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With mean instrumental variables regression, k-class estimators have the potential to reduce bias, which is larger with weak instruments. With instrumental variables quantile regression, weak instrument-robust estimation is even more important because there is less guidance for assessing instrument strength. Motivated by this, we introduce an analogous k-class of estimators for instrumental variables quantile regression. We show the first-order asymptotic distribution under strong instruments is equivalent for all conventional choices of k. We evaluate finite-sample median bias in simulations for a variety of k, including the k for the conventional k-class estimator corresponding to limited information maximum likelihood (LIML). Computation is fast for all k, and compared to the k = 1 benchmark estimator (analogous to 2SLS), using the LIML k reliably reduces median bias in a variety of data-generating processes, especially when the degree of overidentification is larger. We also revisit some empirical estimates of consumption Euler equations derived from quantile utility maximization. All code is provided online (https://kaplandm.github.io). [ABSTRACT FROM AUTHOR]

The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5'-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development. Here the authors demonstrate how protein translation, controlled by Ire1α, regulates neuronal diversification in the developing neocortex. [ABSTRACT FROM AUTHOR]

This paper aims to showcase the value of implementing a Bayesian framework to analyze and report results from international large-scale assessments and provide guidance to users who want to analyse ILSA data using this approach. The motivation for this paper stems from the recognition that Bayesian statistical inference is fast becoming a popular methodological framework for the analysis of educational data generally, and large-scale assessments more specifically. The paper argues that Bayesian statistical methods can provide a more nuanced analysis of results of policy relevance compared to standard frequentist approaches commonly found in large-scale assessment reports. The data utilized for this paper comes from the Teaching and Learning International Survey (TALIS). The paper provides steps in implementing a Bayesian analysis and proposes a workflow that can be applied not only to TALIS but to large-scale assessments in general. The paper closes with a discussion of other Bayesian approaches to international large-scale assessment data, in particularly for predictive modeling. [ABSTRACT FROM AUTHOR]

Extreme winter temperatures govern the northern range limit of black mangroves (Avicennia germinans) in southeastern North America. There is a pressing need for studies that advance our understanding of how extreme cold temperature events affect mangroves near their range limits. However, such events are infrequent and challenging to study at regional scales. Here, we compared the damage to mangroves from extreme freeze events in 2018 and 2021, using local data from sites in USA (Florida, Louisiana, and Texas) and northeastern Mexico (Tamaulipas). In 2018, mangrove damage was concentrated in Louisiana and the upper Texas coast, where minimum temperatures ranged from -4 °C to -7 °C. In 2021, damage from a more severe freeze event was concentrated along the central to northern coasts of Texas, where minimum temperatures ranged from -4 °C to -10 °C. We used regional temperature and vegetation data from these events to quantify temperature thresholds for A. germinans leaf damage. Our results indicate that A. germinans leaf damage is likely to occur when temperatures are between -4 °C and -6 °C. These findings help refine temperature thresholds for A. germinans leaf damage and advance understanding of the effects of extreme freeze events on mangrove range expansion. This information is valuable for anticipating future range dynamics in a warming world. [ABSTRACT FROM AUTHOR]

Climate change is altering the frequency and intensity of extreme weather events. Quantifying ecosystem responses to extreme events at the landscape scale is critical for understanding and responding to climate-driven change but is constrained by limited data availability. Here, we integrated remote sensing with ground-based observations to quantify landscape-scale vegetation damage from an extreme climatic event. We used ground- and satellite-based black mangrove (Avicennia germinans) leaf damage data from the northern Gulf of Mexico (USA and Mexico) to examine the effects of an extreme freeze in a region where black mangroves are expanding their range. The February 2021 event produced coastal temperatures as low as − 10 °C in some areas, exceeding thresholds for A. germinans damage and mortality. We used Sentinel-2 surface reflectance data to assess vegetation greenness before and after the freeze, along with ground-based observations of A. germinans leaf damage. Our results show a negative, nonlinear threshold relationship between A. germinans leaf damage and minimum temperature, with a temperature threshold for leaf damage near − 6 °C. Satellite-based analyses indicate that, at the landscape scale, damage was particularly severe along the central Texas coast, where the freeze event affected > 2000 ha of A. germinans-dominated coastal wetlands. Our analyses highlight the value of pairing remotely sensed data with regional, ground-based observations for quantifying and extrapolating the effects of extreme freeze events on mangroves and other tropical, cold-sensitive plants. The results also demonstrate how extreme freeze events govern the expansion and contraction of mangroves near northern range limits in North America. [ABSTRACT FROM AUTHOR]

Volumetric additive manufacturing is a novel fabrication method allowing rapid, freeform, layer-less 3D printing. Analogous to computer tomography (CT), the method projects dynamic light patterns into a rotating vat of photosensitive resin. These light patterns build up a three-dimensional energy dose within the photosensitive resin, solidifying the volume of the desired object within seconds. Departing from established sequential fabrication methods like stereolithography or digital light printing, volumetric additive manufacturing offers new opportunities for the materials that can be used for printing. These include viscous acrylates and elastomers, epoxies (and orthogonal epoxy-acrylate formulations with spatially controlled stiffness) formulations, tunable stiffness thiol-enes and shape memory foams, polymer derived ceramics, silica-nanocomposite based glass, and gelatin-based hydrogels for cell-laden biofabrication. Here we review these materials, highlight the challenges to adapt them to volumetric additive manufacturing, and discuss the perspectives they present. [ABSTRACT FROM AUTHOR]

