bluuebunny/crossref_metadata_2025 huggingface dataset:
Coping Styles and Cognitive Function in Older Non-Hispanic Black and White Adults
Authors: Lee Ji Hyun , Sol Ketlyne , Zaheed Afsara B , Morris Emily P , Meister Lindsey M , Palms Jordan D , Zahodne Laura B
Published: January 2023

Objectives

Coping styles refer to cognitive and behavioral patterns used to manage the demands of stressors, and effective coping represents a psychological resource. Some studies have linked coping styles to executive functioning, but less is known about coping styles and their associations with cognition across social groups known to differ in stress exposure and dementia risk. This study aimed to characterize associations between coping styles and cognitive functioning across non-Hispanic Black and non-Hispanic White older adults.

Methods

Participants were drawn from the Michigan Cognitive Aging Project (N = 453; age mean (SD) = 63.6 (3.2); 53% non-Hispanic Black). Problem-focused and emotion-focused coping were measured using the Coping Orientation to Problems Experienced Inventory. Global cognition was a composite of 5 cognitive domain scores derived from comprehensive neuropsychological tests. Cross-sectional associations between coping styles and cognition were examined using race-stratified regressions controlling for demographic and health covariates.

Results

Black older adults reported more emotion-focused coping than White older adults, but there were no race differences in problem-focused coping. Among Black older adults, less problem-focused coping and more emotion-focused coping were each associated with worse cognition. Among White older adults, emotion-focused coping was marginally linked to cognition.

Discussion

Greater emotion-focused coping among Black older adults may reflect greater exposure to stressors that are uncontrollable. Patterns of racial differences in coping–cognition links are in line with the social vulnerabilities hypothesis. Coping style may be a particularly important psychosocial resource for cognitive health among Black older adults that could be incorporated into culturally relevant interventions.
Jasmonic acid regulates the biosynthesis of medicinal metabolites via the JAZ9-MYB76 complex inSalvia miltiorrhiza
Authors: Liu Shucan , Gao Xiankui , Shi Min , Sun Meihong , Li Kunlun , Cai Yan , Chen Chengan , Wang Can , Maoz Itay , Guo Xinhong , Kai Guoyin
Published: January 2023

Jasmonic acid (JA) signaling pathway plays an important role in tanshinone and phenolic acid biosynthesis in Salvia miltiorrhiza. However, the specific regulatory mechanism remains largely unclear. Previous work showed that a JASMONATE ZIM-domain (JAZ) protein, SmJAZ9, acted as a repressor of tanshinone production in S. miltiorrhiza. In this study, we revealed that SmJAZ9 reduced both phenolic acid accumulation and related biosynthetic gene expression, confirming that SmJAZ9 also negatively affected phenolic acid biosynthesis. Then, we identified a novel MYB transcription factor, SmMYB76, which interacted with SmJAZ9. SmMYB76 repressed phenolic acid biosynthesis by directly downregulating SmPAL1, Sm4CL2, and SmRAS1. Further investigation demonstrated that JA mediated phenolic acids biosynthesis via SmJAZ9-SmMYB76 complex. Taken together, these findings state the molecular mechanism that SmJAZ9-SmMYB76 regulated phenolic acid biosynthesis at the transcriptional and protein levels, which provided new insights into JA signaling pathway regulating plant metabolism.
A comparative assessment of combustion behavior and emissions characteristics of DI diesel engine fueled with waste plastic oil and eucalyptus biofuel for sustainable development applications
Authors: Naima Khatir , Bousbaa Hamza , Ahmad Hijaz , Al-Bahrani Mohammed , Tarabet Lyes , Menni Younes , Lorenzini Giulio
Published: January 2023

The increase in population growth rates led to a high rate of production and use of plastic materials, which created a problem in the collection and management of this waste [1]. This created severe threats to the environment and the ecosystem. The main objective of this paper is to conduct an experimental assessment of a direct diesel engine fueled with waste plastic oil (WPO), eucalyptus biofuel (EB) and conventional diesel. The engine operated in the same operating condition with all fuels. The results show that WPO has a shorter ignition delay, resulting in lower in-cylinder temperature and pressure than EB and diesel fuel. The brake thermal efficiency of WPO is significant over all the range of engine loading. Carbon monoxide emissions of WOP fuel are lower than diesel fuel and higher than EB oil. Nitrogen oxide emissions of WPO are lower at low and full loads but higher at medium load. Considerable decrease in unburned hydrocarbons and particulate matter emissions with EB compared with WPO and diesel fuels. The results of this study concluded that both fuels are considered a viable solution for achieving sustainably.
Study on low temperature phase change heat storage and its performance of solar and air source heat pump system
Authors: Zhan Hao , Wu Ronghua , Yu Hao , Liu Changqing , Li Kang
Published: January 2023

In view of the deterioration of the performance of air source heat pump at low temperature in cold regions and the large fluctuation of solar heating systems, a heat pump system with low-temperature heat storage using sodium chloride aqueous solution as the phase change thermal storage material is proposed. The system form and its operation scheme, unit energy consumption model and economic evaluation index are given. The influence of different concentrations of sodium chloride solution corresponding to different heat storage temperatures and different areas of solar collectors on the system operation economy is studied, and simulation analysis and optimization are carried out and the operation efficiency and operation economy of the system are analyzed with an actual residential building in a cold region as an example. The results show that with the increase of collector area, the lower the sodium chloride concentration, the higher the heat storage temperature and the higher the coefficient of performance (COP) of the system; the larger the collector area, the higher the COP of the system, but the payback period decreases first and then extends with the increase of the collector area. When the system sodium chloride solution concentration is 5.3% and the collector area is 372m2, there is a minimum payback period for the winter heating of 3000m2 building in this case, and at this time, the COP of the system is 2.37, which is 20% higher than that of the traditional air source heat pump. The payback period of the system is 7.7 years, and the contribution rate of the solar collector system is 53%. The solar air source heat pump system with low temperature phase change heat storage significantly improves the operation performance of the system and has good energy saving benefits.
A Rough Colony Morphology ofMycobacterium abscessusIs Associated With Cavitary Pulmonary Disease and Poor Clinical Outcome
Authors: Hedin Wilhelm , Fröberg Gabrielle , Fredman Kalle , Chryssanthou Erja , Selmeryd Ingrid , Gillman Anna , Orsini Letizia , Runold Michael , Jönsson Bodil , Schön Thomas , Davies Forsman Lina
Published: January 2023

Background

The Mycobacterium abscessus complex (MABC) is a difficult to treat mycobacterium with two distinct morphologies: smooth and rough. As the clinical implications are unclear, we explored the morphology of MABC in relation to disease and outcome.

Methods

We performed a retrospective multicenter cohort study including patients with confirmed MABC in Sweden, 2009–2020, with treatment outcome as the primary outcome. MABC colony morphology was determined by light microscopy on Middlebrook 7H10 agar plates.

Results

Of the 71 MABC isolates, a defined morphology could be determined for 63 isolates, of which 40 were smooth (56%) and 23 were rough (32%). Immunosuppression, pulmonary disease, and cavitary lesion on chest radiographs were significantly associated with a rough isolate morphology. Participants with smooth isolates had more favorable treatment outcomes (12/14, 86%) compared to those with rough isolates (3/10, 30%). In an age-adjusted logistic regression, rough morphology of MABC was associated to lower odds of clinical cure compared to smooth morphology (adjusted odds ratio, 0.12; P = .049).

Conclusions

Study participants with rough MABC colony morphology of isolates had a worse clinical outcome compared to those with smooth isolates. The biological mechanisms should be further characterized and colony morphology of MABC taken into account during clinical management.
Framing States: Unitary Actor Language and Public Support for Coercive Foreign Policy
Authors: Altier Mary Beth , Kane John V
Published: January 2023

A defining feature of public (and, often, scholarly) discussion of international affairs is the treatment of states as unitary actors, that is, akin to individual persons. Drawing upon social–psychological research, we theorize that such unitary actor (UA) framing increases the degree to which adversarial states are perceived as entitative—that is, as relatively united—and, thus, the perceived complicity of a country's people in their government's actions. We therefore hypothesize that UA framing increases citizens’ support for indiscriminate, coercive policies against target states. In a content analysis of US elite statements spanning three decades, we first establish that UA framing is exceedingly common, occurring in nearly two-thirds of all references to adversarial states. We then conduct a series of survey experiments on US adults, finding that, compared to frames in which a state is described as more factious and disunited, UA framing is associated with significantly greater willingness to impose harmful, indiscriminate economic sanctions and military strikes against target states. Our results highlight the utility and applicability of entitativity to political science research, and have important implications for the role of elite discourse in bolstering public support for hawkish foreign policymaking.
Design and Evaluation of an Authoring Platform for Therapeutic Digital Games
Authors: da Hora Rodrigues Kamila Rios , Elias Cardoso Verhalen Aline , Willian da Silva Jonattan , Marino Silva Tiago , Geurgas Zavarizz Rodrigo , de Almeida Neris Vânia Paula , Maia de Souza Paula
Published: January 2023

Therapeutic digital games aim to support rehabilitation treatments and help patients understand, motivate and persist in therapeutic practices. Although there are several therapeutic digital games available, their development highly depends on the involvement of computer science professionals. This paper’s contribution is about how RUFUS was designed as a platform to provide EUP (End-User Programming) for healthcare professionals. This platform enables these professionals to author digital games aiming at performing therapeutic activities with their patients and/or caregivers. The platform has a web interface for game authoring, currently composed of three different game mechanics, as well as the possibility of viewing interaction reports. It also encompasses a mobile app that displays the games created for patients. Participatory design techniques were used during the design and evaluation of the three games to engage different stakeholders and also empower healthcare providers. A preliminary evaluation of the RUFUS point to an easy-to-use design solution, but which still needs further testing to ensure intuitiveness for users who have no experience with games or with authoring interfaces.
Retracted: Suboptimal dalbavancin dosages in an adult with sickle-cell disease and glomerular hyperfiltration
Authors: Abdellaoui Salomé , Gregoire Matthieu , Dubert Marie , Cheminet Geoffrey , Arlet Jean-Benoît , Lafont Emmanuel
Published: January 2023

This article has been retracted. Please see: https://doi.org/10.1093/jac/dkad283
The Role of ICSID in International Economic Law
Authors: Kinnear Meg
Published: January 2023

The International Centre for Settlement of Investment Disputes was established in 1966 as a facility for the resolution of international investment disputes. Today, it has 158 member states and has administered roughly 70% of all known investor-state cases. International Centre for Settlement of Investment Disputes has taken a leadership role in modernizing the procedures for investor-state dispute resolution, especially in the 2006 and 2022 amendments to those rules.
Interaction of circular cavity and crack near anisotropic bi-material interface under SH-waves incidence
Authors: Zhang Jian-wei , Lan Guo-guan , Chen Shui-mei , Xu Hua-nan , Yang Zai-lin
Published: January 2023

An anisotropic bi-material interface with a circular hollow and a crack was used to explore the scattering of SH waves using complex variables and Green's function techniques. A horizontal interface in a bi-material media forms an elastic anisotropic half-space with a circular cavity and a linear crack, whereas the other half-space is an elastic isotropic half-space. The Green's function approach is used to derive the relevant Green's functions, which are then used in the “crack division” procedure to create a crack. During the joining of the two pieces, unknown anti-plane forces are applied to the horizontal surfaces to ensure the interface maintains its continuity criteria. For weakly singular integral equations, Fredholm integral equations are inferred and solved using the direct discrete technique. The simulation results were represented graphically to show how different parameters affect the influence of dynamic stress concentration factors around the cavity and dynamic stress intensity factors toward the crack tip. For example, a cavity's wave number and angle of incidence, as well as the distance between the cavity's center and its horizontal interface and its radius, are all elements that must be taken into consideration.
Hirst on rational moral education
Authors: Hand Michael
Published: January 2023

In Moral Education in a Secular Society, Paul Hirst offers accounts of the content and justification of morality and the aims and methods of moral education. My own recent book, A Theory of Moral Education, does the same. Here I explore the similarities and differences between our theories. In the first part of the paper, I outline what Hirst calls the ‘sophisticated view of education’, which I wholeheartedly endorse, and highlight his attention to the noncognitive as well as the cognitive aspects of morality. In the second part, I explain how Hirst’s transcendental justification of morality differs from my contractarian justification and trace the implications of this difference for our respective accounts of moral education.
Paul Hirst, education and epistemic injustice
Authors: Marabini Alessia
Published: January 2023

In this paper I individuate and analyse a new type of epistemic injustice that can arise in education and depends on the so-called ‘backtracking fallacy’ in student assessment, which occurs when a teacher confuses (or does not distinguish between) the logical dimension of a framework of disciplinary concepts and its psychological dimension. I will also touch upon a different type of social injustice that might transpire in education. I suggest that familiarity with Paul Hirst's view of liberal education, which presupposes a neat distinction between public framework of knowledge and the psychological process of gradually learning it, can contribute to prevent or reduce both forms of injustice.
Education since 2010: Hirstian echoes
Authors: White John
Published: January 2023

Although Paul Hirst was no longer working in the educational field between 2010 and 2020, echoes of his ideas resonate through the decade. I look at three examples. [1] The National Curriculum. In the 1990s Hirst had been critical of the newly introduced National Curriculum of 1988, built as it was around ten foundation subjects rather than practices of everyday life. While curricular reforms under the Labour governments of 1997–2010 came somewhat closer to his ideas, there has been a reversion since then to a subject-centred curriculum, with tests and examinations based on it much to the fore. But calls for more attention to social issues like climate change and ethnic diversity have Hirstian resonances, as have critical comments on the status quo from leading figures in politics and the inspectorate. [2] ‘Powerful knowledge.’ This notion, closely associated with the sociologist Michael Young, has been widely influential in educational circles since 2010. Its original definition in terms of bodies of knowledge with their own systems of concepts, is reminiscent of Hirst's celebrated and later abandoned ‘forms of knowledge’ theory. The paper speculates on possible biographical explanations of this commonality. [3] Teacher education. In 2017 HMCI Amanda Spielman commented on the need to improve teachers’ poor understanding of curriculum theory and notes that in the past it was better. This chimes with comments of Paul Hirst in 1994, although it is not clear how far Spielman would support his view that this work should first be rooted in practical teaching experience.
Nutritional benefits, ethnomedicinal uses, phytochemistry, pharmacological properties and toxicity of Spondias mombin Linn: a comprehensive review
Authors: Ogunro Olalekan Bukunmi , Oyeyinka Barnabas Oluwatomide , Gyebi Gideon Ampoma , Batiha Gaber El-Saber
Published: January 2023

Objectives

Spondias mombin is traditionally used as an herbal medicine for several human diseases and ailments in the tropical regions across the globe including the African countries. This study aimed to provide comprehensive information on nutritional benefits, ethnomedicinal uses, phytochemical constituents, pharmacological properties and toxicology study of S. mombin. Information was gathered from documented literatures in scientific database.

