Transforming healthcare documentation: harnessing the potential of AI to generate discharge summaries.

BACKGROUND: Hospital discharge summaries play an essential role in informing GPs of recent admissions to ensure excellent continuity of care and prevent adverse events; however, they are notoriously poorly written, time-consuming, and can result in delayed discharge. AIM: To evaluate the potential of artificial intelligence (AI) to produce high-quality discharge summaries equivalent to the level of a doctor who has completed the UK Foundation Programme. DESIGN & SETTING: Feasibility study using 25 mock patient vignettes. METHOD: Twenty-five mock patient vignettes were written by the authors. Five junior doctors wrote discharge summaries from the case vignettes (five each). The same case vignettes were input into ChatGPT. In total, 50 discharge summaries were generated; 25 by Al and 25 by junior doctors. Quality and suitability were determined through both independent GP evaluators and adherence to a minimum dataset. RESULTS: Of the 25 AI-written discharge summaries 100% were deemed by GPs to be of an acceptable quality compared with 92% of the junior doctor summaries. They both showed a mean compliance of 97% with the minimum dataset. In addition, the ability of GPs to determine if the summary was written by ChatGPT was poor, with only a 60% accuracy of detection. Similarly, when run through an AI-detection tool all were recognised as being very unlikely to be written by AI. CONCLUSION: AI has proven to produce discharge summaries of equivalent quality to a junior doctor who has completed the UK Foundation Programme; however, larger studies with real-world patient data with NHS-approved AI tools will need to be conducted.

Hidden Fluids in Plain Sight: Identifying Intravenous Medication Classes as Contributors to Intensive Care Unit Fluid Intake.

Introduction: Fluid stewardship targets optimal fluid management to improve patient outcomes. Intravenous (IV) medications, flushes, and blood products, collectively referred to as hidden fluids, contribute to fluid intake in the intensive care unit (ICU). The impact of specific IV medications on fluid intake is unknown. Objective: Characterize IV medication classes based on contribution to ICU fluid intake by frequency of administration and total volume infused to identify targets for fluid stewardship. Methods: This multi-center, retrospective nested cohort study included patients admitted to a medical or surgical ICU between January 2017 and December 2018. The primary outcome was to identify the volume contribution of specific IV medication classes administered over the first 3 ICU days. Secondary outcomes were the administration frequency of these medications and their proportion of total daily volume intake over the first 3 ICU days. Results: The study included 210 patients. The largest mean administration volumes over the course of the first 3 ICU days were attributed to antibacterials (968 ± 846 mL), vitamins/minerals/electrolytes (416 ± 935 mL), pain/agitation/delirium agents (310 ± 512 mL), and vasoactive agents (282 ± 744 mL). The highest frequencies over the course of the first 3 ICU days were attributed to antibacterials (n = 180; 86%), pain/agitation/delirium agents (n = 143; 68%), vitamins/minerals/electrolytes (n = 123; 59%), and vasoactive agents (n = 96; 46%). IV medications contributed 2601 ± 2573 mL of fluid volume per patient over the first 3 ICU days, accounting for 42% ± 29% of overall volume. Conclusion: IV medications contribute over 40% of total fluid intake within the first 3 days of ICU admission, with antibacterials as top contributors by administration volume and frequency. Future research implementing fluid stewardship to ICU fluid sources, such as concentrating IV medications, switching IV medications to oral formulations, de-escalation of antibacterials, and reduction of maintenance fluids, should be performed to minimize hidden fluids from IV medications.

Aviation Turbine Fuel Thermal Conductivity: A Predictive Approach Using Entropy Scaling-Guided Machine Learning with Experimental Validation.

Although typical aircraft fuel thermal management analysis relies upon temperature-dependent thermodynamic and transport properties of aviation turbine fuel, the variation in properties associated with compositional variation in fuels and the subsequent impacts on system performance are not well established. With this in mind, the present work aimed to develop a predictive model of aviation turbine fuel thermal conductivity which utilized only compositional (hydrocarbon) and state (temperature and pressure) inputs and had errors within the bounds of typical uncertainty of the associated test data (3%). A novel modeling approach was developed to predict thermal conductivity using pseudo-component entropy scaling techniques with a machine learning-developed intermediate step in the overall model. Simple hyper-parameter optimization techniques were developed to promote model stability, computational efficiency, and long-term repeatability of the novel architecture. Validation data were gathered which included four fuel samples (3 JP-5 and 1 F-24), which underwent two-dimensional gas chromatography compositional testing and temperature-dependent density, viscosity, thermal conductivity, and specific heat testing. Model performance on the validation data set assembled from the literature data and present efforts showed an average deviation of 1% and an absolute average deviation of 2.5%. Model outputs outside the validation range are well-behaved and are expected to perform well on a large range of liquid hydrocarbon mixtures with the overall process expected to be well suited to prediction of other properties.

