bluuebunny/crossref_metadata_2025 huggingface dataset:
Better Than “Democracy”
Authors: Cappelen Herman
Published: August 2023

This chapter shows how we can do better than “democracy” and “democratic.” Speakers who use the D-words—be they theorists or ordinary citizens—could easily use other terminology. We have easy access to alternative terminology that’s more effective, and it takes minimal effort to find all these alternative ways of speaking. The chapter presents this as a challenge, and sets out an argument from alternative vocabulary. It complements the previous chapter (which shows how the D-words are defective) and shows how we can do better. Finally, the chapter lists points that can be used to quantify what might be called “democracy.”
Objections and Replies
Authors: Cappelen Herman
Published: August 2023

In its earlier chapters, this book has been somewhat tentative in its defense of abandonment. This final chapter lists, considers, and responds to a series of objections (that the reader may have) to abandonment, including some further-refined versions of the objections. One such objection claims that “democracy” is the paradigm of what has been called an essentially contested concept, and another that the phenomenon of metalinguistic negotiation undermines the argument for abandonment. Following the replies to these objections, the chapter addresses a concern that the arguments in the book overgenerate, and stresses some proposals for how speakers can do better.
The ventral visual system
Authors: Rolls Edmund T.
Published: August 2023

The brain processes involved in visual object recognition are described. Evidence is presented that what is computed are sparse distributed representations of objects that are invariant with respect to transforms including position, size, and even view in the ventral stream towards the inferior temporal visual cortex. The cortical connectivity of the human ventral visual cortical stream for object and face recognition is described, and also a stream to the cortex in the superior temporal sulcus for socially relevant moving stimuli. Then biologically plausible unsupervised learning computations for invariant visual object recognition that use a synaptic modification rule that utilises a memory trace are described. These are compared with deep learning and other machine learning approaches that typically require supervision.
The parietal cortex, spatial functions, and navigation
Authors: Rolls Edmund T.
Published: August 2023

The parietal areas that are involved in the dorsal visual stream are described in Chapter 3. This Chapter builds on that, and considers the functions of spatial information in the parietal cortex in navigation, actions in space, and semantic representations. The superior parietal areas including the intraparietal cortex and area 7 regions are implicated in actions in space and the coordinate transforms required for these; and may thereby contribute to the self-motion update of spatial view cells in the parahippocampal and hippocampal cortex for memory and navigation. The anterior inferior temporal cortex regions process somatosensory information that reaches region PF at the top of the somatosensory hierarchy. The posterior inferior parietal regions in humans include visual regions PGi, PGs and PFm which have strong connectivity with temporal lobe semantic regions to which they contribute visuo-spatial information.
The cingulate cortex
Authors: Rolls Edmund T.
Published: August 2023

The pregenual anterior cingulate cortex receive information from the orbitofrontal and ventromedial prefrontal cortex, and connect with the hippocampal and posterior cingulate cortex to provide reward information for memory and the goals for navigation. The dorsal or supracallosal anterior cingulate cortex also receives reward/non-reward information, but associates this as outcome information with actions recently made to implement action-outcome learning. is involved in action-outcome learning. The posterior cingulate postero-ventral regions receive information from the visual inferior temporal cortex and auditory and semantic superior temporal sulcus regions, and from vmPFC and pregenual cingulate reward regions. They have connectivity to the hippocampal system thereby contributing to ‘what’ information for hippocampal episodic memory. The posterior cingulate division antero-dorsal regions (including the RSC region) receive inputs from the parietal cortex, including areas 7a, VIP and LIP laterally, and area 7m medially, and have effective connectivity to the hippocampal systems thereby contributing to ‘where’ information for the idiothetic update of scene representations used for hippocampal episodic memory.
Helena Petrovna Blavatsky (The Theosophical Society), The Secret Doctrine (1888)
Authors: Faxneld Per
Published: August 2023

This chapter focuses on Helena Petrovna Blavatsky’s The Secret Doctrine (1888). Blavatsky, the chief ideologist of the Theosophical Society, was the first person to present a positive understanding of Satan in an exclusively esoteric or religious (as opposed to literary or political) context. She argues that Satan—or Lucifer, or the Devil, as she often uses the names interchangeably—brought humankind spiritual wisdom by offering us the forbidden fruit from the Tree of Knowledge in the Garden of Eden. He is therefore “the spirit of Intellectual Enlightenment and Freedom of Thought,” and the so-called Fall of Man was in fact a positive event, an initiation into esoteric knowledge. An important building block in Blavatsky’s construction of Satan was contemporary (semi-) scholarly understandings of ancient Gnosticism.
Anton LaVey (Church of Satan), Interview in John Fritscher’s Popular Witchcraft: Straight from the Witch’s Mouth (1972)
Authors: Holt Cimminnee
Published: August 2023

This chapter examines an excerpt from an interview with Church of Satan founder Anton LaVey in John Fritscher’s Popular Witchcraft: Straight from the Witch’s Mouth (1972). Emerging from the counterculture movements of the 1960s, LaVey claimed to blend the discourses of science and magic to present a “rational” religion that caters to the “true” nature of humankind. LaVey’s Satanism views Satan as a symbol of liberty, antinomianism, and Epicureanism, wherein the satanic figure is a rebellious hero representing sexual freedom, intellectual curiosity, and unapologetic materialism. Fritscher’s interview with LaVey is perhaps one of the most circulated and influential, as it captures LaVey just beyond the initial foundational years of the Church of Satan. In the interview, LaVey denies the existence of a literal Satan, interpreting a satanic “presence” as an exteriorized version of his own ego. He also targets Christianity’s apparent duplicity in terms of human sexuality, as it (and all religion) denies and suppresses the essential carnal, animal nature of humankind.
Thomas Karlsson (Dragon Rouge), Kabbala, kliffot och den goetiska magin (2004)
Authors: Gregorius Fredrik
Published: August 2023

This chapter explores the magical order Dragon Rouge, which was founded in Stockholm, Sweden, in 1989 by Thomas Karlsson. It focuses on “The Fall of Lucifer,” an excerpt from Qabalah, Qliphoth and Goetic Magic (2004). Dragon Rouge does not regard itself as a Satanic organization and has from the start rejected the designation. Instead, members of the order often see themselves as followers of the Left-hand Path and practitioners of what the order calls “Dark Magic.” “The Fall of Lucifer” is a retelling of the story of the Garden of Eden, a recurring narrative in Satanic discourse. In Dragon Rouge’s version, the story is told imbedded in a rather technical kabalistic exegesis and is used to differentiate the Left-hand Path, as understood by the order, from other spiritual traditions built around the aspiration to reconcile humanity with God and reclaim the harmony that existed before the Fall.
Taxes and Growth: New Narrative Evidence from Interwar Britain
Authors: Cloyne James , Dimsdale Nicholas , Postel-Vinay Natacha
Published: August 2023

The impact of fiscal policy on economic activity is still a matter of great debate. And, ever since Keynes first commented on it, interwar Britain, 1918–39, has remained a particularly interesting and contentious case—not least because of its high-debt environment and turbulent business cycle. This debate has often focused on the effects of government spending, but little is known about the effects of tax changes. In fact, a number of tax reforms in the period focused on long-term and social objectives, often reflecting the personality of British Chancellors. Based on extensive historiographical research, we apply a narrative approach to the interwar period in Britain and isolate a new series of exogenous tax changes. We find that tax changes have a sizable effect on GDP, with multipliers exceeding 2 within two years. Our estimates provide new evidence on the effects of tax changes, contribute to the historical debate about fiscal policy in the interwar period and are also consistent with the sizable tax multipliers found after World War II.
Knowledge and experiences of healthcare workers in managing children with neurometabolic disorders in a developing country: a cross-sectional study
Authors: Saini Arushi Gahlot , Singanamalla Bhanudeep , Gunasekaran Pradeep Kumar , Didwal Gunjan , Attri Savita Verma
Published: August 2023

Objective

To evaluate the knowledge and experiences of healthcare workers in the management of neurometabolic disorders.

Methods

A cross-sectional study was carried out among the 132 participants of a continued medical education program conducted in the Department of Pediatrics at a tertiary-care teaching hospital. A questionnaire-based feedback form was circulated among the participants, and their responses were analyzed.

Results

Ninety-three responses were analyzed. The most common pediatric illnesses identified were infections (91%), nutritional (91%), birth-related injuries (44.4%) and metabolic disorders (44.4%). Consanguinity (81.5%) and genetic heterogeneity (42.4%) were recognized as most important causes of neurometabolic disorders. Important steps identified for prevention were prenatal testing (65.6%) and newborn screening at birth (61%); while for improving the diagnosis were routine availability of metabolic investigations (65.3%) and screening at birth (46.6%). Most respondents (58.7%) expressed discomfort in managing a case with inherited metabolic defect due to a lack of knowledge (46.8%) and diagnostic facilities (44.6%). Despite access to testing in the majority, a high cost of testing was noticed for biochemical and genetic investigations. The majority of participants (73%) considered some of the inherited metabolic disorders as treatable. Dietary substitution (89.3%), enzyme replacement (69%), cofactor replacement (53.6%), gene therapy (35.7%) and regular dialysis (16.7%) were considered the treatment options.

Conclusion

In spite of growing awareness of inherited metabolic disorders, there are still gaps in knowledge among healthcare workers. It is challenging to diagnose and manage these disorders. Cost-reduction of diagnostic tests, routine newborn screening and increased educational activities are key challenges to be addressed.
Résumé-Writing for Success
Authors: Gary Annette
Published: August 2023

Creating a standout professional résumé can be challenging, particularly for new graduate nurses (NGNs) who may have limited work experience or those who want to go into specialty areas. This article outlines strategies to help NGNs draft a comprehensive résumé and help improve their chances of getting a nursing job.
Twenty-three-hour stays in the ambulatory surgical center: benefits, pathways and protocols
Authors: Ardon Alberto E. , Nimma Sindhuja , Nin Olga C.
Published: August 2023

Purpose of review

To summarize recent evidence that discusses the clinical, financial, and logistical implications of a 23 h stay postsurgical stay unit in an ambulatory surgical center (ASC).

Recent findings

Twenty-three-hour stays in ambulatory surgery centers are safe, but proper patient selection and optimization are key to maintaining a high level of safety. The financial implications of overnight stays in ASCs rely heavily on payment structures and comparative costs at hospital-based outpatient surgery centers. The establishment of pathways and protocols for clinical care are key to the success of a 23 h stay at an ASC

A concurrent concern with the recent increase in outpatient surgery and medical complexity of cases performed in an ambulatory surgical center (ASC) is the possibility that patients may need overnight stay. Further, whether certain patients would benefit from anticipated 23 h observation rather than same-day discharge is an emerging topic. Overnight stays in ASCs may have financial advantages and decrease the risk of unanticipated admission with proper patient selection. The use of protocols and established pathways is key to the success of this model.
Functional outcome of a patient after hip disarticulation due to an infection 10 years after limb salvage surgery for osteosarcoma: A case report
Authors: Aoki Masahiro , Murakami Takanori , Ishiai Sumio , Nosaka Toshiya
Published: August 2023

Limb salvage is a common procedure after extensive osteosarcoma resection. However, the long-term outcomes after limb salvage surgery (LSS) remain unclear. In this article, the case of a 24-year-old man who underwent hip disarticulation (HD) after an uncontrollable infection is presented. He was previously diagnosed with right distal femoral osteosarcoma and underwent LSS 10 years before disarticulation. Four years after LSS, an uncontrollable infection developed around the endoprosthesis, which eventually prompted HD. The Musculoskeletal Tumor Society (MSTS) functional rating system and the Toronto Extremity Salvage Score were used to compare the subject's activity statuses after LSS and HD. MSTS functional scores were 53.3% after LSS and 60% after HD. Toronto Extremity Salvage Scores were 78.3% after LSS and 95.8% after HD. The subject's emotional acceptance was 3 for LSS and 5 for HD (0 = worst and 5 = best). Both the MSTS and Toronto Extremity Salvage Scores were greater after HD than after LSS. The subject's improved emotional acceptance of the affected limb after HD contributed to the improved functional assessment scores. Alleviation of pain and other disabilities associated with the infection may have contributed to the higher functional scores after the more recent HD surgery. Even if amputation is unavoidable because of complications, high psychological acceptance may prevent a decrease in patient mobility and quality of life after amputation.
Design and mechanical testing of an adjustable posterior leaf spring ankle-foot orthosis for patients with drop foot
Authors: Khaing May Su , Samala Manunchaya , Guerra Gary , Wisessint Attaporn
Published: August 2023

Objectives:

This study aimed to design an adjustable posterior leaf spring (PLS) ankle-foot orthosis (AFO) with an affordable material in low-income countries and investigate the mechanical properties between an adjustable PLS AFO and a standard PLS AFO.

Study Design:

Static and dynamic mechanical testing.

Methods:

This study preliminarily tested a new adjustable PLS AFO against a standard PLS AFO. Each AFO design was tested with mechanical testing using an Instron 8801 universal testing machine.

Results:

The stiffness value of the adjustable PLS AFO was greater than that of the standard PLS AFO during the static loading test. The energy dissipated ratios were lower in the adjustable PLS AFO than in the standard PLS AFO. After 110,000 cycles of fatigue testing, the distal rivet of the adjustable PLS AFO became loose, although the standard PLS AFO had no problem.

Conclusions:

The novel adjustable PLS AFO achieved noninferior mechanical properties except fatigue strength. The connecting area always initiated fatigue failure. It is suggested that this area must be prevented for stress concentration. As a preliminary study, this study is fundamental for future studies.
High-Frequency rTMS Could Improve Impaired Memory in Mild Cognitive Impairment Patients in China
Authors: Wang Tao , Guo Zhiwei , Wu Hongxia , Jiang Yi , Mu Qiwen
Published: August 2023

Objective:

The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on improving memory deficits in mild cognitive impairment (MCI), as well as to provide visualized evidence for neuronal specificity by using resting-state functional magnetic resonance imaging.

Materials and Methods:

Forty MCI patients were enrolled to receive 10-session and sham-controlled 10Hz-rTMS over the left dorsolateral prefrontal cortex. The resting-state functional magnetic resonance imaging combined with memory scales assessment were performed before and after the intervention. To elucidate the therapeutic mechanism of rTMS, amplitude of low-frequency fluctuations (ALFF) and functional connectivity were calculated. The Pearson correlation was used to measure the relationship between ALFF and memory performance.

Results:

Compared with the sham group, ALFF significantly increased in the right insula, right inferior frontal gyrus-opercular part, and decreased in the left middle occipital gyrus, left angular gyrus, and left lingual gyrus after rTMS. The change in Auditory Verbal Learning Test scores were negatively correlated with ALFF decreases in the left lingual gyrus. Functional connectivity significantly increased between the posterior cingulate cortex and right supramarginal gyrus, and decreased between the right frontoinsular cortex and right supramarginal gyrus after intervention.

Conclusion:

High-frequency rTMS over the left dorsolateral prefrontal cortex could facilitate improvement on impaired memory in patients with MCI via modulating the neuronal activity and brain network.
Unusually isolated Staphylococcus arlettae in intra-oral sutures - Case series
Authors: Kherdekar Radhika Sunil , Dixit Ashutosh , Kothari Ashish , Pandey Kamal Prasad , Advani Hoshang , Gaurav Amit , Omar Balram Ji
Published: August 2023

Introduction. The human oral cavity comprises various niches such as teeth, gingiva, tongue, soft and hard palate, and various dental prostheses, all inhabited by different bacterial species. Although more than 600 taxa belong to the oral cavity, identifying

Staphylococcus arlettae

, an incompletely understood bacterium, has been rare.

Methods. Three patients who underwent periodontal flap surgeries were reported with the incidental finding of

S. arlettae

associated with the intra-oral sutures placed. Environmental sampling was performed, to establish the exact source of this bacterium.

Results.

Staphylococcus arlettae

was isolated in three patients’ intra-oral sutures. All environmental samples were negative for the presence of the bacterium.

Conclusion. To this date, no studies have identified such an occurrence of

Staphylococcus arlettae

with intra-oral sutures. Its identification in association with foreign materials, such as sutures, can be considered a potential for surgical site infections and requires further investigation.
Antimicrobial susceptibility patterns of community-acquired uropathogenic Escherichia coli, Dublin 2010–2022
Authors: Ali Saied , Ryan Laura
Published: August 2023

Background.

Escherichia coli

is a common cause of urinary tract infections. Due to the increase in antimicrobial resistance (AMR) and global differences in antimicrobial susceptibility data, routine assessment of local antimicrobial susceptibility patterns is necessary to guide the selection of appropriate empirical therapy. The aim of this study was to evaluate the antimicrobial susceptibility patterns of community-acquired uropathogenic

Escherichia coli

within a catchment area in Dublin over a 13 year period, 2010–2022.

Methods. All mid-stream urine samples received from local general practitioners in which there was significant

E. coli

bacteriuria during the study period, 2010–2022, were included in the analysis. Antimicrobial susceptibility testing was performed by disc diffusion as per the European Committee on Antimicrobial Susceptibility Testing recommendations.

Results. An average of 11 407 urine samples per month had significant bacteriuria, with

E. coli

accounting for an average of 67 % of those. Overall AMR rates were highest for ampicillin (53.9 %), followed by trimethoprim (32.4 %), gentamicin (18.6 %), co-amoxiclav (16.5 %), ciprofloxacin (12.3 %), cephalexin (8.3 %), cefpodoxime (6.8 %) and nitrofurantoin (2 %). While rates appeared grossly static, statistically significant reduced resistance rates were noted for co-amoxiclav (rs=−0.95; P=<0.001), cephalexin prior to 2019 (rs=−0.783; P=0.013) and trimethoprim (rs=−0.639; P=0.019), with a statistically significant increase in non-susceptibility to cefpodoxime (rs=0.802; P=0.001).

Conclusions. In order to generate efficient empirical antimicrobial prescribing guidelines, knowledge of region-specific contemporaneous antimicrobial susceptibility patterns is pivotal. Our findings support the use of nitrofurantoin or cephalexin as empirical antimicrobial therapy within our setting.
Risk factors for acquiring Acinetobacter baumannii infection in the intensive care unit: experience from a Moroccan hospital

Authors: BENAISSA ELMOSTAFA , Belouad Elmehdi , Maleb Adil , Elouennass Mostafa
Published: August 2023

Introduction ; Acinetobacter spp is a non-fermenting and ubiquitous Gram-negative coccobacillus, which is in recent years the leading cause of healthcare-associated infections worldwide. Our objective is to study the epidemiology and risk factors associated with A. baumannii infections in the ICU.
Methods. This retrospective case-control study was conducted collaboratively between the Medical Bacteriology Department and the two ICU of the Military Hospital of Instruction Mohammed V-Rabat over a 3-month period.
Results. We included 180 patients, out of which 60 had A. baumannii infection. We observed a male predominance in both matched groups, with a sex ratio of 1.6. The median age was 67 years IQR [59.5-77]. The median length of stay in the ICU  before infection was 8.5days IQR [5-14]. Multi-variate logistic regression analysis identified the risk factors statistically associated with A. baumannii infection at the ICU level as follows: duration of invasive procedures˃ 7days (OR=1. 02), parenteral nutrition (OR=3.514), mechanical ventilation (OR=3.024), imipenem (OR=18.72), colistin (OR=5.645), probabilistic antibiotic therapy ˃4days (OR=9.063) and neoplastic pathology(OR=5.727).
Conclusion. Based on our results, it can be inferred that shortening the duration of stay in the resuscitation setting, implementing rational use of medical devices, and optimizing antibiotic therapy could decrease the incidence of these infections.
ACCORD (ACcurate COnsensus Reporting Document): A reporting guideline for consensus methods in biomedicine developed via a modified Delphi
Authors: Gattrell William T. , Logullo Patricia , van Zuuren Esther J. , Price Amy , Hughes Ellen L. , Blazey Paul , Winchester Christopher C. , Tovey David , Goldman Keith , Hungin Amrit Pali , Harrison Niall
Published: August 2023

Background

In biomedical research, it is often desirable to seek consensus among individuals who have differing perspectives and experience. This is important when evidence is emerging, inconsistent, limited or absent. Even when research evidence is abundant, clinical recommendations, policy decisions and priority-setting may still require agreement from multiple, sometimes ideologically opposed parties. Despite their prominence and influence on key decisions, consensus methods are often poorly reported. We aimed to develop the first reporting guideline applicable to all consensus methods used in biomedical research, called ACCORD (ACcurate COnsensus Reporting Document).

Methods

We followed methodology recommended by the EQUATOR Network for the development of reporting guidelines: a systematic review was followed by a Delphi process and meetings to finalise the ACCORD checklist. The preliminary checklist was drawn from the systematic review of existing literature on the quality of reporting of consensus methods and suggestions from the Steering Committee.

Results

A Delphi panel (n=72) was recruited with representation from six continents and a broad range of experience, including clinical, research, policy and patient perspectives. The three rounds of the Delphi process were completed by 58, 54 and 51 panellists. The preliminary checklist of 56 items was refined to a final checklist of 35 items relating to the article title (n=1), introduction (n=3), methods (n=21), results (n=5), discussion (n=2) and other information (n=3).

Conclusions

The ACCORD checklist is the first reporting guideline applicable to all consensus-based studies. It will support authors in writing accurate, detailed manuscripts, thereby improving the completeness and transparency of reporting and providing readers with clarity regarding the methods used to reach agreement. Furthermore, the checklist will make the rigour of the consensus methods used to guide the recommendations clear for readers. Reporting consensus studies with greater clarity and transparency may enhance trust in the recommendations made by consensus panels.
Incidence and Severity of COVID-19 with the use of the MMR Vaccine before or after the COVID-19 Vaccine
Authors: Fedrizzi Edison Natal , Trapani Alberto , Reis Girondi Juliana Balbinot , Silvestrin Aldanéa Norma de Souza , Nunes Maria Veronica
Published: August 2023

Introduction

The MMR vaccine has been shown by several studies over the years to have a potent effect on heterologous immunity. The reduction in mortality and respiratory and gastrointestinal diseases in childhood has been consolidated with recent studies demonstrating a better evolution of COVID-19 with the use of this vaccine. Stimulation of innate immunity by the MMR vaccine can be very useful, both used alone or in association with other vaccines, especially those for COVID-19.

Objectives

To evaluate the decrease in the incidence of infection or severity of COVID-19 with the use of the MMR vaccine before and after the use of specific vaccines against COVID-19.

Methods

This extension analysis followed 120 volunteer healthcare professionals aged 18 to 60 who received the MMR vaccine before the specific COVID-19 vaccine and 73 volunteers who used the MMR vaccine after the COVID-19 vaccine. Visits to the Research Center were carried out at an average interval of 4 weeks for 12 weeks. The diagnosis of COVID-19 was performed using the RT-PCR technique for the SARS-CoV-2 virus.

Results

The most used vaccine against COVID-19 was Coronavac in 59.1%. A total of 44 cases of COVID-19 were diagnosed (20% of the sample), the vast majority of which were mild cases (70.5%). There was no difference in the incidence and severity of COVID-19 in health professionals who used the MMR vaccine before or after the specific vaccine against the SARS-CoV-2 virus (Coronavirus or AstraZeneca).

Conclusion

The incidence and severity of COVID-19 does not differ with the use of the MMR vaccine before or after the specific vaccine against COVID-19.
Single Cell Measurements and Modeling and Computation of Decision Making Errors in a Molecular Signaling System with Two Output Molecules
Authors: Emadi Ali , Lipniacki Tomasz , Levchenko Andre , Abdi Ali
Published: August 2023

A cell constantly receives signals and takes different fates accordingly. Given the uncertainty rendered by signal transduction noise, the cell may incorrectly perceive the signals. It may mistakenly behave as if there is a signal - although there is none, or may miss the presence of a signal that actually exists. In this paper, we consider a signaling system that has two outputs, and introduce and develop methods to model and compute key cell decision making parameters based on the two outputs, and in response to the input signal. In the considered system, the tumor necrosis factor (TNF) regulates the two transcription factors, the nuclear factor κB (NFκB) and the activating transcription factor-2 (ATF-2). These two system outputs are involved in important physiological functions such as cell death and survival, viral replication, and pathological conditions such as autoimmune diseases and different types of cancer. Using the introduced methods, we compute and show what the decision thresholds are, based on the single cell measured concentration levels of NFκB and ATF-2. We also define and compute the decision error probabilities, i.e., false alarm and miss probabilities, based on the concentration levels of the two outputs. By considering the joint response of the two outputs of a signaling system, one can learn more about complex cellular decision making processes, the corresponding decision error rates, and their possible involvement in the development of some pathological conditions.
Tgfbr1regulates lateral plate mesoderm and endoderm reorganization during the trunk to tail transition
Authors: Lozovska Anastasiia , Casaca Ana , Nóvoa Ana , Kuo Ying-Yi , Jurberg Arnon D. , Martins Gabriel G. , Hadjantonakis Anna-Katerina , Mallo Moises
Published: August 2023

During the trunk to tail transition the mammalian embryo builds the outlets for the intestinal and urogenital tracts, lays down the primordia for the hindlimb and external genitalia, and switches from the epiblast/primitive streak to the tailbud as the driver of axial extension. Genetic and molecular data indicate thatTgfbr1is a key regulator of the trunk to tail transition.Tgfbr1has been shown to control the switch of the neuro mesodermal-competent cells from the epiblast to the chordo-neural hinge to generate the tail bud. We now show that Tgfbr1 signaling also controls the remodeling of the lateral plate mesoderm (LPM) and of the embryonic endoderm associated with the trunk to tail transition. In the absence ofTgfbr1the two LPM layers do not converge at the end of the trunk, extending instead as separate layers enclosing the celomic cavity until the caudal embryonic extremity, and failing to activate markers of primordia for the hindlimb and external genitalia. However, this extended LPM, does not exhibit the molecular signatures characteristic of this tissue in the trunk. The vascular remodeling involving the dorsal aorta and the umbilical artery leading to the connection between embryonic and extraembryonic circulation was also affected in theTgfbr1mutant embryos. Similar alterations in the LPM and vascular system were also observed inIsl1null mutants, indicating that this factor acts in the regulatory cascade downstream ofTgfbr1in LPM-derived tissues. In addition, in the absence ofTgfbr1the embryonic endoderm fails to expand to form the endodermal cloaca and to extend posteriorly to generate the tail gut. We present evidence suggesting that the remodeling activity ofTgfbr1in the LPM and endoderm results from the control of the posterior primitive streak fate after its regression during the trunk to tail transition. Our data, together with previously reported observations, placeTgfbr1at the top of the regulatory processes controlling the trunk to tail transition.
Prognostic Utility of Total Kidney Volume for Chronic Kidney Disease Risk Prediction: An Observational and Mendelian Randomization Study
Authors: Wu Jianhan , Wang Yifan , Vlasschaert Caitlyn , Lali Ricky , Feiner James , Gaheer Pukhraj , Yang Serena , Perrot Nicolas , Chong Michael , Lanktree Matthew B. , Paré Guillaume
Published: August 2023

Importance

Low total kidney volume (TKV) is a risk factor for chronic kidney disease (CKD). However, evaluations of causal inference and prognostic utility beyond traditional biomarkers are lacking.

Objective

To investigate the observational and Mendelian randomization (MR) association of TKV with kidney and cardiovascular traits and assess improvement in CKD risk prediction when TKV is added to estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (uACR).

Design

Case-control study based on UK Biobank and two-sample MR analysis.

Setting

22 assessment centers, United Kingdom.

Participants

Individuals of European ancestry with kidney volume assessment derived from magnetic resonance imaging. Exclusion criteria include records of kidney transplantation, excision, congenital malformation, and cystic kidney disease.

Exposures

TKV, height adjusted (htTKV), and body surface area adjusted TKV (BSA-TKV).

Main Outcomes

Observational and bidirectional MR association estimates of TKV with CKD risk. Incident CKD stage G3 or worse prediction performance using likelihood ratio, C-statistic, calibration, and category-free net absolute reclassification index (NARI).

Results

Observational analysis included 34,595 individuals [median (IQR) age 64 (12) years, 17,835 (51.6%) females]. Adjusted for confounders and risk factors including eGFR and uACR, a 10 mL decrease in TKV was associated with 7% increase in the risk of incident CKD stage G3 or worse (HR 1.07, 95% CI 1.04 to 1.10, P < 0.001). Addition of prognostically significant BSA-TKV thresholds of 119 and 145 mL/m2led to the greatest improvement in prediction performance beyond eGFR and uACR across likelihood ratio, discrimination (C-statistic 0.87, 95% CI 0.85 to 0.89, P = 0.017), calibration, and reclassification (NARI 228 per 1,000, P < 0.001). In MR, a 10 mL decrease in genetically predicted TKV was associated with 10% increase in CKD risk (OR 1.10, 95% CI 1.05 to 1.15, P < 0.001). Reciprocally, an increased risk of genetically predicted CKD by 2-fold was associated with an 8.75 mL reduction in TKV (95% CI -10.8 to -6.66, P < 0.001). There were no significant observational or MR associations of TKV with cardiovascular complications.

Conclusions

A bidirectional relationship exists between TKV and CKD. Addition of TKV thresholds to eGFR and uACR can improve CKD risk stratification.
Synaptic inhibitory dynamics drive benzodiazepine response in paediatric status epilepticus
Authors: Fedele Tommaso , Burman Richard J. , Steinberg Anne , Selmin Giorgio , Ramantani Georgia , Rosch Richard E.
Published: August 2023

