ß-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, ß-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo ß-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT.

A blueprint for health technology assessment capacity building: lessons learned from Malta.

OBJECTIVES: The development and strengthening of health technology assessment (HTA) capacity on the individual and organizational level and the wider environment is relevant for cooperation on HTAs. Based on the Maltese case, we provide a blueprint for building HTA capacity. METHODS: A set of activities were developed based on Pichler et al.'s framework and the starting HTA capacity in Malta. Individual level activities focused on strengthening epidemiological and health economic skills through online and in-person training. On the organizational level, a new HTA framework was developed which was subsequently utilized in a shadow assessment. Awareness campaign activities raised awareness and support in the wider environment where HTAs are conducted and utilized. RESULTS: The time needed to build HTA capacity exceeded the planned two years accommodating the learning progress of the assessors. In addition to the planned trainings, webinars supplemented the online courses, allowing for more knowledge exchange. The advanced online course was extended over time to facilitate learning next to the assessors' daily tasks. Training sessions were added to implement the new economic evaluation framework, which was utilized in a second shadow assessment. Awareness by decision-makers was achieved with reports, posters, and an article on the current and developing HTA capacity. CONCLUSIONS: It takes time and much (hands-on) training to build skills for conducting complex assessment such as HTAs. Facilitating exchange with knowledgeable parties is crucial for succeeding as well as the buy-in of local managers motivating staff. Decision-makers need to be on-boarded for the continued success of HTA capacity building.

Staged esthetic crown lengthening: Classification and guidelines for periodontal-restorative therapy.

OBJECTIVE: This article presents technical guidelines for perio-restorative esthetic crown lengthening, along with a discussion of the biologic rationale. A classification system is proposed to assist in treatment planning and sequencing the surgical and restorative phases. CLINICAL CONSIDERATIONS: When esthetic crown lengthening is performed as an adjunct to restorative therapy, the surgical approach must be determined by the anticipated position of the restorative margins. The removal of sufficient bone to achieve the desired clinical crown length and preserve the supracrestal gingival tissue dimensions is facilitated by the use of a surgical guide fabricated according to the design of the restorations. A staged approach allows sequencing the provisional restoration to minimize unesthetic sequelae during the healing period. Inadequate bone resection and/or alteration of the soft tissue dimensions results in delayed healing, leading to coronal gingival rebound and biologic width impingement. CONCLUSION: The identification and preservation of appropriate restorative and biologic landmarks is essential for success in pre-prosthetic esthetic crown lengthening treatment. A staged approach improves the esthetic management during the postsurgical healing and maturation period. CLINICAL SIGNIFICANCE: A restorative driven classification system for sequencing and staging adjunctive esthetic crown lengthening procedures is presented. Technical guidelines to enhance gingival margin predictability are suggested, accompanied by relevant evidence. In addition, wound healing timelines following gingival and osseous resection are provided.

Artificial Intelligence Sensing: Effective Flavor Blueprinting of Tea Infusions for a Quality Control Perspective.

Tea infusions are the most consumed beverages in the world after water; their pleasant yet peculiar flavor profile drives consumer choice and acceptance and becomes a fundamental benchmark for the industry. Any qualification method capable of objectifying the product's sensory features effectively supports industrial quality control laboratories in guaranteeing high sample throughputs even without human panel intervention. The current study presents an integrated analytical strategy acting as an Artificial Intelligence decision tool for black tea infusion aroma and taste blueprinting. Key markers validated by sensomics are accurately quantified in a wide dynamic range of concentrations. Thirteen key aromas are quantitatively assessed by standard addition with in-solution solid-phase microextraction sampling followed by GC-MS. On the other hand, nineteen key taste and quality markers are quantified by external standard calibration and LC-UV/DAD. The large dynamic range of concentration for sensory markers is reflected in the selection of seven high-quality teas from different geographical areas (Ceylon, Darjeeling Testa Valley and Castleton, Assam, Yunnan, Azores, and Kenya). The strategy as a sensomics-based expert system predicts teas' sensory features and acts as an AI smelling and taste machine suitable for quality controls.