Domestication of Oryza species eco-evolutionarily shapes bacterial and fungal communities in rice seed.

BACKGROUND: Plant-associated microbiomes, which are shaped by host and environmental factors, support their hosts by providing nutrients and attenuating abiotic and biotic stresses. Although host genetic factors involved in plant growth and immunity are known to shape compositions of microbial communities, the effects of host evolution on microbial communities are not well understood. RESULTS: We show evidence that both host speciation and domestication shape seed bacterial and fungal community structures. Genome types of rice contributed to compositional variations of both communities, showing a significant phylosymbiosis with microbial composition. Following the domestication, abundance inequality of bacterial and fungal communities also commonly increased. However, composition of bacterial community was relatively conserved, whereas fungal membership was dramatically changed. These domestication effects were further corroborated when analyzed by a random forest model. With these changes, hub taxa of inter-kingdom networks were also shifted from fungi to bacteria by domestication. Furthermore, maternal inheritance of microbiota was revealed as a major path of microbial transmission across generations. CONCLUSIONS: Our findings show that evolutionary processes stochastically affect overall composition of microbial communities, whereas dramatic changes in environments during domestication contribute to assembly of microbiotas in deterministic ways in rice seed. This study further provides new insights on host evolution and microbiome, the starting point of the holobiome of plants, microbial communities, and surrounding environments.

A 0.0023 mm 2/ch. Delta-Encoded, Time-Division Multiplexed Mixed-Signal ECoG Recording Architecture With Stimulus Artifact Suppression.

This article demonstrates a scalable, time-division multiplexed biopotential recording front-end capable of real-time differential- and common-mode artifact suppression. A delta-encoded recording architecture exploits the power spectral density (PSD) characteristics of Electrocorticography (ECoG) recordings, combining an 8-bit ADC, and an 8-bit DAC to achieve 14 bits of dynamic range. The flexibility of the digital feedback architecture is leveraged to time-division multiplex 64 differential input channels onto a shared mixed-signal front-end, reducing channel area by 2x compared to the state-of-the-art. The feedback DAC used for delta-encoding also serves to cancel differential artifacts with an off-chip adaptive loop. Analysis of this architecture and measured silicon performance of a 65 nm CMOS test-chip implementation, both on the bench and in-vivo, are included with this paper.

High-sensitivity troponin I for cardiovascular risk stratification in the general asymptomatic population: Perspectives from Asia-Pacific.

Cardiac troponin is a sensitive and specific biomarker for acute myocardial injury and has been used in the diagnosis of acute coronary syndromes, and has emerged as a tool for identifying high risk individuals for primary preventive therapy. Recent evidence has emerged indicating that high-sensitivity cardiac troponin assays, which allow robust detection of very low troponin concentrations, could detect subclinical injury in asymptomatic patients. On 24 March 2018, a group of cardiologists from the Asia Pacific region convened to review the data and discuss the potential utility of high-sensitivity troponin I (hsTnI) in the risk assessment of cardiovascular disease in the general population. The group recognized the immense burden of cardiovascular disease in the Asia-Pacific region, and the limitations of current risk stratification strategies. Data demonstrates that cardiac biomarkers like hsTnI could improve risk stratification, and thresholds for hsTnI in cardiovascular disease risk classification have been developed in Caucasian populations but not validated in Asian populations. There is an urgent need to improve cardiovascular risk assessment in the Asia Pacific general population, validate the Asian threshold of high risk and prove the utility of targeting these high-risk individuals for primary preventive strategies.

PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis.

Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine's reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ∼30% reduction in synaptosomal DA uptake observed in PICK1 KO mice. The PICK1 KO mice demonstrated preserved behavioral responses to DA receptor agonists supporting intact downstream DA receptor signaling. Unexpectedly, we found a prominent increase in striatal DA content and levels of striatal tyrosine hydroxylase (TH) in PICK1 KO mice. Chronoamperometric recordings showed enhanced DA release in PICK1 KO mice, consistent with increased striatal DA pools. Viral-mediated knock-down (KD) of PICK1 in cultured dopaminergic neurons increased TH expression, supporting a direct cellular effect of PICK1. In summary, in addition to demonstrating a key role of PICK1 in mediating behavioral effects of cocaine, our data reveal a so far unappreciated role of PICK1 in DA homeostasis that possibly involves negative regulation of striatal TH levels.

