Stemming Tumoral Growth: A Matter of Grotesque Organogenesis.

The earliest metazoans probably evolved from single-celled organisms which found the colonial system to be a beneficial organization. Over the course of their evolution, these primary colonial organisms increased in size, and division of labour among the cells became a remarkable feature, leading to a higher level of organization: the biological organs. Primitive metazoans were the first organisms in evolution to show organ-type structures, which set the grounds for complex organs to evolve. Throughout evolution, and concomitant with organogenesis, is the appearance of tissue-specific stem cells. Tissue-specific stem cells gave rise to multicellular living systems with distinct organs which perform specific physiological functions. This setting is a constructive role of evolution; however, rebel cells can take over the molecular mechanisms for other purposes: nowadays we know that cancer stem cells, which generate aberrant organ-like structures, are at the top of a hierarchy. Furthermore, cancer stem cells are the root of metastasis, therapy resistance, and relapse. At present, most therapeutic drugs are unable to target cancer stem cells and therefore, treatment becomes a challenging issue. We expect that future research will uncover the mechanistic "forces" driving organ growth, paving the way to the implementation of new strategies to impair human tumorigenesis.

Azot expression in the Drosophila gut modulates organismal lifespan.

Cell Competition emerged in Drosophila as an unexpected phenomenon, when confronted clones of fit vs unfit cells genetically induced. During the last decade, it has been shown that this mechanism is physiologically active in Drosophila and higher organisms. In Drosophila, Flower (Fwe) eliminates unfit cells during development, regeneration and disease states. Furthermore, studies suggest that Fwe signaling is required to eliminate accumulated unfit cells during adulthood extending Drosophila lifespan. Indeed, ahuizotl (azot) mutants accumulate unfit cells during adulthood and after physical insults in the brain and other epithelial tissues, showing a decrease in organismal lifespan. On the contrary, flies carrying three functional copies of the gene, unfit cell culling seems to be more efficient and show an increase in lifespan. During aging, Azot is required for the elimination of unfit cells, however, the specific organs modulating organismal lifespan by Azot remain unknown. Here we found a potential connection between gut-specific Azot expression and lifespan which may uncover a more widespread organ-specific mechanism modulating organismal survival.

To fit or not to fit: death decisions from morphogen fields.

The transforming growth factor-ß (TGF-ß)-type morphogens are conserved throughout the animal kingdom. TGF-ß-type molecules form spatial concentration gradients whose length scales with the size of growing, developing organs. Scaling of these morphogens can also be mediated by death, adjusting the size of the tissue to the range of the gradient. Death-mediated scaling might provide a molecular toolbox exploited by cancer cells.

Validation Study of a Value-Based Digital Health Questionnaire.

The paradigm of value-based health care is spreading worldwide; however, Value-Based Digital Health (VBDH) is still an emerging concept. VBDH is understood as the use of digital tools to facilitate the generation of value in health. It is accelerated by technological change, cultural, and organizational factors. An accurate diagnosis of the organizational VBDH maturity is crucial to define and implement strategic actions to progress with VBDH transformation. This study aimed to validate a VBDH questionnaire, which measures the degree of maturity of VBDH from the perspective of managers (N = 146) in Spanish healthcare organizations. Results show good internal consistency of the questionnaire. Factor analysis identified seven dimensions to measure VBHC maturity: (1) Resources, incentives, and financing; (2) Knowledge and participation of patients and workers in the strategy of progress towards VBDH; (3) Training of professionals and tool knowledge for advancement in VBDH; (4) Innovation initiatives; (5) Information and its quality; (6) Leadership, strategy and governance; and (7) Knowledge of the fundamentals and objectives, as well as access to relevant VBDH information. The questionnaire presents good validity and internal consistency and meets the requirements to be an instrument for routine use to assess VBDH organizational maturity.

A role for Flower and cell death in controlling morphogen gradient scaling.

During development, morphogen gradients encode positional information to pattern morphological structures during organogenesis1. Some gradients, like that of Dpp in the fly wing, remain proportional to the size of growing organs-that is, they scale. Gradient scaling keeps morphological patterns proportioned in organs of different sizes2,3. Here we show a mechanism of scaling that ensures that, when the gradient is smaller than the organ, cell death trims the developing tissue to match the size of the gradient. Scaling is controlled by molecular associations between Dally and Pentagone, known factors involved in scaling, and a key factor that mediates cell death, Flower4-6. We show that Flower activity in gradient expansion is not dominated by cell death, but by the activity of Dally/Pentagone on scaling. Here we show a potential connection between scaling and cell death that may uncover a molecular toolbox hijacked by tumours.

