bluuebunny/crossref_metadata_2025 huggingface dataset:
Period-multiplying pulses generation by total self-mode-locking of Nd:YVO4 lasers
Authors: Xu M M , Li Z R , Hu M , Ji Y Y , Bi M H , Li H Z , Zhou X F , Pan S Q , Liu C
Published: April 2024

We experimentally demonstrated the phenomenon of period-multiplying pulses in the self-mode-locking Nd:YVO4 laser. With a fixed cavity length of 50 mm and the input mirrors in the resonator with radii of curvature of 100 mm, 200 mm, and 500 mm, the mode-locked pulses with pulse periods 4 times, 6 times and 10 times the fundamental mode-locked pulse period are observed respectively. Besides, by tilting the angle of the output mirror to control the spatial distribution of transverse modes, the switching between the period-multiplication state and its harmonic self-locking state can be achieved. Numerical simulations further confirm that this period-multiplying phenomenon results from the simultaneous locking of multi-longitudinal and multi-transverse modes. This study is of great significance for understanding the complex transverse dynamics in the self-mode-locking lasers.
On an X-ray 3-block Laue-interferometer with violation of ideal geometry
Authors: Mkhitaryan S.A. , Margaryan H.G. , Vasilyan M.S. , Drmeyan H.R.
Published: April 2024

An X-ray monolithic 4-block interference system has been developed and manufactured, in which the first 3 blocks are thin and form a 3- block Laue interferometer with disrupted geometry, and the 4th additional block is thick and is in the reflection position. It is shown that fine structures of interference patterns registered from 3-block interferometers with thin blocks and distorted geometry are observed in cases where an additional 4th thick block is used. The calculations show that when the ideal geometry of a 3-block interferometer is violated, an interference pattern is formed in the form of families of parallel stripes (lines) on the recording plate lying perpendicular to the incident beam. The coordinates of the interference stripes maxima, their periods, as well as the coefficient of a linear enlargement in the presence and absence of the 4th thick block, are calculated. It has been experimentally proven that a thick block does not introduce new information into the interference pattern, but will only enlarge its dimensions in the scattering plane. The limits for reducing the period of interference stripes and their complete disappearance are determined depending on the size of violations from the ideal geometry of a 3-block interferometer.
Laser and microwave instrumentation for ITER and future reactors
Authors: Vayakis G. ,   the ITER diagnostics teams
Published: April 2024

ITER diagnostics include an extensive set of
laser and microwave diagnostics to give access to a wealth of information on the
core and edge plasma and to support high performance operation of ITER. For
example, Core and Edge Thomson scattering systems build detailed density and
temperature profiles on time scales much faster than τ
E
to follow transient
events; ECE and reflectometry add time resolution to follow MHD
events. Implementing these diagnostics is challenging, needing a panoply of
technologies to keep them functioning reliably for thousands of hours despite
extreme events such as disruptions and wall conditioning cycles. Shielding,
shutters and cleaning systems protect the forward elements of most optical
systems from the build-up of deposits and damage. Still, plasma-facing mirrors
must survive laser loads and endure erosion, deposition and in-situ RF
cleaning. Calibration and monitoring systems ensure accurate and drift-free
operation. These support systems are also not straightforward and required
specific R&D. Access also drives the design: to deal with the neutron
and gamma sources yet allow maintenance of activated components, ITER uses
large, multi-purpose ports that couple otherwise distinct systems into modules
for maintenance. Machine movement requires provisions to maintain alignment and
calibration, from these port plugs, shown in figure 1, to the
accessible areas 10–50 m away. A final complication comes from the difficulty of
employing electronics near the plugs. Extensive qualification for radiation
resistance is needed. This paper examines design adaptations that ITER adopted
for its near-reactor environment, consider the lessons learnt from the ITER
design activity specifically for laser and microwave systems and lays out some
possible evolution paths for the reactor diagnostician that must follow a more
industrial approach.
Counting alpha particles produced by radon daughters using commercial off-the-shelf complementary metal oxide semiconductor (COTS CMOS) image sensors
Authors: Lin Fen , Xie Ruomei , Li Huiying , Liu Shuaibin , Hu Tao , Fan Zhongkai , Mo Yixiang , Yuan Shuai , Sun Jiale , Yi Haibo , Liu Zhipeng , Wu Jiulin , Tang Jianfeng , Yuan Hongzhi , Tan Yanliang
Published: April 2024