The (ongoing) problem of relative growth.

Differential growth, the phenomenon where parts of the body grow at different rates, is necessary to generate the complex morphologies of most multicellular organisms. Despite this central importance, how differential growth is regulated remains largely unknown. Recent discoveries, particularly in insects, have started to uncover the molecular-genetic and physiological mechanisms that coordinate growth among different tissues throughout the body and regulate relative growth. These discoveries suggest that growth is coordinated by a network of signals that emanate from growing tissues and central endocrine organs. Here we review these findings and discuss their implications for understanding the regulation of relative growth and the evolution of morphology.

Neuroscience research in Africa: Current status.

There are limited data on the contribution of the African continent to neuroscience research and publications. This review aims to provide a clear view on the state of neuroscience research among African countries, and to compare neuroscience research within the 52 African countries. A literature review search was conducted for all published articles by African authors in both local and international journals using Medline and other primary databases. Neuroscience represents 9.1% of the total medical publications. The highest percentage of neuroscience publications comes from South Africa. There is a positive correlation between the Gross Domestic Product and the total number of neuroscience publications among African countries. There is therefore an urgent need to develop strategies to improve neuroscience research in African countries.

Acid Mediated Ring Closing Metathesis: A Powerful Synthetic Tool Enabling the Synthesis of Clinical Stage Kinase Inhibitors.

The powerful olefin metathesis reaction was employed for the construction of late-phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid).

Blocking monocyte transmigration in in vitro system by a human antibody scFv anti-CD99. Efficient large scale purification from periplasmic inclusion bodies in E. coli expression system.

Migration of leukocytes into site of inflammation involves several steps mediated by various families of adhesion molecules. CD99 play a significant role in transendothelial migration (TEM) of leukocytes. Inhibition of TEM by specific monoclonal antibody (mAb) can provide a potent therapeutic approach to treating inflammatory conditions. However, the therapeutic utilization of whole IgG can lead to an inappropriate activation of Fc receptor-expressing cells, inducing serious adverse side effects due to cytokine release. In this regard, specific recombinant antibody in single chain variable fragments (scFvs) originated by phage library may offer a solution by affecting TEM function in a safe clinical context. However, this consideration requires large scale production of functional scFv antibodies and the absence of toxic reagents utilized for solubilization and refolding step of inclusion bodies that may discourage industrial application of these antibody fragments. In order to apply the scFv anti-CD99 named C7A in a clinical setting, we herein describe an efficient and large scale production of the antibody fragments expressed in E. coli as periplasmic insoluble protein avoiding gel filtration chromatography approach, and laborious refolding step pre- and post-purification. Using differential salt elution which is a simple, reproducible and effective procedure we are able to separate scFv in monomer format from aggregates. The purified scFv antibody C7A exhibits inhibitory activity comparable to an antagonistic conventional mAb, thus providing an excellent agent for blocking CD99 signaling. This protocol can be useful for the successful purification of other monomeric scFvs which are expressed as periplasmic inclusion bodies in bacterial systems.

A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane.

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.

Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3).

A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.

Global biogeography of highly diverse protistan communities in soil.

Protists are ubiquitous members of soil microbial communities, but the structure of these communities, and the factors that influence their diversity, are poorly understood. We used barcoded pyrosequencing to survey comprehensively the diversity of soil protists from 40 sites across a broad geographic range that represent a variety of biome types, from tropical forests to deserts. In addition to taxa known to be dominant in soil, including Cercozoa and Ciliophora, we found high relative abundances of groups such as Apicomplexa and Dinophyceae that have not previously been recognized as being important components of soil microbial communities. Soil protistan communities were highly diverse, approaching the extreme diversity of their bacterial counterparts across the same sites. Like bacterial taxa, protistan taxa were not globally distributed, and the composition of these communities diverged considerably across large geographic distances. However, soil protistan and bacterial communities exhibit very different global-scale biogeographical patterns, with protistan communities strongly structured by climatic conditions that regulate annual soil moisture availability.

SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis.

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3).

Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis.

Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Structure-based optimization of morpholino-triazines as PI3K and mTOR inhibitors.

A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties.