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Drawing on the narrative inquiry method, a qualitative study of 49 engaged scholar interviews at the University of California, Davis was conducted to understand motivations for practicing engaged scholarship. Notwithstanding the significant contributions to understanding faculty motivations in this field, we argue that previous research details the roles of individuals and institutions of higher learning while leaving room for further theorization of other important influences and their intersections. The study findings reveal that faculty report intrinsic, extrinsic, and relational motivations that interact at multiple levels of influence. These multilevel motivational influences have implications for faculty recruitment and retention, implementation of institutional support strategies, and recognition in merit and promotion.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Primary fallopian tube carcinoma (PFTC) is seldom diagnosed preoperatively and is often mistaken for epithelial ovarian carcinoma (EOC). This report details a case of primary high-grade serous carcinoma (HGSC) of the fallopian tube, highlighting radiological and clinical indicators to aid in accurate diagnosis and avoid misdiagnosis. A 46-year-old premenopausal woman presented with symptoms and a transvaginal ultrasound (TVUS) indicating a malignant ovarian tumor. Further imaging with CT and MRI revealed a solid-cystic mass suggestive of a fallopian tube tumor rather than an ovarian origin. Oncological surgery confirmed the presence of a high-grade serous carcinoma in the fallopian tube. This case underscores the diagnostic challenges of PFTC and the superior sensitivity and specificity of MRI over CT and US in distinguishing adnexal lesions. Key MRI features such as the sausage-shaped mass and associated hematosalpinx were crucial in differentiating PFTC from EOC. The report emphasizes the importance of considering PFTC in differential diagnoses of adnexal masses to ensure accurate preoperative identification.

IntroductionDistinct androgen formulations have been used as gender-affirming hormone treatment, but little is known about the specific changes that may occur in the ovary depending on the testosterone preparation used. The study aims to evaluate the histological modifications of the ovarian tissue and the hormonal changes after gender-affirming surgery based on the testosterone preparation employed, such as testosterone cypionate or undecanoate.DesignUnicenter transversal cohort study.Materials and methodsSixty transmasculine persons before and after gender-affirming surgery. A histological examination of the ovaries was conducted, including the follicular population and the characterization of the ovarian stroma. Hormonal status (testosterone, estradiol, FSH, and LH) were also assessed before and after the procedure.ResultsThe median age of participants was similar between the two groups (27.9 vs. 26.7 years, p = 0.27). There were no differences in all hormonal determinations before gender-affirming surgery between the groups. After surgery, FSH levels increased significantly, especially in the testosterone undecanoate group compared to the cypionate group (72.3 vs. 38.3 U/L, p = 0.02), consistent with LH determinations (43.0 vs. 23.4 U/L, p = 0.02). However, no regimen modification was required for any individual. No statistical differences were observed in any parameter concerning the follicular population, nor were there any variances in the thickness of the tunica albuginea (p = 0.85) or the proportion of luteinized stromal cells. Nevertheless, there was a tendency toward increased luteinization in the testosterone cypionate group (88.2% vs. 76.9%, p > 0.05).ConclusionsIn a cohort of transmasculine individuals using different androgen preparations, histological analysis of ovarian tissue revealed comparable findings. Both groups exhibited similar follicular populations and comparable modifications in stromal tissue. However, significant differences were observed in hormonal profiles, although no modification in testosterone dosage was needed.