Purpose: Tumor-associated macrophages are present within neuroblastoma, and interferon-gamma (IFN-γ) can polarize macrophages into cancer-inhibiting M1 type. We hypothesize that treating neuroblastoma with interferon-gamma (IFN-γ) can suppress tumor growth, and the concurrent treatment with IFN-γ and vincristine can lead to enhanced tumor killing as compared to vincristine alone. Methods: We loaded IFN-γ or vincristine into silk biomaterials and recorded the amount released over time. Orthotopic, syngeneic neuroblastoma xenografts were generated by injecting 9464D cells into adrenal gland of C57BL/6 mice, and IFN-γ-loaded and/or vincristine-loaded silk biomaterials were implanted into the tumor once the tumors reached 100 mm3. Drug release at different timepoints was measured and tumor growth after different treatments were compared. Results: 1–2% of IFN-γ and 70% of vincristine were released from the biomaterials by the fifth day. Combining IFN-γ and vincristine significantly slowed tumor growth as compared to the controls (12.2 ± 2.7 days to reach 800 mm3 versus 5.7 ± 1.2 days, p = 0.01), and IFN-γ alone also delayed tumor growth as compared to the controls (10.9 ± 1.5 days versus 5.7 ± 1.2 days, p = 0.001). Hematoxylin and eosin staining demonstrated tumor necrosis adjacent to the drug-loaded silk biomaterials. Conclusion: Local delivery of sustained release IFN-γ can inhibit neuroblastoma tumor growth by itself and in combination with vincristine. [ABSTRACT FROM AUTHOR]

Background and Aims: A rapid increase in the use of telemedicine for delivering healthcare has occurred since the onset of the Covid-19 pandemic. There is evidence for using telemedicine to facilitate cancer care delivery for patients with hepatocellular carcinoma (HCC). Examining how telemedicine can be used to communicate multidisciplinary tumor board (MTB) recommendations for HCC has not been studied. This study has two specific aims: (1) to evaluate the patient perspective of the MTB review process and identify best strategies for communicating treatment recommendations for HCC and (2) to pilot test a telemedicine intervention following MTB review to assess patient feasibility and satisfaction with using telemedicine to facilitate treatment decision-making and treatment referral. Methods: We conducted a mixed-methods study. First, semi-structured qualitative interviews were conducted among patients diagnosed with HCC who were discussed in MTB review at one of three VA Medical Centers (VAMC). We collected information about the MTB process from the patient perspective and identified strategies for improving communication and delivery of care. Rapid qualitative analysis was used to inform intervention development. Using our qualitative data, a MTB telemedicine pilot intervention was developed and implemented to assess the feasibility of using this approach for patients with HCC. Results: Almost all patients (94%) in the pilot study would recommend telemedicine to other patients with HCC, and half of the patients (50%) preferred telemedicine over in-person visits. Many patients (81%) found communication through telemedicine an acceptable platform to deliver difficult cancer information. Overall, patients felt they understood their treatment recommendations and found them clear and useful. Further, patients reported that they enjoyed being included in the decision-making process and appreciated being able to have family members easily join them for the telemedicine visit. Conclusions: Using telemedicine to communicate treatment recommendations following MTB review was found to be feasible and an acceptable alternative to an in-person visit for patient with HCC. Future studies could include expanding this approach for communicating MTB recommendations to patients with other types of cancers. [ABSTRACT FROM AUTHOR]

Background: Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis. Methods: This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality. Results: A total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58–2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42–0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001). Conclusions: The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all patients with ACLF. [ABSTRACT FROM AUTHOR]

Cell-cultivated fish offers the potential for a more ethical, sustainable, and safe seafood system. However, fish cell culture is relatively understudied in comparison to mammalian cells. Here, we established and characterized a continuous Atlantic mackerel (Scomber scombrus) skeletal muscle cell line ("Mack" cells). The cells were isolated from muscle biopsies of fresh-caught fish, with separate isolations performed from two distinct fish. Mack1 cells (cells from the first isolation) were cultured for over a year and subcultured over 130 times. The cells proliferated at initial doubling times of 63.9 h (± 19.1 SD). After a spontaneous immortalization crisis from passages 37–43, the cells proliferated at doubling times of 24.3 h (± 4.91 SD). A muscle phenotype was confirmed through characterization of muscle stemness and differentiation via paired-box protein 7 and myosin heavy chain immunostaining, respectively. An adipocyte-like phenotype was also demonstrated for the cells through lipid accumulation, confirmed via Oil Red O staining and quantification of neutral lipids. New qPCR primers (HPRT, PAX3B, MYOD1, MYOG, TNNT3A, and PPARG) were tailored to the mackerel genome and used to characterize mackerel cell genotypes. This work provides the first spontaneously immortalized fish muscle cell line for research, ideally serving as a reference for subsequent investigation. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to demonstrate and evaluate the use of Bayesian dynamic borrowing (Viele et al, in Pharm Stat 13:41-54, 2014) as a means of systematically utilizing historical information with specific applications to large-scale educational assessments. Dynamic borrowing via Bayesian hierarchical models is a special case of a general framework of historical borrowing where the degree of borrowing depends on the heterogeneity among historical data and current data. A joint prior distribution over the historical and current data sets is specified with the degree of heterogeneity across the data sets controlled by the variance of the joint distribution. We apply Bayesian dynamic borrowing to both single-level and multilevel models and compare this approach to other historical borrowing methods such as complete pooling, Bayesian synthesis, and power priors. Two case studies using data from the Program for International Student Assessment reveal the utility of Bayesian dynamic borrowing in terms of predictive accuracy. This is followed by two simulation studies that reveal the utility of Bayesian dynamic borrowing over simple pooling and power priors in cases where the historical data is heterogeneous compared to the current data based on bias, mean squared error, and predictive accuracy. In cases of homogeneous historical data, Bayesian dynamic borrowing performs similarly to data pooling, Bayesian synthesis, and power priors. In contrast, for heterogeneous historical data, Bayesian dynamic borrowing performed at least as well, if not better, than other methods of borrowing with respect to mean squared error, percent bias, and leave-one-out cross-validation. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to extend and evaluate methods of Bayesian historical borrowing applied to longitudinal data with a focus on parameter recovery and predictive performance. Bayesian historical borrowing allows researchers to utilize information from previous data sources and to adjust the extent of borrowing based on the similarity of current data to historical data. We examine the utility of three static historical borrowing methods including complete pooling, Bayesian synthesis with aggregated data-dependent priors, traditional power priors, and two dynamic borrowing methods including Bayesian dynamic borrowing and commensurate priors. Using data from two administrations of the United States Early Childhood Longitudinal Study, we evaluate these methods in terms of in-sample simulation statistics, as well as pseudo out-of-sample measures of predictive performance. A case study examining growth in reading competency over time revealed that for one historical cycle, most methods of historical borrowing perform similarly with respect to predictive performance and parameter recovery. Pooling and power priors performed relatively poorly across the conditions in this study, particularly when the current data and the historical data were heterogeneous. Results from a comprehensive simulation study revealed that the advantages of different historical borrowing methods vary across different evaluation criteria. Overall, Bayesian dynamic borrowing and commensurate priors are no worse, and in some cases better, than other methods in terms of parameter recovery and predictive performance, and considering a previous paper by Kaplan et al. (Psychometrika, 10.1007/s11336-022-09869-3, 2022) found clear benefits of Bayesian dynamic borrowing over other methods of historical borrowing in the multilevel context using data from the Program for International Student Assessment (PISA) with five historical cycles, this paper argues that Bayesian dynamic borrowing or commensurate priors is a prudent choice for borrowing information from previous cycles of longitudinal data. [ABSTRACT FROM AUTHOR]

