bluuebunny/crossref_metadata_2025 huggingface dataset:
Archetypes and the ‘impoverished environment’ argument: a response to Goodwyn (2020)
Authors: Merchant John
Published: January 2021

Goodwyn's (2020) paper ‘Archetypes and the “Impoverished Genome” argument: updates from evolutionary genetics’ continues the ongoing discussion forged in this Journal to do with the bio‐genetic, socio‐cultural and environmental underpinnings to archetypal experience. Goodwyn's central focus considers the way in which the genome and environment both contribute causally to the development of the collective unconscious across the lifespan, arguing that others in the debate have minimized the genome's contribution. This paper contrasts the research evidence Goodwyn outlines with contemporary gene‐environment coaction research within the psychological domain, concluding that the issue may be more one of emphasis by showing that both genome and environment are important in the activation of archetypal imagery. This highlights that ‘pre‐formationism’ (as some kind of automatic archetypal read‐out mechanism) and the idea of ‘autochthonous revival’ of archetypes are suspect concepts, and this needs to be taken into account in clinical work. Furthermore, the central issue as to which is causally more significant in generating archetypal imagery, the genome or the environment, will be examined. Illustrative examples of the importance of environmental input in activating archetypal imagery are presented from Jung's own life experience, alongside a contemporary case, as well as with an historical case of Jung's.
Time for space at the table: an African American ‐ Native American analyst‐in‐training’s first‐hand reflections. A call for the IAAP to publicly denounce (but not erase) the White supremacist writings of C.G. Jung
Authors: Carter Christopher J.
Published: January 2021

This article provides an African American‐Native American analyst‐in‐training’s first‐hand reflections on Jung’s firm depiction of Blacks of African descent and America’s First Nations People (the Red man) as inferior, through a theory of primitivity that unveils Jung’s belief in and support of White supremacy. With no intended disrespect or neglect intended toward America’s First Nations, this article focuses primarily on Jung’s apparent disdain for Blacks (the Negro). Utilizing writings from Frederick Douglass, W.E.B. Du Bois and Na’im Akbar, this article highlights ways in which Jung’s biases align with the White supremacist perspective of the Negro as a problem, detrimental to social order. The paper concludes with an Appendix which outlines a call to the International Association for Analytical Psychology (IAAP) to take corrective action and to publicly denounce those facets of Jung’s writings that diverge from the core of his theory and that promote toxic attitudes of bigotry, perhaps discouraging many people of colour from enrolling in analytic training.
Microbiota modulates gut immunity and promotes baculovirus infection in Helicoverpa armigera
Authors: Yuan Chuanfei , Xing Longsheng , Wang Manli , Hu Zhihong , Zou Zhen
Published: January 2021

Baculoviruses are natural enemies of agricultural and forest insect pests and play an important role in biological pest control. Oral infection by baculovirus in the insect midgut is necessary for establishing systemic infection and eventually killing the insect. Since the insect midgut continuously encounters microbiota, the gut microbiota could affect baculovirus infection. Here, we demonstrated that gut microbiota modulates immune responses and promotes baculovirus infection in the cotton bollworm, Helicoverpa armigera. After oral infection, numerous host immunity‐related genes including genes encoding Toll and immune deficiency (IMD) pathway components were upregulated in the midgut. Elimination of the gut microbiota significantly increased the resistance to viral infection in H. armigera. Quantitative real‐time reverse transcription polymerase chain reaction and proteomic analysis showed that downregulation of the antiviral factor prophenoloxidase (PPO) could be mediated by microbiota during infection. It implied that midgut microbiota diminishes the expression of PPO to facilitate viral infection in H. armigera. Our findings revealed that the microbiota plays an important role in modulating the resistance of H. armigera to baculovirus infection, providing new insights in applying biopesticide.
Investigation on the biological activity of anthocyanins and polyphenols in blueberry
Authors: Yang Sen , Wang Chao , Li Xingyuan , Wu Caie , Liu Chen , Xue Zhaohui , Kou Xiaohong
Published: January 2021

Blueberry (Vaccinium spp.) is a fruit recognized in the world as healthy, and many of its active ingredients have important physiological functions. This study analyzed the antioxidant activity, antitumor activity, and immune function of anthocyanins and polyphenols extracted from blueberries. The crude extracts of anthocyanins and polyphenols were obtained from blueberries and then purified, and the extract exhibited excellent dose‐dependent antitumor activity and antioxidant activity in vivo and in vitro. The purified anthocyanins and polyphenol compounds showed higher antioxidant activity, whereas the crude extract had a better inhibitory effect on tumor proliferation than pure extract, and the blueberry anthocyanin and polyphenol crude product mixture showed a more powerful tumor suppressor, which may be the result of the synergistic effect of multiple compounds. The crude extracts were also more efficient at improving immune function, as reflected by measurements of change in body weight, thymus and spleen indices, macrophage phagocytosis, lymphocyte transformation capacity, superoxide dismutase activity, malondialdehyde content, and serum nitric oxide levels. These results indicate that blueberry anthocyanins and polyphenol extracts can improve immune function and reduce the metastasis and proliferation of cancer cells. This study reveals the functions of important active substances in blueberries and provides support for the development of functional health products and therapeutic drugs.

