bluuebunny/crossref_metadata_2025 huggingface dataset:
Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration
Authors: Tonietto Matteo , Poirion Emilie , Lazzarotto Andrea , Ricigliano Vito , Papeix Caroline , Bottlaender Michel , Bodini Benedetta , Stankoff Bruno
Published: September 2022

In multiple sclerosis, spontaneous remyelination is generally incomplete and heterogeneous across patients. A high heterogeneity in remyelination may also exist across lesions within the same individual, suggesting the presence of local factors interfering with myelin regeneration. In this study we explored in vivo the regional distribution of myelin repair and investigated its relationship with neurodegeneration. We first took advantage of the myelin binding property of the amyloid radiotracer 11C-PiB to conduct a longitudinal 11C-PiB PET study in an original cohort of 19 participants with a relapsing–remitting form of multiple sclerosis, followed-up over a period of 1–4 months. We then replicated our results on an independent cohort of 40 people with multiple sclerosis followed-up over 1 year with magnetization transfer imaging, an MRI metrics sensitive to myelin content. For each imaging method, voxel-wise maps of myelin content changes were generated according to modality-specific thresholds.

We demonstrated a selective failure of remyelination in periventricular white matter lesions of people with multiple sclerosis in both cohorts. In both the original and the replication cohort, we estimated that the probability of demyelinated voxels to remyelinate over the follow-up increased significantly as a function of the distance from ventricular CSF. Enlarged choroid plexus, a recently discovered biomarker linked to neuroinflammation, was found to be associated with the periventricular failure of remyelination in the two cohorts (r = −0.79, P = 0.0018; r = −0.40, P = 0.045, respectively), suggesting a role of the brain–CSF barrier in affecting myelin repair in surrounding tissues. In both cohorts, the failure of remyelination in periventricular white matter lesions was associated with lower thalamic volume (r = 0.86, P < 0.0001; r = 0.33; P = 0.069, respectively), an imaging marker of neurodegeneration. Interestingly, we also showed an association between the periventricular failure of remyelination and regional cortical atrophy that was mediated by the number of cortex-derived tracts passing through periventricular white matter lesions, especially in patients at the relapsing–remitting stage.

Our findings demonstrate that lesion proximity to ventricles is associated with a failure of myelin repair and support the hypothesis that a selective periventricular remyelination failure in combination with the large number of tracts connecting periventricular lesions with cortical areas is a key mechanism contributing to cortical damage in multiple sclerosis.
Multimodal prediction of residual consciousness in the intensive care unit: the CONNECT-ME study
Authors: Amiri Moshgan , Fisher Patrick M , Raimondo Federico , Sidaros Annette , Cacic Hribljan Melita , Othman Marwan H , Zibrandtsen Ivan , Albrechtsen Simon S , Bergdal Ove , Hansen Adam Espe , Hassager Christian , Højgaard Joan Lilja S , Jakobsen Elisabeth Waldemar , Jensen Helene Ravnholt , Møller Jacob , Nersesjan Vardan , Nikolic Miki , Olsen Markus Harboe , Sigurdsson Sigurdur Thor , Sitt Jacobo D , Sølling Christine , Welling Karen Lise , Willumsen Lisette M , Hauerberg John , Larsen Vibeke Andrée , Fabricius Martin , Knudsen Gitte Moos , Kjaergaard Jesper , Møller Kirsten , Kondziella Daniel
Published: September 2022

Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary centre cohort, diagnostic phase IIb study ‘Consciousness in neurocritical care cohort study using EEG and fMRI’ (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks was assessed. Next, we used EEG and fMRI data at study enrolment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel) to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS) at time of study enrolment and at ICU discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC patients (mean age, 50.0 ± 18 years, 43% female), 51 (59%) were ≤UWS and 36 (41%) were ≥ MCS at study enrolment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrolment and ICU discharge, with maximum AUCs of 0.79 (95% CI 0.77–0.80) and 0.71 (95% CI 0.77–0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrolment and ICU discharge with maximum AUCs of 0.78 (95% CI 0.71–0.86) and 0.83 (95% CI 0.75–0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.
Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States
Authors: Zanni Markella V , Foldyna Borek , McCallum Sara , Burdo Tricia H , Looby Sara E , Fitch Kathleen V , Fulda Evelynne S , Autissier Patrick , Bloomfield Gerald S , Malvestutto Carlos D , Fichtenbaum Carl J , Overton Edgar T , Aberg Judith A , Erlandson Kristine M , Campbell Thomas B , Ellsworth Grant B , Sheth Anandi N , Taiwo Babafemi , Currier Judith S , Hoffmann Udo , Lu Michael T , Douglas Pamela S , Ribaudo Heather J , Grinspoon Steven K
Published: September 2022

Background

Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein.

