bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender differences in scholarly productivity of early‐career transfusion medicine physicians
Authors: Ipe Tina S. , Tanhehco Yvette C. , Booth Garrett S. , Adkins Brian D.
Published: March 2024

Background and Objectives

Promotion in academic medicine requires evidence of the creation and dissemination of scholarly output, primarily through peer‐reviewed publications. Studies demonstrate that scholarly activity and impact are lower for women physicians than for men physicians, especially during the early stages of their academic careers. This report reviewed physicians' academic productivity after passing their Blood Banking/Transfusion Medicine (BBTM) subspecialty exam to determine if gender discrepancies exist.

Methods

A cross‐sectional analysis was designed to determine trends in scholarly activity for women physicians versus men physicians in BBTM. Indexed publications were reviewed using iCite, the National Institutes of Health (NIH) Office of Portfolio Analysis tool, from 1 January 2017 to 1 December 2021, for BBTM examinees who passed the sub‐speciality fellowship exam in the years 2016 through 2018.

Results

Overall, women physicians had statistically significant fewer total career publications (median 6 vs. 9 cumulative papers, p = 0.03). Women published at a lower rate after passing BBTM boards, which was not statistically significant (0.7 vs. 1.3 publications per year). Other statistically significant findings include fewer early‐career BBTM women physicians were first authors compared with men physicians (p = 0.03) and impact as assessed by relative citation ratio was higher for men (p = 0.01).

Conclusions

This study demonstrates that there are gender differences in scholarly productivity and impact on early‐career BBTM physicians. Given that this cohort of BBTM physicians are early‐career professionals, the significant difference in first authorship publications between women and men physicians is especially concerning. Publication metrics should be followed to ensure equitable research environments for early‐career BBTM physicians.
Current and future glyphosate use in European agriculture
Authors: Neve Paul , Matzrafi Maor , Ulber Lena , Baraibar Bàrbara , Beffa Roland , Belvaux Xavier , Farré Joel Torra , Mennan Hüsrev , Ringselle Björn , Salonen Jukka , Soukup Josef , Andert Sabine , Duecker Rebecka , Gonzalez Emilio , Hamouzová Katerina , Karpinski Isabella , Travlos Ilias S. , Vidotto Francesco , Kudsk Per
Published: March 2024

There has been a longstanding and contentious debate about the future of glyphosate use in the European Union (EU). In November 2023, the European Commission approved the renewal of the use registration for glyphosate for a further 10 years. Nevertheless, the EU Farm to Fork strategy calls for a 50% reduction in pesticide use by 2030. In November 2022, the European Weed Research Society organised a 2 day workshop to identify critical glyphosate uses in current EU cropping systems and to review the availability of glyphosate alternatives. Workshop participants identified four current, critical uses in EU cropping systems; control and management of perennial weeds, weed control in conservation agriculture, vegetation management in tree and vine crops and herbicide resistance management. There are few herbicide alternatives that provide effective, economic, broad‐spectrum control of weeds, particularly perennial weeds. Mechanical weed control, and in particular, soil cultivation is the most obvious glyphosate alternative. However, this is not possible in conservation agriculture systems and, in general, increased soil cultivation has negative impacts for soil health. Emerging technologies for precision weed control can enable more targeted use of glyphosate, greatly reducing use rates. These technologies also facilitate the use and development of alternative targeted physical weed control (e.g. tillage, lasers, electricity), reducing the energy and environmental costs of these approaches. In tree crops, the use of organic and inorganic mulches can reduce the need for glyphosate use. In general, reduced use of glyphosate will require an even greater focus on integrated weed management to reduce weed establishment in agroecosystems, increase weed management diversity and limit the use of alternative resistance‐prone herbicides.
Direct Current Motor Velocity Control With Integral Retarded Controller Under Unintentional Delay
Authors: Fan Haonan , Ramírez Adrián , Mondié Sabine , Sipahi Rifat
Published: March 2024

