Resistance to KRAS inhibition in advanced non-small cell lung cancer.

Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an 'undruggable' target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS-mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS, its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.

Frequency of low-dose dexamethasone suppression test (LDDST) response patterns and their correlation with clinicopathologic signs in dogs suspected of having Cushing's syndrome: A retrospective study.

A retrospective cross-sectional study was conducted to assess the frequency of low-dose dexamethasone suppression test (LDDST) patterns in canine patients that had clinicopathologic signs consistent with Cushing's syndrome (CS). Medical records for patients of interest (N = 128) were reviewed between January 2014 and December 2020 to analyse and classify LDDST results based upon the following patterns: lack of suppression, partial suppression, complete suppression, escape, or inverse. Complete suppression, lack of suppression, partial suppression, escape, and inverse patterns were identified in 39.1%, 31.2%, 14.1%, 10.1% and 5.5% of cases respectively. LDDST results were also evaluated with respect to clinical signs, serum alkaline phosphatase (ALP) activity, urine specific gravity (USG) and adrenal ultrasonographic findings. There was no association between LDDST patterns and clinical signs (p = 0.11), increased ALP (p = 0.32), USG (p = 0.33) or adrenal ultrasonographic findings (p = 0.19). In all dogs that demonstrated complete suppression or an inverse pattern, CS was excluded by the attending clinician. The diagnosis of CS was also excluded without further exploration in 23.1%, 7.5% and 5.6% of dogs that demonstrated an escape pattern, lack of suppression and partial suppression pattern, respectively. These results suggest that the clinical significance of LDDST patterns, particularly escape and inverse patterns, are misunderstood by some clinicians, leading them to prematurely exclude the diagnosis of CS.

Development and Validation of the Serious Educational Game in Nursing Appraisal Scale.

OBJECTIVES: This study aims to develop and validate the Serious Educational Game in Nursing Appraisal Scale (SEGiNAS), a tool designed to evaluate the implementation of serious games within nurse education contexts of quantity of process, quality of process, and learning outcomes. METHODS AND MATERIALS: This methodological and psychometric study aimed to develop and validate a scale. The item generation phase was based on the cognitive theory of multimedia learning, resulting in a 20-item scale. The validation phase involved evaluating the psychometric scale by surveying 160 Portuguese nurses. RESULTS: A factor analysis revealed a three-factor structure corresponding to the scale's designed dimensions, explaining a total variance of 64.5%. The scale demonstrated high internal consistency for all factors, including engagement and teaching effectiveness (0.925), learning impact and practical application (0.883), and content relevance and clarity (0.848). The dimensions were engagement and teaching effectiveness, learning impact and practical application, and content relevance and clarity. CONCLUSIONS: The SEGiNAS scale represents a valid and reliable tool for evaluating serious games in nursing education. Its development fills an existing gap in assessing the teaching-learning process with serious games. This study was not registered.

Repeated human leukocyte antigens eplets, importance of typing the partner.

INTRODUCTION: Antibody-mediated rejection (AMR) is the most common cause of immune-mediated allograft failure after kidney transplant and impacts allograft survival. Previous sensitization is a major risk factor for development of donor specific antibodies (DSA). AMR can have a wide range of clinical features such as impaired kidney function, proteinuria/hypertension or can be subclinical. HLA molecules have specific regions of antigens binding antibodies called epitopes and eplets are considered essential components responsible for immune recognition. We present a patient with subclinical AMR 1 week post transplantation. CASE REPORT: A 48-year-old, caucasian woman with end-stage kidney disease (ESKD) secondary to autosomal dominant polycystic kidney disease (ADPKD) on peritoneal dialysis was registered in deceased donor waitlist. She was a hypersensitized patient from 3 prior pregnancies with a calculated panel reactive antibody of 93,48%. She was transplanted through kidney paired exchange donation with no evidence of DSA pre transplantation. Surgery and post-op were unremarkable with excellent and immediate graft function. Per protocol DSA levels on the 5th day was DR1 of 3300 MFI, with an increase in MFI by day 13 with 7820 MFI and a new B41 1979MFI. Allograft kidney biopsy findings were diagnostic of AMR and she was treated with immunoglobulin and plasmapheresis. As early onset AMR post transplantation was observed an anamnestic response was hypothesized from a previous exposure to allo-HLA. We decided to type her husband, her son's father, which was presented with DSA. Mismatch eplet analysis revealed a shared 41 T and 67LQ eplets between the donor and husband, responsible for the reactivity and new HLA class I B41 and HLA class II DR1 DSA, respectively. DISCUSSION: Shared eplets between the patient husband and donor was responsible for the alloimmune response and early development of DSAs. This case highlights the importance of early monitoring DSA levels in highly sensitized patients after transplant in order to promptly address and lower inflammatory damage. Mismatch eplet analysis can provide a thorough and precise evaluation of immune compatibility providing a useful technique to immune risk stratification, donor selection and post-transplant immunosuppressive therapy and monitoring.

Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves, and support memory consolidation.

Family Nursing Care during the Transition to Parenthood: A Scoping Review.

BACKGROUND: Family-centered care places the family at the core of care, with family nurses playing a pivotal role in supporting and guiding members through pregnancy and the transition to parenthood and acknowledging the significant adjustments during these phases. AIM: To map the evidence concerning family nurses' care for families during the transition to parenthood. METHOD: The scoping review followed the Joanna Briggs Institute (JBI) methodology, focusing on family-centered care during pregnancy adaptation and the initial months of parenthood. Using a PCC (population, concept, and context) strategy, the research covered various databases: Scopus; Web of Science; and CINAHL Complete, MedLine Complete, and MedicLatina by EBSCOhost. RESULTS: A Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) flow diagram was used to present the results. Eighteen articles were included, mainly from the Middle East and Europe, including cross-sectional studies and reviews. Key findings addressed the transitioning process to parenthood, the impact of family characteristics, and the role of family nurses in enhancing these processes. CONCLUSION: Home care is considered vital during this transition. Family nursing should concentrate on both individuals and the parental subsystem, addressing social determinants equitably. Through these efforts, they empower families to establish an optimal environment for children's development.

On the potential role of naturally occurring carboxylic organic acids as anti-infective agents: opportunities and challenges.

Carboxylic organic acids are intermediates of central carbon metabolic pathways (e.g. acetic, propionic, citric, and lactic acid) long known to have potent antimicrobial potential, mainly at acidic pHs. The food industry has been leveraging those properties for years, using many of these acids as preservatives to inhibit the growth of pathogenic and/or spoilage fungal and bacterial species. A few of these molecules (the most prominent being acetic acid) have been used as antiseptics since Hippocratic medicine, mainly to treat infected wounds in patients with burns. With the growth of antibiotic therapy, the use of carboxylic acids (and other chemical antiseptics) in clinical settings lost relevance; however, with the continuous emergence of multi-antibiotic/antifungal resistant strains, the search for alternatives has intensified. This prospective article raises awareness of the potential of carboxylic acids to control infections in clinical settings, considering not only their previous exploitation in this context (which we overview) but also the positive experience of their safe use in food preservation. At a time of great concern with antimicrobial resistance and the slow arrival of new antimicrobial therapeutics to the market, further exploration of organic acids as anti-infective molecules may pave the way to more sustainable prophylactic and therapeutic approaches.

Multiple basal infusion rates in open-loop insulin delivery systems: is there a metabolic benefit?

Objective: To evaluate glycemic control according to the number of daily basal rates (BRs) in type 1 diabetes patients using continuous subcutaneous insulin infusion (CSII). Subjects and methods: Cross-sectional study of patients treated with an open-loop CSII for at least 6 months and using a flash glucose monitoring system. Patients were divided into 2 groups: group 1 (G1) and group 2 (G2), with ≤4 and >4 BRs/24h, respectively. The groups were compared regarding HbA1c, time in range (TIR), time above range (TAR), time below range (TBR), glucose management indicator (GMI), glucose variability and data related to hypoglycemia. Regression models were performed. Results: The study included 99 patients (n = 55 in G1; n = 44 in G2). Median (Interquartile range) overall age was 30 (17) years, with 19.5 (48) and 51 (77) months of CSII use, respectively. The median number of different BRs was 3 (2) for G1 and 6 (2) for G2. There were no differences concerning age, sex, educational stage, weight, and insulin analog used. G2 had longer disease duration, longer CSII use, and higher total basal daily dose/kg. No significant differences regarding HbA1c, median glucose, GMI, TIR, TAR, and CV were found. G2 patients had more hypoglycemia, more asymptomatic hypoglycemia, and higher TBR. After adjusting for potential confounders, G1 maintained a lower risk of asymptomatic hypoglycemia. Conclusion: Programming open-loop CSII devices with more than 4 BRs does not improve metabolic control. Additionally, it seems to be a risk factor for hypoglycemia and was an independent predictor for asymptomatic hypoglycemia.

ERS International Congress 2023: highlights from the Thoracic Oncology Assembly.

Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients' quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational landscape, and the development of targeted therapies and immune checkpoint inhibitors, have led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the 2023 European Respiratory Society Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.

