bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of Tgfbr2 in hepatocytes alleviates liver fibrosis and restores hepatic function in fibrotic mice
Authors: Liu Shu Qing , Deng Xing , Zhu Chang Peng , Cui Ya Lu , Xie Wei Fen , Zhang Xin 
Published: February 2023

ObjectivesPrevious studies have demonstrated the pivotal role of transforming growth factor (TGF)‐β signaling in activating hepatic stellate cells during liver fibrosis. In this study we aimed to demonstrate the effects and underlying mechanism of TGF‐β signaling in hepatocytes on hepatic fibrogenesis.MethodsHepatocyte‐specific Tgfbr2‐knockout (Tgfbr2HKO) mice were generated by AAV8‐TBG‐Cre injection via the tail vein of Tgfbr2f/f mice. CCl4 was injected intraperitoneally twice a week for 4 weeks to establish the fibrotic mouse model. The expression of the fibrogenesis markers was evaluated by immunohistochemistry, western blot, and real‐time polymerase chain reaction (PCR). RNA‐seq analysis was used to detect the transcriptional profiles of primary hepatocytes isolated from Tgfbr2HKO mice and control mice.ResultsThe expression of TβR2 (Tgfbr2) was markedly upregulated in hepatocytes of the fibrotic liver. Tgfbr2 depletion in hepatocytes decreased the expressions of profibrogenic markers (Col1a1 and Acta2) in the CCl4‐treated fibrotic liver. RNA‐seq analysis revealed that Tgfbr2 deletion in hepatocytes significantly reduced the inflammatory response and suppressed epithelial–mesenchymal transition of hepatocytes accompanied by upregulation of the metabolic pathways during liver fibrosis. Moreover, the expressions of hepatocyte nuclear factors (HNFs), including Hnf4α, Foxa1, Foxa2, and Foxa3, which are important for maintaining liver metabolism and homeostasis, were decreased in fibrotic livers and significantly increased after Tgfbr2 blockade.ConclusionBlocking the TGF‐β signaling pathway in hepatocytes reduces hepatic fibrosis and improves hepatic function in fibrotic livers.
Storing power: market structure matters
Authors: Andrés‐Cerezo David , Fabra Natalia 
Published: February 2023

AbstractWe assess how firms' incentives to operate and invest in energy storage depend on the market structure. For this purpose, we characterize equilibrium market outcomes allowing for market power in storage and/or production, as well as for vertical integration between storage and production. Market power reduces overall efficiency through two channels: It induces an inefficient use of the storage facilities, and it distorts investment incentives. The worst outcome for consumers and total welfare occurs under vertical integration. The results are key to understanding how to regulate energy storage, an issue which is critical for the deployment of renewable energies.
Functional correlates of neurological soft signs in heavy cannabis users
Authors: Wolf Robert Christian , Werler Florian , Schmitgen Mike M. , Wolf Nadine D. , Wittemann Miriam , Reith Wolfgang , Hirjak Dusan 
Published: February 2023

AbstractSensorimotor dysfunction has been previously reported in persons with cannabis dependence. Such individuals can exhibit increased levels of neurological soft signs (NSS), particularly involving motor coordination, sensorimotor integration and complex motor task performance. Abnormal NSS levels can also be detected in non‐dependent individuals with heavy cannabis use (HCU), yet very little is known about the functional correlates underlying such deficits. Here, we used resting‐state functional magnetic resonance imaging (MRI) to investigate associations between NSS and intrinsic neural activity (INA) in HCU (n = 21) and controls (n = 26). Compared with controls, individuals with HCU showed significantly higher NSS across all investigated subdomains. Three of these subdomains, that is, motor coordination, sensorimotor integration and complex motor task behaviour, were associated with specific use‐dependent variables, particularly age of onset of cannabis use and current cannabis use. Between‐group comparisons of INA revealed lower regional homogeneity (ReHo) in left precentral gyrus, left inferior occipital gyrus, right triangular pat of the inferior frontal gyrus and right precentral gyrus in HCU compared with controls. In addition, HCU showed also higher ReHo in right cerebellum and left postcentral gyrus compared with controls. Complex motor task behaviour in HCU was significantly related to INA in postcentral, inferior frontal and occipital cortices. Our findings indicate abnormal ReHo in HCU in regions associated with sensorimotor, executive control and visuomotor‐integration processes. Importantly, we show associations between ReHo, cannabis‐use behaviour and execution of complex motor tasks. Given convergent findings in manifest psychotic disorders, this study suggests an HCU endophenotype that may present with a cumulative risk for psychosis.
Incentive mechanisms to exploit intraseasonal price arbitrage opportunities for smallholder farmers: Experimental evidence from Malawi
Authors: Nindi Tabitha , Ricker‐Gilbert Jacob , Bauchet Jonathan 
Published: February 2023