Objetivo: Diseñar un procedimiento para la gestión del proceso de formación del liderazgo en directivos de la provincia de Camagüey. Materiales y métodos: La propuesta se sustentó en una metodología cualitativa con enfoque descriptivo, en la que se aplicaron métodos de investigación científica tales como, el Inductivo-Deductivo, Analítico–Sintético y el Histórico–Lógico. Estos permitieron conocer las relaciones esenciales para el procedimiento propuesto, la formación del liderazgo y su gestión como proceso dinámico, sistémico y estructural. A través del estudio de documentos y la revisión bibliográfica, como métodos empíricos, se aportaron evidencias que enriquecieron cualitativamente el conocimiento precedente, lo que propició el desarrollo de la propuesta y la determinación de potencialidades para su estudio posterior. Resultados: El procedimiento diseñado para la gestión del proceso de formación del liderazgo en directivos de la provincia de Camagüey, contribuyó desde un enfoque de procesos, al liderazgo como atributo fundamental de un directivo en Cuba. Conclusiones: El procedimiento diseñado, facilitó la gestión del proceso de la formación del liderazgo integrando, además de los aspectos teóricos, actividades prácticas que le permitieron al directivo fortalecer su formación para la transformación social.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Abstract Objectives To evaluate the efficacy of the O-RADS MRI criteria in the stratification of risk of malignancy of solid or sonographically indeterminate ovarian masses and assess the interobserver agreement of this classification between experienced and inexperienced radiologists. Methods This single-centre retrospective study included patients from 2019 to 2022 with sonographically indeterminate or solid ovarian masses who underwent MRI with a specific protocol for characterisation according to O-RADS MRI specifications. Each study was evaluated using O-RADS lexicon by two radiologists, one with 17 years of experience in gynaecological radiology and another with 4 years of experience in general radiology. Findings were classified as benign, borderline, or malignant according to histology or stability over time. Diagnostic performance and interobserver agreement were assessed. Results A total of 183 patients with US indeterminate or solid adnexal masses were included. Fifty-seven (31%) did not have ovarian masses, classified as O-RADS 1. The diagnostic performance for scores 2–5 was excellent with a sensitivity, specificity, PPV, and NPV of 97.4%, 100%, 96.2%, and 100%, respectively by the experienced radiologist and 96.1%, 92.0%, 93.9%, and 94.8% by the inexperienced radiologist. Interobserver concordance was very high (Kappa index 0.92). Almost all the misclassified cases were due to misinterpretation of the classification similar to reports in the literature. Conclusion The diagnostic performance of O-RADS MRI determined by either experienced or inexperienced radiologists is excellent, facilitating decision-making with high diagnostic accuracy and high reproducibility. Knowledge of this classification and use of assessment tools could avoid frequent errors due to misinterpretation. Critical relevance statement Up to 31% of ovarian masses are considered indeterminate by transvaginal US and 32% of solid lesions considered malignant by transvaginal US are benign. The O-RADs MRI accurately classifies these masses, even when used by inexperienced radiologists, thereby avoiding incorrect surgical approaches. Key points • O-RADS MRI accurately classifies indeterminate and solid ovarian masses by ultrasound. • There is excellent interobserver agreement between experienced and non-experienced radiologists. • O-RADS MRI is a helpful tool to assess clinical decision-making in ovarian tumours. Graphical Abstract

Algunas tradiciones míticas chinas, como la que se refiere a los Augustos y Soberanos, probable recuerdo de arcaicas jefaturas neolíticas o de grupos legendarios de antepasados predinásticos, son aprovechadas para establecer paradigmas didácticos aplicables a la política, el buen gobierno y a la moral de un gobernante muy idealizado. Deidades y héroes originales, salvadores y fundacionales, aunque humanizados, son concebidos como modelos y estereotipos ideales de perfección. Héroes, reyes y sabios míticos, ancestros culturales, espíritus ancestrales, son utilizados en la literatura confuciana como modelos prototípicos que estimulan, y a la par justifican, el modo ético y moral de conducirse en el gobierno del Estado y en la organización socio-familiar. En la taoísta, se emplean como paradigmas que sirven como medio de argumentar principios, conceptos y especulaciones de diversa consideración. Toda una serie de tales héroes y ancestros sirven de explicación de los inicios del tiempo histórico, empleándose con el objetivo de ensamblar un sistema unitario y centralizado asentado en aspectos metafísicos, mitológicos y religioso-morales.

The present study aims to evaluate the quality of the national talent support system for people with High Ability (HA) in the educational context of Argentina. The objective is to offer a comprehensive review of education talent support, using the Actiotopic model to understand how the resources available in the educational environment affect the development of talent in HA people. A systemic approach was employed to recognize the complexity and interaction of endogenous and exogenous resources in talent development. An exploratory study was carried out using an online questionnaire aimed at 23 education and health professionals, both from the private and public sectors, who regularly work with HA people. The sample selection was accidental, and all participants were women between 25 and 50 years old. The research results show an important influence of socioeconomic and political factors where the poor identification and persistence of stereotypes show the urgent need to improve teacher training, implement concrete measures and demystify misconceptions about HA. In addition, the need to have official statistical data at the country to guide future educational interventions and public policies focused on valuing the HA as an engine of national progress.

BackgroundInterferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway.MethodsWe performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.ResultsWe show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins.ConclusionsOur results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Abstract The Google Earth Engine (GEE) was used to investigate the performance of the Global Land Data Assimilation System (GLDAS) soil temperature (ST) data against observed ST from 13 synoptic stations over a semiarid region in Iran. Three‐hourly ST data were collected and analyzed in two depths (0–10 cm; 40–100 cm) and 5 years. In each depth, GLDAS‐Noah ST data were evaluated for daily minimum, maximum, and average ST (i.e., Tmin, Tmax, and Tavg). Based on the correlation coefficient, Kling–Gupta Efficiency, and Nash–Sutcliffe Efficiency the overall performance of the GLDAS‐Noah is 0.96, 0.66, and 0.79 for Tmin; 0.97, 0.84, and 0.89 for Tavg; and 0.95, 0.89, and 0.89 for Tmax, respectively in the first layer. Likewise, 0.97, 0.85, and 0.86 for Tmin; 0.97, 0.77, and 0.80 for Tavg; and 0.97, 0.69, and 0.69 for Tmax are obtained in the second layer. However, there is a significant negative bias which tends to underestimate ST in the two investigated layers, given by an average bias over all the stations analyzed of −24%, −12%, and −5% for Tmin, Tavg, and Tmax in the first layer, and average bias of −8%, −13%, and −17% for Tmin, Tavg, and Tmax in the second layer. This study reveals that GLDAS‐Noah‐derived ST can be used in arid regions where little or no observation data is available. Moreover, GEE performed as an advanced geospatial processing tool in regional scale analysis of ST in different layers.

Coastal wetlands play an important role in the global water and biogeochemical cycles. Climate change makes it more difficult for these ecosystems to adapt to the fluctuation in sea levels and other environmental changes. Given the importance of eco-geomorphological processes for coastal wetland resilience, many eco-geomorphology models differing in complexity and numerical schemes have been developed in recent decades. However, their divergent estimates of the response of coastal wetlands to climate change indicate that substantial structural uncertainties exist in these models. To investigate the structural uncertainty of coastal wetland eco-geomorphology models, we developed a multi-algorithm model framework of eco-geomorphological processes, such as mineral accretion and organic matter accretion, within a single hydrodynamics model. The framework is designed to explore possible ways to represent coastal wetland eco-geomorphology in Earth system models and reduce the related uncertainties in global applications. We tested this model framework at three representative coastal wetland sites: two saltmarsh wetlands (Venice Lagoon and Plum Island Estuary) and a mangrove wetland (Hunter Estuary). Through the model–data comparison, we showed the importance of using a multi-algorithm ensemble approach for more robust predictions of the evolution of coastal wetlands. We also found that more observations of mineral and organic matter accretion at different elevations of coastal wetlands and evaluation of the coastal wetland models at different sites in diverse environments can help reduce the model uncertainty.

Introducción: la pedagogía cubana asume el reto de generar nuevos perfiles profesionales que puedan ofrecer soluciones efectivas a las problemáticas e incertidumbres, siempre crecientes que la sociedad demanda para elevar la calidad educativa del docente universitario como protagonista de este proceso. Objetivo: fundamentar la superación profesional como reto del docente en la formación del liderazgo para la dirección. Métodos: se realizó una revisión bibliográfica con un análisis crítico reflexivo, se consideraron documentos normativos de la actividad de liderazgo en dirección, tesis, artículos y libros, publicados a partir del 2020 y 2023 en español e inglés. La búsqueda fue realizada en las bases de datos SciELO, SCOPUS y Google Académico durante el período comprendido entre diciembre de 2023 y marzo de 2024; las palabras clave utilizadas fueron: superación, liderazgo, dirección y retos. Desarrollo: destaca la necesidad de gestionar, desde la docencia, el vínculo de las líneas temáticas relacionadas con la demanda social; de transitar, en la conducción de la sociedad, del dirigente dirigido al líder-seguidores. Se demuestra la necesidad de lograr la superación profesional de los docentes para el liderazgo en la dirección, a partir de los documentos rectores. Conclusiones: sistematiza la interacción teoría-práctica, en consonancia con los retos de la educación superior que influyen en la formación de nuevos perfiles profesionales. Recomienda una superación vinculada con las soluciones efectivas a las problemáticas, incertidumbres y contingencias.

PAK4 inhibition can sensitize tumors to immune checkpoint blockade (ICB) therapy, however, the underlying mechanisms remain unclear. We report that PAK4 inhibition reverses immune cell exclusion by increasing the infiltration of CD8 T cells and CD103+ dendritic cells (DCs), a specific type of DCs that excel at cross-presenting tumor antigens and constitute a source of CXCL10. Interestingly, in melanoma clinical datasets, PAK4 expression levels negatively correlate with the presence of CCL21, the ligand for CCR7 expressed in CD103+ DCs. Furthermore, we extensively characterized the transcriptome of PAK4 knock out (KO) tumors, in vitro and in vivo, and established the importance of PAK4 expression in the regulation of the extracellular matrix, which can facilitate immune cell infiltration. Comparison between PAK4 wild type (WT) and KO anti-PD-1 treated tumors revealed how PAK4 deletion sensitizes tumors to ICB from a transcriptomic perspective. In addition, we validated genetically and pharmacologically that inhibition of PAK4 kinase activity is sufficient to improve anti-tumor efficacy of anti-PD-1 blockade in multiple melanoma mouse models. Therefore, this study provides novel insights into the mechanism of action of PAK4 inhibition and provides the foundation for a new treatment strategy that aims to overcome resistance to PD-1 blockade by combining anti-PD-1 with a small molecule PAK4 kinase inhibitor.

