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Provides historical information on The legend of Zelda franchise, including the history of Hyrule and the official chronology of the games.

BackgroundTo date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies.MethodsRelevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM. Immune gene expression profiling was conducted by NanoString analysis on pre-treatment and post-treatment tumors from patients (n=6) receiving immune checkpoint blockade or 4-1BB and OX40 dual costimulation. The immune signature of UM tumors responding to immunotherapy was further characterized by Ingenuity Pathways Analysis and validated in The Cancer Genome Atlas data set.ResultsBoth primary and metastatic UM tumors showed detectable infiltrating lymphocytes. Compared with primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3+, CD8+, FoxP3+ T cells, and CD68+ macrophages. Notably, levels of PD-1+ infiltrates and PD-L1+ tumor cells were low to absent in primary and metastatic UM tumors. No metastatic organ-specific differences were seen in immune infiltrates. Our NanoString analysis revealed significant differences in a set of immune markers between responders and non-responders. A group of genes relevant to the interferon-γ signature was differentially up-expressed in the pre-treatment tumors of responders. Among these genes, suppressor of cytokine signaling 1 was identified as a marker potentially contributing to the response to immunotherapy. A panel of genes that encoded pro-inflammatory cytokines and molecules were expressed significantly higher in pre-treatment tumors of non-responders compared with responders.ConclusionOur study provides critical insight into immune profiles of UM primary and metastatic tumors, which suggests a baseline tumor immune signature predictive of response and resistance to immunotherapy in UM.

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier stages of genetic evolution than larger tumors. Further, the 15-GEP support vector machine discriminant score predicts small tumors undergoing transformation from low-risk Class 1 to high-risk Class 2 profile. These results shed light on the early genetic evolution of UM and move us closer to a molecular definition of malignant transformation in this cancer type. The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

PurposeTo determine the safety and efficacy of transurethral resection of the prostate (TUR-P) in patients 85 years or older.MethodsIn this retrospective, multicentre study, patients equal or older than 85 years at the time of surgery (2015–2020) were included. Several pre-, peri- and postoperative parameters were collected. The main outcome criterion was spontaneous voiding with a post-void residual (PVR) volume < 100 ml at dismission and at 12 months after surgery.ResultsOne hundred sixty-eight patients (median age: 87 years, interquartile range [IQR]: 86–89) were recruited. The patients took on average 5.2 permanent medications (3–8), 107 (64%) were anticoagulated preoperatively and neurological co-morbidities were present in 29 (17%). The indication for surgery was recurrent urinary retention in 66.3% (n = 110) with a mean retention volume of 849 ml. The mean PVR volume of the remaining 35% was 146 ml. Surgery was successfully completed in all patients. A perioperative surgical revision had to be performed in 3% and 13 patients (7.7%) required blood transfusion. After catheter removal, 85% of patients were able to void spontaneously with a PVR < 100 ml, and 14.3% were dismissed with a catheter. Twelve months data were available for 93 patients (55%). Of this cohort, 78 (83.9%) were able to void spontaneously with a PVR < 100 ml, 12 (12.9%) were on permanent catheterization. One patient (0.6%) died perioperatively. The only significant factor associated with an unsuccessful outcome was the number of permanent medications (6.8 vs. 5.0, p = 0.005).ConclusionThis retrospective multicentre study documents the safety and efficacy of TURP (monopolar and bipolar) in the old-old cohort.

Correction to: Nature Medicinehttps://doi.org/10.1038/s41591-024-03261-7, published online 13 September 2024. In the version of this article initially published, members of the DESTINY-Breast12 study group were not included by the journal in the full text. In Table 1, under the “Prior CNS therapies n (%)” section, seven rows have been added, in addition to the original CNS radiotherapy, WBRT and SRS rows. In Table 1 and in the Results: Patients section, “intracranial therapy” has been amended to “CNS radiotherapy,” while the text “the type of intracranial radiotherapy was not always recorded by investigators, and only WBRT and SRS intracranial radiotherapy were reported” has been removed. All changes appear in the HTML and PDF versions of the article.