AbstractSeasonal commodity price fluctuations can potentially offer farmers arbitrage opportunities to increase their income. However, smallholder farmers in most of sub‐Saharan Africa often do not exploit these opportunities to the fullest extent possible. To inform this issue, we conducted a randomized controlled trial among 1739 smallholder farmers in Malawi to estimate the impact of two key post‐harvest constraints, lack of appropriate storage technology and commitment issues, on farmers' legume storage and sales decisions. The treated groups received (i) an improved storage technology in the form of two hermetic (airtight) bags, (ii) the same improved storage technology under the condition that farmers store collectively with members of their farmer club in their village, and/or (iii) the improved storage technology under the condition that farmers store collectively at a centralized association warehouse. We analyzed the impacts of these treatments on storage behavior and revenue from sales. Results indicated that addressing the technological and commitment constraints simultaneously had the largest average impacts. One year after the intervention, farmers offered hermetic bags and the village storage program (Treatment 2) stored 24% more legumes at harvest, stored 27% longer, received a 3% higher price for their legumes and ultimately made 12% more on average than farmers in the control group. Farmers in that treatment also improved some (but not all) outcomes compared to farmers in other treatment groups. These findings suggest that combining technology with collective action that is localized and flexible can lead to better post‐harvest outcomes for smallholder farmers.
Equity preferences and abatement cost sharing in international environmental agreements
Authors: Börger Tobias , Hanley Nick , Johnston Robert J. , Meginnis Keila , Ndebele Tom , Ali Siyal Ghamz E. , de Vries Frans 
Published: February 2023

AbstractThis paper examines empirically the importance of equity preferences for the formation of international environmental agreements (IEA) for transboundary pollution control. Although it has been shown theoretically that the existence of equity preferences among countries considering an IEA increases the chances for formation and stability of a coalition, empirical assessments of such preferences have been limited to climate change mitigation and single‐country studies. We consider the case of marine plastic pollution, of which a large share consists of food and beverage containers, representing a transboundary pollution control problem of increasing policy concern, with properties that lead to distinct considerations for equity and the sharing of abatement costs. We employ a coordinated choice experiment in the United Kingdom and United States to assess preferences for abatement‐cost allocations in a marine plastics IEA. Pairs of cooperating countries and the relative allocation of abatement costs are varied experimentally. Results show systematic aversion to both advantageous and disadvantageous inequality with respect to abatement costs but also that the relative strength of advantageous and disadvantageous inequality aversion differs across countries. Across both countries, there is evidence that left‐leaning voters generally favor more equal international sharing of abatement costs. Differences of these results from the case of greenhouse gas emission reduction, and implications for current efforts to establish a legally binding global treaty on marine plastic pollution, are discussed.
Effects on neonatal immunoglobulin concentrations by infant mode of delivery in the upstate KIDS study (2008–2010)
Authors: Adeyeye Temilayo E. , Jones Laura E. , Yeung Edwina , Mendola Pauline , Lawrence David A. , Lin Shao , Bell Erin M. 
Published: February 2023

AbstractProblemPrevious studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS).Method of studyThe Upstate KIDS Study (2008–2010) is a prospective cohort of mother‐child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1, IgG2, IgG3, IgG4, and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status.ResultsIgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively.ConclusionsMOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD.Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted.
Mifepristone priming and subsequent misoprostol for second trimester medical abortion in women with previous caesarean delivery
Authors: Dickinson Jan E. , Doherty Dorota A. 
Published: February 2023

AimsTo assess clinical outcomes and complications in women with ≥1 prior caesarean delivery (CS) during mid‐pregnancy medical abortion with misoprostol following mifepristone priming.Materials and MethodsRetrospective analysis of abortions at 13–28 weeks gestation using sequential mifepristone and misoprostol at a single centre from 1/2008–12/2018. Procedural outcomes were compared between cases with no prior CS, one prior and ≥2 prior CS.ResultsThere were 1399 consecutive women who underwent a medical abortion, with 304 (21.7%) having ≥1 prior lower segment CS (241 one, 49 two, 12 three, one four) and one a prior classical CS. Median gestation was 19 weeks (interquartile range (IQR) 17–21) among nulliparas, multiparas with no prior CS and multiparas with prior CS, P = 0.505. Compared with nulliparas (median procedural duration 10.8 h, IQR 7.5–16.5; adjusted hazards ratio (aHR) = 1.20 95%CI 1.04–1.40, P = 0.015), multiparas with prior CS had a shorter procedural duration (9.5 h, IQR 6.5–13.5) while multiparas with no CS had the shortest duration (7.0 h, IQR 5.0–9.8; aHR = 2.28 95%CI 2.01–2.58, P < 0.001). Complications were more frequent with prior CS: estimated blood loss (medians: 100 cc no CS vs 150 cc ≥1 CS, P = 0.002), blood loss >1000 cc (3.6% no CS vs 7.2% ≥1 CS; odds ratio (OR) = 2.11 95%CI 1.23–3.62, P = 0.007) and placental retention (17.3% no CS vs 25.3% ≥1 CS; adjusted OR = 1.44 95%CI 1.05–1.99, P = 0.024). Uterine rupture occurred in 4/304 women with ≥1 prior CS (1.3%).ConclusionsMifepristone‐misoprostol abortion in women with prior CS is generally safe but associated with an increased risk of procedural complications. Lowering of the misoprostol dosage with prior CS may reduce uterine rupture, although this hypothesis requires ongoing research.
The role of screening colonoscopy after appendicitis in patients over 40 years of age
Authors: Jolly Samantha , McCullough Timothy , Gunning Thomas , Maddern Guy , Wichmann Matthias 
Published: February 2023