Methods

REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)–treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score.

Results

The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055).

Conclusions

Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters.

Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).
A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin
Authors: Någård Mats , Choudhury Nurul , Al-Shurbaji Ayman , Lisovskaja Vera , Mackillop Neil
Published: September 2022

Background

Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants.

Methods

This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration–time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model.

Results

Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus + SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44–77.24], AUCinf 62.91% (55.64–71.13). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11–110.10), AUCinf 97.23% (92.93–101.70).

Conclusions

Tacrolimus exposure was lower when co-administered with SZC 15 g and should be administered ≥2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.
Incidence, causes, correlates, and outcome of bioprosthetic valve dysfunction and failure following transcatheter aortic valve implantation
Authors: Nitsche Christian , Koschutnik Matthias , Donà Carolina , Mutschlechner David , Halavina Kseniya , Spinka Georg , Dannenberg Varius , Mascherbauer Katharina , Sinnhuber Leah , Kammerlander Andreas , Winter Max-Paul , Bartko Philipp , Goliasch Georg , Pibarot Philippe , Hengstenberg Christian , Mascherbauer Julia
Published: September 2022

Aims

Bioprosthetic valve dysfunction (BVD) is a major concern regarding transcatheter aortic valve implantation (TAVI) durability. We aimed to assess incidence, correlates, causes, and outcome of early to mid-term BVD after TAVI in relation to patient’s life expectancy.

Methods and results

Consecutive TAVI recipients (2007–20) with a follow-up ≥1 year were prospectively included. BVD and bioprosthetic valve failure (BVF) were assessed according to Valve-Academic-Research-Consortium-3. BVD/BVF and all-cause death served as endpoints. Average life expectancy was calculated from National Open Health Data and patients were stratified according to tertiles (1st: <6.85 years, 2nd: 6.85–9.7 years, 3rd: >9.7 years). Of 1047 patients (81.6 ± 6.8 years old, EuroSCORE II 4.5 ± 2.5), ≥2 follow ups were available from 622 (serial echo cohort). After a median echo follow up of 12.2 months, incidence rates of BVD/BVF were 8.4% (95% confidence interval 6.7–10.3), and 3.5% (2.5–4.9) per valve-year, respectively, without differences between life expectancy tertiles. The incidence of BVD was two-fold higher within the first year of implant (9.9% per valve-year) vs. beyond (4.8% per valve-year). Valve-in-valve procedure and residual stenosis, but not age/life expectancy predisposed for BVD. BVD/BVF were independently associated with outcome for patients in the first [adjusted hazard ratio (AHR) 1.72 (1.06–2.88)/2.97 (1.72–6.22)] and second [AHR 1.96 (1.02–3.73)/2.31 (1.00–5.30)], but not the third tertile of life expectancy (P = n.s.)

Conclusions

In this large prospective observational cohort, early to mid-term BVD after TAVI occurred at the same rate across the spectrum of life expectancy and was associated with increased mortality in patients with short but not in those with the longest life expectancy.
Successful treatment of recurrent thoracic aortic prosthetic graft infection after omentopexy by free latissimus dorsi and rectus abdominis muscle flap
Authors: Miura Shuhei , Shichinohe Ryuji , Iba Yutaka
Published: September 2022

A 50-year-old patient who underwent total aortic arch replacement for acute type A aortic dissection developed recurrent thoracic prosthetic graft infection after omentopexy for the treatment of initial postoperative graft infection of the ascending aorta and transverse aortic arch. We report the successful treatment of the disastrous complication by covering the prosthetic graft with a free latissimus dorsi muscle flap coupled with a pedicled rectus abdominis myocutaneous flap for the reduction of mediastinal dead space, following surgical disinfection with partial graft reconstruction.
TheFoxGene Repertoire in the AnnelidOwenia fusiformisReveals Multiple Expansions of thefoxQ2Class in Spiralia
Authors: Seudre Océane , Martín-Zamora Francisco M , Rapisarda Valentina , Luqman Imran , Carrillo-Baltodano Allan M , Martín-Durán José M
Published: September 2022

