Uncovering the historical roots of naturalistic, secular contemporary ethics, in this 2006 volume Michael Gill shows how the British moralists of the seventeenth and eighteenth centuries completed a ...Copernican revolution in moral philosophy. They effected a shift from thinking of morality as independent of human nature to thinking of it as part of human nature itself. He also shows how the British Moralists - sometimes inadvertently, sometimes by design - disengaged ethical thinking, first from distinctly Christian ideas and then from theistic commitments altogether. Examining in detail the arguments of Whichcote, Cudworth, Shaftesbury, and Hutcheson against Calvinist conceptions of original sin and egoistic conceptions of human motivation, Gill also demonstrates how Hume combined the ideas of earlier British moralists with his own insights to produce an account of morality and human nature that undermined some of his predecessors' most deeply held philosophical goals.
Marine protected areas (MPAs) are increasingly being used globally to conserve marine resources. However, whether many MPAs are being effectively and equitably managed, and how MPA management ...influences substantive outcomes remain unknown. We developed a global database of management and fish population data (433 and 218 MPAs, respectively) to assess: MPA management processes; the effects of MPAs on fish populations; and relationships between management processes and ecological effects. Here we report that many MPAs failed to meet thresholds for effective and equitable management processes, with widespread shortfalls in staff and financial resources. Although 71% of MPAs positively influenced fish populations, these conservation impacts were highly variable. Staff and budget capacity were the strongest predictors of conservation impact: MPAs with adequate staff capacity had ecological effects 2.9 times greater than MPAs with inadequate capacity. Thus, continued global expansion of MPAs without adequate investment in human and financial capacity is likely to lead to sub-optimal conservation outcomes.
Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types ...forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.
We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant ...progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8+ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy.
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•Differential progression of metastases during off-treatment period.•Coexistence of distinct tumor-immune microenvironments within the same individual.•Tumor regression and progression correlated with T cell infiltration and exclusion.•Clonal neoepitopes elicited reactivity of circulating CD8+ T cells.
Distinct tumor immune microenvironments co-exist within a single individual and may help to explain the heterogeneous fates of metastatic lesions often observed post-therapy.
Biodiversity conservation interventions often aim to benefit both nature and people; however, the social impacts of these interventions remain poorly understood. We reviewed recent literature on the ...social impacts of four marine conservation interventions to understand the synergies, tradeoffs, and equity (STE) of these impacts, focusing on the direction, magnitude, and distribution of impacts across domains of human wellbeing and across spatial, temporal, and social scales. STE literature has increased dramatically since 2000, particularly for marine protected areas (MPAs), but remains limited. Few studies use rigorous counterfactual study designs, and significant research gaps remain regarding specific wellbeing domains (culture, education), social groups (gender, age, ethnic groups), and impacts over time. Practitioners and researchers should recognize the role of shifting property rights, power asymmetries, individual capabilities, and resource dependency in shaping STE in conservation outcomes, and utilize multi-consequential frameworks to support the wellbeing of vulnerable and marginalized groups.
Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the ...biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtypespecific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.
Bleeding is the most common severe complication after endoscopic mucosal resection of large colon polyps and is associated with significant morbidity and cost. We examined whether prophylactic ...closure of the mucosal defect with hemoclips after polyp resection reduces the risk of bleeding.
We performed a multicenter, randomized trial of patients with a large nonpedunculated colon polyp (≥20 mm) at 18 medical centers in North America and Spain from April 2013 through October 2017. Patients were randomly assigned to groups that underwent endoscopic closure with a clip (clip group) or no closure (control group) and followed. The primary outcome, postprocedure bleeding, was defined as a severe bleeding event that required hospitalization, a blood transfusion, colonoscopy, surgery, or another invasive intervention within 30 days after completion of the colonoscopy. Subgroup analyses included postprocedure bleeding with polyp location, polyp size, or use of periprocedural antithrombotic medications. We also examined the risk of any serious adverse event.