Radon (Rn-222) is the main source of radiation exposure to
human beings from natural radiation; it is of great significance to
study the measuring methods and measuring instruments of radon for
natural radiation protection. In recent years, the application of
pixel detectors in radiation detection has attracted attention. In
this paper, a Commercial Off-the-Shelf Complementary Metal Oxide
Semiconductor (COTS CMOS) image sensor which replaces the glass for
protection covering in front of the sensors was used to perform a
series of measurements to identify alpha particles. During the
experiment, the CMOS image sensor was used to record a video during
the sampling period, and then use the FFmpeg software to take
screenshots of the video by frame. MATLAB was used to count bright
spots from the image frames. A measurement chamber was designed to
measure radon concentrations, and when the relative humidity was
constant, the count of alpha particles by the CMOS image sensor
increased along with the increase of the concentration. The
experiments verified the feasibility of the low-cost COTS CMOS image
sensors to monitor radon.
Computation cost reduction in 3D shape optimization of nanophotonic components
Authors: Masnad Md Mahadi , Salsabil Nishat , Xu Dan-Xia , Liboiron-Ladouceur Odile , Grinberg Yuri
Published: April 2024

Inverse design methodologies effectively optimize many design parameters of a photonic device with respect to a primary objective, uncovering locally optimal designs in a typically non-convex parameter space. Often, a variety of secondary objectives (performance metrics) also need to be considered before fabrication takes place. Hence, a large collection of optimized designs is useful, as their performance on secondary objectives often varies. For certain classes of components such as shape-optimized devices, the most efficient optimization approach is to begin with 2D optimization from random parameter initialization and then follow up with 3D re-optimization. Nevertheless, the latter stage is substantially time- and resource-intensive. Thus, obtaining a desired collection of optimized designs through repeated 3D optimizations is a computational challenge. To address this issue, a machine learning-based regression model is proposed to reduce the computation cost involved in the 3D optimization stage. The regression model correlates the 2D and 3D optimized structural parameters based on a small dataset. Using the predicted design parameters from this model as the initial condition for 3D optimization, the same optima are reached faster. The effectiveness of this approach is demonstrated in the shape optimization-based inverse design of TE0-TE1 mode converters, an important component in mode-division multiplexing applications. The final optimized designs are identical in both approaches, but leveraging a machine learning-based regression model offers a 35% reduction in computation load for the 3D optimization step. The approach provides a more effective means for sampling larger numbers of 3D optimized designs.
Scattering matrix for chiral harmonic generation and frequency mixing in nonlinear metasurfaces
Authors: Koshelev Kirill , Toftul Ivan , Hwang Yongsop , Kivshar Yuri
Published: April 2024

We generalize the concept of optical scattering matrix (S-matrix) to characterize harmonic generation and frequency mixing in planar metasurfaces in the limit of undepleted pump approximation. We show that the symmetry properties of such nonlinear S-matrix are determined by the metasurface symmetries at the macroscopic and microscopic scale. We demonstrate that for description of degenerate frequency mixing processes such as optical harmonic generation, the multidimensional S-matrix can be replaced with a reduced two-dimensional S-matrix. We show that for metasurfaces possessing specific point group symmetries, the selection rules determining the transformation of the reduced nonlinear S-matrix are simplified substantially and can be expressed in a compact form. We apply the developed approach to analyze chiral harmonic generation in nonlinear metasurfaces with various symmetries including rotational, inversion, in-plane mirror, and out-of-plane mirror symmetries. For each of those symmetries, we confirm the results of the developed analysis by full-wave numerical calculations. We believe our results provide a new paradigm for engineering nonlinear optical properties of metasurfaces which may find applications in active and nonlinear optics, biosensing, and quantum information processing.
Narrowband Mg/SiC multilayer mirror working as high-harmonic selector at 30.4 nm wavelength
Authors: Zhang Zhe , Qi Runze , Huang Qiushi , Feng Yufei , Zhang Zhong , Huo Tonglin , Zhou Hongjun , Wang Zhanshan
Published: April 2024

Multilayers (MLs) are a good choice for high-harmonic generation (HHG) sources for selecting single-wavelength radiation. MLs working around 30.4 nm with a significantly reduced bandwidth based on high Bragg order reflection have been designed and fabricated. The narrowband MLs were characterized using grazing incidence x-ray reflectometry, extreme ultraviolet reflectivity, and intrinsic stress measurements. The results indicate that Mg/SiC MLs designed with 3rd Bragg order have narrowest bandwidth of 0.71 nm (full width half maximum) with a spectral resolution (λ/Δλ) of 42, and reflectance of 30% under near normal incidence geometry. Based on these results, the simulation of narrowband MLs working at large incident angles demonstrates that 3rd Bragg order ML has a better spectral selectivity compared with 1st Bragg order ML for HHG sources.
Validity of the Groningen Effort Test in patients with suspected chronic solvent-induced encephalopathy
Authors: van Vliet Fabienne I M , van Schothorst Henrita P , Donker-Cools Birgit H P M , Schaafsma Frederieke G , Ponds Rudolf W H M , Geurtsen Gert J
Published: April 2024