Practical Application

We compared the biological activity of crude and purified anthocyanins and polyphenol extracts from blueberries and tested their effects on improving immune function. This study contributes to a better understanding of the bioactivity of blueberry extracts and is valuable for further applications of blueberries in medicine.
Impact of sustainability and nutritional messaging on Italian consumers’ purchase intent of cereal bars made with brewery spent grains
Authors: Stelick Alina , Sogari Giovanni , Rodolfi Margherita , Dando Robin , Paciulli Maria
Published: January 2021

This work focuses on the reuse of brewery spent grains (BSGs), the most abundant by‐product of the beer industry, today mainly used as animal feed. BSGs are rich in fibers and proteins as well as phenolic compounds, all of which are beneficial for human nutrition. Cereal bars containing 12% BSG were formulated and characterized instrumentally. Moreover, 159 panelists representative of young Italian consumers evaluated the bars in a central location test, along with a commercial cereal bar. Products were first evaluated blind, and then in an informed condition where additional product‐specific nutritional and sustainability information was revealed, thus the purchase intent was determined. While the control product outperformed the BSG bar in most of the hedonic and sensory measures, the BSG sample was perceived as “natural/made with natural ingredients” by a significantly higher number of panelists (49%) compared to the control (30%). Additionally, even in the lower performing formulation, a significant positive effect on purchase intent was observed when providing either nutrition (fiber content) or sustainability (use of upcycled ingredients) information. The acceptable price range for the BSG and the commercial bar was very similar, whereas the optimal pricing point for the BSG was lower than the control. For the BSG product, sustainability information had significantly higher impact on purchase intent than nutrition‐based information. Results highlight the importance of understanding consumer attitudes toward upcycling and the use of byproducts as ingredients in new food formulations.

Practical Application

Results show how providing information on product nutrition and sustainability can increase purchase intent in the context of a cereal bar containing upcycled ingredients. The findings of this study can help food and consumer researchers to develop acceptable products that include BSG as an ingredient, potentially replacing other cereals in the recipe. The use of this brewery by‐product could add value to the beer supply chain and to the final product as well, being also aligned with the current market trend of sustainability and functional health benefits.
ANME‐1 archaea may drive methane accumulation and removal in estuarine sediments
Authors: Kevorkian Richard T. , Callahan Sean , Winstead Rachel , Lloyd Karen G.
Published: January 2021

ANME‐1 archaea subsist on the very low energy of anaerobic oxidation of methane (AOM). Most marine sediments shift from net AOM in the sulfate methane transition zone (SMTZ) to methanogenesis in the methane zone (MZ) below it. In White Oak River estuarine sediments, ANME‐1 comprised 99.5% of 16S rRNA genes from amplicons and 100% of 16S rRNA genes from metagenomes of the Methanomicrobia in the SMTZ and 99.9% and 98.3%, respectively, in the MZ. Each of the 16 ANME‐1 OTUs (97% similarity) had peaks in the SMTZ that coincided with peaks of putative sulfate‐reducing bacteria Desulfatiglans sp. and SEEP‐SRB1. In the MZ, ANME‐1, but none of the putative sulfate‐reducing bacteria or cultured methanogens, increased with depth. Our meta‐analysis of public data showed only ANME‐1 expressed methanogenic genes during both net AOM and net methanogenesis in an enrichment culture. We conclude that ANME‐1 perform AOM in the SMTZ and methanogenesis in the MZ of White Oak River sediments. This metabolic flexibility may expand habitable zones in extraterrestrial environments, since it enables greater energy yields in a fluctuating energetic landscape.
A World after COVID‐19: Business as Usual, or Building Bolder and Better?
Authors: Erdelen Walter R. , Richardson Jacques G.
Published: January 2021

The authors propose a holistic approach to life and living after the coronavirus crisis of 2020 has become history. Their method is to postulate studied reconsideration of the true needs of the human species, new know‐how for all, novel codes of behavior, and drastic change to how we treat nature. Their findings name humanity's ballooning population as problem Number One. Without reverting to former ways, we need to apply our imagination to sound demographic principles, accept modest economic growth, and create much better stewardship of nature. Stated in terms of the futurist, a Great Acceleration should give way to a process we might call the Great Deceleration of humanity's tempo of life and mode of action. Readers are encouraged to eschew all thought of continuing with ‘business as usual’. A purposeful limitation is the absence of all encouragement towards regrowth of wasteful manufacture and commerce. A systemic shift towards circular and green economies should be a key advance in all business revival. Another mode of being awaits; success of the encounter depends on humankind, not on theory.
Tegafur‐uracil‐induced pericardial effusion during adjuvant chemotherapy for resected lung adenocarcinoma: A case report
Authors: Kawamoto Nobutaka , Okita Riki , Hayashi Masataro , Okada Masanori , Inokawa Hidetoshi
Published: January 2021

In Japan, oral administration of tegafur‐uracil is recommended as postoperative adjuvant chemotherapy for patients diagnosed with primary lung adenocarcinomas of >2 cm size and staged as IA, IB, and IIA. Reports on chemotherapy‐induced pericardial effusion are rare. Herein, we report a rare case of tegafur‐uracil‐induced pericardial effusion during postoperative adjuvant chemotherapy for primary lung cancer. A 60‐year‐old man underwent left lower lobectomy and mediastinal lymph node dissection for left lower lung adenocarcinoma. Lung cancer was staged as IB, and tegafur‐uracil was administered as postoperative adjuvant chemotherapy from 1 month after the surgery. A computed tomography (CT) scan revealed a pericardial effusion 5 months after the surgery. A malignant pericardial effusion was suspected, and tegafur‐uracil was discontinued. Pericardiocentesis could not be performed owing to a small amount of pericardial effusion. An 18F‐fluorodeoxyglucose (FDG) positron emission tomography/CT scan revealed no abnormal FDG uptake. During a short follow‐up period after discontinuation of tegafur‐uracil, a CT scan revealed a decrease in pericardial effusion, suggesting that the pericardial effusion was induced by tegafur‐uracil. Follow‐up of pericardial effusion is required while administering tegafur‐uracil. In cases of pericardial effusion without symptoms and no suspicious metastatic lesions in other organs, we should be concerned about tegafur‐uracil‐induced pericardial effusion.
A first pass, using pre‐history and contemporary history, at understanding why Australia and England have such different policies towards electronic nicotine delivery systems, 1970s–c. 2018
Authors: Berridge Virginia , Hall Wayne , Taylor Suzanne , Gartner Coral , Morphett Kylie
Published: January 2021

Aims

The United Kingdom and Australia have developed highly divergent policy responses to electronic nicotine delivery systems (ENDS). To understand the historical origins of these differences, we describe the history of tobacco control in each country and the key roles played in setting ENDS policy in its early stages by public health regulations and policy networks, anti‐smoking organizations, ‘vaper’ activist networks and advocates of harm reduction policies towards injecting drug use.

Methods

We analysed key government reports, policy statements from public health bodies and non‐government organizations (e.g. cancer councils and medical organizations) on ENDS; submissions to an Australian parliamentary inquiry; media coverage of policy debates in medical journals; and the history of tobacco control policy in Australia and England. Key discourses about ENDS were identified for each country. These were compared across countries during a multi‐day face‐to‐face meeting, where consensus was reached on the key commonalities and divergences in historical approaches to nicotine policy. This paper focuses on England, as different policy responses were apparent in constituent countries of the United Kingdom, and Scotland in particular.

Results

Policymakers in Australia and England differ markedly in the priority that they have given to using ENDS to promote smoking cessation or restricting smokers’ access to prevent uptake among young people. In understanding the origins of these divergent responses, we identified the following key differences between the two countries’ approaches to nicotine regulation: an influential scientific network that favoured nicotine harm reduction in the United Kingdom and the absence of such a network in Australia; the success of different types of health activism both in England and in Europe in opposing more restrictive policies; and the greater influence on policy in England of the field of illicit drug harm reduction.

Conclusions

An understanding of the different policy responses to electronic nicotine delivery systems (ENDS) in England and Australia requires an appreciation of how actors within the different policy structures, scientific networks and activist organizations in each country and region have interpreted the evidence and the priority that policymakers have given to the competing goals of preventing adolescent uptake and encouraging smokers to use ENDS to quit smoking.
Coordination, framing and innovation: the political sophistication of public health advocates in Ireland
Authors: Lesch Matthew , McCambridge Jim
Published: January 2021

Background and Aims

This study explores the role of the public health advocacy coalition in alcohol policy development in Ireland. Compared with industry actors, much less is known about the membership, activities and influence of public health advocates in alcohol policymaking. To address this gap, this paper identifies several advocacy strategies, drawn from the advocacy coalition framework and other policy theories, and then analyses them in the context of recent Irish developments.

Methods

The study used theory‐building process‐tracing to construct a record of the public health advocacy coalition and its campaign to promote the Public Health (Alcohol) Act 2018 in Ireland. Specifically, we drew upon 131 primary documents produced by advocates, 464 newspaper articles and 18 semi‐structured interviews with key advocates, public health experts and elected officials to undertake a thematic analysis.

Results

Public health advocates in Ireland have developed sophisticated political strategies to foster major alcohol policy change. First, public health advocates led the formation of a broad‐based advocacy coalition that helped members to effectively pool their limited resources as well as coordinate their strategy and messaging. Secondly, issue‐framing and message discipline played a key role in the coalition's success. Advocates strategically focused upon the policy problem, specifically health harms, rather than the detailed content of the proposed measures. Finally, there is evidence of political learning, where advocates’ prior experiences and knowledge of the political system in Ireland spurred innovations in campaigning. These strategies were interdependent and mutually reinforcing, and succeeded in building support for public health advocates’ preferred policies among politicians and the general public.

Discussion/conclusion

There are distinct capabilities that public health actors can mobilize in the policy process to win alcohol policy debates and capitalize on the constraints on industry influence on alcohol policymaking.
Effects of cannabis use on alcohol consumption in a sample of treatment‐engaged heavy drinkers in Colorado
Authors: Karoly Hollis C. , Ross J. Megan , Prince Mark A. , Zabelski Alexandra E. , Hutchison Kent E.
Published: January 2021

Background and Aims

Cannabis is commonly used among people who drink alcohol, but evidence suggests a nuanced relationship between alcohol consumption and cannabis use. In particular, among individuals undergoing alcohol treatment the impact of cannabis on alcohol intake may depend upon cannabis use frequency. We aimed to test the effects of within‐day cannabis use on total drinks consumed and likelihood of binge drinking on a given day among all participants and compare these relationships between males and females and between individuals who reported infrequent and frequent cannabis use.

Design

This observational study is a substudy of a larger randomized controlled trial (RCT). Individuals were included from the RCT if they reported any cannabis use and were divided into groups based on cannabis use patterns. Alcohol use was compared within and between groups.

Setting

Individuals were recruited from 2016 to 2020 from community and university settings in Denver and Boulder, CO, USA.

Participants

Of the 182 individuals enrolled in the RCT, 96 cannabis‐using subjects were included in these analyses.

Measurements

Subjects completed a time‐line follow‐back (TLFB) at baseline, 4, 8 (end of treatment) and 20 weeks. Daily data on alcohol and cannabis use from the TLFB at all time‐points were analyzed.

Findings

Across the sample (n = 96), individuals drank approximately 29% fewer drinks [95% confidence interval (CI) = 18–39%, P < 0.001] and were 2.06 times (95% CI =1.37–3.08, P < 0.001) less likely to have a binge‐drinking episode on days that cannabis was used compared with days that cannabis was not used. These patterns were observed in males, females and the infrequent and frequent cannabis use groups. Findings were inconclusive regarding differences in the association between cannabis use and alcohol outcomes when comparing males and females and when comparing infrequent and frequent cannabis use groups.

Conclusions

Heavy drinkers engaged in treatment to reduce their alcohol consumption who also use cannabis appear to increase their cannabis use on days when they reduce their alcohol consumption.
Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome
Authors: Nakajima Tadashi , Dharmawan Tommy , Kawabata‐Iwakawa Reika , Tamura Shuntaro , Hasegawa Hiroshi , Kobari Takashi , Ota Masaki , Tange Shoichi , Nishiyama Masahiko , Kaneko Yoshiaki , Kurabayashi Masahiko
Published: January 2021

Background

SCN5A‐related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX).

Objective

We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects.

Methods

Target panel sequencing was performed. Wild‐type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24–36 hr, whole‐cell sodium currents (INa) were recorded using patch‐clamp techniques.

Results

The proband was 29‐year‐old male who experienced cardiopulmonary arrest. Later, his 36‐year‐old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G‐INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady‐state activation (SSA) was shifted to depolarizing potentials compared with WT‐INa (V1/2‐WT: −39.1 ± 0.8 mV, W374G: −30.9 ± 1.1 mV, p < .01). Incubation of W374G‐transfected cells with MEX (W374G‐MEX) increased INa density, but it was still reduced compared with WT‐INa (W374G‐MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G‐MEX‐INa was comparable to W374G‐INa (V1/2‐W374G‐MEX: −31.6 ± 0.7 mV, P = NS).