Impact of the CareWell integrated care model for older patients with multimorbidity: a quasi-experimental controlled study in the Basque Country.

BACKGROUND: Older patients with multimorbidity have complex health and social care needs, associated with elevated use of health care resources. The aim of this study is to evaluate the impact of CareWell integrated care model for older patients with multimorbidity in the Basque Country. METHODS: The CareWell program for older patients with multimorbidity, based on the coordination between health providers, home-based care and patient empowerment, supported by information and communication technology tools. The program was deployed in four healthcare areas in the Basque Country. The control group was formed by two organizations in which the program had not been deployed and regular care procedures were applied. Participants, older patients (aged ≥65) with two or more chronic conditions (at least one being chronic obstructive pulmonary disease, chronic heart failure, or diabetes mellitus), categorized as complex according to a risk stratification algorithm, were followed up to 12 months. The impact of the program on the use of health resources, clinical effectiveness, and satisfaction was evaluated using a mixed-method approach. Semi-structured interviews were performed to assess satisfaction with the newly deployed model and mixed regression models to measure the effect of the intervention throughout the follow-up period. RESULTS: Two hundred patients were recruited (101 intervention and 99 control), mostly males (63%) with a mean age of 79 years and age-adjusted Charlson Comorbidity Index of 9.7 on average. Relevant differences between the groups were observed for all dimensions. In the intervention group, the number of hospitalizations and visits to emergency centers was reduced, and the number of primary care contacts increased. Clinical changes were also observed, such as a decrease in the body mass index and blood glucose levels. The satisfaction level was high for all stakeholders. CONCLUSION: The implementation of CareWell integrated care model changed the profile of health resource utilization, strengthening the key role of primary care and reducing the number of emergency visits and hospitalizations. The satisfaction with this model of care was high. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03042039 . Registered 3 February 2017 - Retrospectively registered.

Impact Assessment of an Innovative Integrated Care Model for Older Complex Patients with Multimorbidity: The CareWell Project.

OBJECTIVES: To evaluate the impact in terms of use of health services, clinical outcomes, functional status, and patient's satisfaction of an integrated care program, the CareWell program, for complex patients with multimorbidity, supported by information and communication technology platforms in six European regions. DATA SOURCES: Primary data were used and the follow-up period ranged between 8 and 12 months. STUDY DESIGN: A quasi-experimental study, targeting chronic patients aged 65 or older, with 2 or more conditions - one of them necessarily being diabetes, congestive heart failure or congestive obstructive pulmonary disease. The intervention group received the integrated care program and the control group received usual care. Generalized mixed regression models were used. DATA COLLECTION: Data were obtained from individual interviews and electronic clinical records. PRINCIPAL FINDINGS: Overall, 856 patients were recruited (475 intervention and 381 control). In the intervention group, the number of visits to emergency rooms was significantly lower, and the number of visits to the general practitioners and primary care nurses was higher than in the control group. CONCLUSION: The CareWell program resulted in improvements in the use of health services, strengthening the role of PC as the cornerstone of care provision for complex patients with multimorbidity.

Impact of stratification on the effectiveness of a comprehensive patient-centered strategy for multimorbid patients.

OBJECTIVE: The objective of this work was to assess the effectiveness of a population-level patient-centered intervention for multimorbid patients based on risk stratification for case finding in 2014 compared with the baseline scenario in 2012. DATA SOURCE: Clinical and administrative databases. STUDY DESIGN: This was an observational cohort study with an intervention group and a historical control group. A propensity score by a genetic matching approach was used to minimize bias. Generalized linear models were used to analyze relationships among variables. DATA COLLECTION: We included all eligible patients at the beginning of the year and followed them until death or until the follow-up period concluded (end of the year). The control group (2012) totaled 3558 patients, and 4225 patients were in the intervention group (2014). PRINCIPAL FINDING: A patient-centered strategy based on risk stratification for case finding and the implementation of an integrated program based on new professional roles and an extensive infrastructure of information and communication technologies avoided 9 percent (OR: 0.91, CI: 0.86-0.96) of hospitalizations. However, this effect was not found in nonprioritized groups whose probability of hospitalization increased (OR: 1.19, CI = 1.09-1.30). CONCLUSIONS: In a before-and-after analysis using propensity score matching, a comprehensive, patient-centered, integrated care intervention was associated with a lower risk of hospital admission among prioritized patients, but not among patients who were not prioritized to receive the intervention.