AbstractBackgroundThere is some evidence of the association between acute appendicitis and colorectal neoplasm in patients over the age of 40 years. Despite this, few centres routinely evaluate the colon endoscopically following an episode of appendicitis in these patients. Our aim was to investigate the incidence of colorectal neoplasm in patients aged 40 years and over who underwent screening colonoscopy following acute appendicitis.MethodsRetrospective cohort study of patients aged 40 years and over who were diagnosed with acute appendicitis via imaging or histology between January 2015 and May 2022. Findings on subsequent screening colonoscopy were evaluated and classified according to adenomatous and non‐adenomatous lesions.ResultsA total of 176 patients met inclusion criteria, with a median age of 54 years (range 40–92) and female to male ratio of 1:1.3. One hundred patients (56%) had a colonoscopy following their admission, at a mean duration of 3.5 months post discharge. 15% of patients had an adenomatous polyp detected (10 adenomas, 4 advanced adenomas, and 1 sessile serrated adenoma), and 9% had a non‐adenomatous lesion detected (8 hyperplastic polyps and 1 lipoma).ConclusionAdenoma detection rate in patients aged 40 years and over undergoing colonoscopy after acute appendicitis was 15% in our cohort. This high adenoma detection rate supports the view of appendicitis as an indication for screening faecal immunochemical testing or colonoscopy in patients above 40 years.
Improvised Hybridity in the “Fixing” of Chinese Infrastructure Capital: The Case of Kenya's Standard Gauge Railway
Authors: Huang Zhengli , Lesutis Gediminas 
Published: February 2023

AbstractThe article explores the role of state‐owned enterprises (SOEs) in the globalisation of China's infrastructure capital. Examining how accumulation strategies of Chinese SOEs are driven by a complex set of political and economic, state and private, interests, it foregrounds the inherently hybrid nature of China's state capitalism. We use Kenya's Standard Gauge Railway (SGR) as a case study to analyse how state infrastructure capital traverses borders, and the specific ways that contradictions of accumulation in China are relocated through the improvised hybridity of SOEs. In Kenya, China Road and Bridge Corporation, the main SGR contractor, shifted and adapted its strategies as the pursuit of economic productivity gave way to political priorities in China, simultaneously responding to changing socio‐political circumstances in Kenya and across East Africa. Analysing these dynamics, we highlight the contingencies of, and limitations to, structural reorganisation of actually existing forms of state capitalism in China and beyond.
Single dose tocilizumab for COVID‐19 associated cytokine storm syndrome: Less is more
Authors: Boone Niels W. , Moes Dirk Jan A. R. , Ramiro Sofia , Mostard Remy L. M. , Magro‐Checa Cesar , van Dongen Christel M. P. , Gronenschild Michiel , van Haren Eric , Buijs Jacqueline , de Vries Annick , Peeters Ralph , Landewé Robert B. M. , Wong Dennis R. 
Published: February 2023

AimsWe aim to evaluate the clinical pharmacokinetics of a single dose interleukin‐6 (IL‐6) antibody tocilizumab (TCZ) in methylprednisolone (MP)‐treated COVID‐19 patients with cytokine storm syndrome (CSS).MethodsMP pre‐treated patients with COVID‐19‐associated CSS, defined as at least two elevations of C‐reactive protein (CRP) >100 mg/L, ferritin >900 μg/L or D‐dimers >1500 μg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear‐mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration–time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model.ResultsIn total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID‐19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 μg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL‐6 receptor occupancy at minimum serum concentration was also met.ConclusionsA single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL‐6‐mediated hyperinflammation in COVID‐19‐induced CSS in MP‐treated patients. Based on body weight PK simulations, a fixed‐dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.
The promises and limitations of codes of medical ethics as instruments of policy change
Authors: Komparic Ana , Garon‐Sayegh Patrick , Bensimon Cécile M. 
Published: February 2023

