SnapShot: Skeletal muscle atrophy.

Skeletal muscle size is highly plastic and sensitive to a variety of stimuli. Muscle atrophy occurs as the result of changes in multiple signaling pathways that regulate both protein synthesis and degradation. The signaling pathways that are activated or inhibited depend on the specific stimuli that are altered. To view this SnapShot, open of download the PDF.

The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn.

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.

Injury-induced myosin-specific tissue-resident memory T cells drive immune checkpoint inhibitor myocarditis.

Cardiac myosin-specific (MyHC) T cells drive the disease pathogenesis of immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis). To determine whether MyHC T cells are tissue-resident memory T (TRM) cells, we characterized cardiac TRM cells in naive mice and established that they have a distinct phenotypic and transcriptional profile that can be defined by their upregulation of CD69, PD-1, and CXCR6. We then investigated the effects of cardiac injury through a modified experimental autoimmune myocarditis mouse model and an ischemia-reperfusion injury mouse model and determined that cardiac inflammation induces the recruitment of autoreactive MyHC TRM cells, which coexpress PD-1 and CD69. To investigate whether the recruited MyHC TRM cells could increase susceptibility to ICI-myocarditis, we developed a two-hit ICI-myocarditis mouse model where cardiac injury was induced, mice were allowed to recover, and then were treated with anti-PD-1 antibodies. We determined that mice who recover from cardiac injury are more susceptible to ICI-myocarditis development. We found that murine and human TRM cells share a similar location in the heart and aggregate along the perimyocardium. We phenotyped cells obtained from pericardial fluid from patients diagnosed with dilated cardiomyopathy and ischemic cardiomyopathy and established that pericardial T cells are predominantly CD69+ TRM cells that up-regulate PD-1. Finally, we determined that human pericardial macrophages produce IL-15, which supports and maintains pericardial TRM cells.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Highly sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies.

Interferons (IFNs) are a critical component of innate immune defenses and limit viral disease severity. To advance studies on IFNs and their neutralization by pathogenic autoantibodies, we generated a Renilla luciferase-based reporter cell line capable of detecting the activities of IFN-Is, IFN-II, and IFN-IIIs. The reporter cell line exhibits a 125- to 2000-fold higher sensitivity to IFNs than a commonly used alternative biological reporter system and allows for a rapid and simple live-cell workflow for detecting low titer amounts of neutralizing anti-IFN antibodies.

A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis.

BACKGROUND: 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056). RESULTS: We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null. CONCLUSION: Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.

How was the Earth-Moon system formed? New insights from the geodynamo.

The most widely accepted scenario for the formation of the Earth-Moon system involves a dramatic impact between the proto-Earth and some other cosmic body. Many features of the present-day Earth-Moon system provide constraints on the nature of this impact. Any model of the history of the Earth must account for the physical, geochemical, petrological, and dynamical evidence. These constraints notwithstanding, there are several radically different impact models that could in principle account for all the evidence. Thus, in the absence of further constraints, we may never know for sure how the Earth-Moon system was formed. Here, we put forward the idea that additional constraints are indeed provided by the fact that the Earth is strongly magnetized. It is universally accepted that the Earth's magnetic field is maintained by a dynamo operating in the outer liquid core. However, because of the rapid rotation of the Earth, this dynamo has the peculiar property that it can maintain a strong field but cannot amplify a weak one. Therefore, the Earth must have been magnetized at a very early epoch, either preimpact or as a result of the impact itself. Either way, any realistic model of the formation of the Earth-Moon system must include magnetic field evolution. This requirement may ultimately constrain the models sufficiently to discriminate between the various candidates.

The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS: We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS: Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION: We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY: The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .

Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Bayesian estimation of the prevalence of antimicrobial resistance: a mathematical modelling study.

BACKGROUND: Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets. OBJECTIVES: To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods. METHODS: Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach. RESULTS: Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [n = 74 (6.4%) versus n = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug-pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%. CONCLUSIONS: Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high.

The role of the gut microbiome in the development of hepatobiliary cancers.

Hepatobiliary cancers, including hepatocellular carcinoma and cancers of the biliary tract, share high mortality and rising incidence rates. They may also share several risk factors related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and rates of obesity. Recent data also suggest a role for the gut microbiome in the development of hepatobiliary cancer and other liver pathologies. The gut microbiome and the liver interact bidirectionally through the "gut-liver axis," which describes the interactive relationship between the gut, its microbiota, and the liver. Here, we review the gut-liver interactions within the context of hepatobiliary carcinogenesis by outlining the experimental and observational evidence for the roles of gut microbiome dysbiosis, reduced gut barrier function, and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to hepatobiliary cancer development. We also outline the latest findings regarding the impact of dietary and lifestyle factors on liver pathologies as mediated by the gut microbiome. Finally, we highlight some emerging gut microbiome editing techniques currently being investigated in the context of hepatobiliary diseases. Although much work remains to be done in determining the relationships between the gut microbiome and hepatobiliary cancers, emerging mechanistic insights are informing treatments, such as potential microbiota manipulation strategies and guiding public health advice on dietary/lifestyle patterns for the prevention of these lethal tumors.