Reflections on the HUPO Human Proteome Project, the Flagship Project of the Human Proteome Organization, at 10 Years.

We celebrate the 10th anniversary of the launch of the HUPO Human Proteome Project (HPP) and its major milestone of confident detection of at least one protein from each of 90% of the predicted protein-coding genes, based on the output of the entire proteomics community. The Human Genome Project reached a similar decadal milestone 20 years ago. The HPP has engaged proteomics teams around the world, strongly influenced data-sharing, enhanced quality assurance, and issued stringent guidelines for claims of detecting previously "missing proteins." This invited perspective complements papers on "A High-Stringency Blueprint of the Human Proteome" and "The Human Proteome Reaches a Major Milestone" in special issues of Nature Communications and Journal of Proteome Research, respectively, released in conjunction with the October 2020 virtual HUPO Congress and its celebration of the 10th anniversary of the HUPO HPP.

Accuracy of Blueprint software in predicting range of motion 1 year after reverse total shoulder arthroplasty.

HYPOTHESIS AND BACKGROUND: Blueprint 3-dimensional computed tomography software has a functionality that predicts impingement-free range of motion (ROM) with determination of the limits of ROM at which bone and/or prosthetic impingement occurs. To our knowledge, only 1 previously published study has assessed the ability of Blueprint software to predict actual postoperative ROM after reverse total shoulder arthroplasty (RTSA). The hypotheses of this study were that (1) mean Blueprint-predicted impingement-free ROM would be statistically similar to the mean actual ROM 1 year after RTSA and (2) there would be a correlation between Blueprint-predicted impingement-free ROM and the actual ROM 1 year after RTSA. MATERIALS AND METHODS: A retrospective review of patients who underwent Blueprint planning prior to undergoing RTSA from March 2017 through May 2021 was performed. At 1-year follow-up, flexion, external rotation at the side, abduction, external rotation in the abducted position, internal rotation in the abducted position, and internal rotation behind the back were measured. The preoperatively predicted flexion, extension, abduction, external rotation, and internal rotation were recorded using Blueprint software. The group 1 analysis examined the predicted vs. actual ROM of all 127 patients regardless of whether intraoperative component modifications were made. The group 2 analysis examined the predicted vs. actual ROM of only the patients who did not undergo intraoperative changes that would affect the preoperative ROM prediction (n = 97). The group 3 analysis examined the predicted vs. actual ROM of group 2 combined with the 30 patients who underwent post hoc Blueprint planning modifications to account for the changes made intraoperatively (combined sample size of 127). RESULTS: Of the 141 patients, 127 (90%) were available for 1-year follow-up. When the mean values of all 3 groups were examined, the actual ROM and predicted ROM were statistically significantly different (P < .0001) for flexion, external rotation, abduction, abduction-external rotation, and abduction-internal rotation. In group 1, a very weak or poor correlation was found between predicted internal rotation and actual abducted internal rotation (r = 0.19, P = .04). For all other ROM metrics in groups 1, 2, and 3, there were no correlations between predicted and actual ROM (P ≥ .07). CONCLUSIONS: In its current state, preoperative Blueprint 3-dimensional computed tomography planning software is unable to accurately predict ROM 1 year after RTSA.

MammaPrint and BluePrint comprehensively capture the cancer hallmarks in early-stage breast cancer patients.

