bluuebunny/crossref_metadata_2025 huggingface dataset:
Directed Blame and Conversation
Authors: McKenna Michael
Published: October 2024

This chapter develops a communicative account of blame, one more specifically designed to model the communication involved in felicitous conversational exchange. Blame is treated as a response to an ongoing meaningful interaction between a morally responsible agent as the blamed party and a member of the moral community holding that person to account by blaming her. Two important points get special attention. One is to clarify and defend a methodology of focusing on only prototypical cases of blame when it is directly targeted at a blamed party. The project of offering necessary and sufficient conditions for the full extension of blame is rejected. Instead, by focusing on crucial central cases, one can then account for other cases of blame by way of family resemblance. A second point is devoted to explaining the extreme variability in felicitous modes of directly blaming one who is blameworthy.
Basically Deserved Blame and Its Value
Authors: McKenna Michael
Published: October 2024

In this chapter, the nature of basic desert for moral blame is explored. Desert, it is argued, offers a unique normative form of appraisal that tends exclusively to feature of its object in justifying blame. Its being basic is a matter of desert itself not being justified by a more fundamental normative consideration, like utility, reasonableness, or fairness. One question as applied to basic desert is whether, in the case of deserved blame, the harms to the deserving are noninstrumentally good. It is argued that claims of basic desert entail that it is noninstrumentally good that the blameworthy are harmed by a blaming response. Many see this as an endorsement of cruelty or vengeance, but these criticisms are resisted.
The Free Will Debate and Basic Desert
Authors: McKenna Michael
Published: October 2024

This chapter resists the familiar thesis that the free will debate is specifically limited to a basic desert conception of blame and punishment. On this view, no other normative bases implicate a robust freedom condition about which there might be any metaphysical controversy. But it is argued that there are other normative bases for blame and punishment that might also require a robust freedom condition. Hence, the free will debate is not held hostage to a commitment to basic desert. Why does this matter? Because it might turn out that basic desert is an indefensible justification for any forms of treatment, especially if desert entails that it is noninstrumentally good to harm the blameworthy and culpable.
Conclusion
Authors: McKenna Michael
Published: October 2024

This chapter reviews the terrain covered in the preceding chapters of the book. It closes by registering a few themes throughout. These include adopting a more critical stance toward some influential themes in Strawson’s seminal paper “Freedom and Resentment,” rejecting essentialism about the role of anger, developing the role of fittingness in a theory of deserved blame and punishment, scrutinizing the use of anger in blame and punishment, and engaging free will skeptics and other abolitionists about desert and punishment by seeking a modest desert thesis, one competing contestants in these debates might agree is a bona fide desert thesis.
Dancing to Schumann
Authors: Hedges Brown Julie
Published: October 2024

Chapter 4 continues the focus on creative inner movements but through a different interdisciplinary lens. Reflecting the burgeoning growth of “choreomusical” analysis within current scholarship, the chapter explores the Adagio from Hans van Manen’s 1975 ballet Four Schumann Pieces, set to Schumann’s complete A-major string quartet. As a devotee of George Balanchine and his creed to “make the music visible,” yet also interested in human relationships, Van Manen explores identity and sexuality as multivalent and relational within his “third piece”—the slow movement; the result is a reconfiguration of normative boundary lines, hierarchies, and gender protocols. This conceptual framework—buttressed by an investigation into Van Manen’s own emancipatory attitudes about identity, especially gay identity—proves remarkably telling for Schumann’s Adagio, a movement that has provoked a variety of contradictory formal interpretations. Indeed, Van Manen’s choreography enables numerous insights into the music that have hitherto escaped notice: for instance, a “primary” theme that resists any fixed version of itself; a large-scale design that allows multiple formal principles to intersect; and a softening of boundaries that exposes ties between seemingly different materials.
Systematic benchmark of single-cell hashtag demultiplexing approaches reveals robust performance of a clustering-based method
Authors: Sayed Mohammed , Wang Yue Julia , Lim Hee-Woong
Published: October 2024

