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| Open AccessPancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis
IL-22RA1 is highly expressed on pancreatic islets and absent on immune cells. Here, the authors investigate its role by generating animals that lack IL-22RA1 on beta cells and reveal IL22RA1 signalling is critical for insulin biosynthesis and beta-cell health, evidenced by its regulation of MHC II expression and its suppressive effect on inflammation and cellular stress.
- Haressh Sajiir
- , Kuan Yau Wong
- & Sumaira Z. Hasnain
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Article
| Open AccessL-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial
Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.
- Frank A. Giordano
- , Julian P. Layer
- & Michael Hölzel
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Article
| Open AccessAssociations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population
Anecdotal reports from patients prescribed semaglutide describe a reduced desire to drink. Here, the authors show that semaglutide is associated with a 50%-56% reduced risk for both the incidence and recurrence of alcohol use disorder in real-world populations.
- William Wang
- , Nora D. Volkow
- & Rong Xu
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Article
| Open AccessLong-read sequencing for 29 immune cell subsets reveals disease-linked isoforms
This paper unveils the complexity of human immune cell splicing, highlighting cell-specific isoforms and establishing connections between alternative splicing and complex traits. These findings have implications for understanding diseases and the evolution of the genome.
- Jun Inamo
- , Akari Suzuki
- & Yuta Kochi
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Article
| Open AccessStructure prediction of protein-ligand complexes from sequence information with Umol
Here the authors report the AI system Umol that predicts flexible all-atom structures of protein-ligand complexes from sequence information, advancing AI-driven drug discovery: accurate structures and affinity can be selected from predicted confidence metrics (plDDT).
- Patrick Bryant
- , Atharva Kelkar
- & Frank Noé
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Article
| Open AccessHuman movement and environmental barriers shape the emergence of dengue
Here, using a dynamic modelling approach, the authors find that the spread of dengue through Mexico and Brazil is shaped by specific interactions between human mobility, climate, and the environment. Their models can also be applied to predict future spread in these geographic areas.
- Vinyas Harish
- , Felipe J. Colón-González
- & Oliver J. Brady
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Article
| Open AccessGut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Here, in a follow-up of a clinical study, the authors show that protein pacing and intermittent fasting improves gut symptomatology and microbial diversity, as well as reduces visceral fat compared to a heart-healthy, calorie-restricted diet matched for overall energy intake and expenditure in free-living humans.
- Alex E. Mohr
- , Karen L. Sweazea
- & Paul J. Arciero
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Article
| Open AccessProteomic analysis of the urothelial cancer landscape
Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.
- Franz F. Dressler
- , Falk Diedrichs
- & Ákos Végvári
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Article
| Open AccessAcute and post-acute respiratory complications of SARS-CoV-2 infection: population-based cohort study in South Korea and Japan
Respiratory complications of SARS-CoV-2 infection have been described in the acute (within 30 days) and post-acute (after 30 days) phase. Here, the authors characterise the risk of acute and post-acute respiratory complications of SARS-CoV-2 using population-based data from South Korea and Japan.
- Yujin Choi
- , Hyeon Jin Kim
- & Dong Keon Yon
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Article
| Open AccessSafety outcomes following COVID-19 vaccination and infection in 5.1 million children in England
COVID-19 vaccines reduce the risk of severe disease in young people, but the absolute risk is low, and side effects have been reported. Here, the authors use data on 5–17 year olds in England to assess the overall risk-benefit profile of the vaccines.
- Emma Copland
- , Martina Patone
- & Julia Hippisley-Cox
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Article
| Open AccessNoninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration
Researchers have developed a noninvasive retina prosthesis based on ultrasound for treating blindness. This device uses ultrasound waves to stimulate the retina, creating artificial vision confirmed through behavior tests, offering a safer alternative to invasive treatments.
- Gengxi Lu
- , Chen Gong
- & Qifa Zhou
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Article
| Open AccessLongitudinal viral shedding and antibody response characteristics of men with acute infection of monkeypox virus: a prospective cohort study
Here the authors measure viral load in samples from skin lesions, saliva, oropharynx, and rectum of 77 patients with acute monkeypox virus infection as well as from environmental fomite swabs and show a high seropositivity rate for antibodies against A29L and H3L.