MammaPrint® (MP) is a 70-gene signature that stratifies early-stage breast cancer patients into low- and high risk of distant relapse. Further stratification of MP risk results identifies four risk subgroups, ultra-low (UL), low, high 1, and high 2, with specific prognostic and predictive outcomes. BluePrint® (BP) is an 80-gene signature that classifies breast tumors as basal, luminal, or HER2 molecular subtype. To gain insight into their biological significance, we annotated the MP 70- and BP 80-genes with respect to the 10 hallmarks of cancer (HoC). Furthermore, we related gene expression profiles of the extreme ends of the MP low- and high-risk patients (here called, ultra-low (UL) and ultra-high (UH) or High2, respectively), to the 10 HoC per BP subtype by differential gene expression and pathway analysis. MP and BP gene functions reflected all 10 HoCs. Most MP and BP genes were associated with sustaining proliferative signaling, followed by genome instability and mutation categories. Based on the gene expression profiles, UL and UH subgroup pathways were down -or upregulated, respectively, reflecting proliferative and metastatic features, such as G2M checkpoint, DNA repair, oxidative phosphorylation, immune invasion, PI3K/AKT/mTOR signaling, and hypoxia pathways. Notably, the UH HER2-type was enriched in several immune signaling pathways, such as IL2/STAT5 signaling and TNFα signaling via NFκB. Our results show that MP and BP gene signatures represent and capture all 10 HoCs and highlight underlying biological processes of MP extreme samples, which might guide treatment decisions as the signature captures the full spectrum of early breast cancers.

Blueprint designing and validation for competency-based curriculum for theory assessment in community medicine.

Background: Blueprint provides a base for assessment by assigning proportionate weightage to various content areas and helps the paper setter to construct a uniform and valid assessment. This study aimed to design and validate a blueprint for theory in Community Medicine as per the new curriculum for Medical Undergraduates in India. Methods: Blueprint in community medicine was designed by assigning impact score (I) and frequency score (F) for the competencies. Blueprint was validated using the Content Validity Index (CVI), and inter-rater agreement for subject experts using Fleiss' kappa statistics was calculated. Feedback from faculty and students was obtained afterward to assess the postimplementation response. Results: Blueprint was designed by an expert group where impact score and frequency score were assigned to 146 competencies in the theory of Community Medicine. In Delphi survey I, 63.2% of subject experts responded, while in Delphi survey II, a response rate of 58.3% was achieved. Value of the Fleiss' Kappa test for an inter-rater agreement was 0.68, i.e. "substantial agreement," while CVI among the raters came out to be 0.86, i.e. overall valid assessment. Feedback of faculty (n = 11) suggested that the blueprint was helpful and standardized the paper setting, whereas feedback from students (n = 138) depicted that it helped in preparing for exams, and they would recommend it to other students. Conclusion: Validated blueprint by consensus of subject experts has impact score and frequency score along with topic-wise distribution of marks for the convenience of faculty and its utility is well proven among learners too.

BluePrint breast cancer molecular subtyping recognizes single and dual subtype tumors with implications for therapeutic guidance.

PURPOSE: BluePrint (BP) is an 80-gene molecular subtyping test that classifies early-stage breast cancer (EBC) into Basal, Luminal, and HER2 subtypes. In most cases, breast tumors have one dominant subtype, representative of a single activated pathway. However, some tumors show a statistically equal representation of more than one subtype, referred to as dual subtype. This study aims to identify and examine dual subtype tumors by BP to understand their biology and possible implications for treatment guidance. METHODS: The BP scores of over 15,000 tumor samples from EBC patients were analyzed, and the differences between the highest and the lowest scoring subtypes were calculated. Based upon the distribution of the differences between BP scores, a threshold was determined for each subtype to identify dual versus single subtypes. RESULTS: Approximately 97% of samples had one single activated BluePrint molecular subtype, whereas ~ 3% of samples were classified as BP dual subtype. The most frequently occurring dual subtypes were the Luminal-Basal-type and Luminal-HER2-type. Luminal-Basal-type displays a distinct biology from the Luminal single type and Basal single type. Burstein's classification of the single and dual Basal samples showed that the Luminal-Basal-type is mostly classified as 'luminal androgen receptor' and 'mesenchymal' subtypes, supporting molecular evidence of AR activation in the Luminal-Basal-type tumors. Tumors classified as Luminal-HER2-type resemble features of both Luminal-single-type and HER2-single-type. However, patients with dual Luminal-HER2-type have a lower pathological complete response after receiving HER2-targeted therapies in addition to chemotherapy in comparison with patients with a HER2-single-type. CONCLUSION: This study demonstrates that BP identifies tumors with two active functional pathways (dual subtype) with specific transcriptional characteristics and highlights the added value of distinguishing BP dual from single subtypes as evidenced by distinct treatment response rates.