Single-cell technology opened up a new avenue to delineate cellular status at a single-cell resolution and has become an essential tool for studying human diseases. Multiplexing allows cost-effective experiments by combining multiple samples and effectively mitigates batch effects. It starts by giving each sample a unique tag and then pooling them together for library preparation and sequencing. After sequencing, sample demultiplexing is performed based on tag detection, where cells belonging to one sample are expected to have a higher amount of the corresponding tag than cells from other samples. However, in reality, demultiplexing is not straightforward due to the noise and contamination from various sources. Successful demultiplexing depends on the efficient removal of such contamination. Here, we perform a systematic benchmark combining different normalization methods and demultiplexing approaches using real-world data and simulated datasets. We show that accounting for sequencing depth variability increases the separability between tagged and untagged cells, and the clustering-based approach outperforms existing tools. The clustering-based workflow is available as an R package from https://github.com/hwlim/hashDemux.
Mid- and long-term renal outcomes after metabolic surgery in a multi-center, multi-ethnic Asian cohort with T2DM
Authors: Sio Yueh-Chu , Chen Ching-Yi , Huang Yu-Min , Lee Wei-Jei , Hur Kyoung Yul , Kasama Kazunori , Cheng Anton Kui Sing , Lee Ming-Hsien , Simon Kin-Hung Wong , Soong Tien-Chou , Lee Kuo-Ting , Lomanto Davide , Lakdawala Muffazal , Su Yen-Hao , Wang Weu , Chen Hsi-Hsien
Published: October 2024

Background

Metabolic surgery is recognized for its effectiveness in weight loss and improving outcomes for individuals with type 2 diabetes mellitus (T2DM). However, its impact on renal function, especially in multi-ethnic Asian populations, remains underexplored. This study investigates mid- and long-term renal outcomes following metabolic surgery in Asian patients with T2DM.

Methods

This retrospective cohort study utilized data from the Asian Diabetes Surgery Study (ADSS), involving T2DM patients aged 20–79 who underwent metabolic surgery from 2008 to 2015. The primary outcome was the change in estimated glomerular filtration rate (eGFR) at 1, 3, and 5 years post-surgery, with adjustments for confounders. Secondary outcomes included changes in chronic kidney disease (CKD) stages and the relationship between weight loss and eGFR changes. Data were analyzed using univariate and multivariable regression analyses, along with the McNemar test.

Results

The study included 1513 patients with a mean age of 42.7 years. The results revealed that a significant improvement in eGFR was observed at 1-year post-surgery (112.4 ± 32.0 ml/min/1.73 m², P < .001), with a shift toward less severe CKD stages. However, this improvement was not sustained at 3 and 5 years. No significant correlation was found between weight loss and eGFR changes at 1-year follow-up.

Conclusion

Metabolic surgery significantly improves renal function at 1 year postoperatively in Asian individuals with T2DM, highlighting its potential benefits beyond glycemic control and weight loss. The long-term effects on renal function require further investigation.
Electrocardiogram-based deep learning to predict mortality in paediatric and adult congenital heart disease
Authors: Mayourian Joshua , El-Bokl Amr , Lukyanenko Platon , La Cava William G , Geva Tal , Valente Anne Marie , Triedman John K , Ghelani Sunil J
Published: October 2024

Background and Aims

Robust and convenient risk stratification of patients with paediatric and adult congenital heart disease (CHD) is lacking. This study aims to address this gap with an artificial intelligence-enhanced electrocardiogram (ECG) tool across the lifespan of a large, diverse cohort with CHD.

Methods

A convolutional neural network was trained (50%) and tested (50%) on ECGs obtained in cardiology clinic at the Boston Children’s Hospital to detect 5-year mortality. Temporal validation on a contemporary cohort was performed. Model performance was evaluated using the area under the receiver operating characteristic and precision-recall curves.

Results

The training and test cohorts composed of 112 804 ECGs (39 784 patients; ECG age range 0–85 years; 4.9% 5-year mortality) and 112 575 ECGs (39 784 patients; ECG age range 0–92 years; 4.6% 5-year mortality from ECG), respectively. Model performance (area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.77–0.81; area under the precision-recall curve 0.17, 95% confidence interval 0.15–0.19) outperformed age at ECG, QRS duration, and left ventricular ejection fraction and was similar during temporal validation. In subgroup analysis, artificial intelligence-enhanced ECG outperformed left ventricular ejection fraction across a wide range of CHD lesions. Kaplan–Meier analysis demonstrates predictive value for longer-term mortality in the overall cohort and for lesion subgroups. In the overall cohort, precordial lead QRS complexes were most salient with high-risk features including wide and low-amplitude QRS complexes. Lesion-specific high-risk features such as QRS fragmentation in tetralogy of Fallot were identified.

Conclusions

This temporally validated model shows promise to inexpensively risk-stratify individuals with CHD across the lifespan, which may inform the timing of imaging/interventions and facilitate improved access to care.
A convergent stochastic scalar auxiliary variable method
Authors: Metzger Stefan
Published: October 2024

We discuss an extension of the scalar auxiliary variable approach, which was originally introduced by Shen et al. (2018, The scalar auxiliary variable (SAV) approach for gradient flows. J. Comput. Phys., 353, 407–416) for the discretization of deterministic gradient flows. By introducing an additional scalar auxiliary variable this approach allows to derive a linear scheme while still maintaining unconditional stability. Our extension augments the approximation of the evolution of this scalar auxiliary variable with higher order terms, which enables its application to stochastic partial differential equations. Using the stochastic Allen–Cahn equation as a prototype for nonlinear stochastic partial differential equations with multiplicative noise we propose an unconditionally energy stable, linear, fully discrete finite element scheme based on our augmented scalar auxiliary variable method. Recovering a discrete version of the energy estimate and establishing Nikolskii estimates with respect to time we are able to prove convergence of discrete solutions towards pathwise unique martingale solutions by applying Jakubowski’s generalization of Skorokhod’s theorem. A generalization of the Gyöngy–Krylov characterization of convergence in probability to quasi-Polish spaces finally provides convergence of fully discrete solutions towards strong solutions of the stochastic Allen–Cahn equation. Finally, we present numerical simulations underlining the practicality of the scheme and the importance of the introduced augmentation terms.
Exploration of UCD Practice Limitations
Authors: Visescu Ioana , Lárusdóttir Marta , Choi Won
Published: October 2024

The integration of user-centred design (UCD) practices in software development is fundamental for enhancing the overall experiences of software users. In this paper, we summarize the results of various research studies on what the stated limitations of UCD practices are. A process called the UCD Sprint was introduced recently with the goal of addressing some of the existing UCD practice limitations for integrating UCD practices in software development. The guided usage of the step-by-step process has been studied with students and UCD practitioners in courses showing positive results, where participants describe benefits while using the process, such as the speed of the process, its clear structure, guidance. In this paper, we describe results from a synthesis study summarizing results on how guided usage of the UCD Sprint can address UCD practice limitations. Furthermore, we describe results from a series of interviews with UCD practitioners on how they currently practice UCD, the challenges and limitations they experience and their views on how unguided usage of the UCD Sprint would potentially fit their UCD practices. While the interviewees recognize the importance of user involvement, they highlight challenges in aligning user interests with other stakeholders' interests. All participants had used processes like design sprints for structuring their UCD practices. Interviewees have generally tailored the traditional approach of design sprints, showcasing a nuanced understanding of UCD practices. The results show that the UCD Sprint process is considered by UCD practitioners as a promising approach for practicing UCD. The process is viewed with enthusiasm, but the need for clear objectives and adaptability to the work contexts of the UCD practitioners remains essential. UCD practitioners’ adaptive strategies of their UCD practices emphasize the need for flexibility and adaptation of UCD practices and processes.
Acute fascioliasis in a returning traveller from Ethiopia
Authors: Salvador Fernando , Serres Xavier , Goterris Lidia , Martínez-Campreciós Joan , Espinosa-Pereiro Juan , Esteban Esperanza , Molina Israel
Published: October 2024

A 30-year-old male with fever after a travel in Ethiopia was visited in a hospital in Spain. Laboratory tests showed eosinophilia and liver alterations. Fasciola hepatica serology was positive, and radiological alterations found were suggestive of acute fascioliasis. After receiving triclabendazole, all the analytical and radiological alterations resolved.
Hyperkalemia and maintenance of renin–angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors
Authors: Bosi Alessandro , Xu Yang , Faucon Anne-Laure , Huang Tao , Evans Marie , Shin Jung-Im , Fu Edouard L , Carrero Juan Jesus
Published: October 2024

Background

Post hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin–angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i).

