Characterizing quantile-varying covariate effects under the accelerated failure time model.

An important task in survival analysis is choosing a structure for the relationship between covariates of interest and the time-to-event outcome. For example, the accelerated failure time (AFT) model structures each covariate effect as a constant multiplicative shift in the outcome distribution across all survival quantiles. Though parsimonious, this structure cannot detect or capture effects that differ across quantiles of the distribution, a limitation that is analogous to only permitting proportional hazards in the Cox model. To address this, we propose a general framework for quantile-varying multiplicative effects under the AFT model. Specifically, we embed flexible regression structures within the AFT model and derive a novel formula for interpretable effects on the quantile scale. A regression standardization scheme based on the g-formula is proposed to enable the estimation of both covariate-conditional and marginal effects for an exposure of interest. We implement a user-friendly Bayesian approach for the estimation and quantification of uncertainty while accounting for left truncation and complex censoring. We emphasize the intuitive interpretation of this model through numerical and graphical tools and illustrate its performance through simulation and application to a study of Alzheimer's disease and dementia.

The prognostic value of the Merkel cell polyomavirus serum antibody test: A dual institutional observational study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.

BACKGROUND: The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1fl/fl mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages. METHODS: AlbuminCre + Cc1fl/fl mice were fed a regular or a high-fat diet before their insulin metabolism and action were assessed during IPGTT, and their livers excised for histochemical, immunohistochemical and Western blot analysis. Sirius red staining was used to assess fibrosis, and media transfer was employed to examine whether mutant hepatocytes activated hepatic stellate cells (HSCs). Hepatic CEACAM1 protein levels in patients with varying disease stages were assessed by ELISA. RESULTS: Hepatocytic deletion of Ceacam1 caused hyperinsulinemia-driven insulin resistance emanating from reduced hepatic insulin clearance. AlbuminCre + Cc1fl/fl livers showed inflammation, fibrosis and hepatic injury, with more advanced bridging and chicken-wire hepatic fibrosis under high-fat conditions. Media transferred from hepatocytes isolated from mutant mice activated control HSCs, likely owing to their elevated endothelin1 content. Interestingly, hepatic CEACAM1 levels were lower in the livers of patients with MASH and declined gradually with advanced fibrosis stage. CONCLUSIONS: Hepatic CEACAM1 levels declined with progression of MASH in humans. The phenotype of AlbuminCre + Cc1fl/fl mice assigned a key role to CEACAM1 loss from hepatocytes in hepatic fibrosis independently of other liver cells.

An augmented illness-death model for semi-competing risks with clinically immediate terminal events.

Preeclampsia is a pregnancy-associated condition posing risks of both fetal and maternal mortality and morbidity that can only resolve following delivery and removal of the placenta. Because in its typical form preeclampsia can arise before delivery, but not after, these two events exemplify the time-to-event setting of "semi-competing risks" in which a non-terminal event of interest is subject to the occurrence of a terminal event of interest. The semi-competing risks framework presents a valuable opportunity to simultaneously address two clinically meaningful risk modeling tasks: (i) characterizing risk of developing preeclampsia, and (ii) characterizing time to delivery after onset of preeclampsia. However, some people with preeclampsia deliver immediately upon diagnosis, while others are admitted and monitored for an extended period before giving birth, resulting in two distinct trajectories following the non-terminal event, which we call "clinically immediate" and "non-immediate" terminal events. Though such phenomena arise in many clinical contexts, to-date there have not been methods developed to acknowledge the complex dependencies between such outcomes, nor leverage these phenomena to gain new insight into individualized risk. We address this gap by proposing a novel augmented frailty-based illness-death model with a binary submodel to distinguish risk of immediate terminal event following the non-terminal event. The model admits direct dependence of the terminal event on the non-terminal event through flexible regression specification, as well as indirect dependence via a shared frailty term linking each submodel. We develop an efficient Bayesian sampler for estimation and corresponding model fit metrics, and derive formulae for dynamic risk prediction. In an extended example using pregnancy outcome data from an electronic health record, we demonstrate the proposed model's direct applicability to address a broad range of clinical questions.

