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Cell migration is a key procedure involved in many biological processes including embryological development, tissue formation, immune defense or inflammation, and cancer progression. How physical, chemical, and molecular aspects can affect cell motility is a challenge to understand migratory cells behavior. assays are excellent approaches to extrapolate to situations and study live cells behavior. Here we present four protocols that describe step-by-step cell migration, invasion and adhesion strategies and their corresponding image data quantification. These current protocols are based on wound healing assays (comparing traditional pipette tip-scratch assay vs. culture insert assay), 2D individual cell-tracking experiments by live cell imaging and spreading and transwell assays. All together, they cover different phenotypes and hallmarks of cell motility and adhesion, providing orthogonal information that can be used either individually or collectively in many different experimental setups. These optimized protocols will facilitate physiological and cellular characterization of these processes, which may be used for fast screening of specific therapeutic cancer drugs for migratory function, novel strategies in cancer diagnosis, and for assaying new molecules involved in adhesion and invasion metastatic properties of cancer cells.

Although early health technology assessment (HTA) is increasingly being used to guide and inform decisions on product development, a consensus definition is currently lacking. A working group under the HTA International Society was established to develop a consensus-based definition of early HTA. The working group developed a definition using an iterative process that comprised five stages of work and included a two-round Delphi survey with 133 respondents in the first and 99 respondents in the second round of the survey, with various backgrounds and levels of expertise. Following this process, the working group reached the first consensus-based definition of early HTA, which is an HTA conducted to inform decisions about subsequent development, research, and/or investment by explicitly evaluating the potential value of a conceptual or actual health technology. In total, 86 (87 percent) of the 99 panelists who participated in the second round of the Delphi survey either strongly agreed or agreed with this definition. This consensus definition represents an important milestone in early HTA. It will enhance the uniformity of terminology, increasing the visibility of research and policy in this field. We also hope that it will act as a catalyst sparkling further research and developments in this discipline.

Germinal center follicular T helper (GCTfh) cells are essential players in the differentiation of B cells. Circulating follicular T helper (cTfh) cells share phenotypic and functional properties with GCTfh cells. Distinct subpopulations of cTfh with different helper capabilities toward B cells can be identified: cTfh1 (CXCR3 CCR6 ), cTfh2 (CXCR3 CCR6 ), and cTfh17 (CXCR3 CCR6 ). Alterations in cTfh function and/or distribution have been associated with autoimmunity, infectious diseases, and more recently, with several monogenic immunodeficiencies. Common variable immunodeficiency (CVID) disease is the commonest symptomatic primary immunodeficiency with a genetic cause identified in only 2-10% of patients. Although a heterogeneous disease, most patients show a characteristic defective B cell differentiation into memory B cells or antibody-secreting cells. We investigated if alterations in CVID cTfh cells frequency or distribution into cTfh1, cTfh2, and cTfh17 subpopulations and regulatory follicular T (Tfr) cells could be related to defects in CVID B cells. We found increased percentages of cTfh exhibiting higher programmed death-1 expression and altered subpopulations distribution in smB CVID patients. In contrast to smB patients and controls, cTfh from smB CVID patients show increased cTfh1 and decreased cTfh17 subpopulation percentages and increased CXCR3 CCR6 cTfh, a population analogous to the recently described pathogenic Th17.1. Moreover, Tfr cells are remarkably decreased only in smB CVID patients. In conclusion, increased cTfh17.1 and cTfh1/cTfh17 ratio in CVID patients could influence B cell fate in smB CVID patients, with a more compromised B cell compartment, and the decrease in Tfr cells may lead to high risk of autoimmune conditions in CVID patients.

T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.

Background: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. Methods: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. Results: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. Conclusions: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.

