ELIXR: Towards a general purpose X-ray artificial intelligence system through alignment of large language models and radiology vision encoders

Our approach, which we call Embeddings for Language/Image-aligned X-Rays, or ELIXR, leverages a language-aligned image encoder combined or grafted onto a fixed LLM, PaLM 2, to perform a broad range of tasks. We train this lightweight adapter architecture using images paired with corresponding free-text radiology reports from the MIMIC-CXR dataset. ELIXR achieved state-of-the-art performance on zero-shot chest X-ray (CXR) classification (mean AUC of 0.850 across 13 findings), data-efficient CXR classification (mean AUCs of 0.893 and 0.898 across five findings (atelectasis, cardiomegaly, consolidation, pleural effusion, and pulmonary edema) for 1% (~2,200 images) and 10% (~22,000 images) training data), and semantic search (0.76 normalized discounted cumulative gain (NDCG) across nineteen queries, including perfect retrieval on twelve of them). Compared to existing data-efficient methods including supervised contrastive learning (SupCon), ELIXR required two orders of magnitude less data to reach similar performance. ELIXR also showed promise on CXR vision-language tasks, demonstrating overall accuracies of 58.7% and 62.5% on visual question answering and report quality assurance tasks, respectively. These results suggest that ELIXR is a robust and versatile approach to CXR AI

Blood transfusion in the critically ill: does storage age matter?

Morphologic and biochemical changes occur during red cell storage prior to product expiry, and these changes may hinder erythrocyte viability and function following transfusion. Despite a relatively large body of literature detailing the metabolic and structural deterioration that occurs during red cell storage, evidence for a significant detrimental clinical effect related to the transfusion of older blood is relatively less conclusive, limited primarily to observations in retrospective studies. Nonetheless, the implication that the transfusion of old, but not outdated blood may have negative clinical consequences demands attention. In this report, the current understanding of the biochemical and structural changes that occur during storage, known collectively as the storage lesion, is described, and the clinical evidence concerning the detrimental consequences associated with the transfusion of relatively older red cells is critically reviewed. Although the growing body of literature demonstrating the deleterious effects of relatively old blood is compelling, it is notable that all of these reports have been retrospective, and most of these studies have evaluated patients who received a mixture of red cell units of varying storage age. Until prospective studies have been completed and produce confirmative results, it would be premature to recommend any modification of current transfusion practice regarding storage age

Moderate exercise and chronic stress produce counteractive effects on different areas of the brain by acting through various neurotransmitter receptor subtypes: A hypothesis

BACKGROUND: Regular, "moderate", physical exercise is an established non-pharmacological form of treatment for depressive disorders. Brain lateralization has a significant role in the progress of depression. External stimuli such as various stressors or exercise influence the higher functions of the brain (cognition and affect). These effects often do not follow a linear course. Therefore, nonlinear dynamics seem best suited for modeling many of the phenomena, and putative global pathways in the brain, attributable to such external influences. HYPOTHESIS: The general hypothesis presented here considers only the nonlinear aspects of the effects produced by "moderate" exercise and "chronic" stressors, but does not preclude the possibility of linear responses. In reality, both linear and nonlinear mechanisms may be involved in the final outcomes. The well-known neurotransmitters serotonin (5-HT), dopamine (D) and norepinephrine (NE) all have various receptor subtypes. The article hypothesizes that 'Stress' increases the activity/concentration of some particular subtypes of receptors (designated nt(s)) for each of the known (and unknown) neurotransmitters in the right anterior (RA) and left posterior (LP) regions (cortical and subcortical) of the brain, and has the converse effects on a different set of receptor subtypes (designated nt(h)). In contrast, 'Exercise' increases nt(h )activity/concentration and/or reduces nt(s )activity/concentration in the LA and RP areas of the brain. These effects may be initiated by the activation of Brain Derived Neurotrophic Factor (BDNF) (among others) in exercise and its suppression in stress. CONCLUSION: On the basis of this hypothesis, a better understanding of brain neurodynamics might be achieved by considering the oscillations caused by single neurotransmitters acting on their different receptor subtypes, and the temporal pattern of recruitment of these subtypes. Further, appropriately designed and planned experiments will not only corroborate such theoretical models, but also shed more light on the underlying brain dynamics