Structure activity relationship and target prediction for ABX464 analogues in Caenorhabditis elegans.

Global challenges with treatment failures and/or widespread resistance in parasitic worms against commercially available anthelmintics lend impetus to the development of new anthelmintics with novel mechanism(s) of action. The free-living nematode Caenorhabditis elegans is an important model organism used for drug discovery, including the screening and structure-activity investigation of new compounds, and target deconvolution. Previously, we conducted a whole-organism phenotypic screen of the 'Pandemic Response Box' (from Medicines for Malaria Venture, MMV) and identified a hit compound, called ABX464, with activity against C. elegans and a related, parasitic nematode, Haemonchus contortus. Here, we tested a series of 44 synthesized analogues to explore the pharmacophore of activity on C. elegans and revealed five compounds whose potency was similar or greater than that of ABX464, but which were not toxic to human hepatoma (HepG2) cells. Subsequently, we employed thermal proteome profiling (TPP), protein structure prediction and an in silico-docking algorithm to predict ABX464-target candidates. Taken together, the findings from this study contribute significantly to the early-stage drug discovery of a new nematocide based on ABX464. Future work is aimed at validating the ABX464-protein interactions identified here, and at assessing ABX464 and associated analogues against a panel of parasitic nematodes, towards developing a new anthelmintic with a mechanism of action that is distinct from any of the compounds currently-available commercially.

Cholesterol depletion decreases adhesion of non-small cell lung cancer cells to E-selectin.

Lipid microdomains, ordered membrane phases containing cholesterol and glycosphingolipids, play an essential role in cancer cell adhesion and ultimately metastasis. Notably, elevated levels of cholesterol-rich lipid microdomains are found in cancer cells relative to their normal counterparts. Therefore, alterations of lipid microdomains through cholesterol modulation could be used as a strategy to prevent cancer metastasis. In this study, methyl-beta-cyclodextrin (MßCD), sphingomyelinase (SMase), and simvastatin (Simva) were used to investigate the effects of cholesterol on the adhesive behaviors of four non-small cell lung cancer (NSCLC) cell lines (H1299, H23, H460, and A549) and a small cell lung cancer (SCLC) cell line (SHP-77) on E-selectin, a vascular endothelial molecule that initiates circulating tumor cell recruitment at metastatic sites. Under hemodynamic flow conditions, the number of adherent NSCLC cells on E-selectin significantly decreased by MßCD and Simva treatments, whereas SMase treatment did not show a significant effect. Significant increases in rolling velocities were detected only for H1299 and H23 cells after MßCD treatment. In contrast, cholesterol depletion did not affect SCLC cell attachment and rolling velocities. Moreover, cholesterol depletion by MßCD and Simva induced CD44 shedding and resulted in an enhanced membrane fluidity in the NSCLC cells, whereas it did not affect the membrane fluidity of the SCLC cells which lacked detectable expression of CD44. Our finding suggests that cholesterol regulates the E-selectin-mediated adhesion of NSCLC cells by redistributing the CD44 glycoprotein and thus modulating the membrane fluidity.NEW & NOTEWORTHY This study investigates the effects of cholesterol on the adhesive behaviors of lung cancer cells in recruitment at metastatic sites. Using cholesterol-modulating compounds, we found that reducing cholesterol decreases the adhesion of non-small cell lung cancer (NSCLC) cells while having no significant effect on small cell lung cancer (SCLC) cells. The study suggests that cholesterol regulates NSCLC cell metastasis by redistributing the adhesion proteins on the cells and modulating cells' membrane fluidity.

Investigations of hypoxia-induced deoxyhemoglobin as a contrast agent for cerebral perfusion imaging.

