bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pain tolerance and the thresholds of human sensory and motor axons to single and repetitive bursts of kilohertz‐frequency stimulation
Authors: Luu Billy L. , Trinh Terry , Finn Harrison T. , Aplin Felix P. , Gandevia Simon C. , Héroux Martin E. , Butler Jane E. 
Published: October 2024

AbstractTranscutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier‐frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10 kHz carrier‐frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1 ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1 mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20 Hz for 1 s. Participants tolerated higher current amplitudes with both carrier‐frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce sensory and motor‐threshold responses and to obtain a maximal motor response (Mmax). When the current at pain tolerance was normalised to the current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier‐frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons.
imageKey points
Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier‐frequency waveform is thought to be less painful than conventional pulsed currents.
For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier‐frequency stimulation than conventional stimulation.
However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (Mmax).
When current at pain tolerance was normalised to current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation.
Carrier‐frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons.
Levofloxacin activity at increasing doses in a murine model of fluoroquinolone-susceptible and -resistant tuberculosis
Authors: Maitre Thomas , Godmer Alexandre , Mory Céline , Chauffour Aurélie , Mai Thi Cuc , El Helali Najoua , Aubry Alexandra , Veziris Nicolas 
Published: October 2024

ABSTRACT

High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 10
6
CFU of
Mycobacterium tuberculosis
H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose–response model, the effective concentration at 50% (EC
50
) produced an AUC/MIC (AUC
0–24h
/MIC) ratio of 167.9 ± 27.5, and at EC
80
it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis.
Genome editing in ubiquitous freshwater Actinobacteria
Authors: Bairagi Nachiketa , Keffer Jessica L. , Heydt Jordan C. , Maresca Julia A. 
Published: October 2024

ABSTRACT

Development of genome-editing tools in diverse microbial species is an important step both in understanding the roles of those microbes in different environments, and in engineering microbes for a variety of applications. Freshwater-specific clades of Actinobacteria are ubiquitous and abundant in surface freshwaters worldwide. Here, we show that
Rhodoluna lacicola
and
Aurantimicrobium photophilum
, which represent widespread clades of freshwater Actinobacteria, are naturally transformable. We also show that gene inactivation via double homologous recombination and replacement of the target gene with antibiotic selection markers can be used in both strains, making them convenient and broadly accessible model organisms for freshwater systems. We further show that in both strains, the predicted phytoene synthase is the only phytoene synthase, and its inactivation prevents the synthesis of all pigments. The tools developed here enable targeted modification of the genomes of some of the most abundant microbes in freshwater communities. These genome-editing tools will enable hypothesis testing about the genetics and (eco)physiology of freshwater Actinobacteria and broaden the available model systems for engineering freshwater microbial communities.

IMPORTANCE
To advance bioproduction or bioremediation in large, unsupervised environmental systems such as ponds, wastewater lagoons, or groundwater systems, it will be necessary to develop diverse genetically amenable microbial model organisms. Although we already genetically modify a few key species, tools for engineering more microbial taxa, with different natural phenotypes, will enable us to genetically engineer multispecies consortia or even complex communities. Developing genetic tools for modifying freshwater bacteria is particularly important, as wastewater, production ponds or raceways, and contaminated surface water are all freshwater systems where microbial communities are already deployed to do work, and the outputs could potentially be enhanced by genetic modifications. Here, we demonstrate that common tools for genome editing can be used to inactivate specific genes in two representatives of a very widespread, environmentally relevant group of Actinobacteria. These Actinobacteria are found in almost all tested surface freshwater environments, where they co-occur with primary producers, and genome-editing tools in these species are thus a step on the way to engineering microbial consortia in freshwater environments.
SARS-CoV-2 N protein coordinates viral particle assembly through multiple domains
Authors: Han Yuewen , Zhou Haiwu , Liu Cong , Wang Weiwei , Qin Yali , Chen Mingzhou 
Published: October 2024