The shape of root systems in a mountain meadow: plastic responses or species-specific architectural blueprints?

The efficient uptake of nutrients depends on the ability of roots to respond to gradients of these resources. Although pot experiments have shown that species differ in their ability to proliferate their roots in nutrient-rich patches, the role of such differences in determining root shapes in the field is unclear. We used fine-scale quantitative (q)PCR-based species-specific mapping of roots in a grassland community to reconstruct species-specific root system shapes. We linked them with data from pot experiments on the ability of these species to proliferate in nutrient-rich patches and their rooting depth. We found remarkable diversity in root system shapes, from cylindrical to conical. Interspecific differences in rooting depths in pots were the main determinant of rooting depths in the field, whereas differences in foraging ability played only a minor role. Although some species with strong foraging ability did place their roots into nutrient-rich soil layers, it was not a universal pattern. The results imply that although the vertical differentiation of grassland species is pronounced, it is primarily not driven by the differential plastic response of species to soil nutrient gradients. This may constrain the coexistence of species with similar rooting depths and may instead favour coexistence of species differing in their architectural blueprints.

Building the blueprint: Formulating a community-generated national plan for future research in inherited bleeding disorders.

INTRODUCTION: Decades of inherited bleeding disorders (BD) research transformed severe haemophilia from a childhood killer to a disorder managed across a full lifespan for many in economically developed countries. Health equity, a life unimpaired by disease complications, however, remains unimaginable for most people with an inherited BD (PWIBD). AIM: The National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network (ATHN) undertook the development of a community-driven United States (US) National Blueprint for Inherited Bleeding Disorders Research to transform the experience of all PWIBD and those who care for them. METHODS: Extensive community consultations were conducted to identify the issues most important to PWIBD and those who love and care for them. Expert multidisciplinary teams distilled these key areas of need into prioritised research questions, and identified the resources and infrastructure required to pursue them. A summit was held to gather feedback and inform the detailed blueprint. RESULTS: Community-prioritised research areas fell into three broad categories: issues common across inherited BDs, those specific to individual disorders, and issues of infrastructure and capacity. NHF State of the Science Research Summit discussions of the research questions derived from the community priorities by six working groups provided important input for the drafting of the research blueprint for the coming decades. CONCLUSION: The inherited BD community came together to develop the US National Blueprint for Inherited Bleeding Disorders Research dedicated to transforming the lives of all PWIBD including innovating solutions for the rarest disorders and under-represented populations.

High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimens in early-stage breast cancer.

BACKGROUND AND OBJECTIVES: With increased neoadjuvant therapy recommendations for early-stage breast cancer patients due to the COVID-19 pandemic, it is imperative that molecular diagnostic assays provide reliable results from preoperative core needle biopsies (CNB). The study objective was to determine the concordance of MammaPrint and BluePrint results between matched CNB and surgical resection (SR) specimens. METHODS: Matched tumor specimens (n = 121) were prospectively collected from women enrolled in the FLEX trial (NCT03053193). Concordance is reported using overall percentage agreement and Cohen's kappa coefficient. Correlation is reported using Pearson correlation coefficient. RESULTS: We found good concordance for MammaPrint results between matched tumor samples (90.9%, κ = 0.817), and a very strong correlation of MammaPrint indices (r = 0.94). The concordance of BluePrint subtyping in matched samples was also excellent (98.3%). CONCLUSIONS: CNB samples demonstrated high concordance with paired SR samples for MammaPrint risk classification and BluePrint molecular subtyping, suggesting that physicians are provided with accurate prognostic information that can be used to guide therapy decisions.

Development of a Blueprint for Integrated Care for Vulnerable Pregnant Women.