Fox genes are a large and conserved family of transcription factors involved in many key biological processes, including embryogenesis and body patterning. Although the role of Fox genes has been studied in an array of model systems, comprehensive comparative studies in Spiralia—a large clade of invertebrate animals including molluscs and annelids—are scarce but much needed to better understand the evolutionary history of this gene family. Here, we reconstruct and functionally characterize the Fox gene complement in the annelid Owenia fusiformis, a slow evolving species and member of the sister group to all remaining annelids. The genome of O. fusiformis contains at least a single ortholog for 20 of the 22 Fox gene classes that are ancestral to Bilateria, including an ortholog of the recently discovered foxT class. Temporal and spatial expression dynamics reveal a conserved role of Fox genes in gut formation, mesoderm patterning, and apical organ and cilia formation in Annelida and Spiralia. Moreover, we uncover an ancestral expansion of foxQ2 genes in Spiralia, represented by 11 paralogs in O. fusiformis. Notably, although all foxQ2 copies have apical expression in O. fusiformis, they show variable spatial domains and staggered temporal activation, which suggest cooperation and sub-functionalization among foxQ2 genes for the development of apical fates in this annelid. Altogether, our study informs the evolution and developmental roles of Fox genes in Annelida and Spiralia generally, providing the basis to explore how regulatory changes in Fox gene expression might have contributed to developmental and morphological diversification in Spiralia.
Genomic selection with fixed-effect markers improves the prediction accuracy for Capsaicinoid contents in Capsicum annuum
Authors: Kim Geon Woo , Hong Ju-Pyo , Lee Hea-Young , Kwon Jin-Kyung , Kim Dong-Am , Kang Byoung-Cheorl
Published: September 2022

Capsaicinoids provide chili peppers (Capsicum spp.) with their characteristic pungency. Several structural and transcription factor genes are known to control capsaicinoid contents in pepper. However, many other genes also regulating capsaicinoid contents remain unknown, making it difficult to develop pepper cultivars with different levels of capsaicinoids. Genomic selection (GS) uses genome-wide random markers (including many in undiscovered genes) for a trait to improve selection efficiency. In this study, we predicted the capsaicinoid contents of pepper breeding lines using several GS models trained with genotypic and phenotypic data from a training population. We used a core collection of 351 Capsicum accessions and 96 breeding lines as training and testing populations, respectively. To obtain the optimal number of single nucleotide polymorphism (SNP) markers for GS, we tested various numbers of genome-wide SNP markers based on linkage disequilibrium. We obtained the highest mean prediction accuracy (0.550) for different models using 3294 SNP markers. Using this marker set, we conducted GWAS and selected 25 markers that were associated with capsaicinoid biosynthesis genes and quantitative trait loci for capsaicinoid contents. Finally, to develop more accurate prediction models, we obtained SNP markers from GWAS as fixed-effect markers for GS, where 3294 genome-wide SNPs were employed. When four to five fixed-effect markers from GWAS were used as fixed effects, the RKHS and RR-BLUP models showed accuracies of 0.696 and 0.689, respectively. Our results lay the foundation for developing pepper cultivars with various capsaicinoid levels using GS for capsaicinoid contents.
Tomato receptor-like cytosolic kinase RIPK confers broad-spectrum disease resistance without yield penalties
Authors: Wang Ran , Li Chenying , Li Qinghong , Ai Yingfei , Huang Zeming , Sun Xun , Zhou Jie , Zhou Yanhong , Liang Yan
Published: September 2022

Production of reactive oxygen species (ROS) is an important immune response in plant multilayer defense mechanisms; however, direct modification of ROS homeostasis to breed plants with broad-spectrum resistance to disease has not yet been successful. In Arabidopsis, the receptor-like cytosolic kinase AtRIPK regulates broad-spectrum ROS signaling in multiple layers of the plant immune system. Upon treatment with immune elicitors, AtRIPK is activated and phosphorylates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to ROS production. In this study, we identified an AtRIPK ortholog in tomatoes and generated knockdown mutants using CRISPR/Cas9 technology. Slripk mutants displayed reduced ROS production in response to representative immune elicitors and were susceptible to pathogenic bacteria and fungi from different genera, including Ralstonia solanacearum, Pectobacterium carotovorum, Botrytis cinerea, and Fusarium oxysporum, which are leaf and root pathogens with hemibiotrophic and necrotrophic infection strategies. In contrast, transgenic tomato plants overexpressing SlRIPK are more resistant to these pathogens. Remarkably, the slripk mutants and SlRIPK-overexpressing transgenic plants did not exhibit significant growth retardation or yield loss. These results suggest that overexpression of SlRIPK confers broad-spectrum disease resistance without a yield penalty in tomato plants. Our findings suggest that modifying ROS homeostasis by altering the regulatory components of ROS production in plant immunity could contribute to engineering or breeding broad-spectrum disease-resistant crops without yield penalty.
Short Proofs of Rainbow Matchings Results
Authors: Correia David Munh , Pokrovskiy Alexey , Sudakov Benny
Published: September 2022

A subgraph of an edge-coloured graph is called rainbow if all its edges have distinct colours. The study of rainbow subgraphs goes back to the work of Euler on Latin squares and has been the focus of extensive research ever since. Many conjectures in this area roughly say that “every edge coloured graph of a certain type contains a rainbow matching using every colour.” In this paper we introduce a versatile “sampling trick,” which allows us to asymptotically solve some well-known conjectures and to obtain short proofs of old results. In particular:

$\bullet $ We give the first asymptotic proof of the “non-bipartite” Aharoni–Berger conjecture, solving two conjectures of Aharoni, Berger, Chudnovsky, and Zerbib.