We describe the model-independent mechanism by which dark matter and dark matter structures heavier than ~ 8 × 1011 GeV form binary pairs in the early Universe that spin down and merge both in the present and throughout the Universe’s history, producing potentially observable signals. Sufficiently dense dark objects will dominantly collide through binary mergers instead of random collisions. We detail how one would estimate the merger rate accounting for finite size effects, multibody interactions, and friction with the thermal bath. We predict how mergers of dark dense objects could be detected through gravitational and electromagnetic signals, noting that such mergers could be a unique source of high frequency gravitational waves. We rule out objects whose presence would contradict observations of the CMB and diffuse gamma-rays. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis (AH) is a clinically diagnosed syndrome with high short-term mortality for which liver transplantation may be curative. A lack of validated algorithms to identify AH hospitalizations has hindered clinical epidemiology research. Methods: This was a retrospective cohort study of patients with cirrhosis using Veterans Health Administration (VHA) data from 2008 to 2015. We randomly sampled hospitalizations based upon abnormal liver tests and administrative codes for acute hepatitis or alcohol-associated liver disease (ALD). Hospitalizations were manually adjudicated for AH per society guidelines. A priori algorithms were evaluated to compute positive predicted value (PPV) and positive likelihood ratio (LR+), and were tested in an external University of Pennsylvania Health System (UPHS) cohort. Results: Of 368 hospitalizations, 142 (38.6%) were adjudicated as AH. AH patients were younger (55 vs. 58 years, p < 0.001), less likely to have prior cirrhosis decompensation (57% vs. 73.9%, p < 0.001), and had higher AST-to-ALT ratios (median 2.9 vs. 1.9 mg/dL, p < 0.001) and higher bilirubin levels (median 2.9 vs. 1.9 mg/dL, p < 0.001). Algorithms combining clinical laboratory criteria (AST > 85 U/L but < 450 U/L, AST-to-ALT ratio > 2, total bilirubin > 5 mg/dL) and administrative coding criteria yielded the highest PPV (96.4%, 95% CI 87.7–99.6) and the highest LR+ (43.0, 95% CI 10.6–173.5). Several algorithms demonstrated 100% PPV for definite AH in the UPHS external cohort. Conclusion: We have identified algorithms for AH hospitalizations with excellent PPV and LR+. These high-specificity algorithms may be used in VHA datasets to identify patients with high likelihood of AH, but should not be used to study AH incidence. [ABSTRACT FROM AUTHOR]

Background: The Freiburg index of post-TIPS survival (FIPS) score was recently demonstrated to improve prediction of post-TIPS mortality relative to existing standards. As this score was derived from a German cohort over an extended time period, it is unclear if performance will translate well to other settings. This study aimed to externally validate the FIPS score in a large Veterans Affairs (VA) cohort over two separate eras of TIPS-related care. Methods: This was a retrospective cohort study of patients with cirrhosis who underwent TIPS placement in the VA from 2008 to 2020. Cox regression models for post-TIPS survival were constructed using FIPS, MELD, MELD-Na, or CTP scores as predictors. Discrimination (Harrell's C) and calibration (joint tests of calibration curve slope and intercept) were evaluated for each score. A stratified analysis was performed for time periods between 2008–2013 and 2014–2020. Results: The cohort of 1,274 patients was 97.3% male with mean age 60.9 years and mean MELD-Na 14. The FIPS score demonstrated the highest overall discrimination versus MELD, MELD-Na, and CTP (0.634 vs. 0.585, 0.626, 0.612, respectively). However, in the modern treatment era (2014–2020), the FIPS score performed similarly to MELD-Na. Additionally, the FIPS score demonstrated poor calibration at one-month and six-month post-TIPS timepoints (joint p = 0.04 and 0.004, respectively). MELD, MELD-Na, and CTP were well-calibrated at each timepoint (each joint p > 0.05). Conclusion: The FIPS score performed similarly to MELD-Na in the modern TIPS treatment era and demonstrated regions of poor calibration. Future models derived with contemporary data may improve prediction of post-TIPS mortality. [ABSTRACT FROM AUTHOR]