Delay-based controllers have been recently revisited over proportional-integral-derivative (PID) controllers, with promising analytical tuning formulae and capabilities to effectively control plants with noisy measurements even without low-pass filters. One such controller is the integral retarded (IR) controller, which utilizes an intentional delay to reduce actuator chattering against noisy measurements while its integral part achieves zero steady-state error for set-point regulation of Type-0 open-loop systems. However, measurements can be unintentionally delayed in many applications. The integral retarded framework for such cases has not been studied in the literature. Here, we provide new analytical tuning rules of the controller in such cases, as well as validations through simulations and a direct current (DC) motor velocity control hardware experiment.
General Muscle Torque Generator Model for a Two Degree-of-Freedom Shoulder Joint
Authors: Bell Sydney , Nasr Ali , McPhee John
Published: March 2024

Muscle torque generators (MTGs) have been developed as an alternative to muscle-force models, reducing the muscle-force model complexity to a single torque at the joint. Current MTGs can only be applied to single Degree-of-freedom (DoF) joints, leading to complications in modeling joints with multiple-DoFs such as the shoulder. This study aimed to develop an MTG model that accounts for the coupling between 2-DoF at the shoulder joint: shoulder plane of elevation (horizontal abduction/adduction) and shoulder elevation (flexion/extension). Three different 2-DoF MTG equations were developed to model the coupling between these two movements. Net joint torques at the shoulder were determined for 20 participants (10 females and 10 males) in isometric, isokinetic, and passive tests. Curve and surface polynomial fitting were used to find the best general fit for the experimental data in terms of the different degrees of coupling. The models were validated against experimental isokinetic torque data. It was determined that implicit coupling that used interpolation between single-DoF MTGs resulted in the lowest root-mean-square percent error of 8.5%. The work demonstrated that general MTG models can predict torque results that are dependent on multiple-DoFs of the shoulder.
Actuation Modeling of a Microfluidically Reconfigurable Radiofrequency Device
Authors: Parsi Behzad , Metten Jason B. , Waite Clinton , Maynes Daniel , Crane Nathan B.
Published: March 2024

Microfluidic-based techniques have been shown to address limitations of reconfigurable radio frequency (RF) antennas and filters in efficiency, power handling capability, cost, and frequency tuning. However, the current devices suffer from significant integration challenges associated with packaging, actuation, and control. Recent advances in reconfigurable microfluidics that utilize the motion of a selectively metalized plate (SMP) for RF tuning have demonstrated promising RF capabilities but have exposed a need for an accurate fluid actuation model. This research presents a model for the mechanical motion of a moving plate in a channel to relate the SMP size, microfluidic channel size, velocity, and inlet pressure. This model facilitates understanding of the actuation response of an RF tuning system based on a moving plate independent of the actuation method. This model is validated using a millimeter-scale plate driven by a gravitational pressure head as a quasi-static pressure source. Measurements of the prototyped device show excellent agreement with the analytical model; thus, the designer can utilize the presented model for designing and optimizing a microfluidic-based reconfigurable RF device and selecting actuation methods to meet desired outcomes. To examine model accuracy at device scale, recent papers in the microfluidics reconfigurable RF area have been studied, and excellent agreement between our proposed model and the literature data is observed.
Oxygen Storage Incorporated Into Net Power and the Allam–Fetvedt Oxy-Fuel sCO2 Power Cycle—Techno-Economic Analysis
Authors: Moore J. Jeffrey , Pryor Owen , Cormier Ian , Fetvedt Jeremy
Published: March 2024

With the planned future reliance on variable renewable energy, the ability to store energy for prolonged time periods will be required to reduce the disruption of market fluctuations. This paper presents a method to analyze a hybrid liquid-oxygen (LOx) storage/direct-fired supercritical carbon dioxide (sCO2) power cycle and optimize the economic performance over a diverse range of scenarios. The system utilizes a modified version of the NET Power process to produce energy when energy demand exceeds the supply while displacing much of the cost of the air separation unit (ASU) energy requirements through cryogenic storage of oxygen. The model uses marginal cost of energy data to determine the optimal times to charge and discharge the system over a given scenario. The model then applies ramp rates and other time-dependent factors to generate an economic model for the system without storage considerations. The size of the storage system is then applied to create a realistic model of the plant operation. From the real plant operation model, the amount of energy charged and discharged, the capital expenditures (CAPEX) of each system, energy costs and revenue and other parameters can be calculated. The economic parameters are then combined to calculate the net present value (NPV) of the system for the given scenario. The model was then run through the SMPSO genetic algorithm in Python for a variety of geographic regions and large-scale scenarios (high solar penetration) to maximize the NPV based on multiple parameters for each subsystem. The LOx storage requirements will also be discussed.
Radiation damage effects on electronic and optical properties of β-Ga2O3 from first-principles
Authors: Zhang Xiaoning , Liang Xi , Li Xing , Li Yuan , Yang Jia-Yue , Liu Linhua
Published: March 2024

