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Takes readers from the African-American roots and all the way to the global mix of styles and performers in today's jazz scene. Along the way, it looks at the shape, style, and instruments of the discipline, key personalities and recordings in the jazz canon, and at what might be expected next from this most diverse of musical forms.

In 15 participants with hemophilia A treated with a single infusion of AAV5 vector containing the factor VIII gene, 7 who received 6×10 13 vector genomes per kilogram had a median factor VIII level of 20 IU per deciliter, and 6 who received 4×10 13 vg per kilogram had a median level of 13 IU per deciliter. Factor VIII levels decreased in years 2 and 3 of follow-up, but the median annualized rate of bleeding events among these 13 participants remained zero.

Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. Three years after infusion, two participants (one who had received 6×10 vector genomes [vg] per kilogram of body weight and one who had received 2×10 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 vg per kilogram or 6×10 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

Detection of groups of interacting people is a very interesting and useful task in many modern technologies, with application fields spanning from video-surveillance to social robotics. In this paper we first furnish a rigorous definition of group considering the background of the social sciences: this allows us to specify many kinds of group, so far neglected in the Computer Vision literature. On top of this taxonomy we present a detailed state of the art on the group detection algorithms. Then, as a main contribution, we present a brand new method for the automatic detection of groups in still images, which is based on a graph-cuts framework for clustering individuals; in particular, we are able to codify in a computational sense the sociological definition of F-formation, that is very useful to encode a group having only proxemic information: position and orientation of people. We call the proposed method Graph-Cuts for F-formation (GCFF). We show how GCFF definitely outperforms all the state of the art methods in terms of different accuracy measures (some of them are brand new), demonstrating also a strong robustness to noise and versatility in recognizing groups of various cardinality.

Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6–4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability. The analysis of liver biopsy samples after AAV gene therapy for hemophilia A reveals normal histology and long-term persistence of the episomal vector, and identifies potential factors contributing to interindividual variability of transgene expression.

Careless speech is a new type of harm created by large language models (LLM) that poses cumulative, long-term risks to science, education and shared social truth in democratic societies. LLMs produce responses that are plausible, helpful and confident, but that contain factual inaccuracies, misleading references and biased information. These subtle mistruths are poised to cumulatively degrade and homogenize knowledge over time. This article examines the existence and feasibility of a legal duty for LLM providers to create models that ‘tell the truth’. We argue that LLM providers should be required to mitigate careless speech and better align their models with truth through open, democratic processes. We define careless speech against ‘ground truth’ in LLMs and related risks including hallucinations, misinformation and disinformation. We assess the existence of truth-related obligations in EU human rights law and the Artificial Intelligence Act, Digital Services Act, Product Liability Directive and Artificial Intelligence Liability Directive. Current frameworks contain limited, sector-specific truth duties. Drawing on duties in science and academia, education, archives and libraries, and a German case in which Google was held liable for defamation caused by autocomplete, we propose a pathway to create a legal truth duty for providers of narrow- and general-purpose LLMs.

Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.

Anthropogenic warming has led to an unprecedented year-round reduction in Arctic sea ice extent. This has far-reaching consequences for indigenous and local communities, polar ecosystems, and global climate, motivating the need for accurate seasonal sea ice forecasts. While physics-based dynamical models can successfully forecast sea ice concentration several weeks ahead, they struggle to outperform simple statistical benchmarks at longer lead times. We present a probabilistic, deep learning sea ice forecasting system, IceNet. The system has been trained on climate simulations and observational data to forecast the next 6 months of monthly-averaged sea ice concentration maps. We show that IceNet advances the range of accurate sea ice forecasts, outperforming a state-of-the-art dynamical model in seasonal forecasts of summer sea ice, particularly for extreme sea ice events. This step-change in sea ice forecasting ability brings us closer to conservation tools that mitigate risks associated with rapid sea ice loss. Accurate seasonal forecasts of sea ice are highly valuable, particularly in the context of sea ice loss due to global warming. A new machine learning tool for sea ice forecasting offers a substantial increase in accuracy over current physics-based dynamical model predictions.

In this 12-week, phase 2 trial, an anti–interleukin-17–receptor antibody was effective in treating moderate-to-severe psoriasis. Adverse events included neutropenia. Larger trials of longer duration are needed to assess the risk of infections. Psoriasis is a chronic T-cell–mediated autoimmune disease 1 that affects 2 to 3% of the U.S. population 2 , 3 and 0.6 to 6.5% of the European population. 4 Emerging data identify a subset of helper T cells, Th17, that preferentially produce interleukin-17 and play a major role in orchestrating inflammation in psoriasis. 5 – 7 Levels of interleukin-17 are elevated in the lesional skin and blood of patients with psoriasis 5 , 8 – 10 and correlate with disease severity. 11 The interleukin-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). 12 The interleukin 17A, 17F, and 17A/F heterodimer ligands share . . .

Dawn's global mapping of Vesta reveals that its observed south polar depression is composed of two overlapping giant impact features. These large basins provide exceptional windows into impact processes at planetary scales. The youngest Rheasilvia, is 500 kilometers wide and 19 kilometers deep and finds its nearest morphologic analog among large basins on low-gravity icy satellites. Extensive ejecta deposits occur, but impact melt volume is low, exposing an unusual spiral fracture pattern that is likely related to faulting during uplift and convergence of the basin floor. Rheasilvia obliterated half of another 400-kilometer-wide impact basin, Veneneia. Both basins are unexpectedly young, roughly 1 to 2 billion years, and their formation substantially reset Vestan geology and excavated sufficient volumes of older compositionally heterogeneous crustal material to have created the Vestoids and howardfte-eucrite-diogerrite meteorites.