$\bullet $ We give a very short asymptotic proof of Grinblat’s conjecture (first obtained by Clemens, Ehrenmüller, and Pokrovskiy). Furthermore, we obtain a new asymptotically tight bound for Grinblat’s problem as a function of edge multiplicity of the corresponding multigraph.

$\bullet $ We give the first asymptotic proof of a 30-year-old conjecture of Alspach.

$\bullet $ We give a simple proof of Pokrovskiy’s asymptotic version of the Aharoni–Berger conjecture with greatly improved error term.
Bridging of a Liquid Chromatography–Tandem Mass Spectrometry Method for Oxytetracycline, Chlortetracycline, and Tetracycline in Bovine Kidney with the Official Microbial Growth Inhibition Assay
Authors: Girard Lauren , Li Hui , Feng Charles , Kijak Philip J , Sklenka Sara , Smith Shani , Rasmussen Sharon , Pugh Carol , McDermott Shawn , Chiesa O Alberto , Ward Jeffrey , Hasbrouck Elizabeth , Smith Elizabeth , Lancaster Vicki , Qiu Junshan
Published: September 2022

Background

Oxytetracycline (OTC), chlortetracycline (CTC), and tetracycline (TC) are approved antibiotics used to treat bacterial infections in cattle. To ensure human food safety, a tolerance has been established for the sum of these three TC residues as 12 parts per million in bovine kidney in the United States The current official regulatory method for quantifying these antibiotics in the target organ is a labor-intensive microbiological assay.

Objective

Our laboratory developed and validated a fast, selective, and less laborious method utilizing LC–tandem mass spectrometry for the determination and confirmation of the three tetracyclines (TET) in bovine kidney.

Methods

Briefly, homogenized kidney tissue was spiked with an internal standard (ISTD), and then was extracted with 1% phosphate buffer. The crude extract was cleaned up using solid-phase extraction cartridges before instrumental analysis.

Results

Accuracies for quantifying these three drugs in fortified kidney homogenate were between 99.9 and 110% at multiple concentrations, with respective CVs all below 9.5%. Quantitative correlation between the two methods (bridging) was evaluated with incurred bovine kidney samples for each of the three tetracyclines separately. The results were statistically evaluated using a measurement model called Functional Relationship Estimation by Maximum Likelihood.

Conclusion

A linear quantitative relationship was demonstrated between the two methods within the concentration range of regulatory relevance.

Highlights

This instrumental method is in addition to the established microbial assay for the detection of tetracyclines residue in beef kidney to ensure the food safety of cattle products.
Shareholding Formulas in International Financial Institutions: Learning From the Asian Infrastructure Investment Bank
Authors: Gu Bin , Liu Tong
Published: September 2022

Shareholding formulas determine member countries’ voice in capital-based international organizations. They are crucial for international finance and draw much attention in negotiations. In principle, these formulas reflect member countries’ relative economic positions, but in practice, they serve as a starting point in negotiations, alongside other economic and political factors. This article investigates the unique shareholding formula of the Asian Infrastructure Investment Bank (AIIB), and compares it with those of the Bretton Woods institutions, that is, the International Monetary Fund (IMF), the International Bank for Reconstruction and Development (IBRD), and the International Finance Corporation (IFC). It shows that both the AIIB and the Bretton Woods institutions have learnt from each other’s shareholding formulas. Built upon the Bretton Woods practice, the AIIB’s gross domestic product-based shareholding formula could stimulate the IMF to establish a new quota formula under the 16th general review of quotas, the IBRD to implement the results calculated from its 2016 Dynamic Formula, and the IFC to develop its own formula by the date of the next shareholding review in 2025.
Dripping with Blood and Dirt from Head to Toe: Marx’s Genealogy of Capitalism in Capital, Volume 1
Authors: Allen Amy
Published: September 2022