Paediatric status epilepticus (SE) is a medical emergency associated with significant morbidity. Benzodiazepines (BZPs) are the current first-line treatment, but do not work in over a third of children presenting with SE. Animal studies have shown that SE can cause changes in synaptic inhibition signalling which can ultimately lead to BZPs becoming ineffective. However, the relevance of these mechanisms in paediatric patients with SE remains unknown. To test this hypothesis, we combine clinical EEG recordings with dynamic causal modelling (DCM). This approach allows model-based inference of cortical synaptic coupling parameters based on EEG recorded across distinct oscillatory states. Our DCM revealed that dynamic changes in inhibitory synaptic coupling explain differences in EEG power spectra associated with BZP-treatment responsiveness, and guide the transition from ictal to interictal state. Furthermore,in silicosimulations demonstrate that there are alternative routes to seizure termination even in cortical circuit models unresponsive to the BZPs. Together, our findings confirm that alterations in synaptic inhibition underlie BZP response during paediatric SE. More broadly this work further demonstrates the utility of computational modelling to validate insights from basic science in clinically accessible recordings in neurological disorders characterised by abnormal brain states.
Comparison of the performance of two targeted metagenomic virus capture probe-based methods using synthetic viral sequences and clinical samples
Authors: Mourik Kees , Sidorov Igor , Carbo Ellen C. , van der Meer David , Boot Arnoud , Kroes Aloysius C. M. , Claas Eric C.J. , Boers Stefan A. , de Vries Jutte J.C.
Published: August 2023

Viral enrichment by probe hybridization has been reported to significantly increase the sensitivity of viral metagenomics.

This study compares the analytical performance of two targeted metagenomic virus capture probe-based methods: i) SeqCap EZ HyperCap by Roche (ViroCap) and ii) Twist Comprehensive Viral Research Panel workflow, for diagnostic use. Sensitivity, specificity, limit of detection, and effect of human background DNA were analysed, using synthetic viral sequences, clinical and reference samples with known viral loads.

Sensitivity and specificity were 95% and higher for both methods. Combining thresholds for viral sequence read counts and genome coverage (respectively 500 reads per million and 10% coverage) resulted in optimal prediction of true positive results. Limits of detection were approximately 50-500 copies/ml for both methods. Increasing proportions of spike-in cell free human background sequences did not negatively affect viral detection.

These data show analytical performances in ranges applicable to clinical samples, for both probe hybridization metagenomic approaches. This study supports further steps towards more widespread use of viral metagenomics for pathogen detection, in clinical and surveillance settings using low biomass samples.
COVID-19 self-testing: Countries accelerating policies ahead of WHO guidelines during pandemics: A Global Survey
Authors: Sakala Melody , Johnson Cheryl , Chirombo James , Sacks Jilian A. , Baggaley Rachel , Divala Titus
Published: August 2023

Introduction

The widespread use of antigen-detection rapid diagnostic tests (Ag-RDTs) has revolutionized SARS-CoV-2 (COVID-19) testing, particularly through the option of self-testing. The full extent of Ag-RDT utilization for self-testing, however, remains largely unexplored. To inform the development of WHO guidance on COVID-19 self-testing, we conducted a cross-sectional survey to gather the views and experiences of policy makers, researchers, and implementers worldwide.

Methods

The survey was shared through professional networks via email and social media, encouraging onward sharing. We used closed and open-ended questions related to policy and program information concerning the regulation, availability, target population, indications, implementation, benefits, and challenges of COVID-19 self-testing (C19ST). We defined self-testing as tests performed and interpreted by an untrained individual, often at home. Descriptive summaries, cross-tabulations, and proportions were used to calculate outcomes at the global level and by WHO region and World Bank income classifications.

Results

Between 01 and 11 February 2022, 844 individuals from 139 countries responded to the survey, with 45% reporting affiliation with governments and 47% operating at the national level. 504 respondents from 101 countries reported policies supporting C19ST for a range of use cases, including symptomatic and asymptomatic populations. More respondents from low-and-middle-income countries (LMICs) than high-income countries (HICs) reported a lack of an C19ST policy (61 vs 11 countries) and low population-level reach of C19ST. Respondents with C19ST experience perceived that the tests were mostly acceptable to target populations, provided significant benefits, and highlighted several key challenges to be addressed for increased success. Reported costs varied widely, ranging from specific programmes enabling free access to certain users and others with high costs via the private sector.

Conclusion

Based on the survey responses, systems for the regulatory review, policy development and implementation of C19STappeared to be much more common in HIC when compared to LIC in early 2022, though most respondents indicated self-testing was available to some extent (101 out of 139 countries) in their country. Addressing such global inequities is critical for ensuring access to innovative and impactful interventions in the context of a public health emergency of international concern. The challenges and opportunities highlighted by survey respondents could be valuable to consider as future testing strategies are being set for outbreak-prone diseases.
An improved PDE6D inhibitor combines with Sildenafil to synergistically inhibit KRAS mutant cancer cell growth
Authors: Kaya Pelin , Schaffner-Reckinger Elisabeth , Manoharan Ganesh babu , Vukic Vladimir , Kiriazis Alexandros , Ledda Mirko , Burgos Maria , Pavic Karolina , Gaigneaux Anthoula , Glaab Enrico , Abankwa Daniel Kwaku
Published: August 2023

The trafficking chaperone PDE6D (or PDEƍ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl-binding pocket. These inhibitors suffered from low solubility and intracellular potency, preventing their clinical development.

Here we developed a highly soluble PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the currently lowest off-target activity, as we demonstrate in dedicated assays. We further increased the K-Ras focus, by exploiting that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, the combination of Deltaflexin3 with the approved PKG2-activator Sildenafil synergistically inhibits cell- and microtumor growth. However, the overall cancer survival of the high PDE6D/ low PKG2 target population is higher than of the group with the opposite signature. Our results therefore suggest re-examining the interplay between PDE6D and K-Ras in cancer, while recommending the development of PDE6Di that ’plug’, rather than ’stuff’ the hydrophobic pocket of PDE6D.

Significance

Combinations of a novel PDE6D inhibitor with Sildenafil synergistically focus the inhibition on K-Ras, however, survival data of the target population suggest an interplay of K-Ras and PDE6D that needs further exploration.
SUPREM: an engineered non-site-specific m6A RNA methyltransferase with highly improved efficiency
Authors: Ochiai Yoshiki , Clifton Ben E. , Coz Madeleine Le , Terenzio Marco , Laurino Paola
Published: August 2023

m6A RNA methylation plays a key role in RNA processing and translational regulation, influencing both normal physiological and pathological processes. Yet, current techniques for studying RNA methylation struggle to isolate the effects of individual m6A modifications. Engineering of RNA methyltransferases (RNA MTases) could enable development of improved synthetic biology tools to manipulate RNA methylation, but it is challenging due to limited understanding of structure-function relationships in RNA MTases. Herein, using ancestral sequence reconstruction we explore the sequence space of the bacterial DNA methyltransferase EcoGII (M.EcoGII), a promising target for protein engineering due to its lack of sequence specificity and its residual activity on RNA. We thereby created an efficient non-specific RNA MTase termed SUPREM, which exhibits 8-fold higher expression levels, 7 °C higher thermostability, and 12-fold greater m6A RNA methylation activity compared with M.EcoGII. Immunofluorescent staining and quantitative LC/MS-MS analysis confirmed SUPREM’s higher RNA methylation activity compared with M.EcoGII in mammalian cells. Additionally, Nanopore direct RNA sequencing highlighted that SUPREM is capable of methylating a larger number of RNA methylation sites than M.EcoGII. Through phylogenetic and mutational analysis, we identified a critical residue for the enhanced RNA methylation activity of SUPREM. Collectively, our findings indicate that SUPREM holds promise as a versatile tool forin vivoRNA methylation and labeling.
Micropillar enhanced FRET-CRISPR biosensor for nucleic acid detection
Authors: Bao Mengdi , Dollery Stephen J. , Yuqing FNU , Tobin Gregory J. , Du Ke
Published: August 2023

CRISPR technology has gained widespread adoption for pathogen detection due to its exceptional sensitivity and specificity. Although recent studies have investigated the potential of high-aspect-ratio microstructures in enhancing biochemical applications, their application in CRISPR-based detection has been relatively rare. In this study, we developed a FRET-based biosensor in combination with high-aspect-ratio microstructures and Cas12a-mediated trans-cleavage for detecting HPV 16 DNA fragments. Remarkably, our results show that micropillars with higher density exhibit superior molecular binding capabilities, leading to a tenfold increase in detection sensitivity. Furthermore, we investigated the effectiveness of two surface chemical treatment methods for enhancing the developed FRET assay. A simple and effective approach was also developed to mitigate bubble generation in microfluidic devices, a crucial issue in biochemical reactions within such devices. Overall, this work introduces a novel approach using micropillars for CRISPR-based viral detection and provides valuable insights into optimizing biochemical reactions within microfluidic devices.
Unveiling metaverse potential in supply chain management and overcoming implementation challenges: an empirical study
Authors: Bag Surajit , Rahman Muhammad Sabbir , Srivastava Gautam , Shrivastav Santosh Kumar
Published: August 2023

Purpose

The metaverse is a virtual world where users can communicate with each other in a computer-generated environment. The use of metaverse technology has the potential to revolutionize the way businesses operate, interact with customers, and collaborate with employees. However, several obstacles must be addressed and overcome to ensure the successful implementation of metaverse technology. This study aims to examine the implementation of metaverse technology in the management of an organization's supply chain, with a focus on predicting potential barriers to provide suitable strategies.

Design/methodology/approach

Covariance-based structural equation modeling (CB-SEM) was used to test the model. In addition, artificial neural network modeling (ANN) was also performed.

Findings

The CB-SEM results revealed that a firm's technological limitations are among the most significant barriers to implementing metaverse technology in the supply chain management (SCM). The ANN results further highlighted that the firm's technological limitations are the most crucial input factors, followed by a lack of governance and standardization, integration challenges, poor diffusion through the network, traditional organizational culture, lack of stakeholder commitment, lack of collaboration and low perception of value by customers.

Practical implications

Because metaverse technology has the potential to provide organizations with a competitive advantage, increase productivity, improve customer experience and stimulate creativity, it is crucial to discuss and develop solutions to implementation challenges in the business world. Companies can position themselves for success in this fascinating and quickly changing technological landscape by conquering these challenges.

Originality/value

This study provides insights to metaverse technology developers and supply chain practitioners for successful implementation in SCM, as well as theoretical contributions for supply chain managers aiming to implement such environments.