Introduction

The use of performance validity tests (PVTs) in a neuropsychological assessment to determine indications of invalid performance has been a common practice for over a decade. Most PVTs are memory-based; therefore, the Groningen Effort Test (GET), a non-memory-based PVT, has been developed.

Objectives

This study aimed to validate the GET in patients with suspected chronic solvent-induced encephalopathy (CSE) using the criterion standard of 2PVTs. A second goal was to determine diagnostic accuracy for GET.

Method

Sixty patients with suspected CSE referred for NPA were included. The GET was compared to the criterion standard of 2PVTs based on the Test of Memory Malingering and the Amsterdam Short Term Memory Test.

Results

The frequency of invalid performance using the GET was significantly higher compared to the criterion of 2PVTs (51.7% vs. 20.0% respectively; p < 0.001). For the GET index, the sensitivity was 75% and the specificity was 54%, with a Youden’s Index of 27.

Conclusion

The GET showed significantly more invalid performance compared to the 2PVTs criterion suggesting a high number of false positives. The general accepted minimum norm of specificity for PVTs of >90% was not met. Therefore, the GET is of limited use in clinical practice with suspected CSE patients.
How to use MRI in cardiac disease with diastolic dysfunction?
Authors: Cadour Farah , Cour Adrien , Senlis Jules , Rapacchi Stanislas , Chennoufi Hajer , Michelin Paul , McQuade Colin , Demeyere Matthieu , Dacher Jean-Nicolas
Published: April 2024

Left ventricular (LV) diastolic dysfunction (DD) is an initially asymptomatic condition that can progress to heart failure, either with preserved or reduced ejection fraction. As such, DD is a growing public health problem. Impaired relaxation, the first stage of DD, is associated with altered LV filling. With progression, reducing LV compliance leads to restrictive cardiomyopathy. While cardiac magnetic resonance (CMR) imaging is the reference for LV systolic function assessment, transthoracic echocardiography (TTE) with Doppler flow measurements remains the standard for diastolic function assessment. Rather than simply replicating TTE measurements, CMR should complement and further advance TTE findings. We provide herein a step-by-step review of CMR findings in DD as well as imaging features which may help identify the underlying cause.
The Perceived Impact of the COVID-19 Pandemic on the Mental Health and Well-being of Care-Experienced People
Authors: Taylor Jonathan , Pooley Siân , Canning Rosie , O’Higgins Aoife , Bowes Lucy
Published: April 2024

The impact of the coronavirus disease 2019 (COVID-19) pandemic on care-experienced people has been the subject of research, but important gaps remain in our understanding of how care-experienced people felt their mental health and well-being were affected by the pandemic. Care-experienced adults from across the UK were invited to complete a survey and submit a diary during the first lockdown. Responses were received from 140 people, aged eighteen to sixty-nine years. Most respondents reported that their mental health deteriorated due to the pandemic and lockdown. However, a substantial minority thought that either there had been no change or the lockdown had helped them make positive improvements. Improvements were attributed to stable housing and employment, support from services and transferable skills they had learnt in care. A minority of respondents referred to their care status in their diaries. Most diarists presented their experiences as being common to other, non-care-experienced, people. This article showcases the resilience of many care-experienced people, including some who made explicit reference to the benefits of coping strategies developed while in care. The findings of this study reveal that when provided with the right support, the care system can assist people to develop important life skills.
Functional implication for myelin regeneration in recovery from ischaemic stroke
Authors: Vagionitis Stavros , Káradóttir Ragnhildur Thóra
Published: April 2024

This scientific commentary refers to ‘Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke’ by Cheng et al. (https://doi.org/10.1093/brain/awae029).
Neuroinflammation is a player in coma, but in which role?
Authors: Tenovuo Olli , Loane David J
Published: April 2024

This scientific commentary refers to ‘Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma’ by Sarton et al. (https://doi.org/10.1093/brain/awae045).
Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons
Authors: Paß Thomas , Ricke Konrad M , Hofmann Pierre , Chowdhury Roy S , Nie Yu , Chinnery Patrick , Endepols Heike , Neumaier Bernd , Carvalho André , Rigoux Lionel , Steculorum Sophie M , Prudent Julien , Riemer Trine , Aswendt Markus , Liss Birgit , Brachvogel Bent , Wiesner Rudolf J
Published: April 2024

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson’s disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons.

Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons.

We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control.
Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia
Authors: Yao Changqun , Fang Xing , Ru Qin , Li Wei , Li Jun , Mehsein Zeinab , Tolias Kimberley F , Li Lingyong
Published: April 2024

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network.

Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management.

These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.
CRL4DCAF4 E3 ligase-mediated degradation of MEN1 transcriptionally reactivates hTERT to sustain immortalization in colorectal cancer cells
Authors: Ao Zhimin , Xiao Dan , Wu Jing , Sun Ji , Liu Hong
Published: April 2024

Telomerase reactivation is implicated in approximately 85% of human cancers, yet its underlying mechanism remains elusive. In this study, we elucidate that the cullin-RING ubiquitin ligase 4 (CRL4) complex drives the reactivation of human telomerase reverse transcriptase (hTERT) in colorectal cancer (CRC) by degrading the tumor suppressor, menin 1 (MEN1). Our data show that, in noncancerous intestinal epithelial cells, the transcription factor specificity protein 1 (Sp1) recruits both the histone acetyltransferase p300 and MEN1 to suppress hTERT expression, thus maintaining telomere shortness post-cell division. Inflammation-induced microenvironments trigger an activation of the CRL4DCAF4 E3 ligase, leading to MEN1 ubiquitination and degradation in CRC cells. This process nullifies MEN1’s inhibitory action, reactivates hTERT expression at the transcriptional level, interrupts telomere shortening and spurs uncontrolled cellular proliferation. Notably, MEN1 overexpression in CRC cells partially counteracts these oncogenic phenotypes. NSC1517, an inhibitor of the CRL4DCAF4 complex identified through high-throughput screening from a plant-derived chemical pool, hinders MEN1 degradation, attenuates hTERT expression and suppresses tumor growth in mouse xenograft models. Collectively, our research elucidates the transcriptional mechanism driving hTERT reactivation in CRC. Targeting the CRL4DCAF4 E3 ligase emerges as a promising strategy to counteract cancer cell immortalization and curb tumor progression.
‘Doctors advised to take medicines to remove these thoughts’: the violence and violations in sexual mental health care in community mental health programmes in Kerala
Authors: Kottai Sudarshan R
Published: April 2024

Community mental health programmes (CMHPs) have proliferated in both governmental and non-governmental sectors in recent times in India. Although CMHPs are mandated to work in close collaboration with the community, the operationalization of community is fraught with exclusionary tendencies, particularly concerning non-cis-heteronormative sexual subjects. Mental health professionals trained in the mainstream western biopsychiatric paradigm are largely silent on the lesbian, gay, bisexual, transgender, queer, intersex and asexual identity discourses as they institute pathological and reductive conceptualization about sexualities, psychosocial disabilities and resultant sufferings. Drawing on ethnographic fieldwork carried out at two non-governmental and a governmental CMHP in Kerala, south India, I illustrate the lack of a human rights–based approach to sex and sexual orientation and gender identity, due to which pressing concerns of sexual life are mis/overdiagnosed as mental ‘disorders’ to be treated within a biomedical framework. The lack of an intersectional approach fails the marginalized sexual subjects to exert their agency, develop critical consciousness and recognize sexuality as a political issue—all vital for transformative social change. The consequence is a dehumanized mental health care system that fails to ‘archive feelings’ that are pivotal in making invisibilized worlds observable to tell ‘unwelcome truths’ that induce psychic pain. Collaborative alliances among other marginalised sections like Queer, Dalit, tribal and Crip (disability) groups are vital in resisting intra-individual prescriptions by increasingly commercializing mental health practice in a country beset by a host of social problems including poverty, discrimination and rising inequalities. It is crucial to understand systems of power (imbalance) that operate as major (social) determinants of (sexual) mental health.
Large Language and Vision Assistant in dermatology: a game changer or just hype?
Authors: Goktas Polat , Gulseren Duygu , Tobin Anne-Marie
Published: April 2024

