bluuebunny/crossref_metadata_2025 huggingface dataset:
Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial
Authors: Takada Marilia , Kitagawa Keita , Zhang Yongzhen , Bulitta Jürgen B. , Moirano Steven , Jones Abigail , Borgen Jennifer , Onsager Ashley , Thaiwong Tuddow , Vail David M.
Published: June 2024

MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG‐CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose‐limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 μg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady‐state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.
A prospective study evaluating the correlation between local weather conditions, pollen counts and pruritus of dogs with atopic dermatitis
Authors: Widorn L. , Zabolotski Y. , Mueller Ralf S.
Published: June 2024

Background

Canine atopic dermatitis (cAD) is a hereditary, generally pruritic and predominantly T‐cell‐driven inflammatory skin disease, involving an interplay between skin barrier abnormalities, allergen sensitisation and microbial dysbiosis. The individual immunological response is predominantly against environmental allergens, including mite antigens; mould spores; and pollen from grasses, trees and weeds. Airborne pollens show fluctuating patterns during the year.

Objective

The aim of this prospective study was to evaluate the influence of local pollen concentrations and weather conditions on the clinical signs of atopic dogs, and to investigate any possible correlations with the results of intradermal testing (IDT).

Materials and Methods

Thirty‐seven privately owned atopic dogs in Bavaria were surveyed from 1 April to 30 November 2021. Owners were asked to record pruritus using a validated Visual Analog Scale (PVAS) score and the weekly medication of their dog. Furthermore, weather data, including pollen count, rainfall, relative humidity, hours of sunshine and temperature from the dog's location were collected daily.

Results

Of the evaluated parameters, only humidity and medication scores correlated positively with the PVAS scores of the atopic dogs. There was no correlation between specific pollen counts and PVAS scores of dogs with positive IDT reactions to that pollen.

Conclusion and Clinical Relevance

The outcome of this study highlights the importance of a careful interpretation of positive IDT results in dogs with cAD and questions the validity of airborne pollen trap methodology in representing pollen exposure for dogs at ground level.
Brief communication: Carrier rate, antimicrobial resistance and molecular typing of Staphylococcus aureus and Staphylococcus pseudintermedius in healthy dogs from Morogoro, Tanzania
Authors: Katakweba Abdul A. S. , Iversen Christine M. , Tsaxra John B. , Muhairwa Amandus P. , Moodley Arshnee , Olsen John E.
Published: June 2024

Background

Staphylococcus pseudintermedius and S. aureus are important pathogens in dogs. This study established carrier rates, strain diversity and antimicrobial resistance of these bacteria among healthy dogs in Tanzania.

Results

Based on cultures of mouth and perineal swabs, 11.3% and 50.3% of 151 healthy dogs were carriers of S. aureus and S. pseudintermedius, respectively. Only four dogs (3%) carried meticillin‐resistant S. aureus (MRSA), while none of the S. pseudintermedius strains were meticillin‐resistant. 12 of 19 S. aureus strains tested were resistant to penicillin G, and resistance to enrofloxacin and tetracycline was also commonly detected. The most common resistances in 103 S. pseudintermedius strains tested were to penicillin G (28.2%) and tetracycline (22.3%). S. pseudintermedius strains showed 65 different random amplified polymorphic DNA (RAPD) fingerprints, and S. aureus strains belonged to eight different spa types, including two novel types (t18988 and t18989). MRSA strains carried SCCmec type V.

Conclusions and Clinical Relevance

Healthy dogs in Tanzania were carriers of MRSA at low frequency, and half of the dogs carried S. pseudintermedius with high strain diversity.
A Fully 3D-Printed Flexible Polymeric Heat Pipe
Authors: Luo Kai , Gross Andrew J. , Brown Jackson , Chang Wei , Li Chen
Published: June 2024

Advancements in flexible electronics demand innovative thermal management solutions that are both flexible and efficient. A fully 3D-printed polymeric heat pipe with high flexibility and low cost was demonstrated in this study. This wickless gravity-assisted heat pipe was fabricated using a commercial stereolithography 3D printer and soft elastomer. An interconnected pocket array was designed to reduce the wall thickness to 0.1 mm. The post-cured heat pipe can be flexed and twisted without tearing or permanent deformation. Experimental studies were conducted to characterize the performance of the heat pipe in vertical and 90-deg flexed configurations. In addition, high-speed imaging was applied to visualize the boiling process within the heat pipe. By charging with a compatible dielectric fluid HFE-7100, the present heat pipe achieved 18.6 W heat dissipation over a hot spot with an area of 25 × 25 mm2, representing about 125% higher heat flux than most reported fully polymeric heat pipes using the same working fluid. When placed vertically, the result showed an effective thermal conductivity of up to 102.7 W/(m · K). The visualization indicated little difference in bubble dynamics between the vertical and flexed configurations owing to a high charging mass. The heat pipe startup occurred at 5.4 W, and no dryout was observed within the test range for either configuration. Finally, a comparison of the present study and other reported fully polymeric flexible heat pipes was made, and future optimization of the heat pipe performance was discussed.
Modeling and Experiment of the Vibro-Acoustic Response of Cylindrical Shells With Internal Substructures
Authors: Zhang Lei , Yu Min , Wang Xianzhong , Ba Mingfei , Pang Zhaoming
Published: June 2024

This study investigates the theoretical and experimental aspects of the vibro-acoustic characteristics of cylindrical shells with internal substructures. On the theoretical side, a hybrid calculation method is proposed, which combines the condensed transfer function method with the direct stiffness method and the precise transfer matrix method. The cylindrical shell with internal substructures is decoupled, and the governing equations for the cylindrical shell substructure and the internal substructure are separately established. Furthermore, the coupling forces between the cylindrical shell substructure and the plate substructure are solved based on the condensed transfer function method. These coupling forces are then incorporated into the overall transfer equation of the cylindrical shell to obtain the vibro-acoustic response of the coupled structure. Compared with the finite element calculation results, the validity of the calculation method in this paper is verified. In terms of experiments, the natural frequency, mode, and vibration acoustic response of the model were tested and compared with the theoretical results, which was in good agreement. The study demonstrates that the proposed hybrid calculation method based on the condensed transfer function is effective in predicting the vibro-acoustic characteristics of cylindrical shells with internal substructures.
Spray Autoignition Study of Bio-Oxygenated Additives Blended With Aviation Kerosene Under Engine-Like Cold-Start Conditions
Authors: Zhang Qiaosheng , Han Yongqiang , Zhang Kechao , Tian Jing
Published: June 2024

Bio-oxygenated fuels are expected to be used as a clean alternative energy source to improve the ignition behavior and pollutant emissions of RP-3 kerosene in compression ignition engines. In this study, the spray autoignition of PR-3 blended with different types of oxygenated fuels (including n-pentanol (PeOH), methyl propionate (MP), methyl ethyl ketone (MEK), 1,2-dimethoxyethane (1,2-DME), and 2-ethylhexyl nitrate (EHN)) was measured using a constant volume combustion chamber. Experiments were performed on three sets of blended fuels with different oxygen contents (2.5 wt%, 5 wt%, and 10 wt%) in the temperature range of 723–863 K and at ambient pressures of 2.2 and 4 MPa. A kinetic analysis utilized a merged RP-3 low-temperature kinetic model containing various oxygenated components. The ignition delay of blended fuels increases with the addition of PeOH, MP, and MEK, particularly PeOH, which demands more energy absorption at low temperatures due to its higher specific heat and latent heat of vaporization. As ambient pressure increased, the ignition delay period shortened for all blended fuels; however, PeOH and MEK demonstrated more significant low-temperature suppression. The combined kinetic model can reasonably predict the trend of the effect of oxygenated additives. 1,2-DME showed significantly more low-temperature reactivity versus PeOH, MP, and MEK. The variability is because the products of secondary O2 addition and isomerization of 1,2-DME undergo low-temperature branched chain reactions, but other oxygenated fuels produce more inert components.
Dynamic Simulation of a Molten Salt-Steam Superheater for Load-Following Applications
Authors: Wenner Jacob , Wagner Michael J.
Published: June 2024

The growing use of intermittent renewables in electrical grids increasingly motivates load-following operations as a crucial capability of dispatchable power plants. However, frequent load variations in steam generation equipment can cause premature heat exchanger failure. This paper simulates the dynamic behavior of a high pressure, U-tube/U-shell, salt-to-steam superheater typically found in tower-type concentrating solar power subcritical Rankine cycles. Results focus on responses during load-following and inlet temperature changes. The proposed model is a finite volume method, and thermodynamic and heat transfer properties of both fluids are allowed to vary spatially and temporally. Several flow ramping schemes are investigated, including proportionally equal ramps and proportionally dissimilar ramping, where one fluid reaches its mass flow setpoint faster than the other. Results indicate that salt outlet temperature overshoot can occur if ramp rates are of sufficiently high magnitude, and that U-bend metal temperature rate of change can be approximately 2.5× that observed at either outlet. If proportionally-matched ramping is not possible, ramping steam more slowly than the salt is preferred over the alternative, as cold side and U-bend temperature responses are better regulated. Additionally, mass flowrate and inlet temperature changes are shown to elicit unique responses in the tube bundle metal.
On the Use of Dimension-Reduction Methods in Fatigue Analysis of Flexible Risers Subjected to Bimodal Seas
Authors: Vaillant Alyson Gomes , Sagrilo Luis Volnei Sudati , Custódio Anderson Barata
Published: June 2024

Fatigue analyses of flexible pipes through the application of long-term response statistics, when considering bimodal seas, are particularly challenging due to the excessive computational costs involved, since they require, generally, to solve numerically a four-dimensional integral associated with time-domain finite element-based analyses of the flexible pipe. This paper investigates different dimension-reduction methods (DRMs) as effective approaches to compute fatigue damage of these structures. The performance of the DRMs was compared with that of the Monte Carlo simulation method (MCSM). Two case studies are presented: a 4 in., and a 7 in., flexible riser connected to a semi-submersible, and a spread-moored floating production storage and offloading unit platform, respectively. The studies demonstrated that some DRMs presented accurate results, exhibiting high efficacy with errors below 3%. Furthermore, the bivariate dimension-reduction method required only 18% of the computational cost associated with the standard Gauss–Hermite quadrature in space R4 (without any reduction), or much less when compared to the MCSM.
Performance evaluation of GaN etching using Cl2-based plasma with bias pulsing
Authors: Ruel Simon , Pimenta-Barros Patricia , Pezeril Maxime , Thoueille Philippe , Gaucher François , Posseme Nicolas
Published: June 2024

Reducing plasma-induced damage (PID) is one of the most challenging goals for the fabrication of GaN-based MOS-HEMT. In this paper, we propose a performance evaluation of a Cl2-based etching chemistry using bias pulsing mode for GaN applications. The plasma-induced damage using bias pulsing has been compared to conventional reactive ion etching (RIE) and atomic layer etching (ALE) processes using sheet resistance (Rsheet) measurements. This pulsing mode showed low plasma-induced damage, similar to ALE. In addition, it keeps an acceptable GaN etching rate, showing that pulsing mode has potential for industrial applications.
A gut punch for PCOS
Authors: Wong Wei
Published: June 2024

Suppression of GLP-1 release by a gut microbiota–derived metabolite induces polycystic ovary syndrome.
Emergent
emm4
group A
Streptococcus
evidences a survival strategy during interaction with immune effector cells
Authors: Odo Chioma M. , Vega Luis A. , Mukherjee Piyali , DebRoy Sruti , Flores Anthony R. , Shelburne Samuel A.
Published: June 2024

The major gram-positive pathogen group A
Streptococcus
(GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence among
emm4
GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. By creating and analyzing isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic anhydrase was responsible for the defective
in vitro
growth observed in the emergent strains. We also identified that the emergent strains survived better inside macrophages and killed macrophages at lower rates than the historic strains.
Via
the creation of isogenic mutant strains, we linked the emergent strain “survival” phenotype to the downregulation of the SLO encoding gene and upregulation of the
msrAB
operon which encodes proteins involved in defense against extracellular oxidative stress. Our findings are in accord with recent surveillance studies which found a high ratio of mucosal (i.e., pharyngeal) relative to invasive infections among
emm4
GAS. Since ever-increasing virulence is unlikely to be evolutionarily advantageous for a microbial pathogen, our data further understanding of the well-described oscillating patterns of virulent GAS infections by demonstrating mechanisms by which emergent strains adapt a “survival” strategy to outcompete previously circulating isolates.
Infection and intracellular transport of white spot syndrome virus require the ESCRT machinery in shrimp
Authors: Lv Li-Xia , Gao Jie , Wang Hao , Zhao Xiao-Fan , Wang Jin-Xing
Published: June 2024

The cellular endosomal sorting complex required for transport (ESCRT) system comprises five distinct components and is involved in many different physiological processes. Recent studies have shown that different viruses rely upon the host ESCRT system for viral infection. However, whether this system is involved in white spot syndrome virus (WSSV) infection remains unclear. Here, we identified 24 homologs of ESCRT subunits in kuruma shrimp,
Marsupenaeus japonicus
, and found that some key components were strongly upregulated in shrimp after WSSV infection. Knockdown of key components of the ESCRT system using RNA interference inhibited virus replication, suggesting that the ESCRT system is beneficial for WSSV infection. We further focused on TSG101, a crucial member of the ESCRT-I family that plays a central role in recognizing cargo and activating the ESCRT-II and ESCRT-III complexes. TSG101 colocalized with WSSV in hemocytes. The addition of N16 (a TSG101 inhibitor) markedly decreased WSSV replication. TSG101 and ALIX of the ESCRT system interact with WSSV envelope proteins. The host proteins TSG101, RAB5, and RAB7, the viral protein VP28, and DNA were detected in endosomes isolated from hemocytes of WSSV-infected shrimp. Knockdown of
Rab5
and
Rab7
expression reduced viral replication. Taken together, these results suggest that the ESCRT system is hijacked by WSSV for transport through the early to late endosome pathway. Our work identified a novel requirement for the intracellular trafficking and infection of WSSV, and provided novel therapeutic targets for the prevention and control of WSSV in shrimp aquaculture.

IMPORTANCE

Viruses utilize the ESCRT machinery in a variety of strategies for their replication and infection. This study revealed that the interaction of ESCRT complexes with WSSV envelope proteins plays a crucial role in WSSV infection in shrimp. The ESCRT system is conserved in the shrimp
Marsupenaeus japonicus
, and 24 homologs of the ESCRT system were identified in the shrimp. WSSV exploits the ESCRT system for transport and propagation via the interaction of envelope proteins with host TSG101 and ALIX in an endosome pathway-dependent manner. Understanding the underlying mechanisms of WSSV infection is important for disease control and breeding in shrimp aquaculture.
Complete genome sequences of six S19 poliovirus reference strains
Authors: Castro Christina J. , Wiese Nicholas , Bullows James E. , Poston Katherine D. , Meade Caeden , Jorba Jaume , Mainou Bernardo A.
Published: June 2024