Key findings

The study revealed that S. mombin has nutritional values; with the leaf, fruit, flower, seed, and stem bark possessing a wide range of ethnomedicinal uses across several regions, with documented pharmacological properties. S. mombin has a frequent rate of ethnomedicinal utility in cases of abortion, constipation, fever, gonorrhea, postpartum hemorrhage, digestive pain, diarrhoea, dysentery and wounds. Ethnopharmacological studies showed that crude extracts and chemical compounds from S. mombin manifested in vivo and in vitro biological and pharmacological activities. About 102 isolated compounds from the leaf, fruit, or stem bark of S. mombin have been reported.

Overall, S. mombin has several nutritive and ethnomedicinal benefits owing to its chemical constituents, which are linkable to the several pharmacological activities. There remains however, the need for dosage intake caution, upon the advice of medical professionals.
Optimal timing of a γH2AX analysis to predict cellular lethal damage in cultured tumor cell lines after exposure to diagnostic and therapeutic radiation doses
Authors: Takano Seiya , Shibamoto Yuta , Wang Zhen , Kondo Takuhito , Hashimoto Shingo , Kawai Tatsuya , Hiwatashi Akio
Published: January 2023

Phosphorylated H2AX (γH2AX) is a sensitive biomarker of DNA double-strand breaks (DSBs). To assess the adverse effects of low-dose radiation (<50 mGy), γH2AX levels have typically been measured in human lymphocytes within 30 min of computed tomography (CT) examinations. However, in the presence of DSB repair, it remains unclear whether γH2AX levels within 30 min of irradiation completely reflect biological effects. Therefore, we investigated the optimal timing of a γH2AX analysis to predict the cell-surviving fraction (SF). Three tumor cell lines were irradiated at different X-ray doses (10–4000 mGy), and the relationships between SF and relative γH2AX levels were investigated 15 min and 2, 6, 12 and 24 h after irradiation. Data were analyzed for high-dose (0–4000 mGy) and low-dose (0–500 mGy) ranges. Correlations were observed between SF and the relative number of γH2AX foci/nucleus at 12 h only (R2 = 0.68, P = 0.001 after high doses; R2 = 0.37, P = 0.016 after low doses). The relative intensity of γH2AX correlated with SF 15 min to 12 h after high doses and 2 to 12 h after low doses, with the maximum R2 values being observed 2 h after high doses (R2 = 0.89, P < 0.001) and 12 h after low doses (R2 = 0.65, P < 0.001). Collectively, cellular lethal damage in tumor cells was more accurately estimated with residual DSBs 12 h after low-dose (10–500 mGy) irradiation. These results may contribute to determination of the optimal timing of biodosimetric analyses using γH2AX in future studies.
Efficacy of collagenaseClostridium histolyticumin men with congenital penile curvature
Authors: Kulkarni Yogesh , Green Benjamin , Pattillo Curtis , Stirland Isaac , Flores Ashley , Ziegelmann Matthew , Kohler Tobias , Helo Sevann , Trost Landon
Published: January 2023

Background

Collagenase Clostridium histolyticum (CCH) has been proven effective in multiple subpopulations of PD men; however, no studies have evaluated its role with congenital penile curvature (CPC).

Aim

To evaluate the safety and efficacy of CCH in men with CPC.

Methods

A prospective registry was queried of men undergoing CCH injections at our institution. Beginning in 2016, CCH was administered to CPC men using a similar protocol to PD. A comparative analysis was performed between cohorts to evaluate the safety and efficacy of therapy.

Outcomes

Objective measures included penile length and curvature, while subjective outcomes included standardized (International Index of Erectile Function and Peyronie’s Disease Questionnaire) and non-standardized assessments. Curvature outcomes were categorized as follows: 1 – included all men, with the most recent assessment considered final, and 2 – only men who had completed eight CCH injections or stopped early due to satisfaction.

Results

From 2014 to Oct 2021, a total of 453 men (408 PD, 45 CPC) underwent one or more CCH injections. In comparing cohorts, CPC men were younger (33 vs 58 years, p<0.0001), had lesser baseline curvatures (52.5 vs 65°, p<0.01), more ventral curves (25.7 vs 9.2%, p<0.01), and longer penile lengths (12.5 vs 12.0 cm, p=0.04). Following treatment, both cohorts experienced similar curvature improvements. Specifically, PD men experienced 20-25° or 33-35% improvements depending on definition compared to 25-30° or 40-50% in CPC men (all p-values >0.05). CPC and PD men also demonstrated similar changes on standardized questionnaires, with the exception of the Psychological and Physical subdomain, which was more improved in CPC men (-11 vs -4, p<0.01). Baseline curvature was positively correlated with greater absolute (degree) and relative (percent) improvements. Adverse events were similar between groups after controlling for confounders.