The assessment of resting perfusion measures (mean transit time, cerebral blood flow, and cerebral blood volume) with magnetic resonance imaging currently requires the presence of a susceptibility contrast agent such as gadolinium. Here, we present an initial comparison between perfusion measures obtained using hypoxia-induced deoxyhemoglobin and gadolinium in healthy study participants. We hypothesize that resting cerebral perfusion measures obtained using precise changes of deoxyhemoglobin concentration will generate images comparable to those obtained using a clinical standard, gadolinium. Eight healthy study participants were recruited (6F; age 23-60). The study was performed using a 3-Tesla scanner with an eight-channel head coil. The experimental protocol consisted of a high-resolution T1-weighted scan followed by two BOLD sequence scans in which each participant underwent a controlled bolus of transient pulmonary hypoxia, and subsequently received an intravenous bolus of gadolinium. The resting perfusion measures calculated using hypoxia-induced deoxyhemoglobin and gadolinium yielded maps that looked spatially comparable. There was no statistical difference between methods in the average voxel-wise measures of mean transit time, relative cerebral blood flow and relative cerebral blood volume, in the gray matter or white matter within each participant. We conclude that perfusion measures generated with hypoxia-induced deoxyhemoglobin are spatially and quantitatively comparable to those generated from a gadolinium injection in the same healthy participant.

A novel approach to joint prediction of preeclampsia and delivery timing using semicompeting risks.

BACKGROUND: Preeclampsia is a pregnancy complication that contributes substantially to perinatal morbidity and mortality worldwide. Existing approaches to modeling and prediction of preeclampsia typically focus either on predicting preeclampsia risk alone, or on the timing of delivery following a diagnosis of preeclampsia. As such, they are misaligned with typical healthcare interactions during which the 2 events are generally considered simultaneously. OBJECTIVE: This study aimed to describe the "semicompeting risks" framework as an innovative approach for jointly modeling the risk and timing of preeclampsia and the timing of delivery simultaneously. Through this approach, one can obtain, at any point during the pregnancy, clinically relevant summaries of an individual's predicted outcome trajectories in 4 risk categories: not developing preeclampsia and not having delivered, not developing preeclampsia but having delivered because of other causes, developing preeclampsia but not having delivered, and developing preeclampsia and having delivered. STUDY DESIGN: To illustrate the semicompeting risks methodology, we presented an example analysis of a pregnancy cohort from the electronic health record of an urban, academic medical center in Boston, Massachusetts (n=9161 pregnancies). We fit an illness-death model with proportional-hazards regression specifications describing 3 hazards for timings of preeclampsia, delivery in the absence of preeclampsia, and delivery following preeclampsia diagnosis. RESULTS: The results indicated nuanced relationships between a variety of risk factors and the timings of preeclampsia diagnosis and delivery, including maternal age, race/ethnicity, parity, body mass index, diabetes mellitus, chronic hypertension, cigarette use, and proteinuria at 20 weeks' gestation. Sample predictions for a diverse set of individuals highlighted differences in projected outcome trajectories with regard to preeclampsia risk and timing, and timing of delivery either before or after preeclampsia diagnosis. CONCLUSION: The semicompeting risks framework enables characterization of the joint risk and timing of preeclampsia and delivery, providing enhanced, meaningful information regarding clinical decision-making throughout the pregnancy.

Penalized estimation of frailty-based illness-death models for semi-competing risks.

Semi-competing risks refer to the time-to-event analysis setting, where the occurrence of a non-terminal event is subject to whether a terminal event has occurred, but not vice versa. Semi-competing risks arise in a broad range of clinical contexts, including studies of preeclampsia, a condition that may arise during pregnancy and for which delivery is a terminal event. Models that acknowledge semi-competing risks enable investigation of relationships between covariates and the joint timing of the outcomes, but methods for model selection and prediction of semi-competing risks in high dimensions are lacking. Moreover, in such settings researchers commonly analyze only a single or composite outcome, losing valuable information and limiting clinical utility-in the obstetric setting, this means ignoring valuable insight into timing of delivery after preeclampsia has onset. To address this gap, we propose a novel penalized estimation framework for frailty-based illness-death multi-state modeling of semi-competing risks. Our approach combines non-convex and structured fusion penalization, inducing global sparsity as well as parsimony across submodels. We perform estimation and model selection via a pathwise routine for non-convex optimization, and prove statistical error rate results in this setting. We present a simulation study investigating estimation error and model selection performance, and a comprehensive application of the method to joint risk modeling of preeclampsia and timing of delivery using pregnancy data from an electronic health record.

Functional principal component analysis and sparse-group LASSO to identify associations between biomarker trajectories and mortality among hospitalized SARS-CoV-2 infected individuals.

BACKGROUND: A substantial body of clinical research involving individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evaluated the association between in-hospital biomarkers and severe SARS-CoV-2 outcomes, including intubation and death. However, most existing studies considered each of multiple biomarkers independently and focused analysis on baseline or peak values. METHODS: We propose a two-stage analytic strategy combining functional principal component analysis (FPCA) and sparse-group LASSO (SGL) to characterize associations between biomarkers and 30-day mortality rates. Unlike prior reports, our proposed approach leverages: 1) time-varying biomarker trajectories, 2) multiple biomarkers simultaneously, and 3) the pathophysiological grouping of these biomarkers. We apply this method to a retrospective cohort of 12, 941 patients hospitalized at Massachusetts General Hospital or Brigham and Women's Hospital and conduct simulation studies to assess performance. RESULTS: Renal, inflammatory, and cardio-thrombotic biomarkers were associated with 30-day mortality rates among hospitalized SARS-CoV-2 patients. Sex-stratified analysis revealed that hematogolical biomarkers were associated with higher mortality in men while this association was not identified in women. In simulation studies, our proposed method maintained high true positive rates and outperformed alternative approaches using baseline or peak values only with respect to false positive rates. CONCLUSIONS: The proposed two-stage approach is a robust strategy for identifying biomarkers that associate with disease severity among SARS-CoV-2-infected individuals. By leveraging information on multiple, grouped biomarkers' longitudinal trajectories, our method offers an important first step in unraveling disease etiology and defining meaningful risk strata.

Electronic Health Record Order Entry-Based Interventions in Response to a Global Iodinated Contrast Media Shortage: Impact on Contrast-Enhanced CT Utilization.

BACKGROUND. Radiology informatics systems and clinical decision support tools in the electronic health record (EHR) can be leveraged to help impact ordering patterns in response to the ongoing global iodinated contrast media shortage. OBJECTIVE. The purpose of our study was to assess the impact of EHR order entry-based interventions, implemented as part of a health system's response to the global contrast media shortage, on contrast-enhanced CT utilization. METHODS. This retrospective study included 79,259 patients who underwent CT at a large multisite health system between April 1, 2022, and July 3, 2022. Two EHR-based interventions were implemented as part of the health system's response to the global contrast media shortage. A first EHR-based intervention on May 10, 2022, entailed creating an alert that appeared in a sidebar after any contrast-enhanced body CT orders, indicating the present shortage and recommending alternate imaging modalities. A second EHR-based intervention on May 16, 2022, required referrers to enter detailed clinical information for all contrast-enhanced body CT orders, which radiologists used when protocoling examinations. Data regarding CT orders and examinations performed were extracted from the electronic data warehouse. RESULTS. During the preintervention, first postintervention, and second postintervention periods, the mean number of patients who underwent contrast-enhanced CT per weekday was 726, 689, and 639, respectively (p for preintervention vs second postintervention periods, < .001). During the three periods, the mean number of patients who underwent CT per weekday was 1350, 1323, and 1314 (p < .001). During the three periods, the mean number of patients who underwent contrast-enhanced body CT per weekday was 561, 532, and 492 (p < .001). During the three periods, the mean number of orders for CT with IV contrast media per weekday was 154, 143, and 131 (p < .001). During the three periods, the mean number of orders for CT without IV contrast media per weekday was 196, 202, and 221 (p < .001). CONCLUSION. EHR order entry-based interventions implemented in response to the global contrast media shortage significantly reduced contrast-enhanced CT utilization in a large health system. CLINICAL IMPACT. The findings indicate the ability to rapidly achieve changes in ordering clinician behavior and subsequent clinical practice using systemwide EHR changes.

Constraining crustal silica on ancient Earth.