Conclusions

Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.
Uptake of fetal aneuploidy screening after the introduction of the non‐invasive prenatal test: A national population‐based register study
Authors: van der Meij Karuna R. M. , de Groot‐van Mooren Maurike , Carbo Ellen W. S. , Pieters Mijntje J. , Rodenburg Wendy , Sistermans Erik A. , Cornel Martina C. , Henneman Lidewij ,   the Dutch NIPT Consortium
Published: January 2021

Introduction

The introduction of the non‐invasive prenatal test (NIPT) has shifted the prenatal screening landscape. Countries are exploring ways to integrate NIPT in their national prenatal screening programs, either as a first‐ or second‐tier test. This study aimed to describe how the uptake of fetal aneuploidy screening changed after the introduction of NIPT as a second‐tier and as a first‐tier test within the national prenatal screening program of the Netherlands.

Material and methods

A population‐based register study in the Netherlands, recording uptake of fetal aneuploidy screening. Data from all pregnant women choosing to have the first‐trimester combined test (FCT) or first‐tier NIPT between January 2007 and March 2019 were retrospectively collected using national registration systems. Uptake percentages for fetal aneuploidy screening (FCT and NIPT) were calculated and stratified by region and maternal age. Statistical significance was determined using trend analysis and chi‐squared tests.

Results

Between 2007 and 2013 FCT uptake increased from 14.8% to 29.5% (P = .004). In April 2014 NIPT was introduced as a second‐tier test for high‐risk women after FCT (TRIDENT‐1 study). FCT uptake rose from 29.5% in 2013 to 34.2% in 2015 (P < .0001). After the introduction of NIPT as a first‐tier test for all women in April 2017 (TRIDENT‐2 study), FCT uptake declined significantly from 35.8% in 2016 to 2.6% in 2018 (P < .0001). NIPT uptake increased to 43.4% in 2018. Regionally, NIPT uptake ranged from 31.8% to 67.9%. Total uptake (FCT and NIPT) between 2007 and 2018 increased significantly from 14.8% to 45.9% (P < .0001). However, total uptake stabilized at 46% for both years of TRIDENT‐2 (April 2017‐March 2019).

Conclusions

An increase in total fetal aneuploidy screening uptake up to 45.9% was observed after the introduction of NIPT. Uptake appears to have stabilized within a year after introducing first‐tier NIPT.
Estimating the potential impact of implementing pre‐emptive pharmacogenetic testing in primary care across the UK
Authors: Youssef Essra , Kirkdale Charlotte L. , Wright David J. , Guchelaar Henk‐Jan , Thornley Tracey
Published: January 2021

Aims

Pharmacogenetics (PGx) in the UK is currently implemented in secondary care for a small group of high‐risk medicines. However, most prescribing takes place in primary care, with a large group of medicines influenced by commonly occurring genetic variations. The goal of this study is to quantitatively estimate the volumes of medicines impacted by implementation of a population‐level, pre‐emptive pharmacogenetic screening programme for nine genes related to medicines frequently dispensed in primary care in 2019.

Methods

A large community pharmacy database was analysed to estimate the national incidence of first prescriptions for 56 PGx drugs used in the UK for the period 1 January–31 December 2019. These estimated prescription volumes were combined with phenotype frequency data to estimate the occurrence of actionable drug–gene interactions (DGI) in daily practice in community pharmacies.

Results

In between 19.1 and 21.1% (n = 5 233 353–5 780 595) of all new prescriptions for 56 drugs (n = 27 411 288 new prescriptions/year), an actionable drug–gene interaction (DGI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group and/or the Clinical Pharmacogenetics Implementation Consortium. In these cases, the DGI would result in either increased monitoring, guarding against a maximum ceiling dose or an optional or immediate drug/dose change. An immediate dose adjustment or change in drug regimen accounted for 8.6–9.1% (n = 2 354 058–2 500 283) of these prescriptions.

Conclusions

Actionable drug–gene interactions frequently occur in UK primary care, with a large opportunity to optimise prescribing.
HIV infection as a risk factor for vaginal dysbiosis, bacterial vaginosis, and candidosis in pregnancy: A matched case‐control study
Authors: Foessleitner Philipp , Petricevic Ljubomir , Boerger Isabell , Steiner Irene , Kiss Herbert , Rieger Armin , Touzeau‐Roemer Veronique , Farr Alex
Published: January 2021

Background

This study aimed to evaluate the vaginal microbiota of HIV‐positive pregnant women relative to HIV‐negative controls, and to compare their risk of vaginal dysbiosis, bacterial vaginosis, and vulvovaginal candidosis (VVC).