β-Ga2O3 with an ultra-wide bandgap demonstrates great promise in applications of space missions as power electronics and solar-blind photodetector. Unraveling the radiation damage effects on its material properties is of crucial importance, especially for improving the radiation tolerance of Ga2O3-based devices. Herein, we evaluate the formation energy of gallium and oxygen vacancy defects and comprehensively investigate their influence on the electronic and optical properties of β-Ga2O3 using first-principles calculations. Ga vacancies act as deep acceptors and produce p-type defects in β-Ga2O3, while the defective Ga2O3 with O vacancies exhibits the n-type characteristics. A semimetal characteristic is observed in the defective Ga2O3 with Ga vacancies, and an apparent optical absorption peak in the infrared spectral range emerges. Moreover, the self-compensation effect emerges when β-Ga2O3 contains both Ga vacancies and O vacancies, leading to the reduced absorption peak. The doping effect on the defect formation energy of β-Ga2O3 is also investigated, and Ga vacancies are found to be easily formed in the case of In doped β-Ga2O3 (InGa2O3) compared to the undoped β-Ga2O3, while O vacancies are much harder to form. This work provides insights into how gallium and oxygen vacancy defects alter electronic and optical properties of β-Ga2O3, seeking to strengthen its radiation tolerance.
Fabrication of slanted gratings by using glancing angle deposition
Authors: Wu Hongwen , Pan Aixi , Zhu Chenxu , Cui Bo
Published: March 2024

Slanted gratings, commonly used for manipulating light in various applications, are typically fabricated using conventional top-down methods. However, these methods have limitations on material choice. This paper explores the use of glancing angle deposition (GLAD) to fabricate slanted gratings with various materials and slant angles on silicon (Si) and quartz (SiO2) substrates. The process involves the first step of creating a template using electron beam lithography, lift-off, and dry etching, and the second step of electron beam evaporation at a glancing angle on the prefabricated template. The template consists of grating structures with very shallow trenches. Different materials, such as chromium (Cr), copper (Cu), aluminum oxide (Al2O3), and titanium oxide (TiO2), were used in the GLAD process to create slanted grating structures on Si or SiO2 substrates, showcasing their versatility. Here, the formation of the slanted grating is due to the shadowing effect that leads to deposition onto the protruded grating lines but not into the trench. Using TiO2 as the source material, the GLAD technique can produce slanted gratings with various angles by adjusting the deposition angle. The optical characteristics of the slanted grating prepared using GLAD were verified through simulations with COMSOL software, confirming its excellent light guide performance.
Bottom water hypoxia suppresses fish chorusing in estuaries
Authors: Luczkovich Joseph J. , Sprague Mark W. , Paerl Hans W.
Published: March 2024

Hypoxia in coastal ecosystems is increasing as a result of water quality declines from nutrient pollution. Hypoxia negatively affects fish populations and marine life, limiting their spawning habitats, population size, and growth. In this study, two approaches were used to understand the effect of hypoxia on the chorusing and reproductive behavior of fishes in estuaries. One approach used a water quality meter integrated with a prototype passive acoustic recorder, developed to monitor dissolved oxygen and fish chorusing simultaneously and continuously at sites with normoxic and hypoxic conditions. In a second approach, passive acoustic recorders were deployed near ambient water quality monitoring stations, monitored by the North Carolina agencies in estuaries where hypoxia occurs periodically. In both approaches, when hypoxia (dissolved oxygen < 4.0 mg/L) occurred, fish chorusing was diminished or ceased. A strong correlation was observed between bottom water dissolved oxygen and the power spectral density in a 100–200 Hz frequency band associated with red drum (Sciaenops ocellatus, Sciaenidae) calling. Passive acoustic monitoring stations and integrated passive acoustic and water quality meters should be used in estuarine hypoxia monitoring efforts to examine the expanding areas of hypoxia and its impact on fish critical spawning habitats.
Does Participating in a Variety of Activities at a Variety of Locations or With Different People Predict Physical Activity Behavior Among Adolescents? The Mediating Role of Perceived Variety
Authors: Murray Ross M. , Sylvester Benjamin D. , Sabiston Catherine M. , Doré Isabelle , Bélanger Mathieu
Published: March 2024

