 210 patients were included. Median age was 58 years (range 29-83) and 99.05% were female. Median follow-up time was 23.22 months and, at cut-off date, treatment had been discontinued in 189 patients, mainly due to disease progression (n = 152). Median rwPFS was 7.43 months (95% confidence interval [CI] 6.28-9.05) and 2-year rwPFS was 16.65% (95%CI 11.97-22.00). Median rwOS was 24.70 months (95%CI 21.58-29.27), median rwTPF was 7.5 months (95%CI 6.51-9.08) and median rwTTNT was 11.74 months (95%CI 10.33-14.08). CONCLUSION: Palbociclib plus fulvestrant seems an effective treatment for ABC in real-world context. Compared to registrations studies, rwPFS and rwOS were shorter in real-life setting.

Pharmacokinetics of oral levonorgestrel and ethinylestradiol in women after Roux-en-Y gastric bypass surgery.

BACKGROUND: Most patients undergoing Roux-en-Y gastric bypass (RYGB) are women in reproductive age. It is not known if bariatric surgery affects the pharmacokinetics of oral contraceptives. OBJECTIVES: The primary objective was to evaluate ethinylestradiol (EE) and levonorgestrel (LNG) absorption in women undergoing RYGB, compared with nonoperated controls matched by age and body mass index (BMI). A secondary objective was to assess whether the time since surgery and BMI in the postoperative period influenced the absorption parameters. SETTING: University hospital, Brazil. METHODS: This study was designed to compare the maximum plasma concentration (Cmax), the time to the peak plasma level (Tmax), the area under the curve (AUC0-8 and AUC0-∞) after a single dose of a combined oral contraceptive with 0.03 mg EE and 0.15 mg LNG among 20 women after RYGB and 20 controls. Blood samples were obtained for 8 hours. RESULTS: The mean LNG AUC0-8 and LNG AUC0-∞ were higher in RYGB group (P = .048 and P = .004, respectively). We found a positive correlation for LNG AUC0-8 (P = .045) and AUC0-∞ (P = .004) and the time since surgery, and we found a negative correlation for LNG Cmax (P = .018), AUC0-8 (P = .003), and AUC0-∞ (P = .001) and BMI. CONCLUSION: No significant differences were found in oral EE pharmacokinetics. The operated group showed higher mean LNG AUC0-8 and AUC0-∞ but it was not considered clinically significant. The present study suggests that RYGB may not affect EE and LNG absorption.

The way of life of the unhoused people as an enhance for COVID-19 care.

OBJECTIVE: To analyze the way of life of the unhoused people to enhance health care in the pandemic. METHODS: A qualitative, interdisciplinary research, with participant observation and 24 interviews with the unhoused people. Empirical categories and bibliographic search on this population and COVID-19 guided simple actions aimed at care. RESULTS: The group at greatest risk for COVID-19 use drugs compulsively; starves constantly; discontinues drug treatment for tuberculosis, HIV, and diabetes; has underdiagnosis of Depression; has difficulty sheltering and uses inhaled drugs. This way of life increases the risk of worsening COVID-19 and brings great challenges to health services. Several proposals to guide care considered these results and the new routine caused by the pandemic. FINAL CONSIDERATIONS: The way of life of the studied population increased their vulnerability in the pandemic, as well as the perception of risk of disease transmission by the population in general.

Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function.

Non-muscle myosin 2A (NM2A) is a motor cytoskeletal enzyme with crucial importance from the early stages of development until adulthood. Due to its capacity to convert chemical energy into force, NM2A powers the contraction of the actomyosin cytoskeleton, required for proper cell division, adhesion and migration, among other cellular functions. Although NM2A has been extensively studied, new findings revealed that a lot remains to be discovered concerning its spatiotemporal regulation in the intracellular environment. In recent years, new functions were attributed to NM2A and its activity was associated to a plethora of illnesses, including neurological disorders and infectious diseases. Here, we provide a concise overview on the current knowledge regarding the structure, the function and the regulation of NM2A. In addition, we recapitulate NM2A-associated diseases and discuss its potential as a therapeutic target.

10-Phenyl-10H-phenoxazine-4,6-diol tetra-hydro-furan monosolvate.

In the crystalline state of the title solvate, C18H13NO3·C4H8O, hydrogen-bonding inter-actions between hydroxyl groups on a phenoxazine backbone and the tetra-hydro-furan solvent are observed that suggest the ability for this compound to act as a chelating ligand. The O⋯O donor-acceptor distances for this hydrogen bonding are 2.7729 (15) and 2.7447 (15) Å. The three-ring backbone of the phenoxazine bends out of planarity by 18.92 (3)°, as computed using mean planes that encompass each half of the three-ring structure, with the central N and O atoms forming the line of flexion. In the crystal, a π-π stacking arrangement exists between inversion-related mol-ecules, with a centroid-to-centroid distance of 3.6355 (11) Å. In the disordered tetra-hydro-furan solvate, all atoms except oxygen were modeled over two positions, with occupancies of 0.511 (8) and 0.489 (8).

Electrocardiogram Beat-Classification Based on a ResNet Network.