PURPOSE: There has been increasing awareness of perinatal health and organisation of maternal and child health care in the Netherlands as a result of poor perinatal outcomes. Vulnerable women have a higher risk of these poor perinatal outcomes and also have a higher chance of receiving less adequate care. Therefore, within a consortium, embracing 100 organisations among professionals, educators, researchers, and policymakers, a joint aim was defined to support maternal and child health care professionals and social care professionals in providing adequate, integrated care for vulnerable pregnant women. DESCRIPTION: Within the consortium, vulnerability is defined as the presence of psychopathology, psychosocial problems, and/or substance use, combined with a lack of individual and/or social resources. Three studies focussing on population characteristics, organisation of care and knowledge, skills, and attitudes of professionals regarding vulnerable pregnant women, were carried out. Outcomes were discussed in three field consultations. ASSESSMENT: The outcomes of the studies, followed by the field consultations, resulted in a blueprint that was subsequently adapted to local operational care pathways in seven obstetric collaborations (organisational structures that consist of obstetricians of a single hospital and collaborating midwifery practices) and their collaborative partners. We conducted 12 interviews to evaluate the adaptation of the blueprint to local operational care pathways and its' embedding into the obstetric collaborations. CONCLUSION: Practice-based research resulted in a blueprint tailored to the needs of maternal and child health care professionals and social care professionals and providing structure and uniformity to integrated care provision for vulnerable pregnant women.

Handheld Device-Based Indoor Localization with Zero Infrastructure (HDIZI).

The correlations between smartphone sensors, algorithms, and relevant techniques are major components facilitating indoor localization and tracking in the absence of communication and localization standards. A major research gap can be noted in terms of explaining the connections between these components to clarify the impacts and issues of models meant for indoor localization and tracking. In this paper, we comprehensively study the smartphone sensors, algorithms, and techniques that can support indoor localization and tracking without the need for any additional hardware or specific infrastructure. Reviews and comparisons detail the strengths and limitations of each component, following which we propose a handheld-device-based indoor localization with zero infrastructure (HDIZI) approach to connect the abovementioned components in a balanced manner. The sensors are the input source, while the algorithms are used as engines in an optimal manner, in order to produce a robust localizing and tracking model without requiring any further infrastructure. The proposed framework makes indoor and outdoor navigation more user-friendly, and is cost-effective for researchers working with embedded sensors in handheld devices, enabling technologies for Industry 4.0 and beyond. We conducted experiments using data collected from two different sites with five smartphones as an initial work. The data were sampled at 10 Hz for a duration of five seconds at fixed locations; furthermore, data were also collected while moving, allowing for analysis based on user stepping behavior and speed across multiple paths. We leveraged the capabilities of smartphones, through efficient implementation and the optimal integration of algorithms, in order to overcome the inherent limitations. Hence, the proposed HDIZI is expected to outperform approaches proposed in previous studies, helping researchers to deal with sensors for the purposes of indoor navigation-in terms of either positioning or tracking-for use in various fields, such as healthcare, transportation, environmental monitoring, or disaster situations.

Integrative Systemic Supervision: Promoting Supervisees' Theoretical Integration in Systemic Therapy.

Integrative systemic therapy (IST) is a meta-theoretical perspective, grounded in systemic theory and integration, that transcends therapy models in individual, couple, and family therapy. To foster supervisees' theoretical integration and systemic thinking, two of IST's primary tools-the essence diagram and blueprint-are described and applied to inform an integrative, systemic meta-perspective for supervision. Recommendations, specific guiding questions, and examples are provided to operationalize these tools in the multi-level supervision system (i.e., supervisor-supervisee-client system). IST supervisors and other supervisors who are interested in integrative, systemic training can use these tools to guide the process of supervision and strengthen supervisees' ability to hypothesize, plan, converse, and read clients' feedback in relation to the various tasks of therapy. The essence diagram and blueprint are applied to facilitate case consultation and cultivate the development of supervisees' clinical competencies. Particularly, the problem-solving focus of IST has been adapted to include a competency-based and professional growth-oriented dimension for supervision to better promote supervisees' development. Lastly, the advantages and challenges of IST-influenced supervision are discussed.