- Yang Yang
- , Shiyu Niu
- & Yingxia Liu
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Article
| Open AccessGlioblastoma disrupts cortical network activity at multiple spatial and temporal scales
The precise onset, temporal progression and spatial extent of neuron-tumor crosstalk in brain with Glioblastoma (GBM) are not fully understood. Here authors, using a genetic GBM mouse model, show widespread glutamate accumulation, chronic neural activity disruption between cells and brain areas, depending on tumor expansion rate and genotype with altered tumor and neural activity dynamics when adding glypican6.
- Jochen Meyer
- , Kwanha Yu
- & Jeffrey Noebels
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Article
| Open AccessC5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC), however resistance and recurrence are often observed. Here, in preclinical models of BRCA1/2 wild type and homologous recombination competent BC, the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance, suggesting targeting C5aR1 as a therapeutic option.
- Xi Li
- , Alfonso Poire
- & Gordon B. Mills
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Article
| Open AccessLateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia
The parabrachial nucleus contains separate populations of neurons that respond to elevated CO2 with EEG arousal and increased breathing. Here we report that the parabrachial respiratory neurons express FoxP2 and are required for respiratory responses to elevated CO2.
- Satvinder Kaur
- , Nicole Lynch
- & Clifford B. Saper
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Article
| Open AccessImmune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer
In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.
- Wolfgang Beckabir
- , Mi Zhou
- & Benjamin G. Vincent
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Article
| Open AccessHIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes
Despite effective antiviral drugs, HIV-1 transcripts can be found in extracellular vesicles (EVs) in people living with HIV-1. Comparing EVs from serum and cerebrospinal fluid (CSF), the authors show compartmentalized defective viral transcripts that are enriched in the CSF and corelate with cognitive dysfunction.
- Catherine DeMarino
- , Julia Denniss
- & Avindra Nath
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Article
| Open AccessThe brain structure, inflammatory, and genetic mechanisms mediate the association between physical frailty and depression
Identifying modifiable risk factors that could prevent depression is important. Here, the authors show increased risks of incident depression in pre-frail and frail individuals and highlight the mediating role of brain structure and inflammation.
- Rongtao Jiang
- , Stephanie Noble
- & Dustin Scheinost
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Article
| Open AccessReduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice
How LGR4 impacts nutrition absorption and energy homeostasis is unknown. Here, the authors show that LGR4 loss in the intestinal epithelium decreases the proportion of enterocytes selective for long-chain fatty acid absorption, reducing lipid absorption and improving lipid and glucose metabolism.
- Yuan Liang
- , Chao Luo
- & Yue Yin
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Article
| Open AccessSingle-cell and spatial transcriptomics analysis of non-small cell lung cancer
Myeloid cell populations play a critical role in lung cancer progression. Here, the authors use scRNA-seq and spatial transcriptomics to identify changes in the phenotype of macrophages within the tumour microenvironment.
- Marco De Zuani
- , Haoliang Xue
- & Ana Cvejic
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Article
| Open AccessA nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila
Amplification of glucose stimulated insulin secretion by lipids is not fully understood due to complex inter organ communication in glycemic regulation. Here the authors show Vaha, a Drosophila lipase synthesized in the gut, concentrates in insulin producing cells in the brain to regulate insulin like peptide release.
- Alka Singh
- , Kandahalli Venkataranganayaka Abhilasha
- & Usha R. Acharya
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Article
| Open AccessCompound mortality impacts from extreme temperatures and the COVID-19 pandemic
Extreme weather and pandemics are classified as two of the most serious risks facing the UK in its National Risk Register. Here, the authors investigate the compound mortality impacts of extreme high and low temperatures and COVID-19 in England and Wales.