Multiple myeloma in dogs: Use of the cell block technique as a new diagnostic tool.

BACKGROUND: The diagnosis of multiple myeloma (MM) in dogs may be challenging and complex. The cell blocks are a diagnostic technique that allows the characterization of neoplastic cells and, therefore, might help in the diagnosis of atypical MM. OBJECTIVE: The objective of the present work is to describe three clinical cases in which the cell blocks and immunohistochemistry contributed to the definitive diagnosis of canine MM. METHODS: Three dogs, one female and two males, with different clinical signs, were presented for consultation with anemia, hyperproteinemia with monoclonal gammopathy, and the presence of plasmacytosis in the bone marrow. Cytologic analysis of the spleen was performed in two dogs and was suggestive of the presence of lymphocytes or plasma cells of a neoplastic nature in one of the cases and plasma cell hyperplasia associated with extramedullary hematopoiesis in the other. Given the hypotheses of lymphoid neoplasms with a plasma cell phenotype, cell blocks from aspiration punctures were performed for immunohistochemical analysis with anti-CD3, CD20, CD79αcy, PAX5, and MUM1 antibodies. RESULTS: The results revealed positive staining for MUM1 in 80% of the cells in the spleen cell block and for CD20 and MUM1 in 70% of the cells in the bone marrow cell blocks, with negative staining for the other antibodies. The immunophenotyping results allowed the diagnosis of MM in the three cases and excluded other lymphoid neoplasms. CONCLUSIONS: This work reinforces the importance of using cell blocks in the diagnosis of neoplasms by demonstrating their potential to aid the diagnosis of MM.

The potential of games for vulnerable groups like refugees: a scoping review.

OBJECTIVE: To map existing studies on the development of games for refugees, identifying the developed games, characteristics and possible application to health care. METHOD: A scoping review study, carried out in July 2022, using the MEDLINE® (Medical Literature Analysis and Retrieval System Online), CINAHL® (Cumulative Index to Nursing and Allied Health Literature), SPORTDiscus, Scopus, SciELO (Scientific Electronic Library Online), Psychology and Behavioral Sciences Collection, Cochrane Central Register of Controlled Trials databases. RESULTS: 8 studies were identified, with 8 different types of games published between 2016 and 2022. The characteristics of the games found essentially fall on their use to increase empathy towards refugees. CONCLUSION: This study identifies opportunities to strengthen the current body of knowledge in nursing, using games as ways of welcoming, training and integrating populations in situations of social vulnerability in which refugees find themselves.

The first Miocene fossils from coastal woodlands in the southern East African Rift.

The Miocene was a key time in the evolution of African ecosystems witnessing the origin of the African apes and the isolation of eastern coastal forests through an expanding arid corridor. Until recently, however, Miocene sites from the southeastern regions of the continent were unknown. Here, we report the first Miocene fossil teeth from the shoulders of the Urema Rift in Gorongosa National Park, Mozambique. We provide the first 1) radiometric ages of the Mazamba Formation, 2) reconstructions of paleovegetation in the region based on pedogenic carbonates and fossil wood, and 3) descriptions of fossil teeth. Gorongosa is unique in the East African Rift in combining marine invertebrates, marine vertebrates, reptiles, terrestrial mammals, and fossil woods in coastal paleoenvironments. The Gorongosa fossil sites offer the first evidence of woodlands and forests on the coastal margins of southeastern Africa during the Miocene, and an exceptional assemblage of fossils including new species.

Clinical findings and prognostic factors for mortality in hospitalized dogs with leishmaniosis: aretrospective study.

This retrospective study evaluated factors responsible for mortality of dogs hospitalized for Canine Leishmaniosis. Medical records of 31 dogs with leishmaniosis from a Portuguese Veterinary Teaching Hospital were examined between August 2018 and January 2022. Females (n = 18) and pure breed dogs (n = 27) were overrepresented, with higher frequency of Labrador Retriever (n = 4). Median age was 7 years (interquartile range=7). Most had historical findings of lethargy (n = 26) and the commonest clinicopathological abnormality was hypoalbuminemia (n = 26). Eleven dogs were classified as LeishVet stage II, 10 stage III and 10 stage IV. Fourteen dogs (45.2%) died or were euthanized, with azotemia, leukocytosis, stage IV, absence of diagnosis before hospitalization and lack of leishmaniosis specific treatment during hospitalization contributing to mortality. Absence of hypoalbuminemia and stages II/III increased survival. Mean hospitalization length prior to discharge was 5.41days ( ± 1.84) and diarrhea prolonged hospital stay.