The integration of artificial intelligence (AI) in healthcare, particularly in the field of dermatology, has experienced significant progress through the creation of advanced tools such as the Large Language and Vision Assistant (LLaVA). This comprehensive review examines whether LLaVA represents a significant breakthrough or merely a passing trend in dermatological practice. By incorporating both language and visual analysis capabilities, LLaVA aims to support enhanced diagnostic accuracy, patient engagement and customized treatment planning, as evidenced by current research and case studies. However, its practical utility in a clinical setting remains a subject of debate. We explore the visual assistant chatbot’s potential in improving diagnostic precision, especially in analysing skin lesions and conditions that are visually complex. The tool’s capacity to process and interpret dermatological images using advanced algorithms could aid clinicians in the early detection and management of skin diseases. Furthermore, LLaVA’s interactive nature potentially improves patient education and adherence to treatment protocols. Despite these advantages, there are noteworthy limitations and risks. The accuracy of LLaVA in handling atypical or rare dermatological cases is an area of concern. The tool’s reliance on existing medical data raises questions about bias and the generalizability of its findings. Additionally, ethical considerations, such as patient data privacy and the potential for overreliance on AI in clinical decision making, are critical issues that need addressing. This article aims to provide dermatologists with a comprehensive understanding of LLaVA’s capabilities and limitations. We discuss practical guidelines for its integration into research and clinical educational augmentation, ensuring that dermatologists can make informed decisions about employing this technology for the enhancement of patient care and treatment outcomes. The question remains: is LLaVA a game changer in dermatology, or is it just hype? This review endeavours to answer this, establishing a foundation for knowledgeable and efficient application of visual AI chatbots in dermatology practices.
Comment on ‘ChatGPT and medical writing in dermatology: why should we keep writing?’
Authors: Daungsupawong Hineptch , Wiwanitkit Viroj
Published: April 2024

We provide a comment on an article by Potestio et al. about ChatGPT and medical writing.
Solid-state nickel(0)-mediated Yamamoto coupling enabled by mechanochemistry
Authors: Kubota Koji , Shizukuishi Naoki , Kubo Shotaro , Ito Hajime
Published: April 2024

Herein, we report the first solid-state protocol for nickel(0)-mediated Yamamoto-coupling reactions using ball milling. A variety of aryl halides reacted efficiently in the presence of bis(cyclooctadiene)nickel(0) [Ni(cod)2] and 4,4'-di-tert-butyl-2,2'-bipyridyl under solid-state mechanochemical conditions, affording the corresponding biaryls in high yields. Considering that potentially harmful and high-boiling organic solvents are not required, the present study provides a more convenient, environmentally friendly, and sustainable alternative to conventional solution-based Yamamoto coupling. Solid-state Yamamoto-coupling polymerization and the development of a catalytic variant are also described.
Highly efficient and air-tolerant calcium-based Birch reduction using mechanochemistry
Authors: Kubota Koji , Fukuzawa Yamato , Kondo Keisuke , Gao Yunpeng , Ito Hajime
Published: April 2024

In this study, we report a mechanochemical protocol for highly efficient and air-tolerant calcium-based Birch reduction. The developed mechanochemical approach allows the use of readily available calcium metal as a safer-to-handle reductant for Birch reduction of various aromatic compounds. The reaction was rapid and the desired dearomatization products were obtained in good yields within 15 min at ambient temperature. Notably, all synthetic operations can be performed under ambient conditions without a complicated reaction setup involving inert gases. The feasibility of the gram-scale synthesis was demonstrated, further highlighting the practical utility of this protocol.
Development of Predictive Models to Inform a Novel Risk Categorization Framework for Antibiotic Resistance in Escherichia coli–Caused Uncomplicated Urinary Tract Infection
Authors: Shields Ryan K , Cheng Wendy Y , Kponee-Shovein Kalé , Indacochea Daniel , Gao Chi , Kuwer Fernando , Joshi Ashish V , Mitrani-Gold Fanny S , Schwab Patrick , Ferrinho Diogo , Mahendran Malena , Pinheiro Lisa , Royer Jimmy , Preib Madison T , Han Jennifer , Colgan Richard
Published: April 2024

Background

In clinical practice, challenges in identifying patients with uncomplicated urinary tract infections (uUTIs) at risk of antibiotic nonsusceptibility may lead to inappropriate prescribing and contribute to antibiotic resistance. We developed predictive models to quantify risk of nonsusceptibility to 4 commonly prescribed antibiotic classes for uUTI, identify predictors of nonsusceptibility to each class, and construct a corresponding risk categorization framework for nonsusceptibility.

Methods

Eligible females aged ≥12 years with Escherichia coli–caused uUTI were identified from Optum's de-identified Electronic Health Record dataset (1 October 2015–29 February 2020). Four predictive models were developed to predict nonsusceptibility to each antibiotic class and a risk categorization framework was developed to classify patients' isolates as low, moderate, and high risk of nonsusceptibility to each antibiotic class.