Background: Little is known about use of specialty care among patients admitted with cirrhosis complications. Aims: We sought to characterize the use and impact of gastroenterology/hepatology (GI/HEP) consultations in hospitalized patients with cirrhosis. We studied two national cohorts—the Veterans Affairs Costs and Outcomes in Liver Disease (VOCAL) and a nationally representative database of commercially insured patients (Optum Clinformatics™ DataMart). Methods: Cirrhosis-related admissions were classified by ICD9/10 codes for ascites, hepatic encephalopathy, alcohol-associated hepatitis, spontaneous bacterial peritonitis, or infection related. We included 20,287/222,166 index admissions from VOCAL/Optum from 2010 to 2016. Propensity-matched analyses were conducted to balance clinical characteristics. Mortality and readmission were evaluated using competing risk regression (subhazard ratios, sHR), and length of stay (LOS) was assessed using negative binomial regression. Results: GI/HEP consultations were completed among 37% and 42% patients in VOCAL and Optum, respectively. In propensity-matched analyses for VOCAL, GI/HEP consultation was associated with adjusted estimates of increased LOS (1.55 + 1.03 additional days), 90-day mortality (sHR 1.23, 95% CI 1.14–1.36), and lower 30-day readmissions (sHR 0.82, 95% CI 0.75–0.89). In Optum, inpatient consultation was associated with higher LOS (1.13 + 1.01 additional days), higher 90-day mortality (sHR 1.57, 95% CI 1.43–1.72), and higher 30-day readmission risk (sHR 1.04, 95% CI 1.02–1.05). Post-discharge primary and specialty care was higher among admissions receiving GI/HEP consultation in both cohorts. Conclusions: Use of GI/HEP consultation for cirrhosis-related admissions was low. Patients who received consultation had higher disease severity, and consultation was not associated with lower mortality but was associated with lower 30-day readmissions in the VA cohort only. [ABSTRACT FROM AUTHOR]

Cell-cultured meat offers the potential for a more sustainable, ethical, resilient, and healthy food system. However, research and development has been hindered by the lack of serum-free media that enable the robust expansion of relevant cells (e.g., muscle satellite cells) over multiple passages. Recently, a low-cost serum-free media (B8) was described for pluripotent stem cells. Here, B8 is adapted for bovine satellite cells through the addition of a single component, recombinant albumin, which renders it suitable for long-term satellite cell expansion without sacrificing myogenicity. This new media (Beefy-9) maintains cell growth over the entire period tested (seven passages), with an average doubling time of 39 h. Along with demonstrated efficacy for bovine cells, Beefy-9 offers a promising starting-point for developing serum-free media for other meat-relevant species. Ultimately, this work offers a foundation for escaping cultured meat research's reliance on serum, thereby accelerating the field. A substitution of FBS in culturing of bovine satellite cells for the purpose of culturing meat is presented, addressing both basal media and growth factors in relation to proliferating and differentiating cells. [ABSTRACT FROM AUTHOR]

Over a dozen millisecond pulsars are ablating low-mass companions in close binary systems. In the original ‘black widow’, the eight-hour orbital period eclipsing pulsar PSR J1959+2048 (PSR B1957+20)1, high-energy emission originating from the pulsar2 is irradiating and may eventually destroy3 a low-mass companion. These systems are not only physical laboratories that reveal the interesting results of exposing a close companion star to the relativistic energy output of a pulsar, but are also believed to harbour some of the most massive neutron stars4, allowing for robust tests of the neutron star equation of state. Here we report observations of ZTF J1406+1222, a wide hierarchical triple hosting a 62-minute orbital period black widow candidate, the optical flux of which varies by a factor of more than ten. ZTF J1406+1222 pushes the boundaries of evolutionary models5, falling below the 80-minute minimum orbital period of hydrogen-rich systems. The wide tertiary companion is a rare low-metallicity cool subdwarf star, and the system has a Galactic halo orbit consistent with passing near the Galactic Centre, making it a probe of formation channels, neutron star kick physics6 and binary evolution.ZTF J1406+1222 is a wide hierarchical triple system that hosts a low-metallicity subdwarf star and a ‘black widow’ millisecond pulsar that has a highly varying optical flux and a 62-minute period. [ABSTRACT FROM AUTHOR]

Background: The Food and Drug Administration requested withdrawal of ranitidine formulations, due to a potentially carcinogenic contaminant, N-nitrosodimethylamine. Aims: We evaluate whether ranitidine use is associated with gastric cancer. Methods: This is a retrospective multicenter, nationwide cohort study within the Veterans Health Administration, among patients with Helicobacter pylori (HP) prescribed long-term acid suppression with either: (1) ranitidine, (2) other histamine type 2 receptor blocker (H2RB), or (3) proton pump inhibitor (PPI)) between May 1, 1998, and December 31, 2018. Covariates included race, ethnicity, smoking, age, HP treatment, HP eradication. Primary outcome was non-proximal gastric adenocarcinomas, using multivariable Cox proportional hazards analysis. Results: We identified 279,505 patients with HP prescribed long-term acid suppression (median 53.4 years; 92.9% male). Compared to ranitidine, non-ranitidine H2RB users were more likely to develop cancer (HR 1.83, 95%CI 1.36–2.48); PPI users had no significant difference in future cancer risk (HR 0.92, 95% CI 0.82–1.04), p < 0.001. Demographics associated with future cancer included increasing age (HR 1.18, 95% CI 1.15–1.20, p < 0.001), Hispanic/Latino ethnicity (HR 1.46, 95% CI 1.21–1.75, p < 0.001), Black race (HR 1.89, 95% CI 1.68–2.14) or Asian race (HR 2.03, 95% CI 1.17–3.52), p < 0.001, and gender (female gender HR 0.64, 95% CI 0.48–0.85, p = 0.02). Smoking was associated with future cancer (HR 1.38, 95% CI 1.23–1.54, p < 0.001). Secondary analysis demonstrated decreased cancer risk in those with confirmed HP eradication (HR 0.24, 95% CI 0.14–0.40). No association between ranitidine and increased gastric cancer was found. Conclusion: There is no demonstrable association between ranitidine use and future gastric cancer among individuals with HP on long-term acid suppression. [ABSTRACT FROM AUTHOR]