ERS International Congress 2022: highlights from the Thoracic Oncology Assembly.

Thoracic malignancies are associated with a substantial public health burden. Lung cancer is the leading cause of cancer-related mortality worldwide, with significant impact on patients' quality of life. Following 2 years of virtual European Respiratory Society (ERS) Congresses due to the COVID-19 pandemic, the 2022 hybrid ERS Congress in Barcelona, Spain allowed peers from all over the world to meet again and present their work. Thoracic oncology experts presented best practices and latest developments in lung cancer screening, lung cancer diagnosis and management. Early lung cancer diagnosis, subsequent pros and cons of aggressive management, identification and management of systemic treatments' side-effects, and the application of artificial intelligence and biomarkers across all aspects of the thoracic oncology pathway were among the areas that triggered specific interest and will be summarised here.

Digitisation of patient preferences in palliative care: mobile app prototype.

BACKGROUND: Engaging in advance care planning can be emotionally challenging, but gamification and technology are suggested as a potential solution. OBJECTIVE: Present the development stages of a mobile app prototype to improve quality of life for patients in palliative care. DESIGN: The study started with a comprehensive literature review to establish a foundation. Subsequently, interviews were conducted to validate the proposed features of the mobile application. Following the development phase, usability tests were conducted to evaluate the overall usability of the mobile application. Furthermore, an oral questionnaire was administered to understand user satisfaction about the implemented features. RESULTS: A three-phase testing approach was employed based on the chosen user-centred design methodology to obtain the results. Three iterations were conducted, with improvements being made based on feedback and tested in subsequent phases. Despite the added complexity arising from the health status of patients in palliative care, the usability tests and implemented features received positive feedback from both patients and healthcare providers. CONCLUSION: The research findings have demonstrated the potential of digitisation in enhancing the quality of life for patients in palliative care. This was achieved through the implementation of patient-centred design, personalised care, the inclusion of social chatrooms and facilitating end-of-life discussions.

Assessing the recovery of Y chromosome microsatellites with population genomic data using Papio and Theropithecus genomes.

Y chromosome markers can shed light on male-specific population dynamics but for many species no such markers have been discovered and are available yet, despite the potential for recovering Y-linked loci from available genome sequences. Here, we investigated how effective available bioinformatic tools are in recovering informative Y chromosome microsatellites from whole genome sequence data. In order to do so, we initially explored a large dataset of whole genome sequences comprising individuals at various coverages belonging to different species of baboons (genus: Papio) using Y chromosome references belonging to the same genus and more distantly related species (Macaca mulatta). We then further tested this approach by recovering Y-STRs from available Theropithecus gelada genomes using Papio and Macaca Y chromosome as reference sequences. Identified loci were validated in silico by a) comparing within-species relationships of Y chromosome lineages and b) genotyping male individuals in available pedigrees. Each STR was selected not to extend in its variable region beyond 100 base pairs, so that loci can be developed for PCR-based genotyping of non-invasive DNA samples. In addition to assembling a first set of Papio and Theropithecus Y-specific microsatellite markers, we released TYpeSTeR, an easy-to-use script to identify and genotype Y chromosome STRs using population genomic data which can be modulated according to available male reference genomes and genomic data, making it widely applicable across taxa.

Plasma and urinary metanephrine and normetanephrine concentrations using liquid chromatography with tandem mass spectrometry in healthy cats and in a cat with pheochromocytoma.

BACKGROUND: Pheochromocytoma (PCC) is rare in cats and plasma (PL) and urinary (U) metanephrines (metanephrine [MN]; normetanephrine [NMN]) measurement is rarely described in cats. OBJECTIVES: We evaluated the utility of PL and U MNs measurement in 10 healthy cats and a cat with a confirmed diagnosis of pheochromocytoma (PheoCat), using liquid chromatography with tandem mass spectrometry (LC-MS-MS). METHODS: Urine and EDTA PL samples collected from each of the 10 cats and the PheoCat were promptly stored at -80°C and remained frozen until analysis. To evaluate U MNs stability, an additional urine sample collected from the healthy cats was refrigerated for 24 hours before freezing. Urinary creatinine concentration (Creat) was assessed using the same spot urine samples to calculate U MNs-to-creatinine ratios. RESULTS: The PL-MN and PL-NMN median concentrations of the healthy cats were 2.73 and 7.02 nmol/L, respectively. The median U-MN/Creat and U-NMN/Creat ratios were 70 and 139 µg/g, respectively. The PheoCat had a PL-MN of 3.68 nmol/L, PL-NMN of 66.27 nmol/L, U-MN/Creat of 179 µg/g, and U-NMN/Creat of 1262 µg/g. The PheoCat had markedly increased concentrations of both PL and U MNs when compared to the healthy cats. No significant difference was found between U MNs measured in urine samples that underwent 24 hours of refrigeration in comparison to those that were frozen immediately. CONCLUSIONS: We report preliminary reference intervals for PL and U MNs in cats using LC-MS-MS and the potential clinical applicability of these biomarkers for the diagnosis of PCC in cats.