Results

Predictive models were developed among 87 487 patients. Key predictors of having a nonsusceptible isolate to ≥3 antibiotic classes included number of previous UTI episodes, prior β-lactam nonsusceptibility, prior fluoroquinolone treatment, Census Bureau region, and race. The risk categorization framework classified 8.1%, 14.4%, 17.4%, and 6.3% of patients as having isolates at high risk of nonsusceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, β-lactams, and fluoroquinolones, respectively. Across classes, the proportion of patients categorized as having high-risk isolates was 3- to 12-fold higher among patients with nonsusceptible isolates versus susceptible isolates.

Conclusions

Our predictive models highlight factors that increase risk of nonsusceptibility to antibiotics for uUTIs, while the risk categorization framework contextualizes risk of nonsusceptibility to these treatments. Our findings provide valuable insight to clinicians treating uUTIs and may help inform empiric prescribing in this population.
Catheter-based therapy for high-risk or intermediate-risk pulmonary embolism: death and re-hospitalization
Authors: Leiva Orly , Alviar Carlos , Khandhar Sameer , Parikh Sahil A , Toma Catalin , Postelnicu Radu , Horowitz James , Mukherjee Vikramjit , Greco Allison , Bangalore Sripal
Published: April 2024

Background and Aims

Catheter-based therapies (CBTs) have been developed as a treatment option in patients with pulmonary embolism (PE). There remains a paucity of data to inform decision-making in patients with intermediate-risk or high-risk PE. The aim of this study was to characterize in-hospital and readmission outcomes in patients with intermediate-risk or high-risk PE treated with vs. without CBT in a large retrospective registry.

Methods

Patients hospitalized with intermediate-risk or high-risk PE were identified using the 2017–20 National Readmission Database. In-hospital outcomes included death and bleeding and 30- and 90-day readmission outcomes including all-cause, venous thromboembolism (VTE)-related and bleeding-related readmissions. Inverse probability of treatment weighting (IPTW) was utilized to compare outcomes between CBT and no CBT.

Results

A total of 14 903 [2076 (13.9%) with CBT] and 42 829 [8824 (20.6%) with CBT] patients with high-risk and intermediate-risk PE were included, respectively. Prior to IPTW, patients with CBT were younger and less likely to have cancer and cardiac arrest, receive systemic thrombolysis, or be on mechanical ventilation. In the IPTW logistic regression model, CBT was associated with lower odds of in-hospital death in high-risk [odds ratio (OR) 0.83, 95% confidence interval (CI) 0.80–0.87] and intermediate-risk PE (OR 0.76, 95% CI 0.70–0.83). Patients with high-risk PE treated with CBT were associated with lower risk of 90-day all-cause [hazard ratio (HR) 0.77, 95% CI 0.71–0.83] and VTE (HR 0.46, 95% CI 0.34–0.63) readmission. Patients with intermediate-risk PE treated with CBT were associated with lower risk of 90-day all-cause (HR 0.75, 95% CI 0.72–0.79) and VTE (HR 0.66, 95% CI 0.57–0.76) readmission.

Conclusions

Among patients with high-risk or intermediate-risk PE, CBT was associated with lower in-hospital death and 90-day readmission. Prospective, randomized trials are needed to confirm these findings.
Changes in Life’s Essential 8 and risk of cardiovascular disease in Chinese people
Authors: Li Wenjuan , Xing Aijun , Lamballais Sander , Xu Wenqi , Chen Shuohua , Zhou Shenghua , Wu Shouling , Chen Zhangling
Published: April 2024

Background

The American Heart Association recently released an updated algorithm for evaluating cardiovascular health—Life’s Essential 8 (LE8). However, the associations between changes in LE8 score over time and risk of cardiovascular disease (CVD) remain unclear.

Methods

We investigated associations between 6-year changes (2006–12) in LE8 score and risk of subsequent CVD events (2012–20) among 53 363 Chinese men and women from the Kailuan Study, who were free from CVD in 2012. The LE8 score was calculated based on eight components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

We documented 4281 incident CVD cases during a median of 7.7 years of follow-up. Compared with participants whose LE8 scores remained stable in a 6-year period, those with the large increases of LE8 score over the 6-year period had a lower risk of CVD, heart disease and stroke in the subsequent 8 years [HRs and 95% CIs: 0.67 (0.64, 0.70) for CVD, 0.65 (0.61, 0.69) for heart disease, 0.71 (0.67, 0.76) for stroke, all Ptrend < 0.001]. Conversely, those with the large decreases of LE8 score had 47%, 51% and 41% higher risk for CVD, heart disease and stroke, respectively. These associations were consistent across the subgroups stratified by risk factors.