Acquisition and Evolution of Plant Pathogenesis–Associated Gene Clusters and Candidate Determinants of Tissue-Specificity in Xanthomonas

is a large genus of plant-associated and plant-pathogenic bacteria. Collectively, members cause diseases on over 392 plant species. Individually, they exhibit marked host- and tissue-specificity. The determinants of this specificity are unknown. lineage. genome and indicate that differentiation with respect to host- and tissue-specificity involved not major modifications or wholesale exchange of clusters, but subtle changes in a small number of genes or in non-coding sequences, and/or differences outside the clusters, potentially among regulatory targets or secretory substrates

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets

Genetic variation affecting DNA methylation and the human imprinting disorder, Beckwith-Wiedemann syndrome

Abstract Background Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with a population frequency of approximately 1 in 10,000. The most common epigenetic defect in BWS is a loss of methylation (LOM) at the 11p15.5 imprinting centre, KCNQ1OT1 TSS-DMR, and affects 50% of cases. We hypothesised that genetic factors linked to folate metabolism may play a role in BWS predisposition via effects on methylation maintenance at KCNQ1OT1 TSS-DMR. Results Single nucleotide variants (SNVs) in the folate pathway affecting methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), cystathionine beta-synthase (CBS) and methionine adenosyltransferase (MAT1A) were examined in 55 BWS patients with KCNQ1OT1 TSS-DMR LOM and in 100 unaffected cases. MTHFR rs1801133: C>T was more prevalent in BWS with KCNQ1OT1 TSS-DMR LOM (p T, rs150331990: A>G and rs757460628: G>A encoding NP_001124295 p.Arg136Cys, p.His1118Arg and p.Arg1223His, respectively. These variants have population frequencies of less than 1 in 1000 and were absent from 100 control cases. Functional characterization using a hemimethylated DNA trapping assay revealed a reduced methyltransferase activity relative to wild-type DNMT1 for each variant ranging from 40 to 70% reduction in activity. Conclusions This study is the first to examine folate pathway genetics in BWS and to identify rare DNMT1 missense variants in affected individuals. Our data suggests that reduced DNMT1 activity could affect maintenance of methylation at KCNQ1OT1 TSS-DMR in some cases of BWS, possibly via a maternal effect in the early embryo. Larger cohort studies are warranted to further interrogate the relationship between impaired MTHFR enzymatic activity attributable to MTHFR rs1801133: C>T, dietary folate intake and BWS

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Kalrn Promoter Usage And Isoform Expression Respond To Chronic Cocaine Exposure

Background The long-term effects of cocaine on behavior are accompanied by structural changes in excitatory glutamatergic synapses onto the medium spiny neurons of the striatum. The Kalrn gene encodes several functionally distinct isoforms; these multidomain guanine nucleotide exchange factors (GEFs) contain additional domains known to interact with phosphatidylinositides as well as with a number of different proteins. Through their activation of Rho proteins and their interactions with other proteins, the different Kalirin isoforms affect cytoskeletal organization. Chronic exposure of adult male rodents to cocaine increases levels of Kalirin 7 in the striatum. When exposed chronically to cocaine, mice lacking Kalirin 7, the major adult isoform, fail to show an increase in dendritic spine density in the nucleus accumbens, show diminished place preference for cocaine, and exhibit increased locomotor activity in response to cocaine. Results The use of alternate promoters and 3\u27-terminal exons of the mouse Kalrn gene were investigated using real-time quantitative polymerase chain reaction. While the two most distal full-length Kalrn promoters are used equally in the prefrontal cortex, the more proximal of these promoters accounts for most of the transcripts expressed in the nucleus accumbens. The 3\u27-terminal exon unique to the Kalirin 7 isoform accounts for a greater percentage of the Kalrn transcripts in prefrontal cortex than in nucleus accumbens. Western blot analyses confirmed these differences. Chronic cocaine treatment increases usage of the promoter encoding the Δ-Kalirin isoforms but does not alter full-length Kalirin promoter usage. Usage of the 3\u27-terminal exon unique to Kalirin 7 increases following chronic cocaine exposure. Conclusions Kalrn promoter and 3\u27-terminal exon utilization are region-specific. In the nucleus accumbens, cocaine-mediated alterations in promoter usage and 3\u27-terminal exon usage favor expression of Kalirin 7 and Δ-Kalirin 7. The Δ-isoform, which lacks a Sec14p domain and four of the nine spectrin-like repeats found in full-length Kalirin isoforms, increases spine headsize without increasing dendritic spine numbers. Thus cocaine-mediated changes in alternative splicing of the Kalrn gene may contribute importantly to the behavioral, morphological and biochemical responses observed