- Y. T. Eunice Lo
- , Dann M. Mitchell
- & Antonio Gasparrini
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Article
| Open AccessPost-COVID conditions following COVID-19 vaccination: a retrospective matched cohort study of patients with SARS-CoV-2 infection
The impact of COVID-19 vaccination on post-COVID conditions is not well understood. Here, the authors use electronic health record data from a network of eight integrated healthcare systems in the United States to compare rates of post-COVID conditions in those with and without vaccination.
- Debbie E. Malden
- , In-Lu Amy Liu
- & Sara Y. Tartof
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Article
| Open AccessUnveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events
Cardiovascular events (CVEs) are the leading cause of death among hip fracture patients. Here, the authors show the findings on subphenotyping the heterogeneous spectrum of hip fracture patients in both Hong Kong and the United Kingdom older adult populations and temporal associations with CVEs across all subphenotypes.
- Warrington W. Q. Hsu
- , Xiaowen Zhang
- & Ching-Lung Cheung
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Article
| Open AccessIntegrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions
Duarte et al. report that common genetic variants linked to psychiatric disorders influence the regulation of ancient retroviruses integrated into the genome. This suggests ancient viruses acquired millions of years ago may have shaped modern human brain function.
- Rodrigo R. R. Duarte
- , Oliver Pain
- & Timothy R. Powell
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Article
| Open AccessArtificial intelligence enables precision diagnosis of cervical cytology grades and cervical cancer
Cervical screening is a key method for detecting cervical cancer, but is limited by pathologist detection. Here, the authors use artificial intelligence to predict cytology grades from whole slide images.
- Jue Wang
- , Yunfang Yu
- & Herui Yao
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Article
| Open AccessDrug screening on digital microfluidics for cancer precision medicine
In-vitro platforms for personalized cancer diagnosis is required high sensitivity. Here, the authors developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine.
- Jiao Zhai
- , Yingying Liu
- & Yanwei Jia
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Article
| Open AccessHippocampal sharp-wave ripples correlate with periods of naturally occurring self-generated thoughts in humans
Whether and how sharp-wave ripples (SWRs) accompany mental states that are less closely linked to events in the immediate environment are not fully understood. Here authors recorded SWRs from hippocampus of 10 epilepsy patients for up to 15 days with experience sampling. SWR rates showed circadian fluctuation and were associated with self-generated thoughts such as mind wandering.
- Takamitsu Iwata
- , Takufumi Yanagisawa
- & Haruhiko Kishima
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Article
| Open AccessCiliary tip actin dynamics regulate photoreceptor outer segment integrity
Photoreceptor outer segment abnormalities cause retinitis pigmentosa, a form of blindness. Here, authors show that the disease-associated gene RPGR regulates actin-mediated outer segment turnover through its interaction with the actin severer, cofilin.
- Roly Megaw
- , Abigail Moye
- & Pleasantine Mill
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Article
| Open AccessDisruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis
Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is implicated in a range of immunopathology. Here the authors show TIGAR drives inflammation and sepsis via activation of TAK1 and that disruption of TIGAR-TAK1 interaction in a murine model of sepsis reduces immunopathology.
- Dongdong Wang
- , Yanxia Li
- & Jingjing Ben
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Article
| Open AccessIn vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model
Oligoclonal mixtures of neutralising antibodies can target multiple antigen components and represent a potential therapeutic solution for the treatment of envenomation. Here, the authors generate mixtures of nanobodies against coral snake venom toxins and demonstrate they can prevent lethality of coral snake venoms in pre-clinical animal models.
- Melisa Benard-Valle
- , Yessica Wouters
- & Andreas Hougaard Laustsen
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Article
| Open AccessFluorescent fatty acid conjugates for live cell imaging of peroxisomes
The array of tools to image peroxisome regulation is still limited. Here, the authors develop improved fatty acid-based probes with high peroxisome specificity and bright fluorescence in the red/far-red spectrum, which makes them ideal to study peroxisomes in live cells and whole organisms.