I argue that Marx’s critique of political economy in volume 1 of Capital relies on a kind of genealogical argument that takes capitalism as its object. In the first section of the article, I sketch out an interpretation of the argumentative structure of Capital 1, highlighting what I take to be the two crucial turning points in Marx’s critique of political economy. Marx’s specifically genealogical argument comes to the foreground with the second of these turning points, which can be found at the start of his account of primitive accumulation in Part 8 of Capital 1. The first part of the paper defends the thought that the genealogy of capitalism’s prehistory is no mere digression from or complement to the main theoretical argument, but rather the crucial completion of Marx’s critique of political economy in Capital 1. In the second part of the paper, I turn to the somewhat thornier question of what sort of genealogy Marx offers. Drawing on and extending Bernard Williams’s distinction between vindicatory and subversive genealogies, I contend that Marx’s genealogy of capitalism, despite containing both subversive and vindicatory strands, is embedded in a longer vindicatory historical arc that, while avoiding crude teleologies and strong claims to unilinearity, nonetheless maintains a kind of necessity claim for its genealogical object.
On Moral Unintelligibility: Beauvoir’s Genealogy of Morality in the Second Sex
Authors: Vaccarino Bremner Sabina
Published: September 2022

This paper offers a reading of Beauvoir’s Second Sex as a genealogy of ‘morality’: the patriarchal system of values that maintains a moral distinction between men and women. This value system construes many of women’s experiences under oppression as evidence of women’s immorality, obscuring the agential role of those who provoke such experiences. Beauvoir’s examination of the origin for this value system provides an important counterexample to the prevailing debate over whether genealogical method functions to debunk or to vindicate: while the currently dominant moral system may have been historically necessary at certain stages in human development, Beauvoir nevertheless debunks it; only the value system itself now remains, without its precipitating needs. Thus, Beauvoir’s critique reveals what I call the moral unintelligibility of women’s experiences of oppression: women encounter difficulty in making sense of the harms wrought against them because the operative value system obscures them as harms in the first place, instead construing women themselves as immoral. Against the prevailing construction of moral blame and responsibility, Beauvoir’s solution is the political virtue of moral invention, a virtue epistemic as well as moral, collective as well as individual.
Reason Versus Power: Genealogy, Critique, and Epistemic Injustice
Authors: Lorenzini Daniele
Published: September 2022

In this paper, I take issue with the idea that Michel Foucault might be considered a theorist of epistemic injustice, and argue that his philosophical premises are incompatible with Miranda Fricker’s. Their main disagreement rests upon their divergent ways of conceiving the relationship between reason and power, giving rise to the contrasting forms of normativity that characterize their critical projects. This disagreement can be helpfully clarified by addressing the different use they make of the genealogical method. While Fricker’s genealogy of Testimonial Justice aims to ground her claim that reason and power can be neatly pulled apart, thus avoiding the reductionist and relativist conclusions entailed (in her view) by Foucault’s genealogies, I argue that Foucault’s mature, overlooked definition of genealogy is based on a sophisticated distinction between games and regimes of truth, and is thus not vulnerable to these criticisms. Consequently, Foucault’s genealogical inquiries prove helpful for understanding issues that normally fall under the umbrella of epistemic injustice in a new light, while also allowing us to avoid some of the main objections that threaten Fricker’s project.
A toolkit for the identification of NEAT1_2/paraspeckle modulators
Authors: An Haiyan , Elvers Karen T , Gillespie Jason A , Jones Kimberley , Atack John R , Grubisha Olivera , Shelkovnikova Tatyana A
Published: September 2022

Paraspeckles are ribonucleoprotein granules assembled by NEAT1_2 lncRNA, an isoform of Nuclear Paraspeckle Assembly Transcript 1 (NEAT1). Dysregulation of NEAT1_2/paraspeckles has been linked to multiple human diseases making them an attractive drug target. However currently NEAT1_2/paraspeckle-focused translational research and drug discovery are hindered by a limited toolkit. To fill this gap, we developed and validated a set of tools for the identification of NEAT1_2 binders and modulators comprised of biochemical and cell-based assays. The NEAT1_2 triple helix stability element was utilized as the target in the biochemical assays, and the cellular assay (‘ParaQuant’) was based on high-content imaging of NEAT1_2 in fixed cells. As a proof of principle, these assays were used to screen a 1,200-compound FDA-approved drug library and a 170-compound kinase inhibitor library and to confirm the screening hits. The assays are simple to establish, use only commercially-available reagents and are scalable for higher throughput. In particular, ParaQuant is a cost-efficient assay suitable for any cells growing in adherent culture and amenable to multiplexing. Using ParaQuant, we identified dual PI3K/mTOR inhibitors as potent negative modulators of paraspeckles. The tools we describe herein should boost paraspeckle studies and help guide the search, validation and optimization of NEAT1_2/paraspeckle-targeted small molecules.
Impact of previous REnal TRansplantation on the mid-term renal Outcome after CARdiac surgery: the RETROCAR trial
Authors: Beurton Antoine , Fajardie Antoine , Rubin Sebastien , Belnou Pierre , Aguerreche Clement , Pernot Mathieu , Mion Stefano , Imbault Julien , Ouattara Alexandre
Published: September 2022

Background

Acute kidney injury (AKI) is one of the most common complications after cardiac surgery with cardiopulmonary bypass (CPB). Renal transplant recipients (RTRs) have a higher risk of cardiac surgery–associated AKI (CSA-AKI). A relationship has been strongly suggested between AKI and poor long-term graft survival. The main objective was to evaluate the impact of on-pump cardiac surgery on the 1-year renal allograft survival rate.