Accurately quantifying the composition of continental crust on Hadean and Archean Earth is critical to our understanding of the physiography, tectonics, and climate of our planet at the dawn of life. One longstanding paradigm involves the growth of a relatively mafic planetary crust over the first 1 to 2 billion years of Earth history, implying a lack of modern plate tectonics and a paucity of subaerial crust, and consequently lacking an efficient mechanism to regulate climate. Others have proposed a more uniformitarian view in which Archean and Hadean continents were only slightly more mafic than at present. Apart from complications in assessing early crustal composition introduced by crustal preservation and sampling biases, effects such as the secular cooling of Earth's mantle and the biologically driven oxidation of Earth's atmosphere have not been fully investigated. We find that the former complicates efforts to infer crustal silica from compatible or incompatible element abundances, while the latter undermines estimates of crustal silica content inferred from terrigenous sediments. Accounting for these complications, we find that the data are most parsimoniously explained by a model with nearly constant crustal silica since at least the early Archean.

Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling.

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood-brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.

The effect of acute intermittent hypoxia on human limb motoneurone output.

NEW FINDINGS: What is the central question of this study? Does a single session of repeated bouts of acute intermittent hypoxic breathing enhance the motoneuronal output of the limb muscles of healthy able-bodied participants? What is the main finding and its importance? Compared to breathing room air, there were some increases in motoneuronal output following acute intermittent hypoxia, but the increases were variable across participants and in time after the intervention and depended on which neurophysiological measure was checked. ABSTRACT: Acute intermittent hypoxia (AIH) induces persistent increases in output from rat phrenic motoneurones. Studies in people with spinal cord injury (SCI) suggest that AIH improves limb performance, perhaps via postsynaptic changes at cortico-motoneuronal synapses. We assessed whether limb motoneurone output in response to reflex and descending synaptic activation is facilitated after one session of AIH in healthy able-bodied volunteers. Fourteen participants completed two experimental days, with either AIH or a sham intervention (randomised crossover design). We measured H-reflex recruitment curves and homosynaptic post-activation depression (HPAD) of the H-reflex in soleus, and motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) and their recruitment curves in first dorsal interosseous. All measurements were performed at rest and occurred at baseline, 0, 20, 40 and 60 min post-intervention. The intervention was 30 min of either normoxia (sham, F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$  ≈ 0.21) or AIH (alternate 1-min hypoxia [ F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$  ≈ 0.09], 1-min normoxia). After AIH, the H-reflex recruitment curve shifted leftward. Lower stimulation intensities were needed to evoke 5%, 50% and 99% of the maximal H-reflex at 40 and 60 min after AIH (P < 0.04). The maximal H-reflex, recruitment slope and HPAD were unchanged after AIH. MEPs evoked by constant intensity TMS were larger 40 min after AIH (P = 0.027). There was no change in MEP recruitment or the maximal MEP. In conclusion, some measures of the evoked responses from limb motoneurones increased after a single AIH session, but only at discrete time points. It is unclear to what extent these changes alter functional performance.

Secondary magnetite in ancient zircon precludes analysis of a Hadean geodynamo.

Zircon crystals from the Jack Hills, Western Australia, are one of the few surviving mineralogical records of Earth's first 500 million years and have been proposed to contain a paleomagnetic record of the Hadean geodynamo. A prerequisite for the preservation of Hadean magnetization is the presence of primary magnetic inclusions within pristine igneous zircon. To date no images of the magnetic recorders within ancient zircon have been presented. Here we use high-resolution transmission electron microscopy to demonstrate that all observed inclusions are secondary features formed via two distinct mechanisms. Magnetite is produced via a pipe-diffusion mechanism whereby iron diffuses into radiation-damaged zircon along the cores of dislocations and is precipitated inside nanopores and also during low-temperature recrystallization of radiation-damaged zircon in the presence of an aqueous fluid. Although these magnetites can be recognized as secondary using transmission electron microscopy, they otherwise occur in regions that are indistinguishable from pristine igneous zircon and carry remanent magnetization that postdates the crystallization age by at least several hundred million years. Without microscopic evidence ruling out secondary magnetite, the paleomagnetic case for a Hadean-Eoarchean geodynamo cannot yet been made.

Metabolic Surgery for Adult Obesity: Common Questions and Answers.