Conclusions

Improving LE8 score in a short- and moderate-term was associated with a lower CVD risk, whereas decreased LE8 score over time was associated with a higher risk.
How Literary Texts ‘Stage’ Code-Switching
Authors: Grutman Rainier
Published: April 2024

This article explores the possibilities and limitations of the sociolinguistic notion of code-switching for the analysis of multilingual texts, in particular those belonging to literature as it is commonly understood (prose fiction, drama and poetry). In such (con)texts, I argue, code-switching is ‘staged’: produced rather than reproduced. Even when texts stage bilingual conversations with the aim of imitating real-life speech events, mimesis is mediated by the shift from spoken to written mode, which contrasts with the presence and proximity typical of (spoken) verbal interaction. While this mediation limits the applicability of sociolinguistic notions when discussing literary corpora, several examples from both North America (Junot Díaz, Gloria Anzaldúa and Ana Lydia Vega) and Europe (Lydie Salvayre, Ágota Kristóf, Franz Kafka and Leo Tolstoy) show how literary texts ‘stage’ code-switching.
Acute Dissociation and Ketamine’s Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial
Authors: Sajid Sumra , Galfalvy Hanga C , Keilp John G , Burke Ainsley K , Mann J John , Grunebaum Michael F
Published: April 2024

Objective

We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial.

Methods

Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment–emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion.

Results

Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P  = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012).

Conclusion

We did not find evidence that ketamine’s acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.
Respiratory Syncytial Virus vs Influenza Virus Infection: Mortality and Morbidity Comparison Over 7 Epidemic Seasons in an Elderly Population
Authors: Recto Caryn Giselle , Fourati Slim , Khellaf Mehdi , Pawlotsky Jean-Michel , De Prost Nicolas , Diakonoff Hadrien , Donadio Cristiano , Pouga Lydia , de Tymowski Christian , Kassasseya Christian
Published: April 2024

Background

Respiratory syncytial virus (RSV) infection is gaining interest due to the recent development of vaccines but is still misdiagnosed in the elderly. The primary objective was to compare all-cause mortality at day 30. Secondary objectives were to compare clinical presentation and rates of consolidative pneumonia, hospitalization, and intensive care unit (ICU) admission.

Methods

A single-center retrospective study was conducted in a French university hospital during 7 epidemic seasons including 558 patients aged ≥75 years: 125 with RSV and 433 with influenza (median age, 84.8 years).

Results

Patients with RSV had more respiratory symptoms (wheezing, dyspnea) whereas patients with influenza had more general symptoms (fever, asthenia, myalgia). The following were higher in the RSV group: consolidative pneumonia (28.8% vs 17.2%, P = .004), hospitalization (83.2% vs 70%, P = .003), ICU admission (7.2% vs 3.0%, P = .034), and length of stay (median [IQR], 9 days [2–16] vs 5 days [0–12]; P = .002). Mortality rates at day 30 were comparable (9.6% vs 9.7%, P = .973).

Conclusions

This study included the largest cohort of patients infected with RSV aged >75 years documented in-depth thus far. RSV shares a comparable mortality rate with influenza but is associated with higher rates of consolidative pneumonia, hospitalization, ICU admissions, and extended hospital stays.
Disruption of post-thymic tolerance in skin-reactive TCR transgenic mice through the interaction of lymphopenia and intestinal microbiota
Authors: Hayabuchi Hodaka , Tokifuji Yukiko , Takahashi Hayato , Amagai Masayuki , Yoshimura Akihiko , Chikuma Shunsuke
Published: April 2024

Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases.
Chemoattractant receptor signaling in humoral immunity
Authors: Shirai Taiichiro , Nakai Akiko , Suzuki Kazuhiro
Published: April 2024

Efficient induction of humoral immune responses depends on the orchestrated migration of B cells within lymphoid organs, which is governed by G protein-coupled receptors (GPCRs) responding to chemoattractants, represented by chemokines. After ligand binding, GPCRs are phosphorylated by different GPCR kinases (GRKs) at distinct sites on the receptor C termini, which dictates functional outcomes of β-arrestin-mediated signaling, ranging from receptor inactivation to effector molecule activation. However, the molecular mechanisms by which individual GRKs are selectively targeted to GPCRs have been poorly understood. Our recent study revealed that a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and 8 (the COMMD3/8 complex) functions as an adaptor that recruits a specific GRK to chemoattractant receptors and plays an important role in the control of B-cell migration during humoral immune responses. In this review, we summarize the current understanding of chemoattractant receptor signaling in the context of humoral immunity and discuss the potential of the COMMD3/8 complex as a therapeutic target for autoimmune diseases.
Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model
Authors: Mariager T , Terkelsen J H , Bue M , Öbrink-Hansen K , Nau R , Bjarkam C R , Nielsen H , Bodilsen J
Published: April 2024

Background

Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB.