Methods

Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014–2021). The outcomes were incident hyperkalemia (potassium >5.0 mmol/l), mild hyperkalemia (potassium >5–≤5.5 mmol/l), and moderate to severe hyperkalemia (potassium >5.5 mmol/l). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs).

Results

In total, 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one-third of participants in each arm discontinued treatment within 1 year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64–0.93), including both mild (0.76; 0.62–0.93) and moderate/severe (0.53; 0.40–0.69) hyperkalemia events. Of 19 116 participants who used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83–1.14). Results were consistent in intention-to-treat analysis and across strata of sex, cardiovascular disease, use of MRA, and use of RASi.

Conclusions

In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.
Opioid deaths in children in Ontario: A province-wide study
Authors: Assen Katrina , Urbantke Elizabeth , Wilson Michael , Rieder Michael
Published: October 2024

Objectives

Opioid-related deaths are an ongoing concern. There have been increasing numbers of fentanyl-related adult deaths with limited knowledge of the characteristics and circumstances of opioid toxicity deaths in children. Our aim was to address this using province-wide data capturing all deaths in children under the age of 10 years in Ontario.

Methods

Data were extracted from the opioid investigative aid database at the Office of the Chief Coroner from the implementation of the system from October 1, 2017, to October 31, 2021. This collects all opioid-related deaths in Ontario (population 14.7 million). A chart review was undertaken on all deaths under 10 years of age. Patient characteristics were calculated as percentages; descriptive analysis was conducted.

Results

Ten deaths in children under the age of 10 occurred during the study period. The average age was 1.9 years with the oldest being 4 years and 9 months. The causative opioid was fentanyl alone in four cases (40%), fentanyl and other drugs in four cases (40%), and hydromorphone and methadone in one case each (10%). Most cases involved improperly stored medication or illicit substances. All children who died had previous child protection service involvement, and at least 70% of their families had previous police involvement.

Conclusions

Fentanyl was the primary substance involved in 80% of deaths. Several potential areas of system change include education on fentanyl risk to young children, careful storage of illicit substances, and implications for how the child protection system intervenes in homes where the use of opioids and illicit substance use is reported to occur.
Inference of Phylogenetic Networks From Sequence Data Using Composite Likelihood
Authors: Kong Sungsik , Swofford David L , Kubatko Laura S
Published: October 2024

While phylogenies have been essential in understanding how species evolve, they do not adequately describe some evolutionary processes. For instance, hybridization, a common phenomenon where interbreeding between 2 species leads to formation of a new species, must be depicted by a phylogenetic network, a structure that modifies a phylogenetic tree by allowing 2 branches to merge into 1, resulting in reticulation. However, existing methods for estimating networks become computationally expensive as the dataset size and/or topological complexity increase. The lack of methods for scalable inference hampers phylogenetic networks from being widely used in practice, despite accumulating evidence that hybridization occurs frequently in nature. Here, we propose a novel method, PhyNEST (Phylogenetic Network Estimation using SiTe patterns), that estimates binary, level-1 phylogenetic networks with a fixed, user-specified number of reticulations directly from sequence data. By using the composite likelihood as the basis for inference, PhyNEST is able to use the full genomic data in a computationally tractable manner, eliminating the need to summarize the data as a set of gene trees prior to network estimation. To search network space, PhyNEST implements both hill climbing and simulated annealing algorithms. PhyNEST assumes that the data are composed of coalescent independent sites that evolve according to the Jukes–Cantor substitution model and that the network has a constant effective population size. Simulation studies demonstrate that PhyNEST is often more accurate than 2 existing composite likelihood summary methods (SNaQand PhyloNet) and that it is robust to at least one form of model misspecification (assuming a less complex nucleotide substitution model than the true generating model). We applied PhyNEST to reconstruct the evolutionary relationships among Heliconius butterflies and Papionini primates, characterized by hybrid speciation and widespread introgression, respectively. PhyNEST is implemented in an open-source Julia package and is publicly available at https://github.com/sungsik-kong/PhyNEST.jl.
A whole-plant perspective of hydraulic strategy in temperate desert shrub species
Authors: Tan Fengsen , Li Xu , Cao Wenxu , Zhu Shidan , Duan Na , Li Qinghe
Published: October 2024

Desert shrubs play a crucial role in controlling desertification and promoting revegetation, but drought often hinders their growth. Investigating the hydraulic strategies of desert shrubs is important in order to understand their drought adaptation and predict future dynamics under climate change. In this study, we measured the hydraulic-related characteristics of roots, stems and leaves in 19 desert shrub species from northern China. We aimed to explore the hydraulic coordination and segmentation between different plant organs. The results were as follows: (i) specific root length was positively correlated with the water potential inducing a 50% loss in stem hydraulic conductivity (P50stem) and negatively correlated with stem hydraulic safety margin. This suggested that water uptake efficiency of the fine roots was traded off with stem embolism resistance and hydraulic safety. (ii) The water potential inducing a 50% loss in leaf hydraulic conductance was significantly less negative than P50stem, and fine root turgor loss point was significantly less negative than P50stem, indicating a hydraulic segmentation between the main stem and terminal organs. (iii) The most negative leaf turgor loss point indicated that leaf wilting occurred after substantial leaf and stem embolism. The high desiccation resistance of the leaves may serve as an important physiological mechanism to increase carbon gain in a relatively brief growth period. In summary, this study elucidated the hydraulic strategies employed by desert shrubs from a whole-plant perspective.
The Efficacy of Orange Terpene and Bacillus mycoides Strain BM103 on the Control of Periwinkle Leaf Yellowing Phytoplasma
Authors: Hung Jui-Chen , Huang Tzu-Pi , Huang Jenn-wen , Chang Chung Jan , Jan Fuh-Jyh
Published: October 2024

Phytoplasmas are obligate phytopathogenic bacteria belonging to the class Mollicutes. The pathogens, transmitted by insect vectors, associated with hundreds of plant diseases worldwide. Due to the regulation on banning use of antibiotics and limited efficacy of the traditional disease management manners, an eco-friendly alternative is needed. Given that terpene and probiotics have antibiotic activity and the ability to induce systemic resistance, in this study, the effectiveness of orange terpene and a Bacillus mycoides strain, BM103, was evaluated in periwinkle plants infected with periwinkle leaf yellowing (PLY) phytoplasma derived from a shoot-tip tissue culture system. Weekly drenching of 1,000 ppm diluted orange terpene emulsion or pre-activated strain BM103 liquid culture dilution exhibited the ability to inhibit PLY phytoplasma accumulation. The expression of the genes associated with plant defense response and flower development was upregulated after treatment. Moreover, pre-treatment of orange terpene or strain BM103 delayed PLY infection via cleft-grafting inoculation. While orange terpene did not suppress the symptoms, strain BM103 did result in a milder symptom expression that might partially attribute to its plant growth-promoting characteristics. Additionally, the pre-activation of strain BM103 may contribute to its efficacy. Taken together, this research indicates that orange terpene and B. mycoides BM103, with the ability to rapidly induce plant defense responses, could potentially be developed into biological control materials as preventive agents or biofertilizers.
Abemaciclib plus non-steroidal aromatase inhibitor or fulvestrant in women with HR+/HER2− advanced breast cancer: Final results of the randomized phase III MONARCH plus trial
Authors: Hu Xichun , Zhang Qingyuan , Sun Tao , Yin Yongmei , Li Huiping , Yan Min , Tong Zhongsheng , Li Man , Teng Yue’e , Oppermann Christina Pimentel , Kanakasetty Govind Babu , Portugal MA Coccia , Yang Liu , Zhang Wanli , Jiang Zefei
Published: October 2024

Background:

In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2− advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis.

Methods:

In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2− ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150 mg twice daily [BID]) or placebo plus: anastrozole (1.0 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL).