In 2019, approximately 256,000 metabolic surgery procedures were performed in the United States, a 32% increase since 2014. The most common procedures are the laparoscopic sleeve gastrectomy and the Roux-en-Y gastric bypass. Choice of procedure depends on concurrent medical conditions, patient preference, and expertise of the surgeon. These procedures have a mortality risk of 0.2% to 0.3%. On average, weight loss of 30 to 50 kg (66 to 110 lb), or a 20% to 30% reduction in total body weight, is achieved, although most patients will experience some weight regain three to 10 years after surgery. In patients who have had metabolic surgery, all-cause mortality is reduced by 30% to 45% at two to 15 years postsurgery compared with patients with obesity who did not have surgery. Remission of type 2 diabetes mellitus occurs in as many as 70% to 80% of patients within one to two years after surgery and is maintained at 10 years in about 30% of patients. Other obesity-related conditions are also greatly reduced, and quality of life improves. Postoperatively, patients require standardized nutritional supplementation and surveillance. Persistent changes in diet, such as consuming protein first at every meal, regular physical activity, and ongoing attention to behavior change are critical for the success of the patient after metabolic surgery. Common adverse outcomes include surgical complications, nutritional deficiencies, bone density loss, dumping syndrome, gastroesophageal reflux disease, and loose skin. The family physician is well positioned to counsel patients about metabolic surgical options and the risks and benefits of surgery and to provide long-term support and medical management for postsurgery patients.

Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene.

(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL/6J.Ldlr-/- background (Ldlr-/-VECadCre+Cc1fl/fl) were fed an atherogenic diet for 3-5 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2/Shc/NF-κB pathway with resultant transcriptional induction of NF-κB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr-/-VECadCre+Cc1fl/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis.

Declines in muscle contractility and activation during isometric contractions of the knee extensors vary with contraction intensity and exercise volume.

NEW FINDINGS: What is the central question of this study? Is there a critical threshold beyond which the loss of muscle contractility is regulated by the level of muscle activation during single-limb exercise of differing intensities and volumes? What is the main finding and its importance? Plateaus in the decline in muscle contractility during single-limb knee extension depended on both exercise volume and contraction intensity.  A plateau was only evident with an increase in exercise volume.  Muscle activation increased and did not decline despite substantial reductions in contractility. The findings indicate that the decrease in muscle contractility exhibited by resistance-trained men during the performance of submaximal isometric contractions with the knee extensors was not regulated by the level of muscle activation. ABSTRACT: Our study examined the influence of contraction intensity and exercise volume on changes in muscle contractility and activation of the knee extensor muscles. Maximal voluntary torque (MVT) and rate of change in torque, surface electromyograms, voluntary activation, V-waves and quadriceps resting twitch measures were assessed in 10 resistance-trained men during two experimental sessions. Each session began with an initial baseline series of contractions at a fixed intensity of 40% or 80% MVT. The 40%-only session continued with five contractions to task failure at 40% MVT. The 80% session continued with five contractions to failure each at 80%, 60% and 40% MVT. Greater reductions in MVT were observed during the baseline contractions of the 40%-only session compared with the 80% session at each matched-volume time point (P < 0.05), with similar changes in twitch values (P < 0.001). MVT and twitch values plateaued at each intensity during the 80% session and were significantly different across intensities: 80% > 60% > 40% (P < 0.001). There were no differences for measures during the five contractions at 40% MVT performed on the different days, despite a greater volume of exercise performed prior to the 40% MVT during the 80% session. At each contraction intensity, a plateau in contractility loss was observed as more contractions were performed. We found that initial increases in muscle activation were maintained in the presence of increases in exercise volume and, in contrast to the critical-threshold hypothesis, did not decline in parallel with reductions in muscle contractility.

Potassic, high-silica Hadean crust.

Understanding Hadean (>4 Ga) Earth requires knowledge of its crust. The composition of the crust and volatiles migrating through it directly influence the makeup of the atmosphere, the composition of seawater, and nutrient availability. Despite its importance, there is little known and less agreed upon regarding the nature of the Hadean crust. By analyzing the 87Sr/86Sr ratio of apatite inclusions in Archean zircons from Nuvvuagittuq, Canada, we show that its protolith had formed a high (>1) Rb/Sr ratio reservoir by at least 4.2 Ga. This result implies that the early crust had a broad range of igneous rocks, extending from mafic to highly silicic compositions.