Despite common associations with plague pits and mass graves, many individuals who succumbed to the Black Death in the mid-fourteenth century AD, and to the numerous subsequent outbreaks of plague, were buried in parish cemeteries. This limits the usefulness of contemporaneous cemetery assemblages for the establishment of comparative, non-catastrophic (or ‘attritional’) demographic profiles for medieval populations in Britain. Drawing from three earlier cemeteries, this study reveals similarities in age-at-death and survivorship profiles for adults, offering a characteristic pre-Black Death profile that helps reinforce the distinctiveness of the over-representation of individuals aged 15–24 years among plague burials.

The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

In recent years, scholars worldwide have begun organising and developing a coherent framework and research agenda focused on the emerging field of ‘global administrative law’. This nascent body of law, unlike domestic or national forms of administrative law, does not operate within the bounds of unitary nation states, and unlike traditional accounts of public international law, it does not arise exclusively between nation states. Instead it operates in a transnational or global space occupied by a vast variety of administrative actors responsible for trans-governmental regulation and administration; the field of ‘global governance’. To combat growing concerns that there are crucial legitimacy, accountability and democratic deficiencies inherent in this system of global governance, numerous administrative law type mechanisms and principles have been developed by global administrative bodies. Global administrative law embodies the totality of these various mechanisms and principles.

On several key issues we agree with the commentators. Perhaps most importantly, everyone seems to agree that psychology has an important role to play in building better models of human vision, and (most) everyone agrees (including us) that deep neural networks (DNNs) will play an important role in modelling human vision going forward. But there are also disagreements about what models are for, how DNN–human correspondences should be evaluated, the value of alternative modelling approaches, and impact of marketing hype in the literature. In our view, these latter issues are contributing to many unjustified claims regarding DNN–human correspondences in vision and other domains of cognition. We explore all these issues in this response.

Medieval hospitals were founded to provide charity, but poverty and infirmity were broad and socially determined categories and little is known about the residents of these institutions and the pathways that led them there. Combining skeletal, isotopic and genetic data, the authors weave a collective biography of individuals buried at the Hospital of St John the Evangelist, Cambridge. By starting with the physical remains, rather than historical expectations, they demonstrate the varied life courses of those who were ultimately buried in the hospital's cemetery, illustrating the diverse faces of medieval poverty and institutional notions of charity. The findings highlight the value of collective osteobiography when reconstructing the social landscapes of the past.

The Eighth World Congress of Pediatric Cardiology and Cardiac Surgery (WCPCCS) will be held in Washington DC, USA, from Saturday, 26 August, 2023 to Friday, 1 September, 2023, inclusive. The Eighth World Congress of Pediatric Cardiology and Cardiac Surgery will be the largest and most comprehensive scientific meeting dedicated to paediatric and congenital cardiac care ever held. At the time of the writing of this manuscript, The Eighth World Congress of Pediatric Cardiology and Cardiac Surgery has 5,037 registered attendees (and rising) from 117 countries, a truly diverse and international faculty of over 925 individuals from 89 countries, over 2,000 individual abstracts and poster presenters from 101 countries, and a Best Abstract Competition featuring 153 oral abstracts from 34 countries. For information about the Eighth World Congress of Pediatric Cardiology and Cardiac Surgery, please visit the following website: [www.WCPCCS2023.org]. The purpose of this manuscript is to review the activities related to global health and advocacy that will occur at the Eighth World Congress of Pediatric Cardiology and Cardiac Surgery.

Acknowledging the need for urgent change, we wanted to take the opportunity to bring a common voice to the global community and issue the Washington DC WCPCCS Call to Action on Addressing the Global Burden of Pediatric and Congenital Heart Diseases. A copy of this Washington DC WCPCCS Call to Action is provided in the Appendix of this manuscript. This Washington DC WCPCCS Call to Action is an initiative aimed at increasing awareness of the global burden, promoting the development of sustainable care systems, and improving access to high quality and equitable healthcare for children with heart disease as well as adults with congenital heart disease worldwide.