Culling Less Fit Neurons Protects against Amyloid-ß-Induced Brain Damage and Cognitive and Motor Decline.

Alzheimer's disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-ß42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays ß-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD.

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer.

Multicellular organisms evolved to resolve conflicts between individual cells, protecting the internal organization of the individual. This is illustrated by cell competition, a process that eliminates suboptimal cells from growing tissues by apoptosis. Since its early characterization in Drosophila an increasing number of conditions have been associated with competition, and mounting evidence demonstrates conservation of this process. We describe here the broad range of contexts that utilize cell competition, including tissue health, aging, and tumor development. We then delineate different models for the processes underlying the recognition and elimination of outcompeted cells.

Elimination of unfit cells maintains tissue health and prolongs lifespan.

Viable yet damaged cells can accumulate during development and aging. Although eliminating those cells may benefit organ function, identification of this less fit cell population remains challenging. Previously, we identified a molecular mechanism, based on "fitness fingerprints" displayed on cell membranes, which allows direct fitness comparison among cells in Drosophila. Here, we study the physiological consequences of efficient cell selection for the whole organism. We find that fitness-based cell culling is naturally used to maintain tissue health, delay aging, and extend lifespan in Drosophila. We identify a gene, azot, which ensures the elimination of less fit cells. Lack of azot increases morphological malformations and susceptibility to random mutations and accelerates tissue degeneration. On the contrary, improving the efficiency of cell selection is beneficial for tissue health and extends lifespan.

"Fitness fingerprints" mediate physiological culling of unwanted neurons in Drosophila.

BACKGROUND: The flower gene has been previously linked to the elimination of slow dividing epithelial cells during development in a process known as "cell competition." During cell competition, different isoforms of the Flower protein are displayed at the cell membrane and reveal the reduced fitness of slow proliferating cells, which are therefore recognized, eliminated, and replaced by their normally dividing neighbors. This mechanism acts as a "cell quality" control in proliferating tissues. RESULTS: Here, we use the Drosophila eye as a model to study how unwanted neurons are culled during retina development and find that flower is required and sufficient for the recognition and elimination of supernumerary postmitotic neurons, contained within incomplete ommatidia units. This constitutes the first description of the "Flower Code" functioning as a cell selection mechanism in postmitotic cells and is also the first report of a physiological role for this cell quality control machinery. CONCLUSIONS: Our results show that the "Flower Code" is a general system to reveal cell fitness and that it may play similar roles in creating optimal neural networks in higher organisms. The Flower Code seems to be a more general mechanism for cell monitoring and selection than previously recognized.

Bayesian classification for the selection of in vitro human embryos using morphological and clinical data.

In vitro fertilization (IVF) is a medically assisted reproduction technique that enables infertile couples to achieve successful pregnancy. Given the uncertainty of the treatment, we propose an intelligent decision support system based on supervised classification by Bayesian classifiers to aid to the selection of the most promising embryos that will form the batch to be transferred to the woman's uterus. The aim of the supervised classification system is to improve overall success rate of each IVF treatment in which a batch of embryos is transferred each time, where the success is achieved when implantation (i.e. pregnancy) is obtained. Due to ethical reasons, different legislative restrictions apply in every country on this technique. In Spain, legislation allows a maximum of three embryos to form each transfer batch. As a result, clinicians prefer to select the embryos by non-invasive embryo examination based on simple methods and observation focused on morphology and dynamics of embryo development after fertilization. This paper proposes the application of Bayesian classifiers to this embryo selection problem in order to provide a decision support system that allows a more accurate selection than with the actual procedures which fully rely on the expertise and experience of embryologists. For this, we propose to take into consideration a reduced subset of feature variables related to embryo morphology and clinical data of patients, and from this data to induce Bayesian classification models. Results obtained applying a filter technique to choose the subset of variables, and the performance of Bayesian classifiers using them, are presented.