Water quality monitoring at the dialysis units (DU) is essential to ensure an appropriate dialysis fluid quality and guarantee an optimal and safe dialysis treatment to patients. This paper aims to evaluate the effectiveness, economic and organizational impact of automation, digitalization and remote water quality monitoring, through a New Water Technology (NWT) at a hospital DU to produce dialysis water, compared to a Conventional Water Technology (CWT). A before-and-after study was carried out at the Hospital Clínic Barcelona. Data on CWT was collected during 1-year (control) and 7-month for the NWT (case). Data on water quality, resource use and unit cost were retrospective and prospectively collected. A comparative effectiveness analysis on the compliance rate of quality water parameters with the international guidelines between the NWT and the CWT was conducted. This was followed by a cost-minimization analysis and an organizational impact from the hospital perspective. An extensive deterministic sensitivity analysis was also performed. The NWT compared to the CWT showed no differences on effectiveness measured as the compliance rate on international requirements on water quality (100% vs. 100%), but the NWT yielded savings of 3,599 EUR/year compared to the CWT. The NWT offered more data accuracy (daily measures: 6 vs. 1 and missing data: 0 vs. 20 days/year), optimization of the DU employees' workload (attendance to DU: 4 vs. 19 days/month) and workflow, through the remote and continuous monitoring, reliability of data and process regarding audits for quality control. While the compliance of international recommendations on continuous monitoring was performed with the CWT, the NWT was efficient compared to the CWT, mainly due to the travel time needed by the technical operator to attend the DU. These results were scalable to other economic contexts. Nonetheless, they should be taken with caution either when the NWT equipment/maintenance cost are largely increased, or the workforce involvement is diminished.

IntroductionIn the past decade, health technology assessment (HTA) has narrowed its scope to the analysis of mainly clinical and economic benefits. However, twenty-first century technology challenges require the need for more holistic assessments to obtain accurate recommendations for decision-making, as it was in HTA's foundations. VALues In Doing Assessments of health TEchnologies (VALIDATE) methodology approaches complex technologies holistically to provide a deeper understanding of the problem through analysis of the heterogeneity of stakeholders’ views, allowing for more comprehensive HTAs. This study aimed to assess a pharmaceutical clinical decision support system (CDSS) using VALIDATE.MethodsA systematic review of the empirical evidence on CDSS was conducted according to PRISMA guidelines. PubMed, the Cochrane Library, and Web of Science databases were searched for literature published between 2000 and 2020. Additionally, a review of grey literature and semi-structured interviews with different hospital stakeholders (pharmacists, physicians, computer engineers, etc.) were conducted. Content analysis was used for data integration.ResultsPreliminary literature results indicated consensus regarding the effectiveness of CDSS. Nevertheless, when including multistakeholder views, CDSS appeared to not be fully accepted in clinical practice. The main reasons for this appeared to be alert fatigue and disruption of workflow. Preliminary results based on information from the literature were contrasted with stakeholder interview responses.ConclusionsIncorporation of facts and stakeholder values into the problem definition and scoping for a health technology is essential to properly conduct HTAs. The lack of an inclusive multistakeholder scoping can lead to inaccurate information, and in this particular case to suboptimal CDSS implementation concerning decision-making for the technology being evaluated.

IntroductionThe assessment of current technologies needs a more holistic approach to obtain accurate recommendations for decision-making. The VALues In Doing Assessments of health TEchnologies (VALIDATE) methodology considers that facts and values from all stakeholders need to be included in the scoping of an assessment to gather the comprehensive information needed for unbiased decision-making. This report aimed to explore how to properly assess the integrated care of patients with aortic valve stenosis (AVS) using the VALIDATE approach.MethodsA literature review was conducted, and 11 semi-structured interviews were performed with various hospital-based healthcare professionals (cardiac surgeon, clinical cardiologist, interventional cardiologist, anesthetist, process coordinator nurse, and others) and patients. Content analysis was used for data analysis and integration.ResultsThe literature review showed that the cardiology and cardiac surgery perspectives were dominant in 90 percent of the articles and present in the remaining ten percent. The perspectives of other specialties (anesthesiology, primary care, and psychology) were included in three percent of the articles and patient perspectives were included in nine percent. Interviewing and considering the perspectives of the different stakeholders involved in the care pathway identified the following indicators that should be included in the assessment care for patients with AVS: difficulties associated with late diagnosis of AVS; the need to incorporate a multidisciplinary approach in patient risk assessment; the importance of geriatric evaluations; considering patient (and family and caregiver) preferences for type of treatment; the importance of following up pharmaceutical treatment and palliative care; use of telemonitoring; and digital exclusion of patients with respect to the use of apps for prehabilitation and rehabilitation.ConclusionsThe stakeholders interviewed were involved in different steps of the care pathway and had differing needs, some of which were not found in the literature. The indicators suggested for inclusion in the assessment differed according to type of stakeholder and their involvement in the care pathway. Therefore, this case study exemplifies the VALIDATE method and endorses the need for multistakeholder involvement in eliciting values when scoping the assessment of a complex technology.