Methods

The study population consisted of 37 RTRs and 56 non-RTRs who underwent cardiac surgery between 1 January 2010 and 31 December 2019. They were matched according to age, sex, preoperative glomerular function, diabetes and type of surgery. The primary composite outcome was renal survival, defined as patient survival without the requirement for permanent dialysis or new kidney transplantation at 1 year after surgery.

Results

The renal survival rate was significantly lower in the RTR group than in the non-RTR group [81% versus 96%; odds ratio 0.16 (95% confidence interval 0.03–0.82), P = .03]. The proportion of patients who returned to permanent dialysis was higher in the RTR group than in the non-RTR group (12% versus 0%; P = .02). The proportion of patients with severe AKI was also higher in the RTR group. At 1 year after surgery, serum creatinine level, glomerular filtration rate and all-cause mortality rates were comparable between both groups.

Conclusion

Patients with a functional renal allograft have a low 1-year renal allograft survival rate after cardiac surgery with CPB. In addition, these patients have significant risks of AKI and acute kidney disease after open-heart surgery.
Pregnancy, Parthood and Proper Overlap: A Critique of Kingma
Authors: Geddes Alexander
Published: September 2022

Elselijn Kingma argues that, in cases of mammalian placental pregnancy, the foster (roughly, the post-implantation embryo/foetus) is part of the gravida (the pregnant organism). But she does not consider the possibility of proper overlap. I show that this generates a number of serious problems for her argument and trace the oversight to a quite general issue within the literature on biological individuality. Doing so provides an opportunity to pull apart and clarify the relations between some importantly distinct questions concerning organismality and organismic parthood, and to identify the implications that this has for those who want to draw on this literature when making metaphysical or mereological arguments.
Do Investors Care about Impact?
Authors: Heeb Florian , Kölbel Julian F , Paetzold Falko , Zeisberger Stefan
Published: September 2022

We assess how investors’ willingness-to-pay (WTP) for sustainable investments responds to the social impact of those investments, using a framed field experiment. While investors have a substantial WTP for sustainable investments, they do not pay significantly more for more impact. This also holds for dedicated impact investors. When investors compare several sustainable investments, their WTP responds to relative, but not to absolute, levels of impact. Regardless of investments’ impact, investors experience positive emotions when choosing sustainable investments. Our findings suggest that the WTP for sustainable investments is primarily driven by an emotional, rather than a calculative, valuation of impact.
A-phase index: an alternative view for sleep stability analysis based on automatic detection of the A-phases from the cyclic alternating pattern
Authors: Mendonça Fábio , Mostafa Sheikh Shanawaz , Gupta Ankit , Arnardottir Erna Sif , Leppänen Timo , Morgado-Dias Fernando , Ravelo-García Antonio G
Published: September 2022

Study Objectives

Sleep stability can be studied by evaluating the cyclic alternating pattern (CAP) in electroencephalogram (EEG) signals. The present study presents a novel approach for assessing sleep stability, developing an index based on the CAP A-phase characteristics to display a sleep stability profile for a whole night’s sleep.

Methods

Two ensemble classifiers were developed to automatically score the signals, one for “A-phase” and the other for “non-rapid eye movement” estimation. Both were based on three one-dimension convolutional neural networks. Six different inputs were produced from the EEG signal to feed the ensembles’ classifiers. A proposed heuristic-oriented search algorithm individually tuned the classifiers’ structures. The outputs of the two ensembles were combined to estimate the A-phase index (API). The models can also assess the A-phase subtypes, their API, and the CAP cycles and rate.

Results

Four dataset variations were considered, examining healthy and sleep-disordered subjects. The A-phase average estimation’s accuracy, sensitivity, and specificity range was 82%–87%, 72%–80%, and 82%–88%, respectively. A similar performance was attained for the A-phase subtype’s assessments, with an accuracy range of 82%–88%. Furthermore, in the examined dataset’s variations, the API metric’s average error varied from 0.15 to 0.25 (with a median range of 0.11–0.24). These results were attained without manually removing wake or rapid eye movement periods, leading to a methodology suitable to produce a fully automatic CAP scoring algorithm.