ABSTRACT

Increasing evidence suggests that mutations in the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may enhance viral replication by modulating the assembly process. However, the mechanisms governing the selective packaging of viral genomic RNA by the N protein, along with the assembly and budding processes, remain poorly understood. Utilizing a virus-like particles (VLPs) system, we have identified that the C-terminal domain (CTD) of the N protein is essential for its interaction with the membrane (M) protein during budding, crucial for binding and packaging genomic RNA. Notably, the isolated CTD lacks M protein interaction capacity and budding ability. Yet, upon fusion with the N-terminal domain (NTD) or the linker region (LKR), the resulting NTD/CTD and LKR/CTD acquire RNA-dependent interactions with the M protein and acquire budding capabilities. Furthermore, the presence of the C-tail is vital for efficient genomic RNA encapsidation by the N protein, possibly regulated by interactions with the M protein. Remarkably, the NTD of the N protein appears dispensable for virus particle assembly, offering the virus adaptive advantages. The emergence of N* (NΔN209) in the SARS-CoV-2 B.1.1 lineage corroborates our findings and hints at the potential evolution of a more streamlined N protein by the SARS-CoV-2 virus to facilitate the assembly process. Comparable observations have been noted with the N proteins of SARS-CoV and HCoV-OC43 viruses. In essence, these findings propose that β-coronaviruses may augment their replication by fine-tuning the assembly process.

IMPORTANCE
As a highly transmissible zoonotic virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve. Adaptive mutations in the nucleocapsid (N) protein highlight the critical role of N protein-based assembly in the virus’s replication and evolutionary dynamics. However, the precise molecular mechanisms of N protein-mediated viral assembly remain inadequately understood. Our study elucidates the intricate interactions between the N protein, membrane (M) protein, and genomic RNA, revealing a C-terminal domain (CTD)-based assembly mechanism common among β-coronaviruses. The appearance of the N* variant within the SARS-CoV-2 B.1.1 lineage supports our conclusion that the N-terminal domain (NTD) of the N protein is not essential for viral assembly. This work not only enhances our understanding of coronavirus assembly mechanisms but also provides new insights for developing antiviral drugs targeting these conserved processes.
mSphere of Influence: Revisiting the central dogma, again!
Authors: Samir Parimal 
Published: October 2024

ABSTRACT

Dr. Parimal Samir works in the field of host–pathogen interactions. In this mSphere of Influence article, he reflects on how the manuscript entitled “
De novo
gene synthesis by an antiviral reverse transcriptase” by Samuel Sternberg and colleagues made an impact by reminding him that there is still so much to discover in life sciences.
How geology and paleontology help build the magic of the Disneyland Resort (Anaheim, California, USA)
Authors: Sturmer* Daniel M. , Vice* Garrett S. , Sumida* Stuart , Mary* Michelle 
Published: October 2024

ABSTRACT
The Disneyland Resort (Anaheim, California, USA) is one of the most iconic theme parks in the world, and is fortuitously located across the street from the 2024 GSA Connects meeting. Geology and paleontology have played an important role in the making of the resort, from initial design and layout to attraction and land conceptualization and design. On this walking tour, we will learn some of the history of the resort and how the geosciences have affected and influenced the design and evolution of several attractions at Disneyland Park, including the Disneyland Railroad, Pirates of the Caribbean, the Matterhorn Bobsleds, Big Thunder Mountain, and the new Star Wars: Galaxy’s Edge. We also include notes on the influence of geology on several of the attractions at Disney California Adventure. Ultimately, we hope participants gain insight and appreciation for the influence that the geosciences have had on the Disneyland Resort and the effort that Disney’s Imagineers put in to accurately incorporate elements of our natural world into the world(s) of the Disneyland Resort. The examples we will see show how incorporating real geology and paleontology into attraction conceptualization and construction results in more believable, engaging, and entertaining attractions for audiences.
For which entrustable professional activities must medical students be prepared if unsupervised patient care without further training is an expectation? An international Global South study
Authors: ten Cate Olle , Nel Daniel , Hennus Marije P , Peters Susanne , Romao Gustavo Salata 
Published: October 2024

IntroductionTraining medical students requires objectives that are often translated into frameworks of competencies. Since the introduction of entrustable professional activities (EPAs), these tasks or ‘units of professional practice’, originally conceived for postgraduate training, define what residents must be prepared to do unsupervised. Nowadays, EPAs are also applied to undergraduate training, with the prospect of entering residency. However, in many countries, especially in the Global South, a substantial number of medical graduates will be working in healthcare with little or no supervision and no further training soon or ever. EPAs for these conditions cannot be copied from undergraduate medical education EPA frameworks in Global North countries.MethodsWe conducted a generative investigation to identify and elaborate EPAs for Global South countries who must train students for unsupervised general practice. We included 39 medical educators from 13 Global South countries and 17 specialties in either one of two online focus group sessions using a nominal group technique (NGT) or as Delphi panel member. Results from the two NGT sessions were merged and fed into the two-round Delphi investigation.ResultsA framework of 11 EPAs resulted, each with an elaborate description (specification, setting and limitations).ConclusionThis framework of undergraduate medical education Global South EPAs differs in its nature and specifications from existing Global North EPAs. The authors do not pretend universality for all Global South countries with graduates who face expectations of unsupervised practice but present it to support countries that consider introducing the model of entrustable professional activities.
Risk factors for antenatal anxiety: a cross-sectional study in field antenatal clinics in Sri Lanka
Authors: Priyadarshanie Manathungei Nirmala , Waas Dulshika A , Goonewardena Sampatha , Balasuriya Aindralal , Senaratna Chamara V , Fernando Sharaine 
Published: October 2024

ObjectivesWe aimed to determine the prevalence and factors affecting antenatal anxiety (AA) among Sri Lankan women.DesignWe conducted a cross-sectional analysis of first trimester data from a population-based cohort of antenatal women.SettingField antenatal clinics of four field health areas in Colombo District, Sri Lanka.ParticipantsAntenatal women (n=535) in the first trimester of pregnancy and aged ≥18 years were sequentially recruited when they attended antenatal clinics selected using random cluster sampling. Those with hearing difficulty, visual and speaking problems or currently on treatment for mental disorders were excluded.MeasuresWe used an interviewer-administered questionnaire to collect data. The AA was identified using the validated Sinhala version of Perinatal Anxiety Screening Scale (PASS-S). Self-reported demographic and pregnancy-related information were verified against health records. Psychosocial risk factors were self-reported. We investigated the associations between potential risk factors and AA using regression models that included confounders identified through a directed acyclic graph and reported using adjusted odds ratios (ORs) with 95% confidence intervals (CIs).ResultsThe prevalence of AA during the first trimester of pregnancy, identified using a PASS threshold of ≥20, was 34.4% (n=184). We found several novel risk factors for AA, namely, physical (OR 2.1; 95% CI 1.4 to 3.2) and mental health problems of self (OR 2.3; 95% CI 1.2 to 4.4), physical (OR 2.1; 95% CI 1.4 to 3.4) and mental health problems of parents/spouse (OR 6.7; 95% CI 2.8 to 16.2), traumatic life situations (OR 2.7; 95% CI 1.5 to 4.8), substance abuse by the spouse (OR 3.5; 95% CI 1.9 to 6.6) and the spouse being away (OR 2.0; 95% CI 1.1 to 3.7). The other risk factors that we identified included domestic violence among family members (OR 6.4; 95% CI 1.3 to 31.0), loss of family support (OR 2.2; 95% CI 1.0 to 5.2), financial hardships (OR 1.7; 95% CI 1.0 to 2.8), accommodation-related issues (OR 2.2; 95% CI 1.0 to 4.9), unplanned pregnancy (OR 3.7; 95% CI 1.9 to 7.3), difficulties due to pregnancy (OR 2.0; 95% CI 1.1 to 3.4), changed or stopped education (OR 2.9; 95% CI 1.7 to 5.1), recent loss of employment (OR 2.9; 95% CI 1.2 to 7.0), recent death of a loved one (OR 3.5; 95% CI 2.0 to 5.9) and sleep problems during pregnancy (OR 1.6; 95% CI 1.1 to 2.3).ConclusionsThe prevalence of antenatal anxiety is high in Sri Lanka and is associated with several risk factors, not previously described, which are potentially modifiable.
Effect of calcium channel blockers on influenza incidence: a population-based retrospective cohort study using administrative claims data in Japan
Authors: Imai Takanori , Hashimoto Hideki , Kanda Naoki , Sasabuchi Yusuke , Matsui Hiroki , Yasunaga Hideo , Hatakeyama Shuji 
Published: October 2024

ObjectivesLaboratory experiments have indicated that calcium channel blockers (CCBs) inhibit the entry and replication of influenza A virus in cells. However, no clinical studies have assessed the incidence of influenza among patients receiving CCBs. This study aimed to investigate the association between CCB use and the incidence of influenza among patients with hypertension using administrative claims data in Japan.DesignRetrospective cohort study.SettingAdministrative health insurance claims database of Kumamoto Prefecture, Japan.Participants360 515 patients with hypertension (10th edition of the International Classification of Diseases code I10) who were prescribed CCBs and 171 142 patients who were prescribed angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) between 2012 and 2016.Primary outcomeWe compared the incidence of influenza between the CCB and ACEI/ARB groups using high-dimensional propensity-score (HD-PS) matching.ResultsA total of 166 814 HD-PS matched pairs were obtained. Before HD-PS matching, the CCB group had a significantly lower influenza incidence than the ACEI/ARB group in the overall analysis (2.4% vs 2.5%, p=0.007; risk ratio 0.95, 95% CI 0.92 to 0.99). However, no significant difference was observed between the two groups after HD-PS matching (2.4% vs 2.5%, p=0.067; risk ratio 0.96, 95% CI 0.92 to 1.00); only in 2012 did the CCB group have a significantly lower likelihood of influenza than the ACEI/ARB group.ConclusionsNo significant difference was observed in the influenza incidence between the CCB and ACEI/ARB groups. A direct comparative study between background-matched patients with and without CCBs is warranted to confirm the effect of CCBs on reducing the incidence of influenza.
Impacts of the COVID-19 pandemic on deprivation-level differences in cardiovascular hospitalisations: a comparison of England and Denmark using the OpenSAFELY platform and National Registry Data
Authors: Costello Ruth E , Pedersen Lars , Henderson Alasdair D , Tazare John , Sorensen Henrik Toft , Vandenbroucke Jan P , Mansfield Kathryn E , Mahalingasivam Viyaasan , Zheng Bang , Carreira Helena , Bidulka Patrick , Piehlmaier Dominik Manuel , Wong Angel Yun Sum , Warren-Gash Charlotte , Hayes Joseph F , Quint Jennifer K , Katikireddi Srinivasa Vittal , Mackenna Brian , Mehrkar Amir , Bacon Sebastian , Goldacre Ben , Tomlinson Laurie A , Langan Sinead M , Mathur Rohini , Collaborative The LH&W NCS (or CONVALESCENCE) , Consortium The OpenSAFELY 
Published: October 2024

ObjectivesTo examine the impact of the COVID-19 pandemic on deprivation-related inequalities in hospitalisations for cardiovascular disease (CVD) conditions in Denmark and England between March 2018 and December 2021.DesignTime-series studies in England and Denmark.SettingWith the approval of National Health Service England, we used English primary care electronic health records, linked to secondary care and death registry data through the OpenSAFELY platform and nationwide Danish health registry data.ParticipantsWe included adults aged 18 and over without missing age, sex or deprivation information. On 1 March 2020, 16 234 700 people in England and 4 491 336 people in Denmark met the inclusion criteria.Primary outcome measuresHospital admissions with the primary reason for myocardial infarction (MI), ischaemic or haemorrhagic stroke, heart failure and venous thromboembolism (VTE).ResultsWe saw deprivation gradients in monthly CVD hospitalisations in both countries, with differences more pronounced in Denmark. Based on pre-pandemic trends, in England, there were an estimated 2608 fewer admissions than expected for heart failure in the most deprived quintile during the pandemic compared with an estimated 979 fewer admissions in the least deprived quintile. For all other outcomes, there was little variation by deprivation quintile. In Denmark, there were an estimated 1013 fewer admissions than expected over the pandemic for MI in the most deprived quintile compared with 619 in the least deprived quintile. Similar trends were seen for stroke and VTE, though absolute numbers were smaller. Heart failure admissions were similar to pre-pandemic levels with little variation by deprivation quintile.ConclusionsOverall, we did not find that the pandemic substantially worsened pre-existing deprivation-related differences in CVD hospitalisations, though there were exceptions in both countries.
National review of end-of-life care withdrawal guidelines for non-invasive advanced respiratory support using document analysis
Authors: Wenzel David , Jeffery Thomas , Davies Rachel , Creese Jennifer , Wilson Eleanor , Faull Christina 
Published: October 2024

ObjectivesThis study aims to understand the breadth of practice around end-of-life withdrawal of non-invasive advanced respiratory support (encompassing both continuous positive airway pressure and non-invasive ventilation) by analysing NHS-published guidelines and guidance for clinicians. This study seeks validity in the guidelines through a confluence of findings and reassurance of practice despite having little to no high-quality research to inform the content of the guidelines. Ultimately, where discordance is found between guidelines, there will be a strong mandate for future research.MethodsGuidelines were gathered through snowball sampling and analysed using document analysis techniques. Analysis was mixed in inductive and deductive and facilitated across several authors using framework analysis. 20 guidelines were analysed but saturation was found after 15. Further guidelines were analysed beyond saturation to provide reassurance of the endpoint of the study.ResultsThere were common components to the guidelines presented as themes: legal and ethical frameworks, decision-making around withdrawal, the process of withdrawal, post-withdrawal care and when to contact palliative care. There were significant areas of confluence, where multiple guidelines were in agreement on best practice. However, there was significant discordance in some key areas including the use of post-withdrawal oxygen therapy and pressure weaning practice.ConclusionThis study provides reassurance through a confluence of findings for the majority of withdrawal practices. However, key areas of discordance highlight an urgent need for further research to support clinicians, patients and their families during challenging clinical events.