IntroductionLimited knowledge of the symptomatology of aortic stenosis (AS) among the general population may delay diagnosis and have a major impact on morbidity and resource use. Training programs have often been advocated by the scientific community. The present study reported the results of an assessment of a training program for the general population.MethodsPatients who attended healthcare centers were asked to answer a questionnaire on their level of knowledge around AS. A cohort of patients without training (n=681) answered the questionnaire and a second cohort answered the questionnaire via phone 24 hours after training (n=197). Propensity score matching by sex and age was used to obtain a balanced sample between the two cohorts, giving a total study sample of 394 individuals (197 without training and 197 with training). A descriptive analysis was performed to compare differences in the level of knowledge between the two cohorts. Predictors of AS symptomatology were identified using multivariate logistic regression.ResultsThe trained cohort was more aware of AS disease than the untrained cohort (79% versus 31%, 95% confidence interval [CI]: 0.39, 0.56; p<0.001). They were also better at distinguishing the symptoms associated with AS (80% versus 43%, 95% CI: 0.28, 0.48, p<0.001) and were more aware of its severity (36% versus 12%; 95% CI: 0.16, 0.32, p<0.001). Moreover, the trained cohort were better at identifying symptoms that should make them consider visiting a doctor (76% versus 65%; 95% CI 0.02, 0.20, p<0.02). No differences were observed in level of concern regarding AS (8% versus 4%; 95% CI: -0.0046, 0.09, p=0.08).The trained people who were aware of AS (p=0.04) correctly classified AS as a valvular disease (p=0.025), would seek medical consultation when AS symptoms occurred (p=0.04), and were more likely to correctly detect AS symptoms.ConclusionsThe training program significantly improved the knowledge and awareness of AS in the general population. This can improve the timeliness of AS diagnosis, reducing the health and economic burden of AS for the healthcare system.

IntroductionInterest in early detection of complications in hospitals has increased recently. Complications after elective or urgent surgery are frequent and are associated with higher mortality rates, longer hospital stays, and more resource utilization. The ZERO project implemented an educational nursing program and developed an innovative algorithm that assesses a patient’s complication risk based on clinical parameters to prevent complications and reduce hospital burden. Our aim was to present the results from one year of implementing ZERO at the Clinic Barcelona University Hospital.MethodsA comparative effectiveness and cost study was conducted. Data from patients admitted after elective or urgent surgery were collected for one year retrospectively (n=8,844 from January 2019 to December 2019) and prospectively (ZERO) (n=8,163 from October 2021 to October 2022). Effectiveness was measured in terms of mortality, complications, and life-years gained (LYG). Length of stay (LoS) at conventional, intermediate, and intensive care units and rates of readmissions were collected for resource use. The chi-square test was used to compare categorical variables. The t-test and Wilcoxon test were used for normally and non-normally distributed continuous variables, respectively.ResultsThere was a significant decrease in the rate of complications (7.8%, 95% confidence interval [CI]: -8.46, -7.19; p<0.001) with ZERO. Moreover, there were statistically significant reductions in mean LoS for readmissions to conventional wards (-5.04 days, 95%CI: -9.9, -0.18; p=0.04) and to the intensive care ward within the same episode (-4.68 days, 95%CI: -9.26, -0.14; p=0.02). The mean cost per patient was EUR2,772.92 and EUR2,591.57 before and after ZERO implementation, respectively. After accounting for the cost of implementing ZERO, there was a cost saving of EUR147.76 per patient (p=0.048), which yielded a yearly impact of EUR1,206,165 for the hospital budget.ConclusionsThis one-year analysis of the effect of ZERO on surgical patients shows that it decreases complication rates and all types of LoS, leading to overall cost savings for the hospital.