Background Having a primary care provider is associated with better care experiences and lower care costs. In 2021, INSPIRE-PHC released Primary Care Data Reports - publicly available summaries of administrative billing data about how populations in each of Ontario’s 60 health teams use primary care services. Given the characterization of Canadian primary care systems as ‘in crisis’, publicly available data about primary care at the regional level presented a significant opportunity for knowledge mobilization. An understandable resource could ground the public conversation about primary care access in data. Recognizing the role that lived experience plays in ensuring the public understands research findings, a partnership between patient advisors, Ontario Health Team representatives, researchers, and trainees was established to co-produce public-facing infographics based on primary care data. Methods Evidence-based guidelines for public health infographic creation and elements of transformative action research guided a six-meeting process to engage up to 14 patient advisors, three Ontario Health Team staff and two primary care trainees. Patient advisors were affiliated with a provincial patient-oriented primary health care research group or a Hamilton-based Ontario Health Team. Ninety-minute meetings were conducted virtually, and notes were shared with attendees to ensure they accurately reflected the conversation. Two consultations with Ontario Health Team-affiliated primary care providers provided direction and ensured project outputs aligned with local priorities. Results Project partners shared feedback on draft infographics, audience identification, priority elements from Primary Care Data Reports to include in the infographics, and aesthetic features (e.g., headings, colour scheme, charts). Project partners felt the most important metrics to convey to the public were those that simultaneously reinforced the benefits of primary care on individual health outcomes and health system costs. Conclusions Patient engagement in research is becoming widespread, but co-developing knowledge products with patient and health system partners is less common. Our approach to engaging patients prevented both oversimplification and unnecessary complexity in a public-facing visual about attachment to primary care. Plain English summary Primary care is the first point of contact for patients accessing the health care system. Primary care providers (i.e., family doctors and nurse practitioners – working individually or in teams of nurses, dieticians, pharmacists, social workers and others) – help patients and families manage health concerns over time by working to prevent, diagnose, and treat illnesses and link patients with specialist care when needed. Having a primary care provider is associated with better healthcare experiences and lower costs of care. In 2021, the Primary Care Data Reports were released to the public. The reports contain administrative data about how patients engage with primary care in each of the 58 Ontario Health Teams. Patient advisors, Ontario Health Team representatives, researchers, and trainees created an infographic to share this data in a way that can be understood by everyone. Infographics use images to help people process information faster, which can make health-related topics easier to understand. By understanding the value of primary care, people can participate in conversations about how to ensure primary care is accessible to everyone. Engaging patients is becoming common in research, but collaborating with patient advisors and health system partners to create visual summaries is less common. We had six virtual meetings that were 90 min each with up to 14 patient advisors, Ontario Health Team representatives, researchers and trainees. Patient advisors helped decide who the audience would be, which information from the Primary Care Data Reports to include, and how the infographic would look. Patient advisors felt it was most important to highlight the benefits patients can get from primary care, and the impact primary care can have to reduce health system costs. We consulted with primary care clinicians to ensure the infographic reflected local priorities. Working with patient advisors and Ontario Health Team representatives helped to create an infographic about Primary Care Data Reports data that is easy to understand by the public.

This article proposes a variational approach to describe the evolution of organization of complex systems from first principles, as increased efficiency of physical action. Most simply stated, physical action is the product of the energy and time necessary for motion. When complex systems are modeled as flow networks, this efficiency is defined as a decrease of action for one element to cross between two nodes, or endpoints of motion—a principle of least unit action. We find a connection with another principle, that of most total action, or a tendency for increase of the total action of a system. This increase provides more energy and time for minimization of the constraints to motion to decrease unit action, and therefore, to increase organization. Also, with the decrease of unit action in a system, its capacity for total amount of action increases. We present a model of positive feedback between action efficiency and the total amount of action in a complex system, based on a system of ordinary differential equations, which leads to an exponential growth with time of each and a power law relation between the two. We present an agreement of our model with data for core processing units of computers. This approach can help to describe, measure, manage, design, and predict future behavior of complex systems to achieve the highest rates of self‐organization and robustness. © 2014 Wiley Periodicals, Inc. Complexity 21: 18–28, 2015

Although acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically \"silent\" infarcts and in-hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR. A secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non-White, 74 ± 7 years). Delirium during in-hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas-based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed-effect, zero-inflated gaussian modeling analyses, accounting for brain region-specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy. 23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct-related structural disconnection (DWI-ISD) was observed in frontal and temporal lobe regions (p-FDR < 0.05). Fewer brain regions demonstrated DWI-ISD loss in the suction-based neuroprotection device group, relative to filtration-based device or standard aortic cannula. Structural disconnection from acute infarcts was greater in patients who experienced postoperative delirium, suggesting that the impact from covert perioperative infarcts may not be as clinically \"silent\" as commonly assumed.