Paired metabolomics and volatilomics provides insight into transient high light stress response mechanisms of the coral Montipora mollis.

The coral holobiont is underpinned by complex metabolic exchanges between different symbiotic partners, which are impacted by environmental stressors. The chemical diversity of the compounds produced by the holobiont is high and includes primary and secondary metabolites, as well as volatiles. However, metabolites and volatiles have only been characterised in isolation so far. Here, we applied a paired metabolomic-volatilomic approach to characterise holistically the chemical response of the holobiont under stress. Montipora mollis fragments were subjected to high-light stress (8-fold higher than the controls) for 30 min. Photosystem II (PSII) photochemical efficiency values were 7-fold higher in control versus treatment corals immediately following high-light exposure, but returned to pre-stress levels after 30 min of recovery. Under high-light stress, we identified an increase in carbohydrates (> 5-fold increase in arabinose and fructose) and saturated fatty acids (7-fold increase in myristic and oleic acid), together with a decrease in fatty acid derivatives in both metabolites and volatiles (e.g., 80% decrease in oleamide and nonanal), and other antioxidants (~ 85% decrease in sorbitol and galactitol). These changes suggest short-term light stress induces oxidative stress. Correlation analysis between volatiles and metabolites identified positive links between sorbitol, galactitol, six other metabolites and 11 volatiles, with four of these compounds previously identified as antioxidants. This suggests that these 19 compounds may be related and share similar functions. Taken together, our findings demonstrate how paired metabolomics-volatilomics may illuminate broader metabolic shifts occurring under stress and identify linkages between uncharacterised compounds to putatively determine their functions.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Exploring Ligand Effects on Structure, Bonding, and Photolytic Hydride Transfer of Cationic Gold(I) Bridging Hydride Complexes of Molybdocene and Tungstenocene.

A diverse family of heterobimetallic bridging hydride adducts of the type [LAu(µ-H)2MCp2][X] (L = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene, IPr; 1,3-bis(1-adamantyl)imidazole-2-ylidene, IAd; 1,3-bis(2,6-di-iso-propylphenyl)-5,5-dimethyl-4,6-diketopyrimidinyl-2-ylidene, DippDAC; triphenylphosphine, PPh3; 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, tBuXPhos; X = SbF6-, BF4- or TfO-) was synthesized by reacting group VI metallocene dihydrides Cp2MH2 (Cp = cyclopentadienyl anion; M = Mo, W) with cationic gold(I) complexes [LAu(NCMe)][X]. Trimetallic [L'Au2(µ-H)2WCp2][X]2 and tetrametallic [L'Au2{(µ-H)2WCp2}2] [X]2 complexes (L' = rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene or bis(diphenylphosphinomethane)) were obtained by reacting digold [L'{Au(NCMe)}2][X]2 with Cp2WH2 in a 1:1 and a 1:2 stoichiometry. Accessing such a broad structural diversity allowed us to pinpoint roles played by the ancillary ligands and group VI metals on the bonding properties of this family of bridging hydrides. In particular, a clear effect of the ligand on the interaction energy and electronic structure was observed, with important implications on photolytic reactivity. UV or visible light irradiation, indeed, leads to the selective cleavage of the heterobimetallic Au(µ-H)2M arrangement and formation of molecular gold hydrides. The photolysis was found to be chromoselective (wavelength-dependent), which can be ascribed to different charge redistributions upon excitation to the first (Kasha's reactivity) and higher (anti-Kasha's reactivity) excited states.

Non-linear Mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol.

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the "residual" exposure). These "local" causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method-the doubly-ranked method-has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects-that of low-density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest there should be extensive simulation and empirical methodological examination of performance of both methods for NLMR under different conditions before further use of these methods. In the interim, use of NLMR methods needs justification, and a number of sanity checks (such as analysis of negative and positive control outcomes, sensitivity analyses excluding removal of strata at the extremes of the distribution, examination of biological plausibility and triangulation of results) should be performed.

Lower hepatocellular carcinoma surveillance in metabolic dysfunction-associated steatotic liver disease: Impact on treatment eligibility.

BACKGROUND AND AIM: This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction-associated steatotic liver disease (MASLD) versus other chronic liver diseases. METHODS: A dataset of HCC patients from a UK hospital (2007-2022) was analyzed. The Mann-Whitney U-test compared continuous variables. The χ2 and two-tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival. RESULTS: A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non-MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3-mm (95% confidence interval [CI] 10.8-14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43-0.91) of receiving curative treatment compared to non-MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non-MASLD HCC (hazard ratio 1.03, 95% CI 0.85-1.25, P = 0.748). CONCLUSION: Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non-cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment.