bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy
Authors: Miller Annie L. , Fuller-Carter Paula I. , Masarini Klaudija , Samardzija Marijana , Carter Kim W. , Rashwan Rabab , Brunet Alicia A. , Chopra Abha , Ram Ramesh , Grimm Christian , Ueffing Marius , Carvalho Livia S. , Trifunović Dragana
Published: February 2022

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD, to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in the development of a broad class of novel therapies to slow cone degeneration.
Creativity in Verbal Associations is Linked to Semantic Control
Authors: Krieger-Redwood Katya , Steward Anna , Gao Zhiyao , Wang Xiuyi , Halai Ajay , Smallwood Jonathan , Jefferies Elizabeth
Published: February 2022

While memory is known to play a key role in creativity, previous studies have not isolated the critical component processes and networks. We asked participants to generate links between words that ranged from strongly related to completely unrelated in long-term memory, delineating the neurocognitive processes that underpin more unique versus stereotypical patterns of retrieval. Less creative responses to strongly associated word pairs were associated with greater engagement of episodic memory: in highly familiar situations, semantic and episodic stores converge on the same information. This pattern of retrieval was associated with greater engagement of core default mode network. In contrast, more creative responses to weakly associated word pairs were associated with the controlled retrieval of less dominant semantic information and greater recruitment of the semantic control network, which overlaps with the dorsomedial subsystem of default mode network. Consequently, although both creative/controlled and stereotypical/more automatic patterns of retrieval are associated with activation within default mode network, these processes show little overlap in activation. These findings show that creativity emerges from controlled aspects of semantic cognition.
The C-terminal domain of Hsp70 is responsible for paralog-specific regulation of ribonucleotide reductase
Authors: Knighton Laura E. , Nitika  , Omkar Siddhi , Truman Andrew. W.
Published: February 2022

The Hsp70 family of molecular chaperones is well-conserved and expressed in all organisms. In budding yeast, cells express four highly similar cytosolic Hsp70s Ssa1, 2, 3 and 4 which arose from gene duplication. Ssa1 and 2 are constitutively expressed while Ssa3 and 4 are induced upon heat shock. Recent evidence suggests that despite their amino acid similarity, these Ssas have unique roles in the cell. Here we examine the relative importance of Ssa1-4 in the regulation of the enzyme ribonucleotide reductase (RNR). We demonstrate that cells expressing either Ssa3 or Ssa4 as their sole Ssa are compromised for their resistance to DNA damaging agents and activation of DDR transcription. In addition, we show that the steady state levels and stability of RNR small subunits Rnr2 and Rnr4 are reduced in Ssa3 or Ssa4-expressing cells, a result of decreased Ssa-RNR interaction. Interaction between the Hsp70 co-chaperone Ydj1 and RNR is correspondingly decreased in cells only expressing Ssa3 and 4. Through studies of Ssa2/4 domain swap chimeras, we determined that the C-terminal domain of Ssas are the source of this functional specificity. Taking together, our work suggests a distinct role for Ssa paralogs in regulating DNA replication mediated by C-terminus sequence variation.

Author Summary

Cells require molecular chaperones to fold proteins into their active conformation. A major mystery however is why cells express so many highly-related and apparently redundant Hsp70 paralogs. We examined the role of four Hsp70 paralogs in budding yeast (Ssa1, 2, 3 and 4) on the activity of the ribonucleotide reductase (RNR complex). Importantly, we demonstrate there is selectivity of RNR subunits for Ssa1 and Ssa2 subunits, which is dictated by the co-chaperone Ydj1. Taken together, our work provides new insight into the functional specificity of Hsp70 paralogs using a native client protein.
Compression-dependent microtubule reinforcement comprises a mechanostat which enables cells to navigate confined environments
Authors: Ju Robert J. , Falconer Alistair D. , Dean Kevin M. , Fiolka Reto P. , Sester David P. , Nobis Max , Timpson Paul , Lomakin Alexis J. , Danuser Gaudenz , White Melanie D. , Oelz Dietmar B. , Haass Nikolas K. , Stehbens Samantha J.
Published: February 2022

Cells migrating through complex 3D environments experience considerable physical challenges including tensile stress and compression. To move, cells need to resist these forces whilst also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in 3D is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of CLASPs (cytoplasmic linker-associated proteins) which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organise contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a new role for microtubules as cellular sensors which detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments.

One Sentence Summary

Mechanically tuned microtubules form a mechanostat to coordinate contractility and nuclear positioning in confined migration.
All-optical manipulation of the Drosophila olfactory system
Authors: Zanon Mirko , Zanini Damiano , Haase Albrecht
Published: February 2022

Thanks to its well-known neuroanatomy, limited brain size, complex behaviour, and extensive genetic methods, Drosophila has become an indispensable model in neuroscience. A vast number of studies have focused on its olfactory system and the processing of odour information. Optogenetics is one of the recently developed genetic tools that significantly advance this field of research, allowing to replace odour stimuli by direct neuronal activation with light. This becomes a universal all-optical toolkit when spatially selective optogenetic activation is combined with calcium imaging to read out neuronal responses. Initial experiments showed a successful implementation to study the olfactory system in fish and mice, but the olfactory system of Drosophila has been so far precluded from an application. To fill this gap, we present here optogenetic tools to selectively stimulate functional units in the Drosophila olfactory system, combined with two-photon calcium imaging to read out the activity patterns elicited by these stimuli at different levels of the brain. This method allows to study the spatial and temporal features of the information flow and reveals the functional connectivity in the olfactory network.
Home-based work and stress in the pandemic period: a case of working women in Kerala
Authors: Soman Sumesh , Mohanan Dhanya
Published: February 2022

Purpose

The study has a twofold purpose. The first purpose is to understand the impact of the Covid-19 pandemic on women's work–home integration and stress from both a constructivist and positivist perspective. The other purpose is to emphasize the need for enterprises to understand the embedded considerations of occupational stress of women for strategy formulation.

Design/methodology/approach

The study has used a convergent parallel design to obtain data. A total of 63 respondents (a survey with a sample of 53 and ten narratives) was identified using the snowball technique. The respondents were married and working professionals from Kerala. Perceived stress scale was used to procure data on their stress in the home-based work during the pandemic lockdown. Simultaneously narratives were taken from ten respondents from the same pool. The data were analyzed using R software version 4.0.2.

Findings

The findings reflect that home-based work was stressful for women, and they weighed home tasks over work needs. There was no age difference in perceived stress, while it significantly differed by profession and designation they hold. Also, a mother felt more stressed than a non-mother. Quantitative data heavily backed up the narratives. Of the sample, 76% experienced higher stress levels.

Practical implications

This research will help users understand the stress distribution in women workers and how various sample characteristics influence stress. The enterprise could use this study to introduce a gender touch to their strategy. The study also adds value to the existing literature on home-based work during the pandemic.

Originality/value

The study systematically measures the stress felt by women during home-based work using a perceived stress scale. The mixed approach to the study helps to gain a deep understanding of the topic. This study is an original contribution by the authors to the collection of home-based work and stress literature.
The impact of the institutional environment on entrepreneurial activity: an analysis of developing and developed countries
Authors: Mello Lucas Pereira de , Moraes Gustavo Hermínio Salati Marcondes de , Fischer Bruno Brandão
Published: February 2022

Purpose

Entrepreneurship can be understood as a systemic phenomenon, thus relying on sets of influential factors associated with socioeconomic contexts. Institutional conditions play a pivotal role in this regard, affecting the allocation of entrepreneurial efforts. The goal of this research is to verify to what extent do the pillars of Countries' Institutional Profiles – regulatory, cognitive and normative – affect both the prevalence and quality of entrepreneurship, assessing the differences between developing and developed countries both in total entrepreneurial activity and in the following qualitative frames: innovation rate, high job creation expectations and motivational index.

Design/methodology/approach

The authors’ assessment uses data from the Global Entrepreneurship Monitor (GEM) with a longitudinal approach for 112 countries over the period 2003–2019. Dynamic panel data regressions are applied.

Findings

By comparing developing and developed countries, findings highlight that institutional effects are heterogeneous among developing and developed countries, with informal institutions being more relevant for developing countries than formal ones. Also, using a broad range of institutional indicators, the authors’ assessment indicated that the association between institutional conditions and productive entrepreneurship seems to be far more intricate than argued by theoretical literature.

Practical implications

The authors’ findings indicate the need for developing countries to address formal institutional voids in order to generate more effective conditions for productive entrepreneurship to emerge. Following prior literature, this can have systemic impacts on trajectories for economic growth and development.

Originality/value

The originality of this research consists in using a longitudinal and integrative approach to compare institutional effects on different types of entrepreneurship, as well as comparing these effects in countries at different stages of development.
Toward accountable human-centered AI: rationale and promising directions
Authors: Qadir Junaid , Islam Mohammad Qamar , Al-Fuqaha Ala
Published: February 2022

Purpose

Along with the various beneficial uses of artificial intelligence (AI), there are various unsavory concomitants including the inscrutability of AI tools (and the opaqueness of their mechanisms), the fragility of AI models under adversarial settings, the vulnerability of AI models to bias throughout their pipeline, the high planetary cost of running large AI models and the emergence of exploitative surveillance capitalism-based economic logic built on AI technology. This study aims to document these harms of AI technology and study how these technologies and their developers and users can be made more accountable.

Design/methodology/approach

Due to the nature of the problem, a holistic, multi-pronged approach is required to understand and counter these potential harms. This paper identifies the rationale for urgently focusing on human-centered AI and provide an outlook of promising directions including technical proposals.

Findings

AI has the potential to benefit the entire society, but there remains an increased risk for vulnerable segments of society. This paper provides a general survey of the various approaches proposed in the literature to make AI technology more accountable. This paper reports that the development of ethical accountable AI design requires the confluence and collaboration of many fields (ethical, philosophical, legal, political and technical) and that lack of diversity is a problem plaguing the state of the art in AI.

Originality/value

This paper provides a timely synthesis of the various technosocial proposals in the literature spanning technical areas such as interpretable and explainable AI; algorithmic auditability; as well as policy-making challenges and efforts that can operationalize ethical AI and help in making AI accountable. This paper also identifies and shares promising future directions of research.
Artificial intelligence and climate change: ethical issues
Authors: Nordgren Anders
Published: February 2022

Purpose

The purpose of this paper is to pinpoint and analyse ethical issues raised by the dual role of artificial intelligence (AI) in relation to climate change, that is, AI as a contributor to climate change and AI as a contributor to fighting climate change.

Design/methodology/approach

This paper consists of three main parts. The first part provides a short background on AI and climate change respectively, followed by a presentation of empirical findings on the contribution of AI to climate change. The second part presents proposals by various AI researchers and commentators on how AI companies may contribute to fighting climate change by reducing greenhouse gas emissions from training and use of AI and by providing AI assistance to various mitigation and adaptation measures. The final part investigates ethical issues raised by some of the options presented in the second part.

Findings

AI applications may lead to substantial emissions but may also play an important role in mitigation and adaptation. Given this dual role of AI, ethical considerations by AI companies and governments are of vital importance.

Practical implications

This paper pinpoints practical ethical issues that AI companies and governments should take into account.

Social implications

Given the potential impact of AI on society, it is vital that AI companies and governments take seriously the ethical issues raised by the dual role of AI in relation to climate change.

Originality/value

AI has been the subject of substantial ethical investigation, and even more so has climate change. However, the relationship between AI and climate change has received only limited attention from an ethical perspective. This paper provides such considerations.
An overview on recent advances in functional properties of dietary lipids, encapsulation strategies and applications
Authors: Dave Jaydeep Pinakin , Moula Ali Ali Muhammed , Bavisetty Sri Charan Bindu
Published: February 2022

Purpose

The purpose of this study was to provide contemporary scientific knowledge on the functionality of edible lipids, sources, health benefits, and a special emphasis on different encapsulation strategies to enhance their dietary application and boost the market value.

Design/methodology/approach

Novel technologies overcoming these issues are in great demand. Given that, several novel encapsulation techniques have been established aiming at most of the aspects of functional lipids. In addition, these techniques have been designed to enhance the storage stability and controlled release of lipids in food systems.

Findings

Plant and marine oils are one of the richest sources of functional lipids but are attached with limitations. Currently, alternative sources, such as different types of algae and microorganisms are gaining attention in terms of sustainable production systems. Advances in various encapsulation techniques have helped to overcome the dispersibility and stability problems of lipids encapsulation. Refinement in physicochemical interaction, colloidal dispersion and core-shell modules between wall and core matrix protect dietary lipids during processing have been implemented. Liposomes, micro/nanoemulsions and micro/nanocapsules are found most suitable for food application by improving the fatty acid profile, stability and sensorial properties.

Originality/value

Functional lipids offer numerous health benefits (i.e., simple health-promoting properties to complex disease preventive and curative effects). However, these functional lipids are associated with several disadvantages, such as region-specific availability, vulnerability to oxidation depending on the level of unsaturation, degradation/hydrolysis on processing, low bioavailability, confined storage stability, and others.
Effect of stress on safety‐critical behaviour: An examination of combined resilience engineering and naturalistic decision‐making approaches
Authors: Steen Riana , Pollock Kevin
Published: February 2022

Combining the conceptual tools and methods of resilience engineering (RE) with naturalistic decision‐making (NDM), in the context of police critical incident command, this study explores the capacity of individual commanders to manage occupational stress during a critical incident or crisis. A case scenario and interviews, together with cognitive task analysis (CTA), are used to investigate how stress affects decision making and performance. The analysis shows: (1) As a social process, sensemaking goes beyond an individual's cognitive capacity. It depends on teams and involves collaboration, sharing and assessing risks and uncertainties. (2) In terms of improvisation, decision‐making requires organisational support in training and authorisation. (3) The mechanisms that ensure the synchronisation of activities link to an operational communication strategy grounded on transparency and trust between the parties involved. (4) Individual adaptive capacity also has organisational characteristics. It improves by facilitating and stimulating proactive learning across the organisation. Bringing RE and NDM together, clarifies interdependencies. Thus, the gap between the organisational system and the individual's performance might be closed, which improves performances at the sharp end by a feedback loop that reconciles bottom‐up and top‐down views.
The association of hospital research publications and clinical quality
Authors: Shahian David M. , McCloskey Dan , Liu Xiu , Schneider Elizabeth , Cheng David , Mort Elizabeth A.
Published: February 2022

Objective

To assess the quantity and impact of research publications among US acute care hospitals; to identify hospital characteristics associated with publication volumes; and to estimate the independent association of bibliometric indicators with Hospital Compare quality measures.

Data Sources

Hospital Compare; American Hospital Association Survey; Magnet Recognition Program; Science Citation Index Expanded.

Study Design

In cross‐sectional studies using a 40% random sample of US Medicare‐participating hospitals, we estimated associations of hospital characteristics with publication volumes and associations of hospital‐linked bibliometric indicators with 19 Hospital Compare quality metrics.

Data Collection/Extraction Methods

Using standardized search strategies, we identified all publications attributed to authors from these institutions from January 1, 2015 to December 31, 2016 and their subsequent citations through July 2020.

Principal Findings

Only 647 of 1604 study hospitals (40.3%) had ≥1 publication. Council of Teaching Hospitals and Health Systems (COTH) hospitals had significantly more publications (average 599 vs. 11 for non‐COTH teaching and 0.6 for nonteaching hospitals), and their publications were cited more frequently (average 22.6/publication) than those from non‐COTH teaching (18.2 citations) or nonteaching hospitals (12.8 citations). In multivariable regression, teaching intensity, hospital beds, New England or Pacific region, and not‐for‐profit or government ownership were significant predictors of higher publication volumes; the percentage of Medicaid admissions was inversely associated. In multivariable linear regression, hospital publications were associated with significantly lower risk‐adjusted mortality rates for acute myocardial infarction (coefficient −0.52, p = 0.01), heart failure (coefficient −0.74, p = 0.004), pneumonia (coefficient −1.02, p = 0.001), chronic obstructive pulmonary disease (coefficient −0.48, p = 0.005), and coronary artery bypass surgery (coefficient −0.73, p < 0.0001); higher overall Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) ratings (coefficient 2.37, p = 0.04); and greater patient willingness to recommend (coefficient 3.38, p = 0.01).

Conclusions

A minority of US hospitals published in the biomedical literature. Publication quantity and impact indicators are independently associated with lower risk‐adjusted mortality and higher HCAHPS scores.
Novel methods for spatial prioritization with applications in conservation, land use planning and ecological impact avoidance
Authors: Moilanen Atte , Lehtinen Pauli , Kohonen Ilmari , Jalkanen Joel , Virtanen Elina A. , Kujala Heini
Published: February 2022

Spatial (conservation) prioritization integrates data on the distributions of biodiversity, costs and threats. It produces spatial priority maps that can support ecologically well‐informed land use planning in general, including applications in environmental impact avoidance outside protected areas. Here we describe novel methods that significantly increase the utility of spatial priority ranking in large analyses and with interactive planning.

Methodologically, we describe a novel algorithm for implementing spatial priority ranking, novel alternatives for balancing between biodiversity features, fast tiled FFT transforms for connectivity calculations based on dispersal kernels, and a novel analysis output, the flexibility map.

Marking by N the number of landscape elements with data, the new prioritization algorithm has time scaling of less than Nlog2N instead of the N2 of its predecessor. We illustrate feasible computation times with data up to billions of elements in size, implying capacity for global analysis at a resolution higher than 0.25 km2, or close to 1‐ha resolution for a continent.

The algorithmic improvements described here bring about improved capacity to implement decision support for real‐world spatial conservation planning problems. The methods described here will be at the technical core of forthcoming software releases.
AHA STEROID trial, dexamethasone in acute high‐risk abdominal surgery, the protocol for a randomized controlled trial
Authors: Cihoric Mirjana , Kehlet Henrik , Lauritsen Morten Laksáfoss , Højlund Jakob , Kanstrup Katrine , Foss Nicolai Bang
Published: February 2022

Introduction

Existing multimodal pathways for patients undergoing acute high‐risk abdominal surgery for intestinal obstruction (IO) and perforated viscus (PV) have focused on rescue in the immediate perioperative period. However, there is little focus on the peri‐operative pathophysiology of recovery in this patient group, as done to develop enhanced recovery pathways in elective care. Acute inflammation is the main driver of the perioperative pathophysiology leading to adverse outcomes. Pre‐operative high‐dose of glucocorticoids provides a reduction in the inflammatory response after surgery, effective pain relief in several major surgical procedures, as well as reduce fatigue and improving endothelial dysfunction.

Aim

To evaluate the effect of high‐dose glucocorticoid on the inflammatory response, fluid distribution and recovery after acute high‐risk abdominal surgery in patients with IO and PV.

Methods

AHA STEROID trial is a sponsor‐initiated single‐center, randomized, double‐blind placebo‐controlled trial, assessing preoperative high‐dose dexamethasone (1 mg/kg) versus placebo (normal saline) in patients undergoing emergency high‐risk abdominal surgery. We plan to enroll 120 patients. Primary outcome is the reduction in C‐reactive protein on postoperative day 1 as a marker of successful attenuation of the acute stress response. Secondary outcomes include perioperative changes in endothelial and other inflammatory markers, fluid distribution, pulmonary function, pain, fatigue, and mobilization. The statistical plan is outlined in the protocol.

Discussion

The AHA STEROID trial will provide important evidence to guide the potential use of high‐dose glucocorticoids in emergency high‐risk abdominal surgery, with respect to different pathophysiologies.
Prospective two‐arm study of the testicular function in patients with COVID‐19
Authors: Enikeev Dmitry , Taratkin Mark , Morozov Andrey , Petov Vladislav , Korolev Dmitry , Shpikina Anastasia , Spivak Leonid , Kharlamova Svetlana , Shchedrina Irina , Mestnikov Oleg , Fiev Dmitry , Ganzha Timur , Geladze Marina , Mambetova Aichurok , Kogan Evgenia , Zharkov Nikolay , Demyashkin Gregory , Shariat Shahrokh F. , Glybochko Petr
Published: February 2022

Background

The COVID‐19 pandemic has led the international community to conduct extensive research into potential negative effects of the disease on multiple organs and systems in the human body. One of the most discussed areas is potential of the virus to compromise the testicular function. However, the lack of prospective studies on this topic makes it impossible to draw reliable conclusions on whether the disease affects the male reproductive system and, if so, to what extent.

Objectives

The current trial is aimed at investigating the effect of SARS‐CoV‐2 on the testicular function, hormone levels and determining the extent of impact on spermatogenesis and damage to testicular tissue.

Materials and methods

This prospective study included healthy controls and cases of patients suffering from viral pneumonia based on chest computed tomography (CT) and a positive SARS‐CoV‐2 throat swab exhibited moderate symptoms (World Health Organization (WHO) classification). Epidemiological, clinical, laboratory and ultrasound data were collected. A semen analysis was performed in cases during their hospital stay and 3 months after the discharge home. We also assessed the testicles obtained during autopsies of patients who died of COVID‐19 (n = 20).

Results

A total of 88 participants were included (44 controls and 44 cases). Blood testosterone levels were significantly decreased in 27.3% of the cases (12/44). The mean level (7.3±2.7 nmol/L) was lower than that in the healthy controls (13.5±5.2 nmol/L, p < 0.001). An increase in luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) was also detected compared to the healthy controls (p = 0.04 and p = 0.002). The semen analysis revealed decreased motility in COVID‐19 patients (p = 0.001), and a higher number of immobile sperm (during COVID‐19: 58.8% and at 3 months 47.4%, p = 0.005). All parameters returned to normal at 3 months after discharge. Direct mixed agglutination reaction (MAR) test at 3 months showed an increase of Ig A (p = 0.03). In the majority of autopsies (18/20), structural disorders of the testicular tissue, with signs of damage to germ cells were observed.

Discussion and conclusion

COVID‐19 and its management strategies significantly affect male hormone levels and sperm quality at the onset of the disease. Postmortem examination of testicular tissue confirmed inflammation and viral infiltration of the testicles. However, in patients with moderate to severe disease, the studied parameters of the testicular function returned to normal values within 3 months.
Landscape of pathogenic variants in six pre‐mRNA processing factor genes for retinitis pigmentosa based on large in‐house data sets and database comparisons
Authors: Wang Junwen , Xiao Xueshan , Li Shiqiang , Jiang Hongmei , Sun Wenmin , Wang Panfeng , Zhang Qingjiong
Published: February 2022

Purpose

Variants in six genes encoding pre‐mRNA processing factors (PRPFs) are a common cause of autosomal dominant retinitis pigmentosa (ADRP). This study aims to determine the characteristics of potential pathogenic variants (PPVs) in the six genes.

Methods

Variants in six PRPF genes were identified from in‐house exome sequencing data. PPVs were identified based on comparative bioinformatics analysis, clinical phenotypes and the ACMG/AMP guidelines. The features of PPVs were revealed by comparative analysis of in‐house data set, gnomAD and previously published literature.

Results

Totally, 36 heterozygous PPVs, including 19 novels, were detected from 45 families, which contributed to 4.4% (45/1019) of RP cases. These PPVs were distributed in PRPF31 (17/45, 37.8%), SNRNP200 (12/45, 26.7%), PRPF8 (10/45, 22.2%) and PRPF3 (6/45, 13.3%) but not in PRPF6 or PRPF4. Different types of PPVs were predominant in different PRPF genes, such as loss‐of‐function variants in PRPF31 and missense variants in the five remaining genes. The clustering of PPVs in specific regions was observed in SNRNP200, PRPF8 and PRPF3. The pathogenicity for certain classes of variants in these genes, such as loss‐of‐function variants in PRPF6 and missense variants in PRPF31 and PRPF4, requires careful consideration and further validation. The predominant fundus changes were early macular involvement, widespread RPE atrophy and pigmentation in the mid‐ and far‐peripheral retina.

Conclusion

Systemic comparative analysis may shed light on the characterization of PPVs in these genes. Our findings provide a brief landscape of PPVs in PRPF genes and the associated phenotypes and emphasize the careful classification of pathogenicity for certain types of variants that warrant further characterization.
Supratherapeutic lithium levels in COVID‐19 infection
Authors: Rojas‐Velasquez Danilo , Lifland Brooke , Caro Mario Andres
Published: February 2022

Lithium levels are often checked in the inpatient setting when a patient has clear indications of acute kidney injury. Lithium levels can become supratherapeutic in COVID‐19 infection even after normalization of creatinine. Lithium levels should be checked routinely in patients with COVID‐19 infection in order to avoid supratherapeutic levels.
Pramlintide for post‐bariatric hypoglycaemia
Authors: Sheehan Amanda , Goldfine Allison , Bajwa Muhammed , Wolfs Danielle , Kozuka Chisayo , Piper Jacqueline , Fowler Kristen , Patti Mary Elizabeth
Published: February 2022

Aims

The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post‐bariatric hypoglycaemia (PBH).

Materials and Methods

Participants with PBH following gastric bypass were recruited from outpatient clinics at the Joslin Diabetes Center, Boston, Massachusetts for an open‐label study of pramlintide efficacy over 8 weeks. Twenty‐three participants were assessed for eligibility, 20 participants had at least one pramlintide dose, and 14 completed the study. A mixed‐meal tolerance test (MMTT) was performed at baseline and after 8 weeks of subcutaneous pramlintide with a sequential dose increase to a maximum of 120 micrograms (mean 69 ± 32 mcg) three times daily. The primary endpoint was change in glucose excursions during the MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose (SG) <3.9 mM, and number of days with minimum SG <3 mM, during masked continuous glucose monitoring.

Results

There were no differences in MMTT glucose, glucagon or insulin between baseline and post treatment. We observed no significant change in satiety or dumping scores. The overall frequency of low SG values did not change, although there was substantial inter‐individual variability.

Conclusions

In PBH, pramlintide does not modulate glycaemic or insulin responses, satiety, or dumping scores during an MMTT and does not impact glycaemic excursions or decrease low SG levels in the outpatient setting.
Effects of glucagon‐like peptide‐1 receptor agonists on cardiovascular and renal outcomes: A meta‐analysis and meta‐regression analysis
Authors: Yoshiji Satoshi , Minamino Hiroto , Tanaka Daisuke , Yamane Shunsuke , Harada Norio , Inagaki Nobuya
Published: February 2022

Aim

To evaluate the cardiovascular and renal outcomes of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and the associations between these outcomes and HbA1c or weight reduction.

Materials and Methods

We searched PubMed/MEDLINE, EMBASE, and CENTRAL databases for randomized, placebo‐controlled trials of GLP‐1 RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta‐regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta‐analysis with a random‐effects model for these outcomes.

Results

We extracted data of 60 800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN‐6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE‐O). GLP‐1 RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80‐0.93; P < .001) and secondary outcomes including the composite renal outcome (0.80; 0.73‐0.87; P < .001). In meta‐regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = .044; R2 = 0.65) and the composite renal outcome (P = .040; R2 = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = .390).

Conclusions

The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for the cardiovascular and renal benefits of treatment with GLP‐1 RAs.
Local glucose metabolism is unaltered in reversible splenial lesion syndrome
Authors: Zöllner Johann Philipp , Wichert Jennifer , Schubert‐Bast Susanne , Hattingen Elke , Rosenow Felix , Strzelczyk Adam
Published: February 2022

Background and purpose

Transient splenial oedema, also known as reversible splenial lesion syndrome (RESLES), is a rare magnetic resonance imaging (MRI) finding that presents as a round or ovoid focal oedema in the posterior corpus callosum, and is associated with a wide range of clinical conditions. The aetiology of RESLES is not fully clear. We aimed to investigate conflicting pathophysiological hypotheses by measuring local glucose metabolism in patients with RESLES.

Methods

We retrospectively analysed patients with RESLES after reductions in antiseizure medications during in‐hospital video electroencephalography monitoring. We measured local glucose uptake using positron emission tomography/computed tomography and compared matched cohorts of patients with and without MRI evidence of RESLES using nonparametric tests.

Results

Local glucose metabolism in the splenium of seven patients with RESLES was not significantly different from the glucose metabolism of the seven patients in the matched cohort. This was true using both regular and normalized standardized glucose uptake value calculation methods (p = 0.902 and p = 0.535, respectively).

Conclusion

We found no evidence of local glucose hypometabolism in RESLES, which supports previous pathophysiological considerations that suggest that RESLES is an intercellular, intramyelinic oedema rather than a typical intracellular cytotoxic oedema, which is not reversible.
Validation of an equine fitness tracker: ECG quality and arrhythmia detection
Authors: ter Woort Fe , Dubois Guillaume , Tansley Grace , Didier Marie , Verdegaal Elisabeth‐Lidwien , Franklin Samantha , Van Erck‐Westergren Emmanuelle
Published: February 2022

Background

Cardiac arrhythmias in exercising horses are the focus of much interest, both in terms of what is considered normal and potential associations with poor performance and sudden cardiac death. One barrier to performing large‐scale studies is the lack of an easily applicable device, to allow recording of large numbers of high‐quality exercising electrocardiograms (ECGs). The EquimetreTM is a new wearable device, which records a single lead ECG, among other parameters. Validation of such wearable devices is essential before further studies are undertaken.

Objectives

To evaluate the quality of ECG using the EquimetreTM and compare arrhythmia detection during exercise with the reference TelevetTM system.

Study design

Prospective blinded clinical study.

Methods

Simultaneous ECGs were recorded with both systems in 49 healthy horses during exercise. High‐intensity exercise (>40 km/h) was performed by 29 racehorses, and lower‐intensity exercise for the remainder of the racehorses and show jumpers. Tracings were excluded if >10% artefact was present (duration of artefact relative to duration of exercise). For included ECGs, the duration of artefact was recorded and compared. ECGs were evaluated using Kubios premium software. Arrhythmia detection (yes/no) and arrhythmia classification (sinus arrhythmia, narrow complex of similar morphology to the sinus complexes or wide complex with a different morphology) were compared using Cohen's Kappa coefficient.

Results

Nine TelevetTM ECGs and 3 EquimetreTM ECGs were excluded due to artefact >10%. TelevetTM ECGs included significantly more artefact during exercise than EquimetreTM ECGs (5% vs. 0.25% P < .001). Arrhythmia analysis was performed on 38 horses’ paired ECGs. The kappa coefficient was excellent for arrhythmia detection (K = 0.97) and arrhythmia classification (K = 0.93).

Main limitations

Relatively low numbers of horses with arrhythmias (n = 21) were included. The ECG recordings only provided one lead, making arrhythmia classification challenging in some cases.

Conclusions

The Equimetre device provides a reliable ECG for arrhythmia detection during exercise. This system may be useful clinically and for future large‐scale investigations into the occurrence and significance of exercising arrhythmias.
Do small‐scale fisheries have the capacity to provide food security to coastal populations?
Authors: Canty Steven W. J. , Deichmann Jessica L.
Published: February 2022

Whilst total global fisheries landed catches declined from 1950 to 2016, small‐scale fisheries (SSFs) landed catches increased. Amongst SSFs landed catches, approximately 95% are consumed domestically. Taken together, these highlight the importance of the potential for SSFs to contribute to food security and well‐being of coastal populations, particularly in Developing Economy Countries (DECs). We used the Sea Around Us database to evaluate long‐term trends of marine SSFs landed catches in 85 DECs. We analyse whether yields from SSFs have the capacity to provide the coastal populations of DECs with a recommended annual intake (RAI) of 10.6 kg of fish per person, and how that capacity has changed over the period of 1960 to 2016. We show that landed catches of SSFs increased in the majority of DECs evaluated from 1950 to 2016. However, in 2016, over one‐third of SSFs in DECs assessed did not have the capacity to provide the RAI of fish to coastal communities, and 64% of all SSFs assessed are exhibiting significant declines in their capacity to fulfil this need. Regional trends in providing RAI were highly variable, putting the long‐term sustainability and capacity of SSFs to contribute meaningfully to food security in doubt. This study demonstrates that landed catches of SSFs alone are not a useful proxy for food security. Implementation of proven effective management practices, policies to improve accessibility and consumption patterns, and the prioritization of small‐scale wild‐caught fisheries are needed to ensure the food security of billions of people in coastal communities.
Separation of powers, opposition strength, and chief executives' strategy
Authors: Lee Don S. , Magyar Zsuzsanna B.
Published: February 2022

One of the main questions about presidential democracies is to what extent the legislature influences executive governance. However, less well‐known in this literature is the influence of opposition parties in policy‐making and government formation processes. We argue that, in multiparty presidential governments, more concentrated opposition forces in the legislature, as opposed to more fragmented, lead to higher government spending and greater chances of coalition formation. Facing more united opposition, presidents who are concerned about passing their agenda in the legislature are willing to pay the price to hold their ruling party or governing coalition together in tighter unity. We test this logic by analyzing data on government spending and cabinet formation in all multiparty presidential democracies in East and Southeast Asia and find strong support for it, controlling for several political and economic variables. Our analysis further shows that chief executives' electoral incentives strongly shape their budget spending and cabinet appointments.
Exploration of the molecular mechanisms underlying the antibiotic resistance of Helicobacter pylori: A whole‐genome sequencing‐based study in Southern China
Authors: Li Ying , Huang Zhixin , Shang Yanyan , Xie Xinqiang , Yang Runshi , Chen Huizhen , Wang Zhi , Xue Liang , Pang Rui , Zhang Jumei , Ding Yu , Chen Moutong , Wang Juan , Chen Jianhui , Wu Qingping
Published: February 2022

Background

Although antimicrobial resistance (AMR) in Helicobacter pylori is a global threat to human health and the underlying molecular mechanisms have been explored previously, only a few of them are fully elucidated.

Materials and Methods

In the present study, we isolated 54 Helicobacter pylori strains from Southern China and assessed their susceptibility to five antibiotics using the agar dilution assay. Whole‐genome sequencing was performed to screen the AMR genotypes of the Helicobacter pylori isolates.

Results

Our study revealed a high prevalence of resistance to clarithromycin (CLR), levofloxacin (LVX), and metronidazole (MTZ) in the Chinese isolates, 55.56% of which showed multidrug‐resistant phenotypes. We screened for the 94 types of previously reported AMR mutations in 12 genes, but only a few of them were related to the AMR phenotype. Furthermore, we discovered four new mutations in the 23S rRNA gene and one mutation in infB related to CLR resistance. Another three mutations in gyrA and one in gyrB were closely correlated with the AMR pattern against LVX. We also demonstrated that the mutations R16C/H in rdxA, V56I in rpsU, and D54A in sodB might contribute to resistance to MTZ, which were previously reported in laboratory experiments but not found in clinical strains. We examined the concordance between the genotype and phenotype of AMR and identified several potential molecular biomarkers for predicting CLR and LVX resistance.

Conclusions

Our study explored the molecular mechanisms underlying the antibiotic resistance of Helicobacter pylori isolates from Southern China. We propose further epidemiologic investigations in China.
Prevalence and predictors of bradyarrhythmias requiring permanent pacing in patients with Anderson–Fabry disease
Authors: Tassetti Luigi , Fumagalli Carlo , Argirò Alessia , Zampieri Mattia , Gori Martina , Verrillo Federica , Zocchi Chiara , Cappelli Francesco , Olivotto Iacopo
Published: February 2022

Introduction

Bradyarrhythmias are an established red flag for storage cardiac conditions including Anderson–Fabry disease (AFD). The prevalence of bradyarrhythmias requiring a pacemaker (PM) and their timing in AFD is unresolved.

Methods

We evaluated the prevalence and predictors of PM requirement in a large AFD cohort, investigating the occurrence of bradyarrhythmias as initial versus late manifestation. We retrospectively evaluated 82 consecutive AFD patients referred to our multidisciplinary referral center from 1994 to 2020 with a median follow‐up of 6.9 years, identifying those requiring pacing. Univariable analysis was performed to identify cardiac features associated with PM implantation.

Results

Five of 82 (6%) AFD patients required PM implantation (5/39, i.e., 13% of those with cardiac involvement), always in the context of advanced cardiomyopathy. In none, bradyarrhythmias were the presenting feature. Indications included sick sinus syndrome in three patients, advanced atrioventricular block in two patients. QRS prolongation during follow‐up strongly correlated with the onset of bradyarrhythmias.

Conclusion

Severe bradyarrhythmias are relatively frequent in patients with AFD cardiomyopathy, but do not represent a mode of presentation, occurring late in the disease course and always in the context of advanced cardiac involvement. Monitoring QRS variations over time may help to identify patients requiring pacing.