Results:

In cohort A (abemaciclib: n = 207; placebo: n = 99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs. placebo (28.27 months vs. 14.73 months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348–0.649). In cohort B (abemaciclib: n = 104; placebo: n = 53), abemaciclib plus fulvestrant improved median PFS vs. placebo (11.41 months vs. 5.59 months, HR: 0.480; 95% CI: 0.322–0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553–1.443; cohort B: HR: 0.512, 95% CI: 0.281–0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs. placebo.

Conclusions:

Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life.

Trial registration:

ClinicalTrials.gov (NCT02763566).
Prompt Initiation of Maternal Antiretroviral Therapy After HIV Seroconversion in Pregnancy Effectively Prevents Vertical Transmission and Other Adverse Infant Outcomes
Authors: Sundar Kavya G. , Yang Lanbo Z. , Cambou Mary C. , Varella Ivana R. S. , Melo Marineide G. , Segura Eddy R. , Ziegler Ângela P. , Santos Breno R. , Nielsen-Saines Karin
Published: October 2024

From January 2008 to December 2018, 1348 HIV-exposed infants were born in Porto Alegre, Brazil; 18.8% had adverse infant outcomes (AIO) including vertical transmission (1.9%), stillbirth/neonatal death (4.0%) and loss to follow-up before HIV diagnosis (12.9%). Timing of maternal HIV diagnosis was not associated with AIO but absent antiretroviral therapy use was. Lack of maternal antiretroviral therapy use is a significant risk factor for AIO.
Therapeutic Drug Monitoring of High-dose Sulbactam in Pediatric Patients: Preliminary Data From a Prospective Observational Pharmacokinetic Study
Authors: Charoenwong Kankamol , Wacharachaisurapol Noppadol , Sukkummee Warumphon , Sophonphan Jiratchaya , Suchartlikitwong Pintip , Chatsuwan Tanittha , Anugulruengkitt Suvaporn , Puthanakit Thanyawee
Published: October 2024

Background:

Rates of carbapenem-resistant Acinetobacter baumannii are rising in Thailand. Although high-dose (HD) sulbactam is recommended for treating carbapenem-resistant A. baumannii infections, data on plasma sulbactam concentrations in children are limited. We aimed to evaluate plasma sulbactam concentrations and pharmacokinetic-pharmacodynamic (PK-PD) target achievement in pediatric patients.

Methods:

Prospective study data (January–November 2023) on children (1 month–18 years) who received sulbactam every 6–8 hours were analyzed. Mid-dosing (C
mid, 50% fT) and trough (C
trough, 100% fT) concentrations were evaluated. PK-PD target achievement [50% fT > minimum inhibitory concentration (MIC), 100% fT > MIC] was evaluated using Clinical and Laboratory Standards Institute 2024 MIC cutoffs and MIC data of isolates of Acinetobacter calcoaceticus–baumannii complex from this study.

Results:

Thirty-five patients (median age 50 months) were categorized into standard-dose (SD) or HD groups. The geometric mean C
mid was higher in the HD (41.3 mg/L) versus SD (19.5 mg/L) groups (P = 0.006). Among 101 isolates of Acinetobacter calcoaceticus–baumannii complex, the MIC50 and MIC90 (concentrations that inhibit 50% and 90% of isolates of the A. calcoaceticus–baumannii complex) were 16 and 128 mg/L, respectively. The HD group achieved C
mid >MIC50 in 87.5% of the patients compared with 63.6% in SD (P = 0.17). Within the HD group, patients with augmented renal clearance (ARC) had lower C
mid (geometric mean 31.9 mg/L) compared with non-ARC (geometric mean 63.4 mg/L) (P = 0.04).

Conclusions:

HD sulbactam resulted in higher C
mid and PK-PD achievement. ARC significantly compromised plasma sulbactam concentration. HD sulbactam may be preferable for treating critically ill pediatric patients and those with ARC, especially during the empirical period.
Necrotizing Fasciitis of the Orbit Managed With Temporary Indwelling Retrobulbar Catheter
Authors: Rachapudi Sruti S. , Xu Haochen , Akella Sruti S.
Published: October 2024