Scientists have identified a diversity gap in genetic samples and health data, which have been drawn predominantly from individuals of European ancestry, as posing an existential threat to the promise of precision medicine. Inadequate inclusion as articulated by scientists, policymakers, and ethicists has prompted large-scale initiatives aimed at recruiting populations historically underrepresented in biomedical research. Despite explicit calls to increase diversity, the meaning of diversity - which dimensions matter for what outcomes and why - remain strikingly imprecise. Drawing on our document review and qualitative data from observations and interviews of funders and research teams involved in five precision medicine research (PMR) projects, we note that calls for increasing diversity often focus on representation as the goal of recruitment. The language of representation is used flexibly to refer to two objectives: achieving sufficient genetic variation across populations and including historically disenfranchised groups in research. We argue that these dual understandings of representation are more than rhetorical slippage, but rather allow for the contemporary collection of samples and data from marginalized populations to stand in as correcting historical exclusion of social groups towards addressing health inequity. We trace the unresolved historical debates over how and to what extent researchers should procure diversity in PMR and how they contributed to ongoing uncertainty about what axes of diversity matter and why. We argue that ambiguity in the meaning of representation at the outset of a study contributes to a lack of clear conceptualization of diversity downstream throughout subsequent phases of the study.

INTRODUCTION In high school, when I read assigned books as a Latina student, I did not find characters that portrayed identities like mine. Characters who did resemble me were either [...]

Abstract A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Abstract Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women’s Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p

ABSTRACT: The aim of this study was to evaluate the effects of colostrum consumption and feed restriction on biomarkers of stress, nutritional and health status, gut functionality, and behavior in male dairy beef calves being marketed and transported. A total of 82 male Holstein calves (42 ± 1.2 kg of body weight and 14 ± 0.9 d of age) were used to study the amount of colostrum given at birth at the dairy farm of origin, the degree of feed restriction suffered at an assembly center simulation (d −4 to d −1), and the effects of a 19 h transportation (d −1). Treatments were as follows: control calves (CTRL; n = 16) were fed 10 L of colostrum at the dairy farm of origin, milk replacer (MR) and concentrate at the assembly center, and were not transported; calves fed high colostrum and milk replacer (HCMR; n = 17) were given 10 L of colostrum at the dairy farm of origin, MR at the assembly center, and transported; calved fed high colostrum and rehydrating solution (HCRS; n = 16) were given 10 L of colostrum at the dairy farm of origin, a rehydrating solution (RS) at the assembly center, and transported; calves fed low colostrum and milk replacer (LCMR; n = 17) were given 2 L of colostrum at the dairy farm of origin, MR at the assembly center, and transported; and calves fed low colostrum and rehydrating solution (LCRS; n = 16) were given 2 L of colostrum at the dairy farm of origin, RS at the assembly center, and transported. Transported calves mimic a 19-h transportation. After transport, all calves were fed 2.5 L of MR twice daily and had ad libitum access to concentrate, straw, and water. Calves' recovery was followed for 7 d. Concentrate intake and health records were collected daily from d −4 until d 7 and body weight (BW) and blood samples were collected on d −4, −1, 0, 1, 2, and 7 of the study. Results showed that the feeding regimen provided at the assembly center reduced BW for the HCRS and LCRS calves compared with the CTRL, HCMR, and LCMR calves. Concentrate intake peaked on d 0 in the transported calves, followed by a reduction of intake on d 1 after transportation. Concentrate intake recovery was lower for the LCRS and LCMR calves. On d −1, nonesterified fatty acids and β-hydroxybutyrate concentrations were greater for the HCRS and LCRS calves compared with the CTRL, HCMR, and HCRS calves. After transportation, serum Cr-EDTA concentration was greater for the HCRS and LCRS calves than the HCMR, LCMR, and CTRL calves. The LCRS calves had the lowest serum concentration of citrulline. Finally, health scores were greater for the LCRS calves from d 0 to 7. In summary, both the greatest degree of feed restriction during the assembly center and the low colostrum consumption at birth negatively affected the recovery of concentrate consumption and BW, gut functionality, health status, and behavior in calves after arrival at the rearing farm.