Background: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. Methods: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. Results: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22–5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15 mL/min/1.73 m2 change (p < 0.001). Conclusions: Race adjustment in eGFR equations did not enhance AKI risk estimation in patients with cirrhosis. Further study is warranted to assess the impacts of removing race from eGFR equations on clinical outcomes and policy. [ABSTRACT FROM AUTHOR]

We present current direct and astrophysical limits on the cosmological abundance of black holes with extremal magnetic charge. Such black holes do not Hawking radiate, allowing those normally too light to survive to the present to do so. The dominant constraints come from white dwarf destruction for low and intermediate masses (2 × 10−5 g – 4 × 1012 g) and Galactic gas cloud heating for heavier masses (> 4 × 1012 g). Extremal magnetic black holes may catalyze proton decay. We derive robust limits — independent of the catalysis cross section — from the effect this has on white dwarfs. We discuss other bounds from neutron star heating, solar neutrino production, binary formation and annihilation into gamma-rays, and magnetic field destruction. Stable magnetically charged black holes can assist in the formation of neutron star mass black holes. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) in vitro culture systems using human induced pluripotent stem cells (hiPSCs) are useful tools to model neurodegenerative disease biology in physiologically relevant microenvironments. Though many successful biomaterials-based 3D model systems have been established for other neurogenerative diseases, such as Alzheimer’s disease, relatively few exist for Parkinson’s disease (PD) research. We employed tissue engineering approaches to construct a 3D silk scaffold-based platform for the culture of hiPSC-dopaminergic (DA) neurons derived from healthy individuals and PD patients harboring LRRK2 G2019S or GBA N370S mutations. We then compared results from protein, gene expression, and metabolic analyses obtained from two-dimensional (2D) and 3D culture systems. The 3D platform enabled the formation of dense dopamine neuronal network architectures and developed biological profiles both similar and distinct from 2D culture systems in healthy and PD disease lines. PD cultures developed in 3D platforms showed elevated levels of α-synuclein and alterations in purine metabolite profiles. Furthermore, computational network analysis of transcriptomic networks nominated several novel molecular interactions occurring in neurons from patients with mutations in LRRK2 and GBA. We conclude that the brain-like 3D system presented here is a realistic platform to interrogate molecular mechanisms underlying PD biology. [ABSTRACT FROM AUTHOR]

Oyster reef chains grow in response to local hydrodynamics and can redirect flows, particularly when reef chains grow perpendicular to freshwater flow paths. Singularly, oyster reef chains can act as porous dams that may facilitate nearshore accumulation of fresh or low-salinity water, in turn creating intermediate salinities that support oyster growth and estuarine conditions. However, oyster-driven freshwater detention has only been confirmed by limited, point-scale observational data, and simplified models. Oyster reef-driven freshwater detention in real ecosystems at the estuary scale remains largely unexplored. In this study, we analyzed the visible bands in 30-m resolution remote sensing (RS) images recorded by the Operational Land Imager aboard Landsat-8 to characterize the freshwater detention effect of oyster reef chains across a set of hydrologic conditions. Our results support prior findings indicating that 30-m resolution RS images recorded by the Operational Land Imager aboard Landsat-8 are useful for analyzing coastal dynamics after atmospheric correction, despite having been originally designed for terrestrial studies. Statistical models of water-leaving reflectance revealed that freshwater detention by oyster reefs was evident across the estuary, with the greatest effect occurring in the region closest to shore. Additionally, statistical modeling results and spatial patterns apparent in the satellite images suggested that reef-driven freshwater detention occurred under high riverine discharge conditions, but was less evident when flow was low. Beyond offering insight on the potential role of oyster reefs as mediators of estuarine hydrology, this study presents a transferable methodological framework for exploring estuarine biophysical feedbacks in blackwater river estuaries using satellite remote sensing. [ABSTRACT FROM AUTHOR]

Introduction: Topical therapies are considered first-line treatment in the management of plaque psoriasis (PSO). However, data on patient-reported outcomes for topicals are scarce. We designed a survey to record the treatment experience of patients with mild-to-moderate PSO using prescription topicals. Methods: An online cross-sectional survey was conducted among adult patients on prescription topicals for mild-to-moderate PSO (body surface area [BSA] ≤ 10%) in the US. Data on treatment goals, changes in PSO after current treatment, satisfaction with current treatment (assessed with the Treatment Satisfaction Questionnaire for Medication [TSQM]), and treatment adherence (how often current treatment was taken as instructed) were collected. Descriptive analysis was used to evaluate outcomes. Results: Of the 175 patients with mild-to-moderate PSO who completed the survey, 67.4% were female, with a median age of 55.0 years and 10.8 years since PSO diagnosis. Patients reported (medians) the use of three topicals since diagnosis, with 5 years on the current prescription topical. The top three treatment goals for current topical treatment were improvements in visible skin, 97.1%; non-skin related symptoms, 62.9%; and social/emotional well-being, 60.0%. Overall, 43.4% of patients reported 0% BSA change and 5.7% reported ≥ 75% BSA reduction. Approximately 75.0% each reported improvement in itch and pain symptoms. Embarrassment/self-consciousness because of skin symptoms persisted in 72.6% of patients. Median TSQM scores for global satisfaction, convenience, and effectiveness ranged between 58 and 72, indicating partial treatment satisfaction, except for side effects, which was high (median: 100). Approximately half of patients (49.7%) reported not being highly adherent to treatment. Conclusion: Contrary to their treatment goals, patients with mild-to-moderate PSO using prescription topicals reported partial effectiveness, incomplete symptom resolution, impacted emotional and social well-being, and suboptimal global satisfaction, effectiveness, adherence, and convenience. Our findings highlight several unmet needs among topical-experienced, systemic-naïve patients with mild-to-moderate PSO using prescription topicals. Plain Language Summary: Psoriasis is a chronic skin disease caused by inflammation in the body. Raised areas, called plaques, are one of the main symptoms. These plaques may be red, flaky, itchy, and/or painful. Living with psoriasis can negatively impact a person's well-being, especially when it affects visible areas such as the head, face, hands and nails, and/or sensitive areas like the genitals. Topical treatments, such as creams and lotions, are often the first therapy a doctor prescribes for psoriasis. Since these treatments are applied directly on the plaques, they can be messy and inconvenient. We conducted an online survey of adults with mild-to-moderate psoriasis, meaning that less than 10% of their body had plaques. We wanted to learn how they felt about their disease and their prescription topical treatments. Most people had psoriasis for about 10 years and had been using their current prescription topical for about 5 years. Approximately three of four people reported embarrassment/self-consciousness because of skin symptoms. Although three of four people reported some improvement in itch and pain, almost all people desired better resolution of plaques in visible areas. People also reported that: their current prescription topical did not completely resolve their symptoms, their emotional and social well-being was still suboptimal, they did not always apply their therapy as often as instructed, and they were not completely satisfied with their treatment overall. These results highlight the need for additional treatment options for people with mild-to-moderate psoriasis, particularly options that offer improved symptom control and are more convenient to use. [ABSTRACT FROM AUTHOR]