Clinical Implications

CCH may be safely and effectively administered in men with CPC. These data provide the first evidence for the efficacy of a non-surgical therapeutic option in this cohort.

Strengths and Limitations

Strengths – large, prospective series with standardized assessments; Limitations - non-randomized study, short-term follow-up, and lack of standardized method to differentiate CPC from PD.

Conclusions

CCH may be safely and effectively administered to men with CPC, with similar success rates compared to PD. Increasing curvature was associated with greater absolute (degree) and relative (percent) improvements, supporting the role for CCH in men with mild, moderate, or severe curvatures. External validation is warranted prior to routine implementation.
Phase Object Reconstruction for 4D-STEM using Deep Learning
Authors: Friedrich Thomas , Yu Chu-Ping , Verbeeck Johan , Van Aert Sandra
Published: January 2023

In this study, we explore the possibility to use deep learning for the reconstruction of phase images from 4D scanning transmission electron microscopy (4D-STEM) data. The process can be divided into two main steps. First, the complex electron wave function is recovered for a convergent beam electron diffraction pattern (CBED) using a convolutional neural network (CNN). Subsequently, a corresponding patch of the phase object is recovered using the phase object approximation. Repeating this for each scan position in a 4D-STEM dataset and combining the patches by complex summation yields the full-phase object. Each patch is recovered from a kernel of 3×3 adjacent CBEDs only, which eliminates common, large memory requirements and enables live processing during an experiment. The machine learning pipeline, data generation, and the reconstruction algorithm are presented. We demonstrate that the CNN can retrieve phase information beyond the aperture angle, enabling super-resolution imaging. The image contrast formation is evaluated showing a dependence on the thickness and atomic column type. Columns containing light and heavy elements can be imaged simultaneously and are distinguishable. The combination of super-resolution, good noise robustness, and intuitive image contrast characteristics makes the approach unique among live imaging methods in 4D-STEM.
Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism
Authors: Demir Merve , Russelburg L Peyton , Lin Wen-Jen , Trasviña-Arenas Carlos H , Huang Beili , Yuen Philip K , Horvath Martin P , David Sheila S
Published: January 2023

DNA glycosylase MutY plays a critical role in suppression of mutations resulted from oxidative damage, as highlighted by cancer-association of the human enzyme. MutY requires a highly conserved catalytic Asp residue for excision of adenines misinserted opposite 8-oxo-7,8-dihydroguanine (OG). A nearby Asn residue hydrogen bonds to the catalytic Asp in structures of MutY and its mutation to Ser is an inherited variant in human MUTYH associated with colorectal cancer. We captured structural snapshots of N146S Geobacillus stearothermophilus MutY bound to DNA containing a substrate, a transition state analog and enzyme-catalyzed abasic site products to provide insight into the base excision mechanism of MutY and the role of Asn. Surprisingly, despite the ability of N146S to excise adenine and purine (P) in vitro, albeit at slow rates, N146S-OG:P complex showed a calcium coordinated to the purine base altering its conformation to inhibit hydrolysis. We obtained crystal structures of N146S Gs MutY bound to its abasic site product by removing the calcium from crystals of N146S-OG:P complex to initiate catalysis in crystallo or by crystallization in the absence of calcium. The product structures of N146S feature enzyme-generated β-anomer abasic sites that support a retaining mechanism for MutY-catalyzed base excision.
Detection of a bright burst from the repeating fast radio burst 20201124A at 2 GHz
Authors: Ikebe Sota , Takefuji Kazuhiro , Terasawa Toshio , Eie Sujin , Akahori Takuya , Murata Yasuhiro , Hashimoto Tetsuya , Kisaka Shota , Honma Mareki , Yoshiura Shintaro , Suzuki Syunsaku , Oyama Tomoaki , Sekido Mamoru , Niinuma Kotaro , Takeuchi Hiroshi , Yonekura Yoshinori , Enoto Teruaki
Published: January 2023

We present a detection of a bright burst from the fast radio burst (FRB) 20201124A, which is one of the most active repeating FRBs, based on S-band observations with the 64 m radio telescope at the Usuda Deep Space Center/JAXA. This is the first FRB observed by using a Japanese facility. Our detection at 2 GHz in 2022 February is the highest frequency for this FRB and the fluence of >189 Jy ms is one of the brightest bursts from this FRB source. We place an upper limit on the spectral index α = −2.14 from the detection of the S band and non-detection of the X band at the same time. We compare the event rate of the detected burst with those from previous research and suggest that the power law of the luminosity function might be broken at lower fluence and the fluences of bright FRBs are distributed up to over 2 GHz with the power law against frequency. In addition, we show that the energy density of the burst detected in this work is comparable to the bright population of one-off FRBs. We propose that repeating FRBs can be as bright as one-off FRBs and only their brightest bursts might be detected, so some repeating FRBs intrinsically might have been classified as one-off FRBs.
WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive interstitial lung disease
Authors: Guo Li , Zhang Xueliang , Pu Weilin , Zhao Jiangfeng , Wang Kaiwen , Zhang Danting , Hong Soonmin , Ma Yanyun , Wang Xiaodong , Ye Shuang , Guo Qiang , Wang Jiucun
Published: January 2023

Objectives

Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM.