- Daria Korotkova
- , Anya Borisyuk
- & Triana Amen
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Article
| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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Article
| Open AccessPost-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia
The post-resolution phase of inflammation is not simply a linear path towards cessation of immune response but rather a regulated process involving fluctuating immune activity. Here authors show a pivotal role for post-resolution macrophages in driving a wave of T cell recruitment and activation via prostaglandin E2 and α-integrin signalling during the resolution phase of murine pneumococcal pneumonia.
- Karen T. Feehan
- , Hannah E. Bridgewater
- & Derek W. Gilroy
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Article
| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessPriming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Phenotypic changes in exhausted T cells are linked to chromatin remodeling. Here the authors show that pharmacological inhibition of the H3K4me1/2 demethylase LSD1 promotes the persistence and enhances the therapeutic activity of adoptively transferred T cells for cancer therapy.
- Fengqi Qiu
- , Peishan Jiang
- & Wanqiang Sheng
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Article
| Open AccessDevelopment of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality
Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.
- Yvan Devaux
- , Lu Zhang
- & Hüseyin Firat
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Article
| Open AccessMedical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats
Preventive interventions often require strategies to identify high-risk individuals. Here, the authors illustrate the potential utility of medical history in predicting the onset risk for thousands of diseases across clinical specialties including COVID-19.
- Jakob Steinfeldt
- , Benjamin Wild
- & Roland Eils
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Article
| Open AccessProduction of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism
Secondary bile acids are microbially produced metabolites linked to metabolic diseases. A challenge in microbiota research is to understand how bacteria collaborate to produce such bioactive molecules. Here, the authors show that adding a single low-abundance bacterial species to a community can significantly affect the metabolic output and host physiology.
- Annika Wahlström
- , Ariel Brumbaugh
- & Fredrik Bäckhed
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Article
| Open AccessInflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis
Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.
- Tanuja Chitnis
- , Ferhan Qureshi
- & Sergio E. Baranzini
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Perspective
| Open AccessPlacing engineering in the earthquake response and the survival chain
This Perspective provides insightful discussion in how engineers can aid human health and safety during earthquake disasters. From search and rescue, helping mobilize patients, and securing medical facilities and treatment engineering can work towards bettering earthquake response.
- Luis Ceferino
- , Yvonne Merino
- & Baturalp Ozturk
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessThe sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of Aspergillus fumigatus, and its repression reduces the virulence of this fungal pathogen in an animal model of infection.
- Jinhong Xie
- , Jeffrey M. Rybak
- & Jarrod R. Fortwendel
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Article
| Open AccessHomozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility
Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.
- Debjit Khan
- , Iyappan Ramachandiran
- & Paul L. Fox
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Article
| Open AccessHistopathologic image–based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer
Predicting the response to platinum-based chemotherapy in high-grade serous ovarian carcinoma (HGSOC) remains challenging. Here, the authors develop the histopathology image-based Pathologic Risk Classifier for HGSOC - PathoRiCH - to predict and stratify HGSOC patient response to therapy, especially when combined with molecular biomarkers.
- Byungsoo Ahn
- , Damin Moon
- & Eunhyang Park
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Article
| Open AccessAI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes
Type 2 diabetes is a global health threat demanding precise healthcare methods. Here, the authors show that their AI-driven risk assessment models, integrating genetic, imaging, and demographic data, achieve high accuracy in identifying high-risk groups, promising advancements in prevention strategies.
- Yi-Jia Huang
- , Chun-houh Chen
- & Hsin-Chou Yang
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Article
| Open AccessSpatial disparities in the mortality burden of the covid-19 pandemic across 569 European regions (2020-2021)
Excess mortality can be used as an indicator of the impacts of the COVID-19 pandemic. Here, the authors estimate excess mortality in 569 European regions in 25 countries for 2020 and 2021 and describe how impacts changed over time.
- Florian Bonnet
- , Pavel Grigoriev
- & Carlo-Giovanni Camarda
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Article
| Open AccessCerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue
After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition with neurological symptoms. Here, the authors show symptom-specific brain microstructure alterations in these patients, providing insights into the underlying pathophysiology.
- Jonas A. Hosp
- , Marco Reisert
- & Alexander Rau