We report the complete genome sequences of six S19 poliovirus reference strains for all three poliovirus serotypes, including three Sabin vaccine-derived and three wild-type-derived strains. The S19 strains are extensively attenuated and genetically stable when compared to the reference poliovirus strains, while maintaining the same antigenicity and immunogenicity.
Whole-genome sequence of
Pseudomonas benzopyrenica
MLY92: isolation from diseased leaves of tobacco in China
Authors: Gao Juntao , Jing Yongfeng , Cheng Zhijun , Huang Ke , Zhang Huilin , Liu Yong , Yang Lei , Liu Shiwang
Published: June 2024

Here we present a sketch of the whole-genome sequence of
Pseudomonas benzopyrenica
. The strain comes from the leaf veins of a diseased tobacco plant. This study has significant research implications for gaining insights into the characteristics of microorganisms belonging to the genus
Pseudomonas
.
Carbon cycling during the India-Asia collision revealed by δ26Mg–δ66Zn–δ98Mo evidence from ultrapotassic volcanoes in NW Tibet
Authors: Wang Jian , Tappe Sebastian , Wang Qiang , Li Jie , Zou Zongqi , Tang Gong-Jian
Published: June 2024

India-Asia continental collision–induced volcanic gas emissions are thought to have played an important role in driving Cenozoic atmospheric CO2 variations, yet the details of how the deep carbon cycle may influence volcanic CO2 degassing are not understood. We present a novel study employing Mg-Zn-Mo isotopic compositions of Cenozoic ultrapotassic lavas from NW Tibet. The negative Mg-Zn isotope correlation (δ26Mg = −0.39‰ to −0.19‰; δ66Zn = +0.27‰ to +0.36‰), bolstered by petrographic analysis of mantle-derived xenoliths from these lavas, demonstrates that the ultrapotassic magmas originated from a lithospheric mantle source that had been enriched by recycled carbonate-bearing sediments rich in calcite and dolomite. Very low δ98Mo values (−0.78‰ to 0‰) relative to the average continental crust (δ98Mo = +0.10‰ to +0.35‰) further indicate that the sedimentary components were derived from the subducted Indian continental crust after its dehydration. Monte Carlo modeling estimates that the input flux of carbon (elemental C) from such sediments into the lithospheric mantle is ~5.6 Mt/yr, with a predicted CO2 emission rate of ~15.5 Mt/yr. We suggest that the still ongoing subduction of the Indian tectonic plate has played a crucial role in introducing substantial quantities of carbonate-rich sediments into the Tibetan lithospheric mantle, leading to the sequestration of large amounts of CO2 via carbonatite metasomatism. Hence, partial melting of such a carbon-rich mantle reservoir in an orogenic setting provides the positive feedback mechanism that can explain the high flux of volcanic CO2 during India-Asia collision. These findings not only highlight the importance of continental subduction, sediment recycling, and mantle metasomatism by carbon-rich melts/fluids in the generation of Tibetan ultrapotassic volcanism, but they also show how the deep carbon cycle influences volcanic CO2 degassing.
Association between TyG index and long-term prognosis of patients with ST-segment elevated myocardial infarction undergoing percutaneous coronary intervention: a retrospective cohort study
Authors: Zeng Deli , Wang Kai , Chen Zijun , Yao Caoyuan
Published: June 2024

Objective

To assess the association between the serum triglyceride-glucose product index (TyG index) and the risk for all-cause mortality in patients with ST-segment elevated myocardial infarction (STEMI).

Design

Retrospective.

Setting and participants

This retrospective study included 896 patients with STEMI who underwent percutaneous coronary intervention (PCI) at a comprehensive university-affiliated hospital between January 2016 and January 2019.

Methods

Patients were equally divided into quartiles (Q1, Q2, Q3 and Q4 group) according to TyG index values.

Primary endpoint

All-cause mortality.

Results

After a median follow-up of 3 years, 108 (17.1%) patients died. TyG index was independently associated with increased all-cause mortality (OR, 1.39; 95% CI, 1.22 to 1.58) after adjusting for age, sex, low-density lipoprotein cholesterol (LDL-c), cardiac troponin I, B-type natriuretic peptide, delayed PCI, post-PCI complications, medication and left ventricular ejection fraction. The adjusted OR was 1.31 (95% CI, 0.62 to 2.77) for Q2, 2.12 (95% CI, 1.01 to 4.53) for Q3 and 4.02 (95% CI, 1.90 to 8.78) for Q4 compared with the lowest quartile (Q1) (p for trend<0.001). In the restricted cubic spline regression model, the relationship between the TyG index and the risk of all-cause mortality was linear (p for non-linear=0.575). Each unit increase in the TyG index was associated with a 68% increase in the multivariate risk for all-cause mortality (OR 1.68; 95% CI, 1.20 to 2.38). In the subgroup analysis, there was an interaction between LDL-c and the TyG index on the risk of all-cause mortality (p for interaction=0.007).

Conclusion

The TyG index was significantly associated with the long-term all-cause mortality among patients with STEMI who underwent PCI.
Development and validation of a model to predict the need for artificial airways for acute trauma patients in the emergency department: a retrospective case–control study
Authors: Li Ping , Zhang Zhuo , Yu Hai Fang , Yao Rong , Wei Wei , Nie Hu
Published: June 2024

Objective

To develop scores for predicting the need for artificial airway procedures for acute trauma patients in the emergency department (ED).

