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'Our country never made the requisite investments in clean air upgrades for buildings. Despite botching our vaccination campaigns, we have refused to impose universal Covid safety rules for workplaces. Although one of the earliest recommendations from the World Health Organization was to remove financial barriers to care, our country still doesn’t have a universal healthcare system. We have even watched millions of Americans get stripped from the Medicaid rolls, while 10 states still refuse to expand Medicaid eligibility. Meanwhile less than half of states have guaranteed paid medical leave.'
@gregggonsalves
thenation.com/article/society/

'Similar to SARS-CoV-2, BANAL-CoVs use human ACE2 to enter cells. However, whether BANAL-CoVs can overcome human innate and adaptive immunity and undergo efficient transmission represents a crucial knowledge gap. Characterizing and defining barriers to efficient human infection is critical to better predict the zoonotic potential of bat CoVs and to enhance pandemic preparedness'

nature.com/articles/s41564-024

VONNEGUT
There has to be. Because you can lose a reader in a blink of an eye. If a person is an engineer or chemist or an anthropologist or whatever, you spoil the whole book for that person if there’s obviously ignorance here. What’s wrong with so much science fiction is that the science is so lousy that it isn’t worth paying attention to. My brother was a distinguished scientist and I hung out more with scientists than I did with writers, so the one thing I’ve always tried to do was to get it right, make it plausible. Scientifically. How long it takes to get somewhere through space and what you ‘re likely to find there, and you have to figure whether it’s going to be plausible or not. So, yeah, I did a book called Galapagos which was about evolution and it’s used in courses now.

robertcaro.org/post/an-intervi

'For many people, a routine blood test is easier to get than a colonoscopy or a fecal sample test. But the blood test, made by Guardant Health of Palo Alto, Calif., comes with a limitation. Unlike other screening tests for colon and rectal cancers, it has a poor record of finding precancerous growths. Removal of those growths can prevent cancer.'

nytimes.com/2024/07/29/health/

'Hungary this month published details of a new fast-track visa system for citizens of eight countries, including Russia and Belarus, to enter Hungary without security checks or other restrictions. Budapest said many would be building a nuclear power plant with Russian technology. '
ft.com/content/b2a4ebd8-df41-4

Large language models for accurate disease detection in electronic health records medrxiv.org/content/10.1101/20

Large language models for accurate disease detection in electronic health records

Importance: The use of large language models (LLMs) in medicine is increasing, with potential applications in electronic health records (EHR) to create patient cohorts or identify patients who meet clinical trial recruitment criteria. However, significant barriers remain, including the extensive computer resources required, lack of performance evaluation, and challenges in implementation. Objective: This study aims to propose and test a framework to detect disease diagnosis using a recent light LLM on French-language EHR documents. Specifically, it focuses on detecting gout ( goutte in French), a ubiquitous French term that have multiple meanings beyond the disease. The study will compare the performance of the LLM-based framework with traditional natural language processing techniques and test its dependence on the parameter used. Design: The framework was developed using a training and testing set of 700 paragraphs assessing goutte , issued from a random selection of retrospective EHR documents. All paragraphs were manually reviewed and classified by two health-care professionals (HCP) into disease (true gout) and non-disease (gold standard). The LLM's accuracy was tested using few-shot and chain-of-thought prompting and compared to a regular expression (regex)-based method, focusing on the effects of model parameters and prompt structure. The framework was further validated on 600 paragraphs assessing Calcium Pyrophosphate Deposition Disease (CPPD) . Setting: The documents were sampled from the electronic health-records of a tertiary university hospital in Geneva, Switzerland. Participants: Adults over 18 years of age. Exposure: Meta's Llama 3 8B LLM or traditional method, against a gold standard. Main Outcomes and Measures: Positive and negative predictive value, as well as accuracy of tested models. Results: The LLM-based algorithm outperformed the regex method, achieving a 92.7% [88.7-95.4%] positive predictive value, a 96.6% [94.6-97.8%] negative predictive value, and an accuracy of 95.4% [93.6-96.7%] for gout. In the validation set on CPPD, accuracy was 94.1% [90.2-97.6%]. The LLM framework performed well over a wide range of parameter values. Conclusions and Relevance: LLMs were able to accurately detect disease diagnoses from EHRs, even in non-English languages. They could facilitate creating large disease registries in any language, improving disease care assessment and patient recruitment for clinical trials. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was funded by the Private Foundation of the Geneva University Hospitals, a not-for-profit foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves human participants and the creation and use of the register for quality improvement programs has been approved by the Geneva ethics commission (CCER 2023-00129). The need for consent was waived by the Geneva Ethics Committee because this study qualifies as a quality improvement initiative. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All prompts and code have been made available at the following gitlab repository: https://gitlab.unige.ch/goutte/llm\_detection\_of_diagnosis. Due to medical confidentiality, we are unable to share the sentences and document data. However, if authorization is obtained from the ethics committee, we may be able to provide access to the data [https://gitlab.unige.ch/goutte/llm\_detection\_of_diagnosis][1] [1]: https://gitlab.unige.ch/goutte/llm_detection_of_diagnosis

www.medrxiv.org

Gold OA down overall in 2024, but Nature and Elsevier buck the trend.