Methods

This is a nested matched case‐control study that analyzed data from women who received pregnancy care at our center from 2003 to 2014. Women routinely underwent screening for asymptomatic vaginal infections using phase microscopy on Gram‐stained smears. HIV‐positive women were assigned to the case group, and HIV‐negative women were assigned to the control group. Cases and controls were matched in a 1:4 ratio. Logistic regression was used to test whether HIV infection was associated with vaginal dysbiosis (Nugent score 4‐6), BV (Nugent score 7‐10), or VVC.

Results

One hundred and twenty‐seven women were assigned to the case group, and 4290 were assigned to the control group (including 508 matched controls). Dysbiosis or BV was found in 29.9% of the cases and 17.6% of the controls. Women in the case group had increased risk of vaginal dysbiosis or BV (odds ratio [OR] 2.09, 95% confidence interval [CI], 1.30‐3.32, P = .002). The risk of VVC was also higher in the case group (OR 2.14, 95% CI, 1.22‐3.77, P = .008). The incidence of preterm birth did not differ significantly between the groups (cases: 8.7%; controls: 10%, P = .887).

Conclusions

HIV‐positive women are at risk of vaginal dysbiosis, BV, and VVC during pregnancy. As imbalances of the vaginal microbiota can lead to preterm birth, screening and treatment of HIV‐positive pregnant women are warranted.
The human G protein‐coupled ATP receptor P2Y11 is a target for anti‐inflammatory strategies
Authors: Gruenbacher Georg , Gander Hubert , Dobler Gabriele , Rahm Andrea , Klaver Dominik , Thurnher Martin
Published: January 2021

Background and Purpose

The ATP receptor P2Y11, which couples to Gq and Gs proteins, senses cell stress and promotes cytoprotective responses. P2Y11 receptors are upregulated during differentiation of M2 macrophages. However, it is unclear whether and how P2Y11 receptors contribute to the anti‐inflammatory properties of M2 macrophages.

Experimental Approach

Transcriptome and secretome profiling of ectopic P2Y11 receptors was used to analyse their signalling and function. Findings were validated in human monocyte‐derived M2 macrophages. The suramin analogue NF340 and P2Y11 receptor‐knockout cells confirmed that agonist‐mediated responses were specific to P2Y11 receptor stimulation.

Key Results

Temporal transcriptome profiling of P2Y11 receptor stimulation showed a strong and tightly controlled response of IL‐1 receptors, including activation of the IL‐1 receptor target genes, IL6 and IL8. Secretome profiling confirmed the presence of IL‐6 and IL‐8 proteins and additionally identified soluble tumour necrosis factor receptor 1 and 2 (sTNFR1 and sTNFR2) as targets of P2Y11 receptor activation. Raised levels of intracellular cAMP in M2 macrophages, after inhibition of phosphodiesterases (PDE), especially PDE4, strongly increased P2Y11 receptor‐induced release of sTNFR2 through ectodomain shedding mediated by TNF‐α converting enzyme (TACE/ADAM17). Both IL‐1α and IL‐1ß synergistically enhanced P2Y11 receptor‐ induced IL‐6 and IL‐8 secretion and release of sTNFR2. During lipopolysaccharide‐induced activation of TLR4, which shares the downstream signalling pathway with IL‐1 receptors, P2Y11 receptors specifically prevented secretion of TNF‐α.

Conclusions and Implications

Targeting P2Y11 receptors activates IL‐1 receptor signalling to promote sTNFR2 release and suppress TLR4 signalling to prevent TNF‐α secretion, thus facilitating resolution of inflammation.
A Little Autonomy Support Goes a Long Way: Daily Autonomy‐Supportive Parenting, Child Well‐Being, Parental Need Fulfillment, and Change in Child, Family, and Parent Adjustment Across the Adaptation to the COVID‐19 Pandemic
Authors: Neubauer Andreas B. , Schmidt Andrea , Kramer Andrea C. , Schmiedek Florian
Published: January 2021

This study examined the effects of daily parental autonomy support on changes in child behavior, family environment, and parental well‐being across 3 weeks during the COVID‐19 pandemic in Germany. Day‐to‐day associations among autonomy‐supportive parenting, parental need fulfillment, and child well‐being were also assessed. Parents (longitudinal N = 469; Mage = 42.93, SDage = 6.40) of school children (6–19 years) reported on adjustment measures at two measurement occasions and completed up to 21 daily online questionnaires in the weeks between these assessments. Results from dynamic structural equation models suggested reciprocal positive relations among autonomy‐supportive parenting and parental need fulfillment. Daily parental autonomy support, parental need fulfillment, and child well‐being partially predicted change in adjustment measures highlighting the central role of daily parenting for children’s adjustment during the pandemic.
Pure red cell aplasia and re‐aggravation of myasthenia gravis as a result of early reduction of steroid and immunosuppressant after starting eculizumab: A case report
Authors: Yamazaki Jun , Ueta Yuki , Akiba Yuki , Taguchi Takeshi , Masuda Masayuki , Aizawa Hitoshi
Published: January 2021

Background

Eculizumab, a humanized monoclonal antibody against complement protein C5, has been approved for the treatment of myasthenia gravis (MG) in Japan since 2017. However, there are few reports on reducing the dose of prednisolone (PSL) and immunosuppressants after eculizumab administration.