The cosmic neutrino background is both a dramatic prediction of the hot Big Bang and a compelling target for current and future observations. The impact of relativistic neutrinos in the early universe has been observed at high significance in a number of cosmological probes. In addition, the non-zero mass of neutrinos alters the growth of structure at late times, and this signature is a target for a number of upcoming surveys. These measurements are sensitive to the physics of the neutrino and could be used to probe physics beyond the standard model in the neutrino sector. We explore an intriguing possibility where light right-handed neutrinos are coupled to all, or a fraction of, the dark matter through a mediator. In a wide range of parameter space, this interaction only becomes important at late times and is uniquely probed by late-time cosmological observables. Due to this coupling, the dark matter and neutrinos behave as a single fluid with a non-trivial sound speed, leading to a suppression of power on small scales. In current and near-term cosmological surveys, this signature is equivalent to an increase in the sum of the neutrino masses. Given current limits, we show that at most 0.5% of the dark matter could be coupled to neutrinos in this way. [ABSTRACT FROM AUTHOR]

The coordination of attention between individuals is a fundamental part of everyday human social interaction. Previous work has focused on the role of gaze information for guiding responses during joint attention episodes. However, in many contexts, hand gestures such as pointing provide another valuable source of information about the locus of attention. The current study developed a novel virtual reality paradigm to investigate the extent to which initiator gaze information is used by responders to guide joint attention responses in the presence of more visually salient and spatially precise pointing gestures. Dyads were instructed to use pointing gestures to complete a cooperative joint attention task in a virtual environment. Eye and hand tracking enabled real-time interaction and provided objective measures of gaze and pointing behaviours. Initiators displayed gaze behaviours that were spatially congruent with the subsequent pointing gestures. Responders overtly attended to the initiator's gaze during the joint attention episode. However, both these initiator and responder behaviours were highly variable across individuals. Critically, when responders did overtly attend to their partner's face, their saccadic reaction times were faster when the initiator's gaze was also congruent with the pointing gesture, and thus predictive of the joint attention location. These results indicate that humans attend to and process gaze information to facilitate joint attention responsivity, even in contexts where gaze information is implicit to the task and joint attention is explicitly cued by more spatially precise and visually salient pointing gestures. [ABSTRACT FROM AUTHOR]

There is an unresolved question about whether realigned visual feedback is beneficial or costly to laparoscopic task performance. We provide evidence that camera realignment imposes a reliable cost on performance across both naive controls and experienced surgeons. This finding clarifies an important ongoing discussion in the literature about the effects of camera realignment, which could inform the strategies that laparoscopic surgeons use in the operating room. [ABSTRACT FROM AUTHOR]

Artificial reefs (ARs) are one of the most popular means of supporting marine ecosystem conservation and coastal fisheries, particularly in developing countries. However, ARs generate complex socio-bio-economic interactions that require careful evaluation. This is particularly the case for ARs outside no-take zones, where fish might be subject to enhanced exploitation due to easier catchability. Here, we conducted an interdisciplinary study on how ARs impact fish and fishing yields, combining mathematical and sociological approaches. Both approaches converge to confirm that fishery yields decline when ARs are exploited as if they were open access areas. This situation typically occurs in areas with weak governance and/or high levels of illegal fishing activity, both of which are common in many developing countries. To avoid these adverse effects and their associated ecological consequences, we recommend prioritizing the onset of a long-term surveillance system against illegal fishing activities, and adapting design and location of the ARs based on both and local and academic knowledge, before the deployment of ARs. [ABSTRACT FROM AUTHOR]

In future trial design and in clinical practice, patients with CTP C cirrhosis or total bilirubin >= 3 mg/dl should not be initiated on statins and if already taking should discontinue therapy. Two CTP C patients developed myonecrosis in this study; it was only patients with CTP C cirrhosis in the Bleeding Prevention With Simvastatin (BLEPS) trial that developed rhabdomyolysis [[6]]. [Extracted from the article]

Of critical importance to education policy is monitoring trends in education outcomes over time. In the United States, the National Assessment of Educational Progress (NAEP) has provided long-term trend data since 1970; at the state/jurisdiction level, NAEP has provided long-term trend data since 1996. In addition to the national NAEP, all 50 states and United States jurisdictions participate in the state NAEP assessment. Thus, NAEP provides important monitoring and forecasting information regarding population-level academic performance of relevance to national and international goals. However, an inspection of NAEP trend reports shows that relatively simple trend plots are provided; and although these plots are important for communicating general trend information, we argue that much more useful information can be obtained by adopting a Bayesian probabilistic forecasting point of view. The purpose of this paper is to provide a Bayesian probabilistic forecasting workflow that can be used with large-scale assessment trend data generally, and to demonstrate that workflow with an application to the state NAEP assessments. [ABSTRACT FROM AUTHOR]