Standardized observation of bed baths and showers for 100 residents in 8 nursing homes revealed inadequate cleansing of body sites (88%–100% failure) and >90% process failure involving lather, firm massage, changing dirty wipes or cloths, and following clean-to-dirty sequence. Insufficient water warmth affected 86% of bathing opportunities. Bathing training and adequate resources are needed.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

Deep neural networks (DNNs) have had extraordinary successes in classifying photographic images of objects and are often described as the best models of biological vision. This conclusion is largely based on three sets of findings: (1) DNNs are more accurate than any other model in classifying images taken from various datasets, (2) DNNs do the best job in predicting the pattern of human errors in classifying objects taken from various behavioral datasets, and (3) DNNs do the best job in predicting brain signals in response to images taken from various brain datasets (e.g., single cell responses or fMRI data). However, these behavioral and brain datasets do not test hypotheses regarding what features are contributing to good predictions and we show that the predictions may be mediated by DNNs that share little overlap with biological vision. More problematically, we show that DNNs account for almost no results from psychological research. This contradicts the common claim that DNNs are good, let alone the best, models of human object recognition. We argue that theorists interested in developing biologically plausible models of human vision need to direct their attention to explaining psychological findings. More generally, theorists need to build models that explain the results of experiments that manipulate independent variables designed to test hypotheses rather than compete on making the best predictions. We conclude by briefly summarizing various promising modeling approaches that focus on psychological data.

Dietary patterns describe the combination of foods and beverages in a diet and the frequency of habitual consumption. Better understanding of childhood dietary patterns and antenatal influences could inform intervention strategies to prevent childhood obesity. We derived empirical dietary patterns in 1142 children (average age 6·0 (sd 0·2) years) in New Zealand, whose mothers had participated in the Screening for Pregnancy Endpoints (SCOPE) cohort study and explored associations with measures of body composition. Participants (Children of SCOPE) had their diet assessed by FFQ, and dietary patterns were extracted using factor analysis. Three distinct dietary patterns were identified: ‘Healthy’, ‘Traditional’ and ‘Junk’. Associations between dietary patterns and measures of childhood body composition (waist, hip, arm circumferences, BMI, bioelectrical impedance analysis-derived body fat % and sum of skinfold thicknesses (SST)) were assessed by linear regression, with adjustment for maternal influences. Children who had higher ‘Junk’ dietary pattern scores had 0·24 (sd 0·08; 95 % CI 0·04, 0·13) cm greater arm and 0·44 (sd 0·05; 95 % CI 0·01, 0·10) cm greater hip circumferences and 1·13 (sd 0·07; 95 % CI 0·03, 0·12) cm greater SST and were more likely to be obese (OR 1·74; 95 % CI 1·07, 2·82); those with higher ‘Healthy’ pattern scores were less likely to be obese (OR 0·62; 95 % CI 0·39, 1·00). In a large mother–child cohort, a dietary pattern characterised by high-sugar and -fat foods was associated with greater adiposity and obesity risk in children aged 6 years, while a ‘Healthy’ dietary pattern offered some protection against obesity. Targeting unhealthy dietary patterns could inform public health strategies to reduce the prevalence of childhood obesity.

This report considers the scientific opportunities and problems for paleoclimatic research for three time intervals, 0-1000 yr, 0-30,000 yr, and 0-1 my. Each of these intervals is appropriate to understanding different parts of the climate problem. The most recent interval is one for which there exists the possibility of determining year-by-year changes in certain parts of the climatic system over a time span which overlaps the instrumental record. The interval 0 to 30,000 yr is one for which the response of many parts of the climate system during a major change in climate can be examined, and for which laC dating provides good chronological control. The interval 0 to 1.000,000 yr is one for which there is reasonably good chronological control. a well-developed global record of changes in the ocean, and the opportunity of investigating glacial-interglacial changes in global climate which appear to have a cyclic or quasi-cyclic component.

Twenty-two plant species were identified from leaves, fruits, or flowers, and 41 taxa from pollen, present in a macrofossil (leaf) layer in a peat swamp formed on Pleistocene dunes on the Aupouri Peninsula in northern New Zealand. Eight genera of gymnosperms are represented. With the exception of Lagarostrobos colensoi, all tree species abundant as macrofossils are also common as pollen. Macrofossils enabled the on-site flora to be compared with the regional flora, represented by the pollen rain. Studies on leaf decomposition rates indicate bias toward sclerophyllous species in the macrofossils. Identification to species level and treering data from preserved kauri logs allow quantitative comparisons with similar extant communities. Current climatic conditions at those analogue sites are cooler (2° to 3°C), cloudier (11%), and much wetter (85%) than those currently prevailing on the Aupouri Peninsula. Dendrochronological results also suggest that the far north of New Zealand had a cooler, cloudier, and wetter climate at the time the fossil leaf assemblage was formed. Radiocarbon dates from possibly contaminated samples suggest that a diverse mixed gymnosperm/angiosperm forest, dominated by kauri (Agathis australis), was present about (or sometime before) 41,00034,000 yr B.P., when the leaf layer was formed. Similar temperature reductions have been postulated for this period in New Zealand by other authors.