Methods

We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n = 53), anti-synthetases syndrome (ASyS, n = 72) and healthy controls (n = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression.

Results

Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype.

Conclusion

We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM.
Pain specialist management of sexual pain–III. Neuromodulation
Authors: Vogel John J
Published: January 2023

Introduction

Some women with sexual pain do not respond to conservative multi-modal care modalities. Neuromodulation is a group of methods which alter nerve activity by delivering electrical energy or pharmaceutical agents directly to target neural structures. Multiple forms of neuromodulation may provide durable treatment options to fill the unmet therapeutic need of a certain population of women with chronic sexual pain.

Objectives

To provide a current review of neuromodulation treatments used for female sexual pain and introduce neuromodulation techniques which may be applied in novel ways to specific sexual pain phenotypes.

Methods

Internet, PubMed and Cochrane Library were searched for relevant articles on female sexual pain within the clinical purview and scope of practice of pain management.

Results

A thorough review of the literature was conducted to include basic science studies, clinical trials, systematic reviews, consensus statements, and case-reports. A sampling of information on real-world patient outcomes was included. The amount and quality of evidence for neuromodulation to treat female sexual pain is low-moderate. Descriptions of neuromodulation procedures for sexual pain were made and clinical studies reviewed. The effects of autonomic nervous system (ANS) dysregulation on the experience of pain were discussed with consideration of interventional procedures to facilitate restoration of ANS equilibrium.

Conclusion

Treating female sexual pain is complex. There are considerable numbers of women who have unsatisfactory sexual pain relief despite evidence-based interdisciplinary care. These women may benefit from referral to consider neuromodulation treatment options. Neuromodulation is a relatively new capability in the arsenal of pain management and other specialists that can be considered for women with treatment refractory sexual pain.
Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS‐CoV‐2
Authors: Kraut Jeffrey A. , Cheetham‐Wilkinson Izaak J. , Swan Laura E. , Stagi Massimiliano , Kurtz Ira
Published: January 2023

Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS‐CoV‐2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS‐CoV‐2 infection. Sodium bicarbonate, carbicarb, and THAM are buffers that can be used clinically to provide base to patients. To examine whether these bases could raise lysosomal pH and therefore be a primary or adjunctive treatment of SARS‐CoV‐2 infection, we measured lysosomal and intracellular pH of mammalian cells after exposure to each of these bases. Mammalian HEK293 cells expressing RpH‐LAMP1‐3xFLAG, a ratiometric sensor of lysosomal luminal pH, were first exposed to Hepes which was then switched to sodium bicarbonate, carbicarb, or THAM and lysosomal pH measured. In bicarbonate buffer the mean lysosomal pH was 4.3 ± 0.1 (n = 20); p = NS versus Hepes (n = 20). The mean lysosomal pH in bicarbonate/carbonate was 4.3 ± 0.1 (n = 21) versus Hepes (n = 21), p = NS. In THAM buffer the mean lysosomal pH was 4.7 ± 0.07 (n = 20) versus Hepes (4.6 ± 0.1, n = 20), p = NS. In addition, there was no statistical difference between pHi in bicarbonate, carbicarb or THAM solutions. Using the membrane permeable base NH4Cl (5 mM), lysosomal pH increased significantly to 5.9 ± 0.1 (n = 21) compared to Hepes (4.5 ± 0.07, n = 21); p < 0.0001. Similarly, exposure to 1 mM hydroxychloroquine significantly increased the lysosomal pH to (5.9 ± 0.06, n = 20) versus Hepes (4.3 ± 0.1, n = 20), p < 0.0001. Separately steady‐state pHi was measured in HEK293 cells bathed in various buffers. In bicarbonate pHi was 7.29 ± 0.02 (n = 12) versus Hepes (7.45 ± 0.03, [n = 12]), p < 0.001. In cells bathed in carbicarb pHi was 7.27 ± 0.02 (n = 5) versus Hepes (7.43 ± 0.04, [n = 5]), p < 0.01. Cells bathed in THAM had a pHi of 7.25 ± 0.03 (n = 12) versus Hepes (7.44 ± 0.03 [n = 12]), p < 0.001. In addition, there was no statistical difference in pHi in bicarbonate, carbicarb or THAM solutions. The results of these studies indicate that none of the buffers designed to provide base to patients alters lysosomal pH at the concentrations used in this study and therefore would be predicted to be of no value in the treatment of SARS‐CoV‐2 infection. If the goal is to raise lysosomal pH to decrease the infectivity of SARS‐CoV‐2, utilizing lysosomal permeable buffers at the appropriate dose that is non‐toxic appears to be a useful approach to explore.
KL-1: HYPERTENSION: PAST PROGRESS, PRESENT CHALLENGES AND FUTURE PROMISES
Authors: Dzau Victor J.
Published: January 2023

Hypertension has been long recognized as a major health challenge. Hypertension research and management have made important progress with considerable success in reducing cardiovascular morbidity and mortality. This progress is the result of basic and translational research in developing animal models, the fundamental understanding of physiology and biochemistry of blood pressure regulation, and the development of therapeutics. More recently, advances in genetics, genomics, molecular pathways, and emerging technology show much promise.

However, there remains substantial challenges. Hypertension is controlled in less than a fifth of patients worldwide. There are vast global disparities in hypertension awareness, treatment, and control, especially problematic in low- and middle-income countries. Challenges include early detection and follow-up that is dependent on cuff-based measurement and drug regimens, which are often not precise, and have side effects. In spite of recent scientific progress and numerous clinical research trials, recent research has not yielded major advances in hypertension control.

Transformation is urgently needed to reduce the global burden of hypertension. The future will depend on effective development of digital technologies, insights from data science and artificial intelligence for detection and management, new techniques such as genome editing which provide potential cures, and the importance of population science for global control.
PL-1: DECIPHERING THE MYSTERY OF SLEEP: TOWARD THE MOLECULAR SUBSTRATE FOR SLEEPINESS
Authors: Yanagisawa Masashi
Published: January 2023

Although sleep is a ubiquitous behavior in animal species with central nervous systems, the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has helped reveal neural pathways in the regulation of sleep/wakefulness. Orexin receptor antagonists, which specifically block the endogenous waking system, have been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.

Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for “sleepiness” (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened > 10,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutations in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Indeed, through a systematic cross-comparison of the Sleepy mutants (with a gain-of-function change in a serine/threonine kinase pathway) and sleep-deprived mice, we have found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.
CL-1: WISDOM FOR CONQUERING HYPERTENSION---FOOD, MOVE, AI: TOWARDS SUSTAINABLE WELL-BEING
Authors: Itoh Hiroshi
Published: January 2023

To obtain the wisdom for conquering hypertension, in ISH2022KYOTO, we propose three new hypertension research fields, that is, FOOD (nutrition), MOVE (physical fitness) and AI (digital transformation). In 2003, I propose the clinical concept of “Metabolic Domino”, which illustrates the whole picture of non-communicable diseases (NCDs), including hypertension, beginning from derangement of lifestyle (FOOD and MOVE) and deposition of visceral fat. 1) FOOD: In 2022, we elucidate the important role of the kidney and intestines which (re)absorb sugar and salt “greedily” by the activation of “greedy genes,” the genes to be activated by excessive sugar and salt, including SGLT (sodium-glucose co-transporter)1,2 and MR (mirenalocorticoid receptor) genes, and cause hypertension/CKD and obesity/diabetes mellitus (“Greedy Organ Hypothesis”). Overactivation of MR by salt or sugar induces “MR-associated hypertension” with wide range of plasma aldosterone level. 2) MOOVE: By exercise, the increase of blood shear stress and heat rate induces the secretion of nitric oxide or natriuretic peptides, which not only reduce blood pressure but also activate mitochondria in the skeletal muscle to prevent sarcopenia and obesity. Angiotensin II has the opposite metabolic actions. 3) AI: The time-course of Metabolic Domino is now highlighted. Pre-emptive medicine or “Me-byo” (“Not-yet disease”) medicine intervenes the most upstream of Metabolic Domino to prevent occurrence of the disease. We demonstrated the transient early blockade of renin-angiotensin system can achieve prevention or regression of hypertension in experimental animals and suggested the possibility in humans. The treatment memory is mediated the alteration of epigenetic status of the organs (e.g. the kidney or blood vessels) (“Organ Memory”2018). Angiotensin II exerts modulatory effect on epigenetic change. Big data science with advanced digital technology for monitoring biorhythm data, such as blood pressure, blood glucose level, sympathetic tone or sleep depth, and also alteration of the life-environment, we will predict the specific trajectory of each individual with elevated blood pressure, and can modify organ memory and modulate the future outcome. By these innovative approaches, I will expect the establishment of the community in which no one with hypertension is left behind to serve for sustainable well-being.
FP-2: HEALTH MAINTENANCE AND TEAMWORK IN SPACE
Authors: Yamazaki Naoko
Published: January 2023

Based on the experience onboard the International Space Station (ISS) and Space Shuttle Discovery, the way we train on the ground and we live in space will be introduced, emphasizing the teamwork. Also, health maintenance system onboard the ISS will be introduced. Since the number of private astronauts has been increasing, health maintenance in space to accommodate wider range of people is becoming more important.
FP-3: RESEARCH ON COMPLETE NUTRITION MEAL TO AVOID THE METABOLIC DOMINO EFFECT, REALIZING MIBYOU PREVENTION (DISEASE-FREE STATE)
Authors: Ando Noritaka
Published: January 2023