Hunger is both a natural and social phenomenon. On one hand, it is a natural, biological state that affects everyone, everywhere, in every historical time. On the other hand, our perceptions, attitudes, and experiences of hunger are far from uniform. We think about it differently in different contexts and settings depending on its causes and consequences. The same event—the same pangs, emptiness, and lack of energy associated with the desire for food—takes on different meanings depending on who is hungry, when, where, and why. That is to say, it is a matter of interpretation like any other human affair. However, just because it is open to interpretation does not mean that all opinions are equally valid, or that there is nothing objectively true about it. On the contrary, there is a good deal of agreement about what hunger is and where it comes from. Both the biological and socio-economic causes are well-researched, albeit far from settled. Yet, hunger is a surprisingly elastic concept that covers a number of different experiences. Consequently, different practical, moral, and political responses might be appropriate depending on how it's interpreted. The four main classes of hunger are: involuntary, voluntary, scientific, and political. Each has its particular actors, explanations, and outcomes; each takes place in different social and historical setting; and each has its own solutions beyond simply putting food into empty stomachs. After briefly examining the relevance of hermeneutics for understanding the variety of hungers, this paper will analyze several different forms and changing definitions of it. Although the meaning of hunger may be indeterminate and solutions to it debatable, we can always explain ourselves and understand conflicting interpretations. [ABSTRACT FROM AUTHOR]

Issues of model selection have dominated the theoretical and applied statistical literature for decades. Model selection methods such as ridge regression, the lasso, and the elastic net have replaced ad hoc methods such as stepwise regression as a means of model selection. In the end, however, these methods lead to a single final model that is often taken to be the model considered ahead of time, thus ignoring the uncertainty inherent in the search for a final model. One method that has enjoyed a long history of theoretical developments and substantive applications, and that accounts directly for uncertainty in model selection, is Bayesian model averaging (BMA). BMA addresses the problem of model selection by not selecting a final model, but rather by averaging over a space of possible models that could have generated the data. The purpose of this paper is to provide a detailed and up-to-date review of BMA with a focus on its foundations in Bayesian decision theory and Bayesian predictive modeling. We consider the selection of parameter and model priors as well as methods for evaluating predictions based on BMA. We also consider important assumptions regarding BMA and extensions of model averaging methods to address these assumptions, particularly the method of Bayesian stacking. Simple empirical examples are provided and directions for future research relevant to psychometrics are discussed. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly.Methods: In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models.Results: Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib.Conclusions: Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed. [ABSTRACT FROM AUTHOR]

Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment. [ABSTRACT FROM AUTHOR]

Advances in farming technology and intensification of animal agriculture increase the cost-efficiency and production volume of meat. Thus, in developed nations, meat is relatively inexpensive and accessible. While beneficial for consumer satisfaction, intensive meat production inflicts negative externalities on public health, the environment and animal welfare. In response, groups within academia and industry are working to improve the sensory characteristics of plant-based meat and pursuing nascent approaches through cellular agriculture methodology (i.e., cell-based meat). Here we detail the benefits and challenges of plant-based and cell-based meat alternatives with regard to production efficiency, product characteristics and impact categories. Large-scale meat production can have negative impacts on public health, the environment and animal welfare. In this Review, the authors consider plant-based and cell-based approaches to meat production and the challenges they face. [ABSTRACT FROM AUTHOR]

The brain's extracellular matrix (ECM) is a dynamic protein-based scaffold within which neural networks can form, self-maintain, and re-model. When the brain incurs injuries, microscopic tissue tears and active ECM re-modelling give way to abnormal brain structure and function including the presence of ectopic cells. Post-mortem and neuroimaging data suggest that the brains of jet pilots and astronauts, who are exposed to rotational forces, accelerations, and microgravity, display brain anomalies which could be indicative of a mechanodisruptive pathology. Here we present a model of non-impact-based brain injury induced by matrix deformation following mechanical shaking. Using a bioengineered 3D neural tissue platform, we designed a repetitive shaking paradigm to simulate subtle rotational acceleration. Our results indicate shaking induced ectopic cell clustering that could be inhibited by physically restraining tissue movement. Imaging revealed that the collagen substrate surrounding cells was deformed following shaking. Applied to neonatal rat brains, shaking induced deformation of extracellular spaces within the cerebral cortices and reduced the number of cell bodies at higher accelerations. We hypothesize that ECM deformation may represent a more significant role in brain injury progression than previously assumed and that the present model system contributes to its understanding as a phenomenon. [ABSTRACT FROM AUTHOR]

Enzymatic crosslinking of tyrosine is a simple and modular method for adding functional peptides to silk fibroin (SF) hydrogels. Silk fibroin is a naturally derived polymer notable for its robust mechanical properties, biological compatibility, and versatility. Hydrogels fabricated from SF are elastic, optically clear, and have tunable moduli, however, they do not contain native biological epitopes for cell interactions. In this work we demonstrate the attachment of peptides to SF hydrogels through crosslinking of tyrosine with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The goal was to understand the utility of this approach and to study how the addition of peptides affects the SF material properties. SF hydrogels conjugated to model peptides with different molecular weights and hydrophobic properties were studied by liquid chromatography/tandem mass spectroscopy (LC–MS/MS) (bond formation), fluorescent imaging (spatial distribution), Fourier transform infrared spectroscopy (FTIR) (protein secondary structure), and rheology (gelation time, modulus). As a proof of concept using a biologically relevant peptide, a peptide containing the cell binding domain Arg-Gly-Asp (RGD) was conjugated to SF, and the density and morphology of primary human fibroblasts were assessed. This work demonstrates a facile method for adding peptides to silk fibroin that can be adopted for a variety of biomaterials applications. [ABSTRACT FROM AUTHOR]