Case presentation

A 78‐year‐old woman with thymoma‐associated MG received an extended thymectomy, and was subsequently treated with PSL and tacrolimus (TAC) for 5 years. She was admitted to the hospital for dysarthria and dysphagia. She developed dyspnea and required mechanical ventilation. High‐dose immunoglobulin therapy, high‐dose methylprednisolone therapy and plasmapheresis were carried out. She was weaned off the ventilator, but dysarthria and dysphagia remained. Meanwhile, eculizumab improved her symptoms significantly. A month after reducing the dosage of PSL and TAC, cervical muscle weakness was observed, followed by pure red cell aplasia. After increasing her PSL and TAC dosage, the patient’s symptoms improved.

Conclusions

Eculizumab might improve the acute phase of MG symptoms, but early reduction of PSL and TAC can aggravate MG pathology and lead to pure red cell aplasia. Autoimmune mechanisms other than the complement‐mediated mechanism might be involved in the development of pure red cell aplasia. We suggest that physicians should not reduce PSL and immunosuppressants quickly after eculizumab administration.
The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility
Authors: Cavarocchi Emma , Whitfield Marjorie , Chargui Ahmed , Stouvenel Laurence , Lorès Patrick , Coutton Charles , Arnoult Christophe , Santulli Pietro , Patrat Catherine , Thierry‐Mieg Nicolas , Ray Pierre F. , Dulioust Emmanuel , Touré Aminata
Published: January 2021

Asthenozoospermia, defined by the absence or reduction of sperm motility, constitutes the most frequent cause of human male infertility. This pathological condition is caused by morphological and/or functional defects of the sperm flagellum, which preclude proper sperm progression. While in the last decade many causal genes were identified for asthenozoospermia associated with severe sperm flagellar defects, the causes of purely functional asthenozoospermia are still poorly defined. We describe here the case of an infertile man, displaying asthenozoospermia without major morphological flagellar anomalies and carrying a homozygous splicing mutation in SLC9C1 (sNHE), which we identified by whole‐exome sequencing. SLC9C1 encodes a sperm‐specific sodium/proton exchanger, which in mouse regulates pH homeostasis and interacts with the soluble adenylyl cyclase (sAC), a key regulator of the signalling pathways involved in sperm motility and capacitation. We demonstrate by means of RT‐PCR, immunodetection and immunofluorescence assays on patient's semen samples that the homozygous splicing mutation (c.2748 + 2 T > C) leads to in‐frame exon skipping resulting in a deletion in the cyclic nucleotide‐binding domain of the protein. Our work shows that in human, similar to mouse, SLC9C1 is required for sperm motility. Overall, we establish a homozygous truncating mutation in SLC9C1 as a novel cause of human asthenozoospermia and infertility.
Are marginal bone level changes around dental implants due to infection?
Authors: Coli Pierluigi , Jemt Torsten
Published: January 2021

Background

Peri‐implant bone level values have been used as the clinical standard of reference to describe the status of a dental implant. Reduction of marginal bone levels in association with bleeding on probing have been claimed to be a sign of pathology and an indication of treatment needs.

Purpose

To assess the available evidence that peri‐implant bone loss is caused by infection.

Materials and methods

This article is a narrative review on the interpretation of marginal bone level changes around dental implants as a consequence of infection.

Results and conclusions

There is evidence that plaque accumulation induces an inflammatory reaction in the peri‐implant soft tissues and that resumption of plaque control measures results in the reduction of the inflammation. Since plaque is always present in the oral cavity, a cause‐effect relationship between plaque accumulation and peri‐implantitis, defined as inflammation of the peri‐implant soft tissues associated with marginal bone loss has been difficult to validate and has not been proven so far. There is no evidence of the mechanisms involved in the tissue reactions resulting in the conversion from a state of an inevitable inflammation contained in the soft tissues to a state of inflammation involving the loss of peri‐implant marginal bone. There is today no consensus whether implants should be expected to be surrounded by tissues which are completely free from inflammation, or that an “immune‐driven”, chronic, subclinical inflammation should be expected at the foreign body implant. The infectious origin theory appears to be mainly supported by ligature‐induced experimental peri‐implantitis investigations in animal models that suffer of several methodological problems, and therefore, provide misleading information with regards to human clinical applications in large, routine populations.
Epilepsy enhance global efficiency of language networks in right temporal lobe gliomas
Authors: Fang Shengyu , Wang Yinyan , Jiang Tao
Published: January 2021

Aims

We analyzed the resting state functional magnetic resonance images to investigate the alterations of neural networks in patients with glioma‐related epilepsy (GRE).