Remediation of soils contaminated with total petroleum hydrocarbons through soil washing with surfactant solutions.

Soil fulfils vital functions for life on Earth and so, just like water and air, its protection from all sources of contamination is a major concern. However, the extensive use of petroleum derived products, either as energy sources or as commodities, leads to important environmental liabilities. Ex situ soil washing is a technology to concentrate contaminants, allowing soil cleaning and the reuse of extracted petroleum derived products. This work focuses on the optimization of ex situ soil washing process using surfactants, introducing an evaluation of the washing solution recycling and its after use safe disposal, promoting the reduction of raw materials, energy and water resources costs. Two surfactants, sodium dodecyl sulphate (SDS) and polyoxyethylene sorbitan monooleate (Tween 80), were tested in the decontamination of an artificially contaminated soil with engine lubricant oil waste. The optimization of the washing conditions, such as stirring speed, liquid-solid ratio, number of washing stages, and surfactant concentration, was carried out using a design of experiments (DOE) software, so that the maximum extraction efficiency of total petroleum hydrocarbons (TPHs) was achieved. A TPH removal efficiency of (80.7 ± 3.2)% was obtained with Tween 80 after 5 h of washing and (90.7 ± 2.8)% with SDS after 2 h at 200 rpm on an orbital shaker with a liquid to solid ratio (L/S) of 15. The potential for reuse of the washing solutions was evaluated. Finally, the discharge of the washing solution was considered using activated carbon to remove the surfactants and ensure its safe disposal.

Challenges to Systems of Long-Term Care: Mapping of the Central Concepts from an Umbrella Review.

The ageing of the population poses urgent challenges to the health and social protection sectors, including the need for greater adequacy and integration of health care services provided to older people. It is considered necessary and urgent to understand the state-of-the-art of community-based models of care for older people in institutional care and at home. This study aims to map the concepts that politicians and providers need to address through an umbrella review as a review method. Articles describing the structuring aspects of care models appropriate to the needs in long-term care and systematic reviews or meta-analyses targeting people aged 65 years or more were considered. A total of 350 studies met the inclusion criteria and were included in the review. The results identified the need to contribute to effective and more efficient integration and articulation of all the stakeholders, based essentially on professional care at the patient's homes, focused on their needs using the available technologies, empowering patients and families. Eight categories emerged that addressed factors and variables involved in care models for the long-term care needs of institutionalised and home-based older people as a guarantee of accessibility to healthcare and to enhance the well-being and quality of life of patients and family caregivers.

Rey-Osterrieth complex figure test: Comparison of traditional and qualitative scoring systems after unilateral temporal lobectomy.

OBJECTIVE: We compared the performance on the Rey-Osterrieth Complex Figure Test (ROCF) of patients that had undergone unilateral anterior temporal lobectomy under both Taylor's and Loring's scoring systems to identify the sensitivity and specificity of each item for differentiating visuospatial memory deficits. METHOD: We administered the ROCF to evaluate the visual memory of 37 left anterior temporal lobectomy (LATL) and 38 right anterior temporal lobectomy (RATL) patients with unilateral temporal lobe epilepsy who had undergone a standard unilateral anterior temporal lobectomy between 1996 and 2010. Fisher's exact and Qui-Quadrado tests were used to analyze the relationships between the qualitative variables. The Mann-Whitney U test was used to compare the quantitative variables from the right and left sides. RESULTS: RATL patients performed worse than LATL patients based on the total score for delayed recall (DR) (p = 0.012). The scoring system's showed a specificity of 97.2% & 78.9% and sensitivity of 10.5% & 62.2% on DR, for the Taylor and Loring systems respectively. Our detailed analysis of certain items showed that some differed between the groups in terms of the presence/absence, correct reproduction, and errors of those items. Loring' errors I, IV, and X on DR and errors IV and X on immediate recall were more frequent in the RATL group. CONCLUSIONS: The use of these two scoring systems combined may help maximize sensitivity and specificity with clinical populations. Further, our analyses showed that items could be clustered better and different weights could be given to them to maximize sensitivity and specificity.