Background and purpose: The diagnosis of acute on chronic liver failure (ACLF) carries a high short-term mortality, making early identification of at-risk patients crucial. To date, there are no models that predict which patients with compensated cirrhosis will develop ACLF, and limited models exist to predict ACLF mortality. We sought to create novel risk prediction models using a large North American cohort. Methods: We performed a retrospective study of 75,922 patients with compensated cirrhosis from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) dataset. Using 70% derivation/30% validation sets, we identified ACLF patients using the Asian Pacific Association of Liver (APASL) definition. Multivariable logistic regression was used to derive prediction models (called VOCAL-Penn) for developing ACLF at 3, 6, and 12 months. We then created prediction models for ACLF mortality at 28 and 90 days. Results: The VOCAL-Penn models for ACLF development had very good discrimination [concordance (C) statistics of 0.93, 0.92, and 0.89 at 3, 6, and 12 months, respectively] and calibration. The mortality models also had good discrimination at 28 and 90 days (C statistics 0.89 and 0.88, respectively), outperforming the Model for End-stage Liver Disease (MELD), MELD-sodium, and the APASL ACLF Research Consortium ACLF scores. Conclusion: We have developed novel tools for predicting development of ACLF in compensated cirrhosis patients, as well as for ACLF mortality. These tools may be used to proactively guide patient follow-up, prognostication, escalation of care, and transplant evaluation. Receiver operating characteristic (ROC) curves for predicting development of APASL ACLF at 3 months (a), 6 months (b), and 1 year (c) [ABSTRACT FROM AUTHOR]

The aim of this study was to study the biocompatibility of an injectable silk gel in the cervix in a rat model of pregnancy. The rationale is to study an injectable gel as an alternate treatment for cervical insufficiency. We further aimed to perform cervical injections via a vaginal route to mimic the clinical procedure of a cervical cerclage. We performed an in vivo study in pregnant female Sprague Dawley rats. Cervical procedures were performed using a customized speculum under general anesthesia. Injections were performed on gestational day 16. The responses to silk gel injections were compared to polyethylene terephthalate suture and saline controls on gestational day 19 and postpartum. The inflammatory response was evaluated by histology, PCR for inflammatory gene expression, and ELISA for protein levels of proinflammatory mediators. Silk gel injections were performed on 13 animals. All animals tolerated the procedure. Silk gel occupied 5% of the stroma after injection. Injected silk gel caused neither preterm birth nor prolonged pregnancy and had no effect on the kits. When comparing inflammatory responses, expression of inflammatory genes and proinflammatory proteins in the silk gel group was intermediate between saline (lowest) and cerclage suture (highest). Injectable silk gel was more inflammatory compared to saline injections but less inflammatory compared to the suture material used for cervical cerclage. This study is an important step toward development of an alternative treatment for cervical insufficiency. [ABSTRACT FROM AUTHOR]

Gene regulation and metabolism are two fundamental processes that coordinate the self-renewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain. However, little is known about how metabolic signals instruct gene expression to control NPC homeostasis. Here, we show that methylglyoxal, a glycolytic intermediate metabolite, modulates Notch signalling to regulate NPC fate decision. We find that increased methylglyoxal suppresses the translation of Notch1 receptor mRNA in mouse and human NPCs, which is mediated by binding of the glycolytic enzyme GAPDH to an AU-rich region within Notch1 3ʹUTR. Interestingly, methylglyoxal inhibits the enzymatic activity of GAPDH and engages it as an RNA-binding protein to suppress Notch1 translation. Reducing GAPDH levels or restoring Notch signalling rescues methylglyoxal-induced NPC depletion and premature differentiation in the developing mouse cortex. Taken together, our data indicates that methylglyoxal couples the metabolic and translational control of Notch signalling to control NPC homeostasis. Gene regulation and metabolism co-ordinate self-renewal and differentiation of neural precursors (NPCs) in the developing brain. Here the authors show that methylglyoxal, a glycolytic intermediate metabolite, promotes GADPH-dependent translational repression of Notch1, thereby promoting NPC differentiation. [ABSTRACT FROM AUTHOR]

Background: The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated.Objective: The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival.Design: Retrospective observational study.Data Source: Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology.Results: Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 ± 0.002 to 0.709 ± 0.002 and the risk ratio per unit change from 1.49 (1.48-1.50) to 1.53 (1.52-1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival.Conclusion: We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

General relativity1 predicts that short-orbital-period binaries emit considerable amounts of gravitational radiation. The upcoming Laser Interferometer Space Antenna2 (LISA) is expected to detect tens of thousands of such systems3 but few have been identified4, of which only one5 is eclipsing—the double-white-dwarf binary SDSS J065133.338+284423.37, which has an orbital period of 12.75 minutes. Here we report the discovery of an eclipsing double-white-dwarf binary system, ZTF J153932.16+502738.8, with an orbital period of 6.91 minutes. This system has an orbit so compact that the entire binary could fit within the diameter of the planet Saturn. The system exhibits a deep eclipse, and a double-lined spectroscopic nature. We see rapid orbital decay, consistent with that expected from general relativity. ZTF J153932.16+502738.8 is a strong source of gravitational radiation close to the peak of LISA's sensitivity, and we expect it to be detected within the first week of LISA observations, once LISA launches in approximately 2034. Observations of an eclipsing double-white-dwarf binary with an orbital period of 6.91 minutes that is decaying as predicted by general relativity are reported; once launched, the Laser Interferometer Space Antenna (LISA) should swiftly detect this binary. [ABSTRACT FROM AUTHOR]