Design

Retrospective case–control.

Setting

A tertiary comprehensive hospital in China.

Participants

8288 trauma patients admitted to the ED within 24 hours of injury and who were admitted from 1 August 2012 to 31 July 2020.

Primary and secondary outcome measures

The study outcome was the establishment of an artificial airway within 24 hours of admission to the ED. Based on the different feature compositions, two scores were developed in the development cohort by multivariable logistic regression. The predictive performance was assessed in the validation cohort.

Results

The O-SPACER (Oxygen saturation, Systolic blood pressure, Pulse rate, Age, Coma Scale, Eye response, Respiratory rate) score was developed based on the patient’s basic information with an area under the curve (AUC) of 0.85 (95% CI 0.80 to 0.89) in the validation group. Based on the basic information and trauma scores, the IO-SPACER (Injury Severity Score, Oxygen saturation, Systolic blood pressure, Pulse rate, Age, Coma Scale, Eye response, Respiratory rate) score was developed, with an AUC of 0.88 (95% CI 0.84 to 0.92). According to the O-SPACER and IO-SPACER scores, the patients were stratified into low, medium and high-risk groups. According to these two scores, the high-risk patients were associated with an increased demand for artificial airways, with an OR of 40.16–40.67 compared with the low-risk patients.

Conclusions

The O-SPACER score provides risk stratification for injured patients requiring urgent airway intervention in the ED and may be useful in guiding initial management. The IO-SPACER score may assist in further determining whether the patient needs planned intubation or tracheotomy early after trauma.
Opportunities and challenges in antimicrobial resistance policy including animal production systems and humans across stakeholders in Argentina: a context and qualitative analysis
Authors: Allel Kasim , Fernandez-Miyakawa Mariano , Gaze William , Petroni Alejandro , Corso Alejandra , Luna Federico , Barcelona Laura , Boden Lisa , Pitchforth Emma
Published: June 2024

Introduction

Gaps in antimicrobial resistance (AMR) surveillance and control, including implementation of national action plans (NAPs), are evident internationally. Countries’ capacity to translate political commitment into action is crucial to cope with AMR at the human–animal–environment interface.

Methods

We employed a two-stage process to understand opportunities and challenges related to AMR surveillance and control at the human–animal interface in Argentina. First, we compiled the central AMR policies locally and mapped vital stakeholders around the NAP and the national commission against bacterial resistance. Second, we conducted qualitative interviews using a semistructured questionnaire covering stakeholders’ understanding and progress towards AMR and NAP. We employed a mixed deductive–inductive approach and used the constant comparative analysis method. We created categories and themes to cluster subthemes and determined crucial relationships among thematic groups.

Results

Crucial AMR policy developments have been made since 1969, including gradually banning colistin in food-producing animals. In 2023, a new government decree prioritised AMR following the 2015 NAP launch. Our qualitative analyses identified seven major themes for tackling AMR: (I) Cultural factors and sociopolitical country context hampering AMR progress, (II) Fragmented governance, (III) Antibiotic access and use, (IV) AMR knowledge and awareness throughout stakeholders, (V) AMR surveillance, (VI) NAP efforts and (VII) External drivers. We identified a fragmented structure of the food production chain, poor cross-coordination between stakeholders, limited surveillance and regulation among food-producing animals and geographical disparities over access, diagnosis and treatment. The country is moving to integrate animal and food production into its surveillance system, with most hospitals experienced in monitoring AMR through antimicrobial stewardship programmes.

Conclusion

AMR accountability should involve underpinning collaboration at different NAP implementation levels and providing adequate resources to safeguard long-term sustainability. Incorporating a multisectoral context-specific approach relying on different One Health domains is crucial to strengthening local AMR surveillance.
Risk-reducing salpingo-oophorectomy among diverse patients withBRCAmutations at an urban public hospital: a mixed methods study
Authors: Lamacki Alexandra J , Spychalska Sandra , Maga Tara , Balay Lara , Lugo Santiago Nicole , Hoskins Kent , Richardson Kimberly , Class Quetzal A , MacLaughlan David Shannon
Published: June 2024

Objectives

To assess the association of socioeconomic demographics with recommendation for and uptake of risk-reducing bilateral salpingo-oophorectomy (rrBSO) in patients withBRCA1andBRCA2(BRCA1/2) mutations.

Design

Retrospective cohort, semistructured qualitative interviews.

Setting and participants

BRCA1/2 mutation carriers at an urban, public hospital with a racially and socioeconomically diverse population.

Intervention

None.

Primary and secondary outcomes

The primary outcomes were rate of rrBSO recommendation and completion. Secondary outcomes were sociodemographic variables associated with rrBSO completion.

Results

The cohort included 167 patients withBRCA1/2mutations of whom 39% identified as black (n=65), 35% white (n=59) and 19% Hispanic (n=32). Over 95% (n=159) received the recommendation for age-appropriate rrBSO, and 52% (n=87) underwent rrBSO. Women who completed rrBSO were older in univariable analysis (p=0.05), but not in multivariable analysis. Completion of rrBSO was associated with residence in zip codes with lower unemployment and documented recommendation for rrBSO (p<0.05). All subjects who still received care in the health system (n=79) were invited to complete interviews regarding rrBSO decision-making, but only four completed surveys for a response rate of 5.1%. Themes that emerged included menopause, emotional impact and familial support.