We examine whether adolescents’ participating in a variety of physical activities, locations, and/or with a variety of people relates to physical activity 16 months later and whether perceptions of variety mediate these relationships. Adolescents (N = 369) completed measures indicating various physical activities they participated in, where they primarily participated, and with whom they primarily participated, at three time points over a year (averaged for baseline measures). Perceptions of variety was measured 8 months later. Physical activity was measured 16 months after baseline. Mediation analyses tested perceptions of variety as a mediator of variety support and physical activity. Results indicated that variety of activities and variety of locations were indirectly associated with physical activity through perceptions of variety. Participating in a breadth of physical activities in a variety of locations during adolescence is positively associated with perceptions of variety, which relates to physical activity 16 months later.
The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P
Authors: Luteijn Rutger D. , van Terwisga Sypke R. , Ver Eecke Jill E. , Onia Liberty , Zaver Shivam A. , Woodward Joshua J. , Wubbolts Richard W. , Raulet David H. , van Kuppeveld Frank J. M.
Published: March 2024

Activation of the endoplasmic reticulum (ER)–resident adaptor protein STING, a component of a cytosolic DNA–sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses. Through a genome-wide CRISPR interference screen, we found that STING activation required the Golgi-resident protein ACBD3, which promotes the generation of phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network, as well as other PI4P-associated proteins. Appropriate localization and activation of STING at the Golgi apparatus required ACBD3 and the PI4P-generating kinase PI4KB. In contrast, STING activation was enhanced when the lipid-shuttling protein OSBP, which removes PI4P from the Golgi apparatus, was inhibited by the US Food and Drug Administration–approved antifungal itraconazole. The increase in the abundance of STING-activating phospholipids at the trans-Golgi network resulted in the increased production of IFN-β and other cytokines in THP-1 cells. Furthermore, a mutant STING that could not bind to PI4P failed to traffic from the ER to the Golgi apparatus in response to a STING agonist, whereas forced relocalization of STING to PI4P-enriched areas elicited STING activation in the absence of stimulation with a STING agonist. Thus, PI4P is critical for STING activation, and manipulating PI4P abundance may therapeutically modulate STING-dependent immune responses.
Clinical utility of multiplex PCR in the detection of pathogens from sterile body fluids
Authors: Cox Christina R. , Weghorn Kristin N. , Ruger Katie , Powers-Fletcher Margaret V. , Powell Eleanor A. , Mortensen Joel E.
Published: March 2024

Rapid identification of pathogens in normally sterile body fluid (NSBF) is essential for appropriate patient management, specifically antimicrobial therapy. Limited sensitivity and increased time to detection of traditional culture prompted us to evaluate additional testing to contribute to the diagnosis of infection. The purpose of this study was to evaluate the GenMark Dx ePlex Blood Culture Identification (BCID) Panels on positive body fluids inoculated into blood culture bottles for the detection of microorganisms. A total of 88 positive body fluids from blood culture bottles were analyzed using a Gram-Positive, Gram-Negative, and/or Fungal pathogen BCID Panel based on the Gram stain result. Each result was compared to routine culture performed from the positive bottle. When using culture as a reference standard, we found the ePlex multiplex panel performed with a positive percent agreement of 96.5% and a negative percent agreement of 99.8%. The use of multiplex PCR may be a useful supplement to routine culture for NSBF in blood culture bottles.