While the modern diet has become richer and more abundant, many diet-related problems exist, including obesity due to excessive calories and hidden malnutrition due to inappropriate dieting. NISSIN FOOD PRODUCTS is engaged in research on Complete Nutrition Meals of the future, leveraging independent and cutting-edge food technologies cultivated through the development of instant foods and other products. Complete Nutrition Meals offer the same appearance and taste as regular means, but control calories, salt, sugar, fat, etc., embodying the concept of food that satisfies all necessary nutrient needs and referencing various nutritional perspectives. In pursuing Complete Nutrition Meals, NISSIN FOOD PRODUCTS aims to create a world where anyone can enjoy whatever they want, as much as they want, whenever they want.

In this presentation, we will introduce the background behind research on Complete Nutrition Meals and the results of clinical trials. We will also cover efforts aimed at preventing frailty and improving quality of life for hypertensive and diabetic patients through Complete Nutrition Meals.
ME-2: MR BLOCKERS AS THE POSSIBLE FIRST-LINE THERAPY IN HYPERTENSION
Authors: Shibata Hirotaka
Published: January 2023

Among 43 million hypertensive patients in Japan, blood pressure levels are controlled below 140/90mmHg in only a quarter of these patients. This fact may be due to poor adherence and inadequate lifestyles as well as “clinical inertia” (“diagnostic inertia” and “treatment inertia”) of health care providers.

Primary aldosteronism (PA) is the most common endocrine hypertension and often associated with resistant hypertension. Five to 10% of all people in hypertension and 20% of resistant hypertension is PA. Most importantly, PA presents with higher prevalence of cardiovascular diseases than essential hypertensive patients whose blood pressure levels are controlled to the similar levels. For the case-detection testing, high plasma aldosterone (PAC) to plasma renin activity (PRA) ratio is useful based on the clinical practice guideline of many countries. However, screening of PA is rarely done between 0.7% to 4.2% of hypertensive patients in daily clinical practice. This situation is a sad state of affairs (“diagnostic inertia”), and the screening of PA should be done at least once in all hypertensive patients. For treatment of PA, administration of a mineralocorticoid receptor blocker (MRB) is recommended in patients with bilateral PA as well as ones who do not willing to undergo surgery. It is therefore crucial to administer a MRB as a first-line therapy, although it is not included in the “first-line antihypertensives”.

In addition, since the PA screening test is done quantitatively, it may be insufficient to evaluate just “non-PA” when the ratio is lower than the cut-off values. It may be rather crucial to consider the pathogenesis as “borderline aldosteronism” or “mineralocorticoid receptor (MR)-associated hypertension” when the ratio is suboptimal, because a MR antagonist would be a better choice to control hypertension under such circumstances.

In diabetes mellitus and chronic kidney disease, MR may be directly overactivated by varied molecular mechanisms. In addition, under the treatment with angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEi) in patients with diabetes and chronic kidney disease, PAC is suppressed firstly, but re-elevated sometimes over baseline levels (“aldosterone breakthrough”). We therefore presume that combination treatment of a MRB with first-line antihypertensives (ARB/ACEi and calcium channel blocker) may resolve “treatment inertia” of hypertension. Considering the resolution of both “diagnostic and treatment inertia” for hypertension, it is conceivable that MRB should be included in the first-line therapy for hypertension.
DB-2-3: ANTIHYPERTENSIVE STRATEGIES IN END-OF LIFE OLD PATIENTS (PRO/CON SESSION)
Authors: Benetos Athanase
Published: January 2023

High blood pressure (BP) especially systolic BP is very common in older persons and is associated with considerable morbidity and mortality. Evidence from a limited number of clinical studies indicates that people 80+ y.o. can get significant benefits from BP lowering treatments and that targeting SBP < 140 mmHg reduces morbidity and mortality. However, these clinical studies excluded patients with high frailty and severe alteration of functionality/autonomy. Indeed, in subjects with this clinical profiles, observational data indicate that low SBP is associated with higher morbidity and mortality particularly in those with antihypertensive medication and multiple other drug regimens. These observations made in very altered or end-of-life patients by several clinical research groups should be taken into account by the clinicians, and therefore deprescription i.e. reduction of the antihypertensive treatment, should be considered in presence of very low SBP levels (<130mmHg). However, this approach should be viewed with great caution: firstly, observational studies provide weak evidence and therefore further data are needed from controlled clinical trials in very old patients with the health condition and of autonomy status described above, i.e. people who have been systematically excluded from clinical trials so far. Second, deprescribing should be done gradually, taking into account comorbidities and patient preferences. Finally, in these patients, emphasis should be given to the quality of life and symptoms relief when choosing therapeutic strategies. Collaboration between hypertension specialists, geriatricians and clinical pharmacists is a key issue in this perspective.