A total of 919 patients were randomly assigned to groups and completed follow-up. Postprocedure bleeding occurred in 3.5% of patients in the clip group and 7.1% in the control group (absolute risk difference ARD 3.6%; 95% confidence interval CI 0.7%–6.5%). Among 615 patients (66.9%) with a proximal large polyp, the risk of bleeding in the clip group was 3.3% and in the control group was 9.6% (ARD 6.3%; 95% CI 2.5%–10.1%); among patients with a distal large polyp, the risks were 4.0% in the clip group and 1.4% in the control group (ARD –2.6%; 95% CI –6.3% to –1.1%). The effect of clip closure was independent of antithrombotic medications or polyp size. Serious adverse events occurred in 4.8% of patients in the clip group and 9.5% of patients in the control group (ARD 4.6%; 95% CI 1.3%–8.0%).
In a randomized trial, we found that endoscopic clip closure of the mucosal defect following resection of large colon polyps reduces risk of postprocedure bleeding. The protective effect appeared to be restricted to large polyps located in the proximal colon. ClinicalTrials.gov no: NCT01936948.
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Annually, about 300 million surgeries lead to significant intraoperative adverse events (iAEs), impacting patients and surgeons. Their full extent is underestimated due to flawed assessment and ...reporting methods. Inconsistent adoption of new grading systems and a lack of standardization, along with litigation concerns, contribute to underreporting. Only half of relevant journals provide guidelines on reporting these events, with a lack of standards in surgical literature. To address these issues, the Intraoperative Complications Assessment and Reporting with Universal Standard (ICARUS) Global Surgical Collaboration was established in 2022. The initiative involves conducting global surveys and a Delphi consensus to understand the barriers for poor reporting of iAEs, validate shared criteria for reporting, define iAEs according to surgical procedures, evaluate the existing grading systems' reliability, and identify strategies for enhancing the collection, reporting, and management of iAEs. Invitation to participate are extended to all the surgical specialties, interventional cardiology, interventional radiology, OR Staffs and anesthesiology. This effort represents an essential step towards improved patient safety and the well-being of healthcare professionals in the surgical field.
Some argue that it is ethically justifiable to unilaterally withdraw life‐sustaining treatment during crisis standards of care without the patient's consent in order to reallocate it to another ...patient with a better chance of survival. This justification has been supported by two lines of argument: the equivalence thesis and the rule of the double effect. We argue that there are theoretical issues with the first and practical ones with the second, as supported by an experiment aimed at exploring whether the Knobe effect, which affects the folk concept of intention, applies to situations of unilateral withdrawal. Fifty‐two critical care physicians from one university were asked to ascribe intention in two hypothetical scenarios A and B in which outcomes differ—the patient from whom life‐sustaining treatment is withdrawn dies in scenario A but survives in scenario B—but the intention, to save the other patient regardless of the outcome of the other, is the same. The survey was administered via a web‐based survey and all answers were anonymous. A paired proportion test was used to compare responses to both questions. All 52 surveyed individuals responded in scenario A and 30 (57.7%) ascribed intention when outcomes were unfavorable, whereas 50 responded in scenario B and 8 (16%) ascribed intention when outcomes were favorable, a difference that was statistically significant (p < 0.001). There are theoretical and practical issues with the arguments proposed to justify the unilateral withdrawal of life‐sustaining treatment based on the equivalence thesis and the rule of double effect.
Untreated tooth decays affect nearly one third of the world and is the most prevalent disease burden among children. The disease progression of tooth decay is multifactorial and involves a prolonged ...decrease in pH, resulting in the demineralization of tooth surfaces. Bacterial species that are capable of fermenting carbohydrates contribute to the demineralization process by the production of organic acids. The combined use of machine learning and 16s rRNA sequencing offers the potential to predict tooth decay by identifying the bacterial community that is present in an individual's oral cavity. A few recent studies have demonstrated machine learning predictive modeling using 16s rRNA sequencing of oral samples, but they lack consideration of the multifactorial nature of tooth decay, as well as the role of fungal species within their models. Here, the oral microbiome of mother-child dyads (both healthy and caries-active) was used in combination with demographic-environmental factors and relevant fungal information to create a multifactorial machine learning model based on the LASSO-penalized logistic regression. For the children, not only were several bacterial species found to be caries-associated (
, and
) but also
detection and lower toothbrushing frequency were also caries-associated. Mothers enrolled in this study had a higher detection of
and
and a higher plaque index. This proof-of-concept study demonstrates the significant impact machine learning could have in prevention and diagnostic advancements for tooth decay, as well as the importance of considering fungal and demographic-environmental factors.
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