IMPORTANCE

The identification of pathogens in normally sterile body fluid (NSBF) is performed using routine culture, the current gold standard. Limitations of this method include sensitivity and increased turnaround times which could potentially delay vital patient care, especially antimicrobial therapy. Adaptations of NSBF in blood culture bottles prompted us to consider the utility of additional methods to bridge the gap in diagnostic challenges for these life-threatening infections. Multiplex molecular panels have been manufactured for use with multiple specimen types including blood, cerebral spinal fluid, stool, and respiratory. Therefore, the purpose of this study was to evaluate the off-label use of ePlex Blood Culture Identification Panels on positive body fluids grown in blood culture bottles for the detection of microorganisms for research purposes.
The integration of
Coxiella burnetii
PCR testing in serum into the diagnostic algorithm of suspected acute Q fever in an endemic setting
Authors: Ghanem-Zoubi Nesrin , Mustafa-Hellou Mona , Zahran Maram , Gazit Liat , Shalaginov Raya , Dabaja-Younis Halima , Szwarcwort Moran
Published: March 2024

Serum polymerase chain reaction (PCR) for the detection of
Coxiella burnetii
DNA has been suggested for rapid Q fever diagnosis. We evaluated the role of PCR testing in serum in the diagnosis of acute Q fever in an endemic setting. We examined patients suspected of acute Q fever tested for
C. burnetii
-specific serum real-time PCR in a tertiary hospital between January 2019 toand December 2022. In the first half, PCR orders were consultation-based by infectious diseases specialists, while in the second half, they were guided by serology, positive IgM2, and negative IgG1 and IgG2, indicating early acute infection. Logistic regression analyzed independent predictors for positive PCR. PCR positivity rates were calculated using various clinical criteria in the diagnostic algorithm. Out of 272 patients, 13 (4.8%) tested positive and 130 exhibited serologically suspected early infection. Presentation during April–July and aspartate aminotransferase (AST) > 3× upper normal limit (UNL) were independently associated with positive PCR with an odds ratio (OR) = 15.03 [95% confidence interval (CI), 1.58–142.46],
P
= 0.018 and OR = 55.44 [95% CI, 6.16–498.69],
P
< 0.001, respectively. PCR positivity rate was 8.5% in serologically suspected early infection vs 1.4% in other serology, yielding OR = 6.4 [95% CI, 1.4–29.7],
P
= 0.009. Adding AST > 3× UNL increased OR to 49.5 [95% CI, 5.9–408.7],
P ≤
0.001 reducing required PCR tests for a single acute Q fever case from 11.8 to 3. Elevated AST in serologically suspected early Q fever is proposed to be used in a diagnostic stewardship algorithm integrating PCR in serum in an endemic setting.

IMPORTANCE

Our study suggests in a diagnostic stewardship approach the integration of molecular testing (Coxiella burnetii targeted PCR) for the diagnosis of acute Q fever in a reliable time in the endemic setting. Integrating PCR detecting
Coxiella burnetii
in serum in routine testing of suspected early acute Q fever based on serology result increased the PCR positivity rate significantly. Adding increased transaminases optimizes PCR utility which is highly requested particularly in endemic areas.
Anaerostipes hadrus
, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil
Authors: Liu Danping , Xie Li-Sheng , Lian Shitao , Li Kexin , Yang Yun , Wang Wen-Zhao , Hu Songnian , Liu Shuang-Jiang , Liu Chang , He Zilong
Published: March 2024

Anaerostipes hadrus
(
A. hadrus
) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that
A. hadrus
may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of
A. hadrus
is complex and unclear. Therefore, comprehensive genomic studies on
A. hadrus
need to be performed. We integrated 527 high-quality public
A. hadrus
genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based
in vitro
assays. We constructed the first large-scale pan-genome of
A. hadrus
(
n
= 527) and identified 5-fluorouracil metabolism genes as ubiquitous in
A. hadrus
genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of
A. hadrus
in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more
A. hadrus
. The predicted high-quality protein structure indicated that
A. hadrus
might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the
preTA
operon). Through
in vitro
assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of
A. hadrus
. We observed for the first time that
A. hadrus
can convert 5-fluorouracil to α-fluoro-β-ureidopropionic acid, which may result from the combined action of the
preTA
operon and adjacent
hydA
(encoding bacterial dihydropyrimidinase). Our results offer novel understandings of
A. hadrus
, exceptionally functional features, and potential applications.