When dealing with electrocardiography (ECG) the main focus relies on the classification of the heart's electric activity and deep learning has been proving its value over the years classifying the heartbeats, exhibiting great performance when doing so. Following these assumptions, we propose a deep learning model based on a ResNet architecture with convolutional 1D layers to classify the beats into one of the 4 classes: normal, atrial premature contraction, premature ventricular contraction and others. Experimental results with MIT-BIH Arrhythmia Database confirmed that the model is able to perform well, obtaining an accuracy of 96% when using stochastic gradient descent (SGD) and 83% when using adaptive moment estimation (Adam), SGD also obtained F1-scores over 90% for the four classes proposed. A larger dataset was created and tested as unforeseen data for the trained model, proving that new tests should be done to improve the accuracy of it.

Situações difíceis e sentimentos no cuidado paliativo oncológico / Difficult situations and feelings in palliative oncology care / Situaciones difíciles y sentimientos en el cuidado paliativo oncológico

O ato de cuidar cotidianamente de pessoas com dor, falta de ar e em morte iminente pode potencializar situações difíceis para profissionais da área. Contudo, raramente são discutidas nos serviços e no processo de formação profissional. Objetivou-se, então, analisar situações difíceis e sentimentos que emergem do cuidado de saúde. Esta é uma pesquisa de perspectiva fenomenológica e qualitativa, baseada em 30 situações difíceis de profissionais de saúde que atuam exclusivamente no cuidado paliativo oncológico. As entrevistas foram realizadas de agosto de 2019 a fevereiro de 2020. Os resultados mostram que as principais dificuldades foram motivadas pela identificação (quando o profissional vê semelhança com o paciente que cuida), morte ruim (com sofrimento), quando o paciente era jovem, morte de mãe com filho pequeno e quando havia divergência entre o proposto pelo profissional e a recusa do paciente. Percebeu-se relação entre tipos de situações difíceis e categoria profissional. Os profissionais expressaram tanto sentimentos desagradáveis (tristeza, impotência, angústia, medo) quanto agradáveis (compaixão, gratidão). Os resultados mostram que o ocultamento do processo de morrer ao longo do desenvolvimento civilizatório transformou-o em tabu, angustiante inclusive para quem trabalha com cuidados paliativos. Contribuem, também, para mostrar uma importante dimensão subjetiva do cuidado, geralmente negligenciada, que gera sofrimento, mas também ressignificação. Para que alguém cumpra seu propósito, é necessário encontrar sentido no trabalho, possibilitado pela modificação do estado interno do profissional pela experiência, que gera transformação e novo significado e saber a partir da práxis.

The act of caring for people in pain, shortness of breath, and imminent death on a daily basis can intensify difficult situations for health professionals. However, difficult situations are rarely discussed in the services and in the professional training process. This study aimed to analyze difficult situations and feelings that emerge from healthcare. This is a phenomenological and qualitative study based on 30 difficult situations of health professionals who work exclusively in palliative oncological care. The interviews were conducted from August to February 2020. The results show that the main difficulties were motivated by identification (when the professional recognizes similarities in the patient they are caring for), a bad death (with suffering), caring for young patients, the death of a mother with a small child, and when there was a divergence between what the professional proposed and the patient's choice. There was a relationship between types of difficult situations and professional category. The professionals expressed both unpleasant feelings (sadness, impotence, anguish, fear) and pleasant feelings (compassion, gratitude). The results show that the concealment of the dying process throughout the societies' development turned it into a taboo, causing distress even in those who work in palliative care. They also show an important subjective dimension of care, usually neglected, which generates suffering, but also resignification. To properly provide care, health professionals must find meaning in the work, made possible by the modification of the their internal mindset via experience, which generates transformation, new meaning, and knowledge from praxis.

El acto de atender diariamente a personas con dolor, dificultad para respirar y muerte inminente puede potenciar situaciones difíciles para los profesionales del área. Sin embargo, casi nunca se discuten en los servicios y en el proceso de formación profesional. El objetivo fue analizar situaciones difíciles y sentimientos que emergen del cuidado de la salud. Investigación de perspectiva fenomenológica y cualitativa, basada en 30 situaciones difíciles de profesionales de la salud que actúan exclusivamente en el cuidado paliativo oncológico. Las entrevistas se realizaron entre agosto y febrero de 2020. Los resultados enseñan que las principales dificultades se motivaron por la identificación (cuando el profesional ve similitud con el paciente que atiende), mala muerte (con sufrimiento), cuando el paciente era joven, muerte de una madre con hijo pequeño y cuando hubo discrepancia entre lo propuesto por el profesional y el rechazo del paciente. Se observó una relación entre tipos de situaciones difíciles y categoría profesional. Los profesionales expresaron tanto sentimientos desagradables (tristeza, impotencia, angustia, miedo) como agradables (compasión, gratitud). Los resultados indican que ocultar el proceso de morir a lo largo del desarrollo de la civilización lo convirtió en un tabú e, incluso, es angustiante para las personas que trabajan con cuidados paliativos. También contribuye a mostrar una importante dimensión subjetiva del cuidado, generalmente ignorada, que genera sufrimiento, pero también resignificación. Para que cumpla con su propósito es necesario encontrar sentido en el trabajo, posibilitado por la modificación del estado interno del profesional a través de la experiencia, generando transformación y un nuevo significado y conocimiento a partir de la praxis.