La terapia sistémica integral (TSI) es una perspectiva metateórica basada en la teoría sistémica y la integración, que trasciende los modelos de terapia en la terapia individual, de pareja y familiar. Para fomentar la integración teórica de los supervisados y el pensamiento sistémico, se describen y se aplican dos de las herramientas principales de la TSI-el diagrama del eje y el diseño- a fin de respaldar una metaperspectiva integradora y sistémica de la supervisión. Se ofrecen recomendaciones, preguntas orientadoras específicas y ejemplos para poner en funcionamiento estas herramientas en el sistema de supervisión multinivel (p. ej.: sistema supervisor-supervisado-paciente). Los supervisores de la TSI y otros supervisores que estén interesados en la capacitación integradora y sistémica pueden usar estas herramientas para guiar el proceso de supervisión y fortalecer la capacidad de los supervisados para plantear hipótesis, planificar, conversar y leer los comentarios de los pacientes en relación con las diferentes tareas de la terapia. El diagrama del eje y el diseño se aplican para facilitar la consulta de casos y cultivar el desarrollo de las competencias clínicas de los supervisados. Particularmente, se ha adaptado el eje de resolución de problemas de la TSI para incluir una dimensión basada en competencias y orientada al crecimiento profesional a fin de que la supervisión promueva mejor el desarrollo de los supervisados. Por último, se comentan las ventajas y las dificultades de la supervisión influida por la TSI.

MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial.

BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

Designing a blueprint for next-generation stem cell bioprocessing development.

The creation of a blueprint for stem cell bioprocess development that it is easily readable and shareable among those involved in the construction of the bioprocess is a necessary step toward full-fledged bioprocess integration. The blueprint provides the culturing tools and methodologies, designed to highlight knowledge gaps within biological sciences and bioengineering. This review highlights a blueprint for stem cell bioprocessing development using a landscape architecture approach that can aid the development of culture technologies and tools that satisfy the demands for stem cell-derived products for use in clinical and industrial applications. This work is intended to provide insights to cell biologists, geneticists, bioengineers, and clinicians seeking knowledge outside of their field of expertise and fosters a leap from a reductionist approach to one, that is, globally integrated in stem cell bioprocessing.

Strong impact of MammaPrint and BluePrint on treatment decisions in luminal early breast cancer: results of the WSG-PRIMe study.

PURPOSE: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer. METHODS: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires. RESULTS: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in "discordant" groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients' State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients. CONCLUSIONS: MammaPrint and BluePrint test results strongly impacted physicians' therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

Transcending Therapy Models and Managing Complexity: Suggestions from Integrative Systemic Therapy.

Integrative Systemic Therapy (IST) is a metatheoretical perspective for the conduct of individual, couple, and family therapy. Following a brief description of IST, this article presents developments in IST and their implication for psychotherapy integration. The nature of problem solving in IST is clarified, and the relationship between IST's essential problem-solving tasks and its core decision-making process is defined. Particular attention is paid to two dimensions of IST that have given it its name: integration and systems theory. The advantages of a therapy that is client system-centered and not model-driven are discussed, and a justification for "good enough" execution of interventions abstracted from specific models is provided. A procedure for balancing pragmatic demands of therapy with a commitment to account, as needed, for broader or deeper systemic issues is presented.

La terapia sistémica integrativa (TSI) es una perspectiva metateórica para llevar a cabo la terapia individual, de pareja y familiar. Después de una breve descripción de la TSI, este artículo presenta avances en dicha terapia y su implicancia para la integración en la psicoterapia. Se aclara la índole de la resolución de problemas en la TSI y se define la relación entre las tareas esenciales de resolución de problemas de la TSI y su proceso fundamental de toma de decisiones. Se presta atención particularmente a dos dimensiones de la TSI que le han dado su nombre: la integración y la teoría de sistemas. Se explican las ventajas de una terapia que está centrada en el sistema del paciente y no dirigida por un modelo, y se justifica la ejecución "suficientemente buena" de intervenciones abstraída de modelos específicos. Finalmente, se presenta un procedimiento para equilibrar las exigencias pragmáticas de la terapia con un compromiso de tener en cuenta, cuando fuera necesario, cuestiones sistémicas más amplias o profundas.