Nature Communications alone predicted to publish >10K papers ($68M). Scientific Reports >30K ($78M).

ck.journalology.com/posts/jour

'We demonstrate the first generalizable strategy using a small molecule to selectively kill TP53 mutant cells. This molecule binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53 Y220C mutations.'

biorxiv.org/content/10.1101/20

p53 protein abundance is a therapeutic window across TP53 mutant cancers and is targetable with proximity inducing small molecules

TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate the first generalizable strategy using a small molecule to selectively kill TP53 mutant cells. This molecule binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53 Y220C mutations. Together, these data demonstrate that the abundance of p53 protein provides a therapeutic window for TP53 missense mutant cancers that can be translated into a cell death signal using proximity-inducing small molecules. ### Competing Interest Statement A patent application naming A.S., W.J.G., and M.M. as inventors has been filed by the Broad Institute covering aspects of this work. W.J.G. is on the scientific advisory board (SAB), and has received consulting fees from Esperion therapeutics, consulting fees from Belharra therapeutics, Boston Clinical Research Institute, Faze Medicines, ImmPACT-Bio, and nference. M.M. reports consultant/advisory board/equity for DelveBio and Isabl; research funding from Janssen and Bayer Pharmaceuticals, and equity in Bayer; patents licensed to LabCorp and Bayer. S.L.S. is the founding C.E.O. of Arena BioWorks, LLC; shareholder and serves on the Board of Directors of Kojin Therapeutics; is a shareholder and advises Jnana Therapeutics, Kisbee Therapeutics, Belharra Therapeutics, Magnet Biomedicine, Exo Therapeutics, Eikonizo Therapeutics, and Replay Bio; advises Vividion Therapeutics, Eisai Co., Ltd., Ono Pharma Foundation, F-Prime Capital Partners, and is a Novartis Faculty Scholar. Except for the patent application, COI listed above are outside the submitted work; all other authors report no COI.

www.biorxiv.org

Wonderful interview/dialogue with Kurt Vonnegut and Robert Caro. Caro gets about 90% of the space but I don't begrudge him that

robertcaro.org/post/an-intervi

So many thoughts. The description of the novelist, novel completely in their head, a terrible partner, is me as a PhD student.

And those quotes!

Metformin + anti-PD1

"We found that the combination therapy promotes the pericyte coverage of tumor vascular endothelial cells (ECs) to improve blood perfusion and that it suppresses the hyperpermeability through the increase of VE-cadherin. Peripheral node addressin(PNAd) and vascular cell adhesion molecule (VCAM)-1"

pnas.org/doi/10.1073/pnas.2404

'Reliant largely on dwindling supplies from Soviet and American cold war-era stockpiles of precursor radioactive materials, companies have struggled to obtain enough actinium to treat the thousands of patients being enrolled in clinical trials.'

ft.com/content/6ce668bc-4180-4

'Alguns dos problemas decorrentes de um crescimento excessivo do turismo são evidentes e bem conhecidos de toda a população. A OCDE alerta para aspectos como as pressões sobre os preços do alojamento (que dificultam o acesso à habitação dos residentes e também dos trabalhadores sazonais), sobre as infra-estruturas e os serviços colectivos (traduzindo-se, por exemplo, na sobrelotação dos transportes públicos ou na acumulação de lixo nas zonas mais frequentadas) e sobre o ambiente (aumentando a poluição e pondo em causa a sustentabilidade dos ecossistemas e a biodiversidade). Os crescentes protestos populares em zonas de grande intensidade turística – como Barcelona ou Málaga, para dar dois exemplos recentes – são um sinal de que o excesso de turismo existe de facto e que está a tornar-se um problema político sério em diferentes partes do mundo.'

publico.pt/2024/07/29/opiniao/

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping biorxiv.org/content/10.1101/20

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease. ### Competing Interest Statement R.F. is scientific founder of and advisor to IsoPlexis, Singleron Biotechnologies, and AtlasXomics. The interests of R.F. were reviewed and managed by Yale University Provost Office in accordance with the University conflict of interest policies. The other authors declare no competing interests.

www.biorxiv.org

Characterization of Eye and Adnexal Tissues in Dogs and Wolves: A Histological and Lectin-Histochemical Approach biorxiv.org/content/10.1101/20

Characterization of Eye and Adnexal Tissues in Dogs and Wolves: A Histological and Lectin-Histochemical Approach

This study explores the ocular anatomy and glandular components of domestic dogs compared to their ancestor, the wolf, with the aim of identifying evolutionary changes due to domestication and their implications for ocular pathologies. Utilizing histological and histochemical techniques, including hematoxylin-eosin, PAS, Alcian Blue, and lectins, this research conducts a detailed analysis of the canine and wolf ocular systems, particularly focusing on the eyelids, tarsal glands, and conjunctival tissues. Results indicate significant histological differences between the two species, particularly in the thickness and secretion levels of the conjunctival epithelia and the structure of the tarsal glands. Dogs exhibit a thicker epithelium with greater PAS and Alcian Blue positive secretion, suggesting enhanced ocular protection and lubrication adapted to domestic environments. Conversely, wolves display more concentrated glandular secretions and a predominance of acidic mucopolysaccharides, aligning with their adaptation to natural habitats. This study also highlights the translational value of dogs as models for human ocular diseases, given their anatomical and physiological similarities with humans. Such comparisons are essential as they provide insights that can lead to advancements in medical research and clinical applications, especially in the development of treatments for ocular surface disorders. ### Competing Interest Statement The authors have declared no competing interest.

www.biorxiv.org
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