Conclusions

Metrics based on API can be understood as a new view for CAP analysis, where the goal is to produce and examine a sleep stability profile.
Explaining the Adoption of Care Policies in Costa Rica and Uruguay: A Multiple Streams Approach
Authors: Leon-Espinoza Diana
Published: September 2022

This article aims to reveal how Costa Rica and Uruguay succeeded in adopting integrated care policies. By adapting the classic “multiple streams approach,” I analyze the processes leading to the adoption of two care policies in Costa Rica and Uruguay. The findings suggest that the key to understanding the adoption of care policies lies within the interplay between agents and contexts in different streams. Problems can be constructed as a top-down process by a women’s agency or as a bottom-up process from a feminist organization. Solutions can be designed in close-knit policy networks of technocrats/bureaucrats or in open policy networks of bureaucrats and civil society organizations. Care policies become prominent items on government agendas in the presence of programmatic political parties and high electoral competition settings that prioritize the issue to attract voters or consolidate support. The alignment of problems, solutions, and politics identify different pathways that lead to the adoption of care policies.
A Systematic Review and Meta-Analysis Evaluating Geographical Variation in Outcomes of Cancer Patients Treated in ICUs
Authors: Nazer Lama H. , Lopez-Olivo Maria A. , Brown Anne Rain , Cuenca John A. , Sirimaturos Michael , Habash Khader , AlQadheeb Nada , May Heather , Milano Victoria , Taylor Amy , Nates Joseph L.
Published: September 2022

OBJECTIVES:

The reported mortality rates of cancer patients admitted to ICUs vary widely. In addition, there are no studies that examined the outcomes of critically ill cancer patients based on the geographical regions. Therefore, we aimed to evaluate the mortality rates among critically ill cancer patients and provide a comparison based on geography.

DATA SOURCES:

PubMed, EMBASE, and Web of Science.

STUDY SELECTION:

We included observational studies evaluating adult patients with cancer treated in ICUs. We excluded non-English studies, those with greater than 30% hematopoietic stem cell transplant or postsurgical patients, and those that evaluated a specific type of critical illness, stage of malignancy, or age group.

DATA EXTRACTION:

Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Studies were classified based on the continent in which they were conducted. Primary outcomes were ICU and hospital mortality. We pooled effect sizes by geographical region.

DATA SYNTHESIS:

Forty-six studies were included (n = 110,366). The overall quality of studies was moderate. Most of the published literature was from Europe (n = 22), followed by North America (n = 9), Asia (n = 8), South America (n = 5), and Oceania (n = 2). Pooled ICU mortality rate was 38% (95% CI, 33–43%); the lowest mortality rate was in Oceania (26%; 95% CI, 22–30%) and highest in Asia (51%; 95% CI, 44–57%). Pooled hospital mortality rate was 45% (95% CI, 41–49%), with the lowest in North America (37%; 95% CI, 31–43%) and highest in Asia (54%; 95% CI, 37–71%).

CONCLUSIONS:

More than half of cancer patients admitted to ICUs survived hospitalization. However, there was wide variability in the mortality rates, as well as the number of available studies among geographical regions. This variability suggests an opportunity to improve outcomes worldwide, through optimizing practice and research.
Modeling Approach with Therapeutic Drug Monitoring Data to Describe Time Course of Clozapine Exposure and Positive and Negative Syndrome Scale Scores
Authors: Park Sang-In , Kim Seoyoung , Kim Min-Gul , Lim Hyeong-Seok , Kim Euitae
Published: September 2022

Objective:

The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ.

Methods:

TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM. Based on published data, intensive PK sampling data collected up to 12 hours postdose from 23 patients was incorporated into the PK data set to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation.

Results:

A 2-compartment model with an absorption lag and a combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (Emax) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model.

Conclusions:

A clozapine PK/PD model based on clinical settings adequately described the PANSS time course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.
Longitudinal associations of psychosocial stressors with menopausal symptoms and well-being among women in midlife
Authors: Faleschini Sabrina , Tiemeier Henning , Rifas-Shiman Sheryl L. , Rich-Edwards Janet , Joffe Hadine , Perng Wei , Shifren Jan , Chavarro Jorge E. , Hivert Marie-France , Oken Emily
Published: September 2022

Objective

We examined longitudinal associations of psychosocial stressors with menopausal symptoms and well-being of women in midlife in a longitudinal cohort.

Methods

This study is based on 682 women from Project Viva, a prospective cohort enrolled in 1999 to 2002 during pregnancy (median age = 33.3 y) and followed for almost two decades. In pregnancy, women self-reported psychosocial stressors (history of physical and sexual abuse and financial instability, from childhood to the current pregnancy). In 2017 to 2021 (median age, 51.6 y), they reported their menopausal symptoms (0‐44 point scale) and well-being (general health [good/fair/poor vs excellent/very good], generalized anxiety symptoms, and depressive symptoms [both—more than minimal levels vs none/minimal]). We performed multivariable and logistic regression models to examine associations of psychosocial stressors with outcomes, adjusting for covariates.