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.

Abstract Background Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway. Methods We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death. Results We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins. Conclusions Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Abstract Background Antibiotics are overprescribed for respiratory tract infections (RTIs). However, the decision to prescribe is often complex. Delayed antibiotic prescription (DAP), a strategy designed to promote more rational antibiotic use, is still not widely used. The aim of this study was to explore perceptions and attitudes in primary care professionals, regarding antibiotic use and different DAP strategies for uncomplicated RTIs. Methods We conducted a qualitative study, using an inductive thematic approach to generate themes, based on focus group discussions and semi-structured interviews with professionals, recruited from 6 primary care centres (Barcelona metropolitan area, Spain). Results 26 professionals (25 family physicians and one nurse) were included in four focus group discussions and three semi-structured interviews. Participants commented that RTIs were a main reason for consultation, motivated often by patient anxiety and fear of possible complications, and this was associated with the patients’ poor health-related education. Acknowledging inappropriate antibiotic use in the health system, participants attributed this, mainly to defensive medicine strategies. DAP was used when in doubt about the aetiology, and considering factors related to patient-physician interactions. The main perceived advantage of DAP was that it could reduce the need for additional visits, while the main disadvantage was uncertainty regarding proper use by the patient. Conclusions DAP was used by participants in cases of doubt, in specific situations, and for specific patient profiles. Weak points were detected in our primary care system and its users that affect the proper use of both antibiotics and DAP, namely, time pressure on professionals, poor patient health-related education, and the lack of a patient-physician relationship in some scenarios.

Abstract Background The concentration of biomarkers in saliva could be influenced by several factors not related to the specific condition under analyses, which should be considered for proper clinical interpretation. In the present study, the circadian rhythm of C-reactive protein (CRP), haptoglobin (Hp), Pig-MAP, S100A12, Cu, Zn, Adenosine deaminase (ADA), total protein (TP), total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), cortisol and α-amylase in saliva of 20 female and 20 male pigs was investigated. Moreover, the influence of sex and production phase (post-weaning, fattening and finishing) on the concentrations of biomarkers in a total of 414 healthy pigs was studied and the reference intervals for all salivary biomarkers were calculated accordingly. Results All parameters except Pig-MAP, OSI and α-amylase varied significantly along the daytime, and most of them peak around early afternoon (13–15 h). The cosinor analysis described the temporal dynamics of circadian rhythms for all parameters. The range values showed differences between male and female pigs in 8 out of the 13 biomarkers, with higher concentrations in females in comparison to male pigs. The influence of the production phase on the salivary concentrations was observed for all the biomarkers. The highest concentrations were observed for Pig-MAP, S100A12 and α-amylase in post-weaning animals, for TP in growing pigs and for OSI in finishing animals. Most of the sex-influenced biomarkers showed the highest concentrations at growing stages with some exceptions such as ADA or Hp that showed the peak at finishing and post-weaning stages respectively. Conclusions It is necessary to establish the optimal daytime for routine saliva sampling to avoid circadian variations and for that end, the time interval between 10:00 a.m. to 12:00 a.m. is highly recommended. The factors sex and production phase influence the concentration of biomarkers and should be considered for proper biomarker interpretation. The reference intervals presented here for each salivary biomarker will help to correctly interpret the results of these analytes and contribute to the use of saliva as a non-invasive sample for the diagnosis and monitoring of the health status of swine farms.

This special issue provides an assessment of the contribution of soils to Nature's Contributions to People (NCP). Here, we combine this assessment and previously published relationships between NCP and delivery on the UN Sustainable Development Goals (SDGs) to infer contributions of soils to the SDGs. We show that in addition to contributing positively to the delivery of all NCP, soils also have a role in underpinning all SDGs. While highlighting the great potential of soils to contribute to sustainable development, it is recognized that poorly managed, degraded or polluted soils may contribute negatively to both NCP and SDGs. The positive contribution, however, cannot be taken for granted, and soils must be managed carefully to keep them healthy and capable of playing this vital role. A priority for soil management must include: (i) for healthy soils in natural ecosystems, protect them from conversion and degradation; (ii) for managed soils, manage in a way to protect and enhance soil biodiversity, health and sustainability and to prevent degradation; and (iii) for degraded soils, restore to full soil health. We have enough knowledge now to move forward with the implementation of best management practices to maintain and improve soil health. This analysis shows that this is not just desirable, it is essential if we are to meet the SDG targets by 2030 and achieve sustainable development more broadly in the decades to come. This article is part of the theme issue 'The role of soils in delivering Nature's Contributions to People'.