IMPORTANCE

This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of
Anaerostipes hadrus
.
Multifactorial genetic control and magnesium levels govern the production of a
Streptomyces
antibiotic with unusual cell density dependence
Authors: ­ Hindra , Elliot Marie A.
Published: March 2024

Streptomyces
bacteria are renowned both for their antibiotic production capabilities and for their cryptic metabolic potential. Their metabolic repertoire is subject to stringent genetic control, with many of the associated biosynthetic gene clusters being repressed by the conserved nucleoid-associated protein Lsr2. In an effort to stimulate new antibiotic production in wild
Streptomyces
isolates, we leveraged the activity of an Lsr2 knockdown construct and successfully enhanced antibiotic production in the wild
Streptomyces
isolate WAC07094. We determined that this new activity stemmed from increased levels of the angucycline-like family member saquayamycin. Saquayamycin has both antibiotic and anti-cancer activities, and intriguingly, beyond Lsr2-mediated repression, we found saquayamycin production was also suppressed at high density on solid or in liquid growth media; its levels were greatest in low-density cultures. This density-dependent control was exerted at the level of the cluster-situated regulatory gene
sqnR
and was mediated in part through the activity of the PhoRP two-component regulatory system, where deleting
phoRP
led to both constitutive antibiotic production and
sqnR
expression. This suggests that PhoP functions to repress the expression of
sqnR
at high cell density. We further discovered that magnesium supplementation could alleviate this density dependence, although its action was independent of PhoP. Finally, we revealed that the nitrogen-responsive regulators GlnR and AfsQ1 could relieve the repression exerted by Lsr2 and PhoP. Intriguingly, we found that this low density-dependent production of saquayamycin was not unique to WAC07094; saquayamycin production by another wild isolate also exhibited low-density activation, suggesting that this spatial control may serve an important ecological function in their native environments.

IMPORTANCE

Streptomyces
specialized metabolic gene clusters are subject to complex regulation, and their products are frequently not observed under standard laboratory growth conditions. For the wild
Streptomyces
isolate WAC07094, production of the angucycline-family compound saquayamycin is subject to a unique constellation of control factors. Notably, it is produced primarily at low cell density, in contrast to the high cell density production typical of most antibiotics. This unusual density dependence is conserved in other saquayamycin producers and is driven by the pathway-specific regulator SqnR, whose expression is influenced by both nutritional and genetic elements. Collectively, this work provides new insights into an intricate regulatory system governing antibiotic production and indicates there may be benefits to including low-density cultures in antibiotic screening platforms.
Semaglutide treatment for children with obesity: an observational study
Authors: van Boxel Elizabeth-Jane , Rahman Saqib , Lai Karen , Boulos Nabil , Davis Nikki
Published: March 2024

Objective

To assess efficacy and tolerability of semaglutide as a weight loss treatment for children living with comorbid obesity.

Design

Retrospective observational study of the first 50 children from a weight management service treated with semaglutide for at least 6 months.

Setting

A tertiary paediatric multidisciplinary weight management clinic in a UK hospital.

Patients

Aged 10–18 years old with a body mass index (BMI) SD score (SDS) >2 with a weight-related comorbidity (including insulin resistance (defined as homeostatic model assessment for insulin resistance >4), type 2 diabetes, metabolic-associated fatty liver disease, obstructive sleep apnoea or hypertension).

Interventions

Once-weekly injectable semaglutide titrated over 8 weeks to a final dose of 1 mg in addition to dietary and lifestyle advice.

Main outcome measures

Primary outcome measures were change in weight, BMI SDS and percentage body weight. Secondary outcomes were side effects and cessation of treatment.

Results

After 6 months of treatment, statistically significant decreases in BMI SDS (0.32±0.27, p<0.001) and body weight (7.03±7.50 kg, p<0.001) were seen. Mean percentage total weight loss was 6.4±6.3% (p<0.001). For the 14 patients for whom 12-month data were available, statistically significant decreases were seen in mean BMI SDS (0.54±0.52, p<0.001). Mean body weight decreased by 9.7±10.8 kg (p<0.001). Percentage total weight loss at 12 months was 8.9±10.0% (p<0.001). Mild gastrointestinal side effects were common. One patient developed gallstones. Five patients discontinued treatment due to side effects.

