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The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

The article "Prediction of COVID-19 severity using machine learning" discusses the development of a machine learning model to predict COVID-19 severity based on age and five long noncoding RNAs (lncRNAs). The study involved 564 patients from four European cohorts, with the model achieving an area under the receiver operating characteristic curve (AUC) of .875 and an accuracy of .783. The ML model could be used to develop a molecular diagnostic assay for predicting disease severity and improving patient management during the COVID-19 pandemic. [Extracted from the article]

Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82–0.84) and a balanced accuracy of 0.78 (95% CI 0.77–0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40–0.74). Quantitative PCR validated LEF1-AS1’s adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management. [ABSTRACT FROM AUTHOR]

The Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser Facility (EuXFEL) is equipped with a multipurpose diagnostic end-station (DES) at the end of the instrument. The imager unit in DES is a key tool for aligning the beam to a standard trajectory and for adjusting optical elements such as focusing lenses or the split-and-delay line. Furthermore, the DES features a bent-diamond-crystal spectrometer to disperse the spectrum of the direct beam to a line detector. This enables pulse-resolved characterization of the EuXFEL spectrum to provide X-ray energy calibration, and the spectrometer is particularly useful in commissioning special modes of the accelerator. Together with diamond-based intensity monitors, the imager and spectrometer form the DES unit which also contains a heavy-duty beamstop at the end of the MID instrument. Here, we describe the setup in detail and provide exemplary beam diagnostic results. [ABSTRACT FROM AUTHOR]

Pharmaceutical companies developed Covid-19 vaccines in record time. However, it soon became apparent that global access to the vaccines was inequitable. Through a qualitative inquiry as the pandemic unfolded (to mid-2021), we provide an in-depth analysis of why companies engaged with the Covid-19 Vaccines Global Access Facility (COVAX), identifying the internal (to the company) and external factors that facilitated or impeded engagement. While all producers of the World Health Organization (WHO)-approved vaccines engaged with COVAX, our analysis highlights the differential levels of COVAX engagement and identifies contractual obligations, opportunities and company strategy, and reputational pressures as key explanatory factors. We discuss our empirical findings relative to the literature on political corporate social responsibility (PCSR). Accordingly, we question whether pharmaceutical companies lived up to their responsibilities as corporate citizens and conclude that they failed to fulfill the implied responsibility of combating inequitable vaccine distribution. We conclude with implications of our research for practice, in relation to the challenges of global access to Covid-19 vaccines and for access to medicines more generally. [ABSTRACT FROM AUTHOR]

Stimuli-responsive polymers are an important class of materials with many applications in nanotechnology and drug delivery. The most prominent one is poly-N-isopropylacrylamide (PNIPAm). The characterization of the kinetics of its change after a temperature jump is still a lively research topic, especially at nanometer-length scales where it is not possible to rely on conventional microscopic techniques. Here, we measured in real time the collapse of a PNIPAm shell on silica nanoparticles with megahertz x-ray photon correlation spectroscopy at the European XFEL. We characterize the changes of the particles diffusion constant as a function of time and consequently local temperature on sub-microsecond timescales. We developed a phenomenological model to describe the observed data and extract the characteristic times associated to the swelling and collapse processes. Different from previous studies tracking the turbidity of PNIPAm dispersions and using laser heating, we find collapse times below microsecond timescales and two to three orders of magnitude slower swelling times. [ABSTRACT FROM AUTHOR]

Altermagnets are an emerging elementary class of collinear magnets. Unlike ferromagnets, their distinct crystal symmetries inhibit magnetization while, unlike antiferromagnets, they promote strong spin polarization in the band structure. The corresponding unconventional mechanism of time-reversal symmetry breaking without magnetization in the electronic spectra has been regarded as a primary signature of altermagnetism but has not been experimentally visualized to date. We directly observe strong time-reversal symmetry breaking in the band structure of altermagnetic RuO2 by detecting magnetic circular dichroism in angle-resolved photoemission spectra. Our experimental results, supported by ab initio calculations, establish the microscopic electronic structure basis for a family of interesting phenomena and functionalities in fields ranging from topological matter to spintronics, which are based on the unconventional time-reversal symmetry breaking in altermagnets. [ABSTRACT FROM AUTHOR]