Diferencias en los costes y resultados de 2 técnicas de encuesta: teléfono y correo / Cost differences and results of 2 survey techniques: telephone and mail

Objetivo: Comparar los resultados ­cualitativos y cuantitativos­ y los costes de 2 encuestas utilizando un mismo cuestionario, una aplicada por correo y la otra, por teléfono. Material y método: Diseño: estudio transversal, con 13 preguntas sobre satisfacción, que se valoraban de 1 (muy insatisfecho) a 10 (absolutamente satisfecho) y 2 abiertas para identificar oportunidades de mejora (¿Qué mejorar?, ¿Qué sugiere?). Emplazamiento: Área Básica de Atención Primaria. Comarca Guipúzcoa Este. Participantes: muestreo aleatorio sistemático de la población asistida en los últimos 15 días. Mediciones: medias de las preguntas cuantitativas y agrupación de los literales de las abiertas para cada una de las técnicas de aplicación de la encuesta. Cálculo del coste por cada cuestionario válido obtenido. Resultados: De 500 cuestionarios por correo, se recuperaron 121 (24%) y de 115 llamadas válidas, aceptaron contestarLas medias obtenidas fueron más altas (mayor satisfacción) en la encuesta por teléfono en todas las preguntas menos en una, en que también fue mayor, pero sin diferencia significativa. Los literales no presentaron diferencias. Los costes por cuestionario fueron similares para esas tasas de respuesta. Conclusiones: Se declara mayor grado de satisfacción en la encuesta telefónica que en la encuesta por correo. Se identifican las mismas oportunidades de mejora. El coste es similar, pero si se lograran mayores tasas de respuesta por correo, resultaría más eficiente. Para el personal que aplica la encuesta, el correo es más cómodo

Objective: To compare the results (qualitative and quantitative) and costs of 2 surveys using the same questionnaire, one sent by mail and the other administered by telephone. Material and method: Design: We performed a cross sectional study using a 13-item questionnaire on satisfaction. Items were evaluated from 1 (highly unsatisfied) to 10 (completely satisfied). There were two open questions to identify opportunities for improvement ("What should be improved?" and "What do you suggest?"). Setting: Basic Primary Care Area in the region of East Guipuzcoa (Spain). Participants: Systematic random sampling was performed of the population attended in the previous 15 days. Measurements: The mean scores of quantitative questions were calculated and literal and open questions were classified for each of the survey techniques. The cost of each valid questionnaire obtained was calculated. Results: Of 500 questionnaires sent by mail, 121 (24%) were returned. Of 115 valid telephone calls, 100 individuals (87%) agreed to respond. The means obtained were higher (greater satisfaction) in the telephone survey in all items except one. This item also showed higher satisfaction but the difference was not statistically significant. No differences were found in literal questions. The cost per questionnaire was similar for both response rates. Conclusions: Reported satisfaction was higher in the telephone survey than when the questionnaire was sent by mail. The same opportunities for improvement were identified in both. Cost was similar. However, if higher response rates were obtained by mail, this technique would be more efficient. For the staff administering the questionnaire, the mail method was easier

Feature selection in Bayesian classifiers for the prognosis of survival of cirrhotic patients treated with TIPS.

The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment for cirrhotic patients with portal hypertension. A subgroup of patients dies in the first 6 months and another subgroup lives a long period of time. Nowadays, no risk factors have been identified in order to determine how long a patient will survive. An empirical study for predicting the survival rate within the first 6 months after TIPS placement is conducted using a clinical database with 107 cases and 77 variables. Applications of Bayesian classification models, based on Bayesian networks, to medical problems have become popular in the last years. Feature subset selection is useful due to the heterogeneity of the medical databases where not all the variables are required to perform the classification. In this paper, filter and wrapper approaches based on the feature subset selection are adapted to induce Bayesian classifiers (naive Bayes, selective naive Bayes, semi naive Bayes, tree augmented naive Bayes, and k-dependence Bayesian classifier) and are applied to distinguish between the two subgroups of cirrhotic patients. The estimated accuracies obtained tally with the results of previous studies. Moreover, the medical significance of the subset of variables selected by the classifiers along with the comprehensibility of Bayesian models is greatly appreciated by physicians.