Conclusion

Semaglutide appears to be a safe and effective weight loss adjunct when used in a multidisciplinary weight management clinic.
Laparoscopic resection of a salpingectomy stump remnant during early pregnancy: the diagnostic challenge posed in diagnosing a heterotopic stump pregnancy
Authors: Dighero Isabel , Shipsey Liam , Elrayes Mohamed
Published: March 2024

In this report, we present a case of a woman admitted in her first trimester of pregnancy with significant intraperitoneal haemorrhage from a left tubal stump remnant occurring concurrent to a viable intrauterine pregnancy. The patient was resuscitated and treated successfully with laparoscopic removal of her stump remnant to achieve haemostasis. However, despite extensive investigation, the pathology of her haemorrhagic stump remained inconclusive. Stump ectopic pregnancy is an established phenomenon, although it presents a diagnostic challenge when occurring as a heterotopic pregnancy. Further, persisting trophoblastic tissue is a rare but established feature of incomplete removal of ectopic pregnancy post salpingectomy. Here, we discuss challenges of diagnosis in such cases and present a case report of a presumed stump remnant heterotopic pregnancy from spontaneous conception.
Association between corneal hysteresis and glaucoma in a Japanese population: the Hisayama Study
Authors: Fujiwara Kohta , Ueda Emi , Hata Jun , Nakano Satoko , Hashimoto Sawako , Nakamura Shun , Murakami Yusuke , Kubota Toshiaki , Yoshitomi Takeshi , Ninomiya Toshiharu , Sonoda Koh-Hei
Published: March 2024

Aims

To investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population.

Methods

We analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles.

Results

Glaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders.

Conclusions

These results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.
What works for whom, how and why in mental health education for undergraduate health profession students? A realist synthesis protocol
Authors: McCormack Zoe , Kerr Aisling , Simpson Andrew , Keating Dolores , Strawbridge Judith
Published: March 2024

Introduction

It has been shown that mental health education can support positive attitudes of health profession students towards people with mental health challenges, which supports them to provide optimal healthcare to this group. There are many different approaches to designing and delivering mental health education to health profession students. Each has their own advantages and disadvantages, and often mental health education programmes incorporate a multimodal approach in order to reap the benefits of a variety of teaching and learning approaches. The aim of this study is to understand the current landscape of teaching and learning approaches to mental health education for undergraduate health profession students. We will examine the features of successful outcomes for health profession students for:

Learning environment.

Knowledge development and retention.

Confidence.

Motivation.

Preparedness for professional practice.

Methods

For this, a realist synthesis has been chosen in order to review the literature. Realist synthesis lends itself to the review of complex interventions such as mental health education for undergraduate health profession curricula because it seeks to uncover the range of different mechanisms and context configurations that produce different outcomes. Health profession education and education practice, in general, is complex. A patient and public involvement (PPI) group is involved throughout this study and includes undergraduate health profession students, and members of the St John of Gods Hospital Consumers and Carers Council who are involved at every stage of the research. This study will engage with a stakeholder group who will support the refining of the programme theory.

Ethics and dissemination

Ethical approval has been sought and approved by Royal College of Surgeons, Ireland Ethical Committee (REC number: 212622783). We will aim to write up and publish the full synthesis as a journal article. We will also discuss ways of dissemination outside of academia with our PPI group.
High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma
Authors: Rischin Danny , Hughes Brett G M , Basset-Séguin Nicole , Schadendorf Dirk , Bowyer Samantha , Trabelsi Messai Sabiha , Meier Friedegund , Eigentler Thomas K , Casado Echarren Victoria , Stein Brian , Beylot-Barry Marie , Dalac Sophie , Dréno Brigitte , Migden Michael R , Hauschild Axel , Schmults Chrysalyne D , Lim Annette M , Yoo Suk-Young , Paccaly Anne J , Papachristos Apostolos , Nguyen Jenny-Hoa , Okoye Emmanuel , Seebach Frank , Booth Jocelyn , Lowy Israel , Fury Matthew G , Guminski Alexander
Published: March 2024

Background

Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctroughof extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W.