Conclusions

In this understudied population, genetic counselling and surrogates of financial health were associated with rrBSO uptake, highlighting genetics referrals and addressing social determinants of health as opportunities to improve cancer prevention and reduce health inequities. Our study demonstrates a need for more culturally centred recruiting methods for qualitative research in marginalised communities to ensure adequate representation in the literature regarding rrBSO.
Cognitive therapy for depression in tuberculosis treatment: protocol for multicentre pragmatic parallel arm randomised control trial with an internal pilot
Authors: Fonseka Nishani , Khan Zohaib , Lewis Martyn , Kibria Zeeshan , Ahmad Fayaz , Khan Muhammad Firaz , Ul-Haq Mian , Ul-Haq Zia , Sanauddin Noor , Majid Mahnoor , Rahim Maryiam , Naeem Farooq , Butt Mirrat , Ashraf Saadia , Komproe Ivan , Mallen Christian , Kellar Ian , Yadegarfar Ghasem , Milner Abbie , Sheikh Saima , Farooq Saeed
Published: June 2024

Introduction and objectives

There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of lower-middle-income countries. This study aims to examine the effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) versus enhanced treatment as usual (ETAU) in improving depressive symptoms in people with TB and comorbid depression, enhancing adherence with anti-TB treatment (ATT) and its implementation in the real-world setting of Pakistan.

Methods

We will conduct a pragmatic parallel arm randomised control trial with an internal pilot. A brief psychological intervention based on CBT has been developed using a combination of qualitative and ethnographic studies. The inbuilt pilot trial will have a sample size of 80, while we plan to recruit 560 (280 per arm) participants in the definitive trial. Participants who started on ATT within 1 month of diagnosis for pulmonary and extrapulmonary TB or multidrug resistant TB (MDR-TB) and meeting the criteria for depression on Patient Health Questionnaire-9 (PHQ-9) will be randomised with 1:1 allocation to receive six sessions of CBT (delivered by TB healthcare workers) or ETAU. Data on the feasibility outcomes of the pilot will be considered to proceed with the definitive trial. Participants will be assessed (by a blinded assessor) for the following main trial primary outcomes: (1) severity of depression using PHQ-9 scale (interviewer-administered questionnaire) at baseline, weeks 8, 24 and 32 postrandomisation and (2) ATT at baseline and week 24 at the end of ATT therapy.

Ethics and dissemination

Ethical approval has been obtained from Keele University Research Ethics Committee (ref: 2023-0599-792), Khyber Medical University Ethical Review Board (ref: DIR/KMU-EB/CT/000990) and National Bioethics Committee Pakistan (ref: No.4–87/NBC-998/23/587). The results of this study will be reported in peer-reviewed journals and academic conferences and disseminated to stakeholders and policymakers.

Trial registration number

ISRCTN10761003.
Association between rural exposure/experience and practice location 10 years postgraduation, stratified by specialty: evidence from a cohort study of graduates from nine Australian universities
Authors: Seal Alexa , McGrail Matthew R , Bain-Donohue Suzanne , Fuller Lara , Kirke Andrew , Garne David , Luscombe Georgina , Allen Penny , Wright Julian , Burrows Julie M
Published: June 2024

Objective

This study aims to determine the associations between specialty type and practice location at postgraduate year 10 (PGY10), matched with PGY5 and PGY8 work locations, and earlier rural exposure/experience.

Design and setting

A cohort study of medicine graduates from nine Australian universities.

Participants

1220 domestic medicine graduates from the class of 2011.

Outcome measures

Practice location recorded by the Australian Health Practitioner Regulation Agency in PGY10; matched graduate movement between PGYs 5, 8 and 10 as classified by the Modified Monash Model, stratified by specialty type (predominantly grouped as general practitioner (GP) or non-GP).

Results

At PGY10, two-thirds (820/1220) had achieved fellowship. GPs were 2.8 times more likely to be in non-metropolitan practice (28% vs 12%; 95% CI 2.0 to 4.0, p<0.001) than graduates with non-GP (all other) specialist qualifications. More than 70% (71.4%) of GPs who were in non-metropolitan practice in PGY5 remained there in both PGY8 and PGY10 versus 29.0% of non-GP specialists and 36.4% of non-fellowed graduates (p<0.001). The proportion of fellowed graduates observed in non-metropolitan practice was 14.9% at PGY5, 16.1% at PGY8 and 19.0% at PGY10, with this growth predominantly from non-GP specialists moving into non-metropolitan locations, following completion of metropolitan-based vocational training.

Conclusions

There are strong differences in practice location patterns between specialty types, with few non-GP specialists remaining in non-metropolitan practice between PGY5 and PGY10. Our study reinforces the importance of rural training pathways to longer-term work location outcomes and the need to expand specialist vocational training which supports more rural training opportunities for trainees outside general practice.
Conservative management versus invasive management of significant traumatic pneumothoraces in the emergency department (the CoMiTED trial): a study protocol for a randomised non-inferiority trial
Authors: Blythe Nicola M , Coates Katherine , Benger Jonathan R , Annaw Ammar , Banks Jonathan , Clement Clare , Clout Madeleine , Edwards Antoinette , Gaunt Daisy , Kandiyali Rebecca , Lane J Athene , Lecky Fiona , Maskell Nick A , Metcalfe Chris , Platt Marie , Rees Sophie , Taylor Jodi , Thompson Julian , Walker Steven , West Douglas , Carlton Edward
Published: June 2024

Introduction

Traumatic pneumothoraces are present in one of five victims of severe trauma. Current guidelines advise chest drain insertion for most traumatic pneumothoraces, although very small pneumothoraces can be managed with observation at the treating clinician’s discretion. There remains a large proportion of patients in whom there is clinical uncertainty as to whether an immediate chest drain is required, with no robust evidence to inform practice. Chest drains carry a high risk of complications such as bleeding and infection. The default to invasive treatment may be causing potentially avoidable pain, distress and complications. We are evaluating the clinical and cost-effectiveness of an initial conservative approach to the management of patients with traumatic pneumothoraces.

Methods and analysis

The CoMiTED (Conservative Management in Traumatic Pneumothoraces in the Emergency Department) trial is a multicentre, pragmatic parallel group, individually randomised controlled non-inferiority trial to establish whether initial conservative management of significant traumatic pneumothoraces is non-inferior to invasive management in terms of subsequent emergency pleural interventions, complications, pain, breathlessness and quality of life. We aim to recruit 750 patients from at least 40 UK National Health Service hospitals. Patients allocated to the control (invasive management) group will have a chest drain inserted in the emergency department. For those in the intervention (initial conservative management) group, the treating clinician will be advised to manage the participant without chest drain insertion and undertake observation. The primary outcome is a binary measure of the need for one or more subsequent emergency pleural interventions within 30 days of randomisation. Secondary outcomes include complications, cost-effectiveness, patient-reported quality of life and patient and clinician views of the two treatment options; participants are followed up for 6 months.

Ethics and dissemination

This trial received approval from the Wales Research Ethics Committee 4 (reference: 22/WA/0118) and the Health Research Authority. Results will be submitted for publication in a peer-reviewed journal.

Trial registration number

ISRCTN35574247.
Associations of schooling type, qualification type and subsequent health in mid-adulthood: evidence from the 1970 British Cohort Study
Authors: Deng Keyao , Wright Liam , Silverwood Richard , Sullivan Alice , Bann David
Published: June 2024

Background

Education is thought to benefit health. However, existing studies have predominantly focused on educational attainment—the type of institution attended has been overlooked, despite being an important indicator of education resources, quality, and future socioeconomic outcomes. In this study, we investigated associations between type of high school or university attended and multiple adult health outcomes.

Methods

The 1970 British Cohort Study was used (n=8107). Associations between high school (comprehensive, grammar, private) and university (classified as normal or higher status (Russell Group)) attended with 10 health outcomes that capture cardiometabolic risks, physical capabilities and cognitive function at age 46 years were investigated. Multivariable regression models were used, adjusting for sex and childhood socioeconomic, health and cognitive factors.

Results

Both private school and higher-status university attendance were related to favourable health outcomes. After adjusting for potential confounders, associations between private school attendance and cardiometabolic risks remained; associations for higher-status university attendance and cognitive function remained, while associations with other outcomes were largely attenuated. For example, after full adjustment, private school attendance was associated with a 0.14 SD (95% CI: 0.04 to 0.23) lower body mass index and higher-status university attendance with a 0.16 SD (0.07 to 0.26) better memory recall.

Conclusion

The type of educational institution attended was associated with multiple health outcomes, suggesting it might be a relevant factor to consider in future health inequality research—particularly in contemporary populations which have high overall attainment levels. Further research is warranted to test the causal nature of this relationship and its generalisability to other contexts.
The quality of qualitative research
Authors: van IJzendoorn Marinus H , Miedema Siebren
Published: June 2024

In this contribution, we discuss criteria for the quality of qualitative research. We consider reliability and validity as specifications of the comprehensive requirement for ‘intersubjective replicability’, with which qualitative research should comply. In the data collection phase, ‘argumentative’ reliability generally must suffice; in the data analysis phase, attention must also be given to ‘technical’ reliability. Validation of qualitative research has to take place via three approaches: ‘communicative’, ‘critical’ or ‘empirical’ validation. This clarifies the relative validity or ‘authenticity’ of qualitative research.
The flavor-dependent $$U(1)_F$$ model
Authors: Yang Jin-Lei , Zhang Hai-Bin , Feng Tai-Fu
Published: June 2024

A flavor-dependent model (FDM) is proposed in this work. The model extends the Standard Model by an extra $$U(1)_F$$

U

(
1
)

F

local gauge group, two scalar doublets, one scalar singlet and two right-handed neutrinos, where the additional $$U(1)_F$$

U

(
1
)