Methods

Fifty‐six patients with right temporal lower‐grade glioma were divided into GRE (n = 28) and non‐GRE groups. Twenty‐eight healthy subjects were recruited after matching age, sex, and education level. Sensorimotor, visual, language, and left executive control networks were applied to generate functional connectivity matrices, and their topological properties were investigated.

Results

No significant alterations in functional connectivity were found. The least significant discovery test revealed differences only in the language network. The shortest path length, clustering coefficient, local efficiency, and vulnerability were greater in the non‐GRE group than in the other groups. The nodal efficiencies of two nodes (mirror areas to Broca and Wernicke) were weaker in the non‐GRE group than in the other groups. The node of degree centrality (Broca), nodal local efficiency (Wernicke), and nodal clustering coefficient (temporal polar) were greater in the non‐GRE group than in the healthy group.

Conclusion

Different tumor locations alter different neural networks. Temporal lobe gliomas in the right hemisphere altered the language network. Glioma itself and GRE altered the network in opposing ways in patients with right temporal glioma.
Gut dysbiosis in stroke and its implications on Alzheimer’s disease‐like cognitive dysfunction
Authors: Cho Justin , Park You Jeong , Gonzales‐Portillo Bella , Saft Madeline , Cozene Blaise , Sadanandan Nadia , Borlongan Cesar V.
Published: January 2021

Various neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut‐brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut‐brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell‐based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut‐microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes.
Gene therapy for diabetic peripheral neuropathy: A randomized, placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor
Authors: Kessler John A. , Shaibani Aziz , Sang Christine N. , Christiansen Mark , Kudrow David , Vinik Aaron , Shin Nari ,   the VM202 study group
Published: January 2021

VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN.

WHAT QUESTION DID THIS STUDY ADDRESS?

Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Nonviral gene therapy can be used safely and practically to treat DPN.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.
Safety and effectiveness of linagliptin in Korean patients with type 2 diabetes: A postmarketing surveillance study
Authors: Bae Jaehyun , Song Kee‐Ho , Park Jong Suk , Lee Jae Hyuk , Jeong In‐Kyung , Kim Hyun Jin , Lim Young‐Hyo , Cho Jae‐Hyoung , Choi Sung Hee , Chung Yoon‐Sok , Kang Eun Seok
Published: January 2021

We designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was −0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.
HbA1c and brain health across the entire glycaemic spectrum
Authors: Garfield Victoria , Farmaki Aliki‐Eleni , Eastwood Sophie V. , Mathur Rohini , Rentsch Christopher T. , Bhaskaran Krishnan , Smeeth Liam , Chaturvedi Nish
Published: January 2021

Aim

To understand the relationship between HbA1c and brain health across the entire glycaemic spectrum.

Materials and Methods

We used data from the UK Biobank cohort consisting of 500,000 individuals aged 40–69 years. HbA1c and diabetes diagnosis were used to define baseline glycaemic categories. Our outcomes included incident all‐cause dementia, vascular dementia (VD), Alzheimer's dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. The reference group was normoglycaemic individuals (HbA1c ≥35 & <42 mmol/mol). Our maximum analytical sample contained 449,973 individuals with complete data.

Results

Prediabetes and known diabetes increased incident VD (HR 1.54; 95% CI = 1.04, 2.28 and HR 2.97; 95% CI = 2.26, 3.90, respectively). Known diabetes increased all‐cause and AD risk (HR 1.91; 95% CI = 1.66, 2.21 and HR 1.84; 95% CI = 1.44, 2.36, respectively). Prediabetes and known diabetes elevated the risks of cognitive decline (OR 1.42; 1.48, 2.96 and OR 1.39; 1.04, 1.75, respectively). Prediabetes, undiagnosed and known diabetes conferred higher WMH volumes (3%, 22% and 7%, respectively) and lower HV (36, 80 and 82 mm3, respectively), whereas low‐normal HbA1c had 1% lower WMH volume and 12 mm3 greater HV.

Conclusion

Both prediabetes and known diabetes are harmful in terms of VD, cognitive decline and AD risks, as well as lower HV. Associations appeared to be somewhat driven by antihypertensive medication, which implies that certain cardiovascular drugs may ameliorate some of the excess risk. Low‐normal HbA1c levels, however, are associated with more favourable brain health outcomes and warrant more in‐depth investigation.