Methods

In this open-label, phase II trial (ClinicalTrials.gov identifierNCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review.

Results

Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0–39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue.

Conclusions

Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit−risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.
Mefloquine enhances the efficacy of anti-PD-1 immunotherapy via IFN-γ-STAT1-IRF1-LPCAT3-induced ferroptosis in tumors
Authors: Tao Qian , Liu Nian , Wu Jie , Chen Jing , Chen Xiang , Peng Cong
Published: March 2024

Background

Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated.

Methods

Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq).

Results

In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy.

Conclusions

In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.
Celastrol ameliorates lupus by promoting apoptosis of autoimmune T cells and preventing autoimmune response in MRL/lpr mice
Authors: Xie Tianhong , Rui Hongliang , Liu Huiqiang , Liu Xin , Liu Xiang , Li Ping
Published: March 2024

Objective

Celastrol is a bioactive constituent extracted fromTripterygium wilfordii(thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice.

Methods

We performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice.

Results

Celastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-γ, and the production of multiple antibody subsets, including total IgG, IgG1and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138− T cells to suppress autoimmune T cell accumulation in MRL/lpr mice.

Conclusions

Celastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response.
Enhanced medullary and extramedullary granulopoiesis sustain the inflammatory response in lupus nephritis
Authors: Zervopoulou Eleni , Grigoriou Maria , Doumas Stavros A , Yiannakou Danae , Pavlidis Pavlos , Gasparoni Gilles , Walter Jörn , Filia Anastasia , Gakiopoulou Harikleia , Banos Aggelos , Mitroulis Ioannis , Boumpas Dimitrios T
Published: March 2024

Objectives

In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders.

Methods

Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through β-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities.

Results

Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice.

Conclusions

These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.
Enhanced supportive care in cancer centres: national cross-sectional survey
Authors: Caulfield Rachel Moya Helen , Selman Lucy E , Gibbins Jane , Forbes Karen , Chamberlain Charlotte
Published: March 2024

Objectives

‘Early’ specialist palliative care (SPC) has been shown to improve outcomes for patients with advanced cancer, yet patients are often referred late. ‘Enhanced supportive care’ (ESC) aims to facilitate earlier integrated supportive care for those with incurable cancer. This study aimed to explore clinicians’ understanding of ESC/SPC delivery through description of current service provision.

Methods

This national cross-sectional survey of 53 cancer centres had two parts. Part 1: Service details, was directed to lead ESC/SPC nurses or consultants about service configuration, and Part 2: Clinician understanding, targeting conceptual understanding of service aims including ESC/SPC teams and oncology consultants (n=262 surveys). Multiple-choice questions explored service provision, referral triggers and evidence of integration with oncology, with free-text responses. Quantitative results were analysed with Fischer’s exact test. Qualitative free text was line-by-line coded by two authors independently to derive themes.

Results

56% (30/53) of SPC and ESC teams and 14% (14/100) of oncologists responded. Those involved in ESC self-reported greater integration with oncology compared with non-ESC teams, for example, joint case discussions (64.3%, 9/14 vs 23.1%, 3/13, p=0.05), and timelier patient referral ((>6 months before death vs <6 months) (10/14 vs 4/13, p=0.06)). Qualitative themes described ambiguity in definitions of supportive and palliative terms and a perception of timelier identification of patients when ESC was involved.

Conclusion

Providers of ESC perceive greater integration with oncology and potentially timelier referral for patients compared with teams not delivering ESC. Terminology around SPC and ESC remains uncertain across England.
Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes
Authors: Antcliffe David Benjamin , Mi Yuxin , Santhakumaran Shalini , Burnham Katie L , Prevost A Toby , Ward Josie K , Marshall Timothy J , Bradley Claire , Al-Beidh Farah , Hutton Paula , McKechnie Stuart , Davenport Emma E , Hinds Charles J , O'Kane Cecilia M , McAuley Daniel Francis , Shankar-Hari Manu , Gordon Anthony C , Knight Julian C
Published: March 2024

Rationale

Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported.

Objectives

We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes.

Methods

Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters.

Measurements and main results

We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes.

Conclusions

These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes.

Trial registration number

ISRCTN20769191,ISRCTN12776039.