Results

History of physical abuse (reported by 37.3%) was associated with worse menopausal symptoms in the somatovegetative (odds ratio [OR], 0.46 points; 95% confidence interval [CI], 0.04-0.87 points) and psychological (OR, 0.52 points; 95% CI, 0.07-0.97 points) domains and with worse general health (OR, 1.73; 95% CI, 1.17-2.55) and greater depressive symptoms (OR, 1.74; 95% CI, 1.05-2.87). History of sexual abuse (7.7%) was associated with worse menopausal symptoms (OR, 2.81 points; 95% CI, 1.05-4.56) and worse general health (OR, 2.04; 95% CI, 1.04-4.03) but not with depressive symptoms. History of financial instability (10.8%) was associated with worse menopausal symptoms (1.92 points; 0.49 to 3.34), worse general health (OR, 2.16; 95% CI, 1.24-3.75), and greater depressive symptoms (OR, 2.68; 95% CI, 1.44-4.98). We observed no association between psychosocial stressors and generalized anxiety symptoms assessed at midlife.

Conclusions

Psychosocial stressors were associated with worse menopausal symptoms and well-being decades after initial report.
A New Treatment Paradigm
Authors: Kane John M.
Published: September 2022

This continuing education supplement is jointly provided by Medical Education Resources and CMEology. The supplement is supported by an independent educational grant from Sunovion Pharmaceuticals Inc. It was edited and peer reviewed by the Journal of Clinical Psychopharmacology.

After reviewing the learning objectives and reading the supplement, please complete the Activity Evaluation/Credit Request form online at https://www.cmesurvey.site/TAAR1.

All currently available antipsychotics work via essentially the same mechanism: by antagonizing the dopamine D2 receptor. However, schizophrenia is an extremely heterogeneous condition, and antipsychotics do not adequately control symptoms for all patients. Negative and cognitive symptoms are especially difficult to manage with existing medications. Therefore, antipsychotic agents with novel mechanisms of action are urgently needed. Recently, a phase 2 clinical trial and extension study demonstrated that, relative to placebo, the trace amine–associated receptor 1 (TAAR1) agonist ulotaront was effective at controlling the positive, negative, and cognitive symptoms of schizophrenia. In addition, ulotaront seems to lack the weight gain, metabolic issues, and extrapyramidal symptoms associated with traditional antipsychotics. This agent is currently undergoing multiple phase 3 trials for the treatment of schizophrenia. Another TAAR1 agonist, ralmitaront, is being investigated for the treatment of schizophrenia and schizoaffective disorders. Two phase 2 clinical trials are underway, evaluating ralmitaront both as a monotherapy and an add-on therapy to traditional antipsychotics. In this supplement, we review the biologic, preclinical, and clinical data available for TAAR1 agonists, so that if and when they are approved for the treatment of schizophrenia, psychiatry specialists will be ready to use them to optimize patient outcomes. We also briefly review other emerging therapies in late-stage development for the treatment of schizophrenia.
Improving diabetes care of community-dwelling underserved older adults
Authors: Marsh Zyrene , Teegala Yamini , Cotter Valerie
Published: September 2022

Background:

Diabetes care among rural underserved older adults is negatively affected by social determinants of health (SDOH). Although there is an increased awareness of this problem, evidence-based clinical and community interventions are not widely integrated. This project implemented telemedicine and community health worker (CHW) interventions to improve diabetes management and outcomes.

Local Problem:

One in five older adults with diabetes mellitus (DM) at a Federally Qualified Health Center in southwest Ohio has uncontrolled disease, largely due to their limited resources and ability to participate in routine clinical management.

Methods:

This quality improvement project used a pre–post intervention design. Participants were adults aged ≥65 years with uncontrolled DM type 1 or 2. The outcomes of interest included A1C values, diabetes self-care activities, diabetes knowledge, and patient and health care provider (HCP) satisfaction levels.

Interventions:

The project involved biweekly CHW home visits and diabetes self-management education for 12 weeks. The CHWs, with supervision from a nurse practitioner, conducted SDOH assessments and basic education, and facilitated same-day telemedicine appointments with the HCP to reinforce disease management.

Results:

The A1C levels and diabetes knowledge of older adults significantly improved after three months. However, there were no statistically significant changes in diabetes self-care activities. The patients and HCPs were highly satisfied with the project interventions.

Conclusions:

This project delivered patient-centered and equitable diabetes care services that were previously unavailable to underserved older patients, while demonstrably improving outcomes. Future research should evaluate the cost-effectiveness, long-term impact, and sustainability of the project in other primary care settings.