Background: Community-acquired pneumonia (CAP) remains a leading cause of infectious disease mortality globally, necessitating intensive care unit (ICU) admission for ∼10% of hospitalised patients. Accurate prediction of disease severity facilitates timely therapeutic interventions., Methods: Our study aimed to enhance the predictive capacity of the clinical CRB-65 score by evaluating eight candidate biomarkers: troponin T high-sensitive (TnT-hs), procalcitonin (PCT), N-terminal pro-brain natriuretic peptide, angiopoietin-2, copeptin, endothelin-1, lipocalin-2 and mid-regional pro-adrenomedullin. We utilised a machine-learning approach on 800 samples from the German CAPNETZ network (competence network for CAP) to refine risk prediction models combining these biomarkers with the CRB-65 score regarding our defined end-point: death or ICU admission during the current CAP episode within 28 days after study inclusion., Results: Elevated levels of biomarkers were associated with the end-point. TnT-hs exhibited the highest predictive performance among individual features (area under the receiver operating characteristic curve, AUC=0.74), followed closely by PCT (AUC=0.73). Combining biomarkers with the CRB-65 score significantly improved prediction accuracy. The combined model of CRB-65, TnT-hs and PCT demonstrated the best balance between high predictive value and parsimony, with an AUC of 0.77 (95% CI: 0.72-0.82), while CRB-65 alone achieved an AUC of 0.67 (95% CI: 0.64-0.73)., Conclusion: Our findings suggest that augmenting the CRB-65 score with TnT-hs and PCT enhances the prediction of death or ICU admission in hospitalised CAP patients. Validation of this improved risk score in additional CAP cohorts and prospective clinical studies is warranted to assess its broad clinical utility., Competing Interests: Conflict of interest: M. Scholz received funding from Pfizer Inc. for epidemiological modelling of pneumococcal serotypes and vaccinations, and has an ongoing cooperation with Owkin for a project not related to this research. M. Witzenrath received funding from Aptarion, Biotest and Pantherna for research outside the current study. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., Competing Interests: IA received speaker’s honorarium Lundbeck; OAA is a consultant to Cortechs.ai and Precision Health, speaker’s honorarium from Lundbeck, Janssen, Otsuka, Sunovion; HB is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes; CRKC has received past partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript; AMD is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a Founder of and hold equity in CorTechs Labs, Inc. I am a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies; BF has received educational speaking fees from Medice; HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care; DPH is a full time employee of Genentech, Inc; NH is a shareholder various manufacturers of medical technology; AM-L has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden, von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague, Vitos Klinik Rheingau and editorial and/or author fees fromAmerican Association for the Advancement of Science, ECNP, Servier Int., Thieme Verlag; WN is founder of Quantib BV and was scientific lead of Quantib BV until Jan 31, 2023; MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029). MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work; BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior); MSreceived funding from Pfizer Inc. for a project not related to this research; ES received speaker fees from bfd buchholz fachinformationsdienst gmbh; PMT receives partial research support from Biogen, Inc., for research unrelated to this manuscript; MWW serves on Editorial Boards for Alzheimer’s & Dementia, and the Journal for Prevention of Alzheimer’s disease. He has served on Advisory Boards for Acumen Pharmaceutical, Alzheon, Inc., Cerecin, Merck Sharp & Dohme Corp., and NC Registry for Brain Health. He also serves on the USC ACTC grant which receives funding from Eisai for the AHEAD study. MWW has provided consulting to Boxer Capital, LLC, Cerecin, Inc., Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme Corp., NC Registry for Brain Health, Prova Education, T3D Therapeutics, University of Southern California (USC), and WebMD. MWW has acted as a speaker/lecturer for China Association for Alzheimer’s Disease (CAAD) and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by: AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning; Health Society (Japan), INSPIRE Project; U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme Corp., National Center for Geriatrics and Gerontology (NCGG; Japan), University of Southern California (USC). MWW holds stock options with Alzeca, Alzheon, Inc., ALZPath, Inc., and Anven. MWW received support for his research from the following funding sources: National Institutes of Health (NIH)/NINDS/National Institute on Aging (NIA), Department of Defense (DOD), California Department of Public Health (CDPH), University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI-BHR), The Stroke Foundation, and the Veterans Administration; AIC is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, Inc., and may hold Regeneron stock or stock options. All other authors declare no competing interests.