F

charges are related to the particles’ flavor. The new fermion sector in the FDM can explain the flavor mixings puzzle and the mass hierarchy puzzle simultaneously, and the nonzero Majorana neutrino masses can be obtained naturally by the Type I see-saw mechanism. In addition, the B meson rare decay processes $${\bar{B}} \rightarrow X_s\gamma ,$$

B

¯

→

X
s

γ
,

$$B_s^0 \rightarrow \mu ^+\mu ^-,$$

B
s
0

→

μ
+

μ
-

,

the top quark rare decay processes $$t\rightarrow ch,$$

t
→
c
h
,

$$t\rightarrow uh$$

t
→
u
h

and the $$\tau $$
τ
lepton flavor violation processes $$\tau \rightarrow 3e,$$

τ
→
3
e
,

$$\tau \rightarrow 3\mu ,$$

τ
→
3
μ
,

$$\mu \rightarrow 3e$$

μ
→
3
e

predicted in the FDM are analyzed.
Household Wattch: Exploring Opportunities for Surveillance and Consent through Families’ Household Energy Use Data
Authors: Snow Stephen , Khan Awais Hameed , Day Kaleb , Matthews Ben
Published: June 2024

Household energy use data may contain sensitive inferences into family life, yet its potential for surveillance is imperfectly understood. To explore this space, we developed Household Wattch, a speculative eco-feedback ‘provotype’ that profiles households according to their energy use data. Evaluated by 16 participants from Australian households engaged in an 18-month energy use monitoring trial, Household Wattch elicited users’ perceptions and expectations about a near future where energy use data is a useful yet potentially sensitive commodity when analysed. We highlight challenges and opportunities for energy use data across three scales: (1) Within the household, (2) Beyond the household (e.g., sharing energy data with third parties) and (3) Post-household (e.g., what happens to energy data when a household re-configures or disbands). Findings suggest users may require support in understanding the sensitivities of their energy use data, particularly when deciding whether to share it with third parties. Opportunities exist for accidental or deliberate surveillance via energy use data, and these need to be identified and managed. Provotypes represent a useful tool for navigating this space, and we provide considerations for how they can support users in speculating over possible energy futures.
Explaining Neural News Recommendation with Attributions onto Reading Histories
Authors: Möller Lucas , Padó Sebastian
Published: June 2024

An important aspect of responsible recommendation systems is the transparency of the prediction mechanisms. This is a general challenge for deep-learning-based systems such as the currently predominant neural news recommender architectures, which are optimized to predict clicks by matching candidate news items against users’ reading histories. Such systems achieve state-of-the-art click-prediction performance, but the rationale for their decisions is difficult to assess. At the same time, the economic and societal impact of these systems makes such insights very much desirable.

In this article, we ask the question to what extent the recommendations of current news recommender systems are actually based on content-related evidence from reading histories. We approach this question from an explainability perspective. Building on the concept of integrated gradients, we present a neural news recommender that can accurately attribute individual recommendations to news items and words in input reading histories while maintaining a top scoring click-prediction performance.

Using our method as a diagnostic tool, we find that: (a), a substantial number of users’ clicks on news are not explainable from reading histories, and many history-explainable items are actually skipped; (b), while many recommendations are based on content-related evidence in histories, for others the model does not attend to reasonable evidence, and recommendations stem from a spurious bias in user representations. Our code is publicly available at
https://github.com/lucasmllr/xnrs
.
Chemical Proteomics–Guided Discovery of Covalent Ligands for Cancer Proteins
Authors: Zhang Xiaoyu , Cravatt Benjamin F.
Published: June 2024

Advances in genome sequencing and editing technologies have enriched our understanding of the biochemical pathways that drive tumorigenesis. Translating this knowledge into new medicines for cancer treatment, however, remains challenging, and many oncogenic proteins have proven recalcitrant to conventional approaches for chemical probe and drug discovery. Here, we discuss how innovations in chemical proteomics and covalent chemistry are being integrated to identify and advance first-in-class small molecules that target cancer-relevant proteins. Mechanistic studies have revealed that covalent compounds perturb protein functions in cancer cells in diverse ways that include the remodeling of protein–protein and protein–RNA complexes, as well as through alterations in posttranslational modification. We speculate on the attributes of chemical proteomics and covalent chemistry that have enabled targeting of previously inaccessible cancer-relevant pathways and consider technical challenges that remain to be addressed in order to fully realize the druggability of the cancer proteome.
An Erratic Path Toward Discovery
Authors: Weinberg Robert A.
Published: June 2024

Through a series of accidents of history, my career began just when the revolution in molecular biology was taking place. The allure of molecular biology attracted me to exploiting tumor viruses as experimental models of the nucleic acid metabolism of cells. The fact that these viruses cause cancer was incidental but eventually led to an interest in cancer pathogenesis, exploiting them to understand the mechanisms of cell transformation. This made it possible to test the speculation that cell transformation derived from the mutation of cellular genes and that cancer cell behavior is driven by the actions of resulting mutant alleles of these genes. In 1979, we showed that cells that had been transformed by 3-methylcholanthrene carried a mutant oncogenic allele. This work progressed so that by 1982 my research group and others demonstrated that human bladder carcinoma cells carried a point-mutated RAS oncogene, providing a direct proof of the mutational theory of cancer pathogenesis.