AbstractCodes of medical ethics (codes) are part of a longstanding tradition in which physicians publicly state their core values and commitments to patients, peers, and the public. However, codes are not static. Using the historical evolution of the Canadian Medical Association's Code of Ethics as an illustrative case, we argue that codes are living, socio‐historically situated documents that comprise a mix of prescriptive and aspirational content. Reflecting their socio‐historical situation, we can expect the upheaval of the COVID‐19 pandemic to prompt calls to revise codes. Indeed, Alex John London has argued in favour of specific modifications to the World Medical Association's International Code of Medical Ethics (which has since been revised) in light of moral and scientific failures that occurred during the COVID‐19 pandemic. Responding to London, we address the more general question: should codes be modified to reflect lessons drawn from the COVID‐19 pandemic or future such upheavals? We caution that codes face limitations as instruments of policy change because they are inherently interpretive and ‘multivocal’, that is, they usually underdetermine or provide more than one answer to the question, ‘What should I do now?’ Nonetheless, as both prescriptive and aspirational documents, codes also serve as tools for reflection and deliberation—collective practices that are necessary to engaging with and addressing the moral and scientific uncertainties inherent to medicine.
Finding Influential Subjects in a Network Using a Causal Framework
Authors: Lee Youjin , Buchanan Ashley L. , Ogburn Elizabeth L. , Friedman Samuel R. , Halloran M. Elizabeth , Katenka Natallia V. , Wu Jing , Nikolopoulos Georgios K. 
Published: February 2023

Abstract
Researchers across a wide array of disciplines are interested in finding the most influential subjects in a network. In a network setting, intervention effects and health outcomes can spill over from one node to another through network ties, and influential subjects are expected to have a greater impact than others. For this reason, network research in public health has attempted to maximize health and behavioral changes by intervening on a subset of influential subjects. Although influence is often defined only implicitly in most of the literature, the operative notion of influence is inherently causal in many cases: influential subjects are those we should intervene on to achieve the greatest overall effect across the entire network. In this work, we define a causal notion of influence using potential outcomes. We review existing influence measures, such as node centrality, that largely rely on the particular features of the network structure and/or on certain diffusion models that predict the pattern of information or diseases spreads through network ties. We provide simulation studies to demonstrate when popular centrality measures can agree with our causal measure of influence. As an illustrative example, we apply several popular centrality measures to the HIV risk network in the Transmission Reduction Intervention Project and demonstrate the assumptions under which each centrality can represent the causal influence of each participant in the study.
A novel sorbicillinoid compound as a potent anti‐inflammation agent through inducing NLRP3 protein degradation
Authors: Wang Fangfang , Zhang Meng , Yuan Meng , Xia Zixuan , Yang Fengge , Zhang Sihao , Lin Tengyu , Luo Lianxiang , Tang Jinshan , Zhang Youwei 
Published: February 2023

Background and PurposeChronic inflammation is pathogenic and contributes to human diseases, causing a significant threat to public health. The NLR family pyrin domain‐containing protein 3 (NLRP3) is the best‐characterized factor regulating inflammation. Therefore, targeting NLRP3 has the potential to treat inflammatory diseases and improve human health.Experimental ApproachLipopolysaccharide was used to induce inflammation in cell cultures. Lipopolysaccharide/d‐galactosamine and dextran sulfate sodium salt were used to induce acute liver inflammation and ulcerative colitis respectively in C57BL/6J mice. Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme‐linked immunosorbent assay (ELISA) were used to evaluate the activation of the inflammatory response in cell cultures and in mice.Key ResultsJNUTS013, a novel sorbicillinoid compound recently synthesized by us, significantly inhibited inflammation both in cell cultures and in mouse models. Mechanistically, JNUTS013 induced proteasome‐dependent degradation of NLRP3. Hence, it suppressed the formation of the NLRP3 inflammasome and the production of downstream inflammatory cytokines and chemokines. The inhibitory effect of JNUTS013 on NLRP3 protein expression was confirmed in mice. Importantly, JNUTS013 failed to ameliorate bowel inflammation in Nlrp3‐/‐ knockout mice, supporting NLRP3 as the biological target by which JNUTS013 inhibits inflammation. Further studies revealed critical chemical moieties of JNUTS013 required for inducing NLRP3 degradation.Conclusion and ImplicationsThis study identifies a novel compound JNUTS013 that inhibits inflammation through inducing NLRP3 protein degradation in vitro and in vivo, which not only supports the development of JNUTS013 as an anti‐inflammation agent but also creates a new way for the treatment of inflammation by chemically inducing NLRP3 degradation.