Importance: Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown., Objective: To identify the genetic loci associated with olfactory dysfunction in the general population., Design Setting and Partiicipants: This genome-wide association study meta-analysis (GWMA) included participants of European ancestry (N = 22,730) enrolled in four different large population-based studies, followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). The data analysis was performed from March 2023 through June 2024., Exposures: Genome-wide single nucleotide polymorphisms., Main Outcomes and Measures: Olfactory dysfunction was the outcome and assessed using a 12-item smell identification test., Results: GWMA revealed a novel genome-wide significant locus (tagged by rs11228623 at 11q12) associated with olfactory dysfunction. Gene-based analysis revealed a high enrichment for olfactory receptor genes in this region. Phenome-wide association studies demonstrated associations between genetic variants related to olfactory dysfunction and blood cell counts, kidney function, skeletal muscle mass, cholesterol levels and cardiovascular disease. Using individual-level data, we also confirmed and quantified the strength of these associations on a phenotypic level. Moreover, employing two-sample Mendelian Randomization analyses, we found evidence for causal associations between olfactory dysfunction and these phenotypes., Conclusions: These findings provide novel insights into the genetic architecture of the sense of smell and highlight its importance for many aspects of human health., Competing Interests: Markus Scholz was funded by Pfizer Inc. for epidemiologic modelling of pneumococcal serotypes and has an ongoing collaboration with Owkin regarding heart failure research.

Background: Statin intolerance is associated with increased cardiovascular risk. Symptoms and patients' characteristics are incompletely known. We aimed to analyse the health-related quality of life (QOL) associated with statin intolerance., Methods: The Statin Intolerance Registry (SIR) is an observational, prospective, multicentre study that included 1111 patients, with intolerance to at least two different statins, between 2021 and 2023 in Germany. SIR baseline data were compared to individuals with and without statin therapy of the population-based LIFE-Adult Study (n = 9983)., Findings: The mean age in SIR was 66.1 years (standard deviation (SD) 9.9). The cohort was characterized by a higher proportion of women compared to patients on statins in LIFE-Adult (57.7% vs. 38.2%). SIR patients had impaired QOL (mean EQ VAS score of 64.9 (SD 18.1)) as measured by EuroQol (EQ-5D-5L)), which further deteriorated with age. Muscle symptoms were frequent (95.8%) and were associated with severe pain in 43.2% and intake of pain medication in 32.3% of statin intolerant patients. 10.3% had a diagnosis of depression. Women reported more pronounced symptoms than men. A data-driven k-means analysis, based on variables predicting severity of pain while on statin therapy, identified five clusters of SIR patients. The clusters differed in sex, prevalence of depression, QOL, comorbidities, and expectations to tolerate statin therapy., Interpretation: Statin intolerance is associated with impaired QOL. Women are more frequently and severely affected. The identified clusters may help to identify patients at risk and to develop individualized strategies to improve patient trajectories and outcomes., Funding: Leipzig University, research grants from Daiichi Sankyo, Novartis, and Amgen to Leipzig University., Competing Interests: PES has received honoraria from Daiichi Sankyo, Amgen, Novartis, Synlab and from Novartis for an advisory board. IGB has received honoraria from Amgen, Regeneron, Sanofi, Aegereon, Akcea Therapeutics, Novartis, Daiichi-Sankyo, Synlab, Ultragenyx, and Amarin. MS received funding from Pfizer Inc., and Owkin for projects not related to this research. US has received honoraria from Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Synlab, Novartis, NovoNordisk. OW reports honoraria for lectures from AMGEN, Berlin-Chemie, Daiichi-Sankyo, Novo Nordisk, Novartis, Sanofi-Aventis, Fresenius, Hexal, Akcea Therapeutics, and honoraria for advisory board activities from AMGEN, Sanofi-Aventis, Berlin-Chemie, Novartis, Hexal, Akcea Therapeutics, Daiichi-Sankyo, Pfizer, and Sobi. UK has received honoraria from Daiichi Sankyo, Amgen, MSD, Synlab. UL has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo, Lilly, MSD, Novartis, NovoNordisk, Pfizer, Sanofi, Synlab. CM, OF, SE, JNB have nothing to declare., (© 2024 The Author(s).)

The liquid-to-solid phase transition is a complex process that is difficult to investigate experimentally with sufficient spatial and temporal resolution. A key aspect of the transition is the formation of a critical seed of the crystalline phase in a supercooled liquid, that is, a liquid in a metastable state below the melting temperature. This stochastic process is commonly described within the framework of classical nucleation theory, but accurate tests of the theory in atomic and molecular liquids are challenging. Here, we employ femtosecond x-ray diffraction from microscopic liquid jets to study crystal nucleation in supercooled liquids of the rare gases argon and krypton. Our results provide stringent limits to the validity of classical nucleation theory in atomic liquids, and offer the long-sought possibility of testing nonclassical extensions of the theory.