Objective

(i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB.

Methods

Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8.

Results

We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0–8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3.

Conclusion

A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.
Association between the lung microbiome and perioperative prognosis in lung transplant recipients
Authors: Wu Yuhan , Huang Linna , Li Min , Cui Xiaoyang , Zhu Jun , Zhan Qingyuan , Wang Chen
Published: April 2024

Rationale

Studies have confirmed that the lung microbiome of lung transplant recipients is altered and serves as a prognostic indicator for long-term mortality. Other studies reported that the lung microbiome affects host immunity and the transcriptome. However, the lung microbiome composition at the early post-transplant period following lung transplantation is unclear, and the relationship of the lung microbiome with pulmonary immunity and the host transcriptome is also not well understood.

Objectives

We hypothesize that changes in the lung microbiome composition in the early post-transplant period may have a predictive value for perioperative outcomes following lung transplantation and that the lung microbiome is correlated with pulmonary immunity and the host transcriptome. Thus, this prospective study aimed at observing the lung microbiome composition in the early post-transplant period and the impact of the lung microbiome on pulmonary cytokines and the host transcriptome. Our findings will help us gain a comprehensive understanding of the distribution and significance of the lung microbiome in the early post-transplant period.

Methods

An observational study was conducted to identify the lung microbiome and the host transcriptome characteristics using next-generation sequencing. Luminex was employed for quantifying alveolar cytokines. Spearman's correlation analysis was utilized to assess the impact of the lung microbiome on pulmonary immunity and differentially expressed genes in patients who died perioperatively after lung transplantation.

Results

Patients with poor perioperative outcomes showed an increase in Mycoplasma and Arcobacter, a decrease of Gemella, and increased interleukin (IL)-10, IL-1β, and tumor necrosis factor (TNF)-α concentration. The lung microbiome correlates with lung immunity in lung transplant recipients. In the death group, the function of differentially expressed genes is associated with cell apoptosis, and promoting TNF production is upregulated. The lung microbiome is related to differentially expressed genes between the two groups.

Conclusions

The lung microbiome and cytokines can be considered as potential biomarkers for early prognosis in lung transplant recipients. The lung microbiome is associated with both lung immunity and differentially expressed genes in lung transplant recipients.
Collaborative and privacy-enhancing workflows on a clinical data warehouse: an example developing natural language processing pipelines to detect medical conditions
Authors: Petit-Jean Thomas , Gérardin Christel , Berthelot Emmanuelle , Chatellier Gilles , Frank Marie , Tannier Xavier , Kempf Emmanuelle , Bey Romain
Published: April 2024

Objective

To develop and validate a natural language processing (NLP) pipeline that detects 18 conditions in French clinical notes, including 16 comorbidities of the Charlson index, while exploring a collaborative and privacy-enhancing workflow.

Materials and Methods

The detection pipeline relied both on rule-based and machine learning algorithms, respectively, for named entity recognition and entity qualification, respectively. We used a large language model pre-trained on millions of clinical notes along with annotated clinical notes in the context of 3 cohort studies related to oncology, cardiology, and rheumatology. The overall workflow was conceived to foster collaboration between studies while respecting the privacy constraints of the data warehouse. We estimated the added values of the advanced technologies and of the collaborative setting.

Results

The pipeline reached macro-averaged F1-score positive predictive value, sensitivity, and specificity of 95.7 (95%CI 94.5-96.3), 95.4 (95%CI 94.0-96.3), 96.0 (95%CI 94.0-96.7), and 99.2 (95%CI 99.0-99.4), respectively. F1-scores were superior to those observed using alternative technologies or non-collaborative settings. The models were shared through a secured registry.

Conclusions

We demonstrated that a community of investigators working on a common clinical data warehouse could efficiently and securely collaborate to develop, validate and use sensitive artificial intelligence models. In particular, we provided an efficient and robust NLP pipeline that detects conditions mentioned in clinical notes.