Necrotizing fasciitis is a rapidly progressive soft tissue infection with high mortality. Aggressive and often repeated surgical debridements are considered the mainstay of treatment, but these interventions may cause significant postoperative morbidity. In this article, the authors present a rare case of orbital necrotizing fasciitis, which was treated with the use of a temporary indwelling retrobulbar drain for antibiotic delivery to deep orbital tissues, in lieu of aggressive debridement. To the authors’ knowledge, this is the first report of this technique.
Addressing Barriers to Implementing and Scaling PrEP in Carceral Settings: Applying Insights From Implementation Science
Authors: Rogers Brooke , Ramsey Susan , Ames Evan , Gomes Nyx , Murphy Matthew
Published: October 2024

Introduction:

Within the United States, individuals experiencing incarceration are at higher risk for HIV acquisition than the general population, yet may face additional difficulty engaging in HIV prevention clinical services. HIV preexposure prophylaxis (PrEP) is an effective approach to preventing HIV transmission, and the Centers for Disease Control recommends that PrEP be offered in carceral settings, particularly during the vulnerable community reentry period. However, there have been few efforts to scale PrEP in this setting.

Methods:

Based on our experience implementing PrEP in Rhode Island's state carceral system, we have identified potential approaches to overcoming barriers to PrEP use in this unique practice environment by using the implementation research logic model. We then evaluated specific implementation determinants and barriers as well as strategies used to overcome those barriers to effectively scale PrEP in this setting.

Results:

We developed a “toolkit,” or 14-step guide, for others in the field to use for implementing PrEP in carceral settings, including the development and use of clinical protocols and community linkage strategies.

Discussion:

Our experiences with barriers in the carceral setting, identifying and leveraging implementation strategies, allowed us to develop a “toolkit” to guide other PrEP implementation projects in carceral settings. We encourage others to scale-out our work to other carceral settings to better reach and engage a group of individuals both at elevated risk for HIV and currently underserved by HIV prevention strategies, including PrEP.
Diagnostic Accuracy of 18F-FES PET/CT for the Detection of Recurrent and Metastatic Breast Cancer
Authors: Shin Eonwoo , Han Sangwon , Ryu Jeongryul , Eom Hye-Joung , Choi Woo Jung , Ahn Jin-Hee , Son Byung Ho , Ahn Seung Do , Gong Gyungyub , Moon Dae Hyuk
Published: October 2024

Purpose

To evaluate the diagnostic value of 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) PET/CT for distant metastasis or recurrence in patients with estrogen receptor (ER)–positive breast cancer.

Methods

Patients with ER-positive breast cancer and suspected of de novo metastasis or recurrence were retrospectively identified from a prospective cohort enrolled for a postmarketing surveillance study of 18F-FES at our institution. Per-patient diagnostic accuracy was assessed using pathology or 2 or more standard-of-care imaging procedures with a minimum of 6 months of follow-up as the reference standard. The per-region detection rate of 18F-FES PET/CT was evaluated and compared with that of standard-of-care imaging.

Results

Of the 162 included patients, 104 and 58 were suspected to have recurrence or de novo metastasis, respectively. The overall sensitivity and specificity of 18F-FES PET/CT were 95% (95% confidence interval [CI], 89%–98%) and 89% (95% CI, 76%–96%), respectively. When stratified according to clinical settings, the sensitivity and specificity were 95% (95% CI, 88%–99%) and 96% (95% CI, 78%–100%), respectively, for detecting recurrence, and 94% (95% CI, 81%–99%) and 82% (95% CI, 60%–95%) for detecting distant metastasis. In region-based analysis, the overall detection rate of 18F-FES PET/CT was significantly higher than that of standard-of-care imaging (92% [95% CI, 89%–94%] vs 83% [95% CI, 79%–87%], P < 0.001).

Conclusions

18F-FES PET/CT showed excellent diagnostic performance in patients with ER-positive breast cancer suspected of de novo metastasis or recurrence.
Hypertrophic Olivary Degeneration
Authors: Ganapathy Chandrasekaran , Tripathi Madhavi , D’Cruz Deula , Lodha Rakesh , Kumar Atin , Pandey Saumya , Bal CS
Published: October 2024

We present a case of 12-year-old boy evaluated in view of refractory ascites in whom 18F-FDG PET/CT incidentally revealed hypermetabolism in the medulla that was proven to be hypertrophic olivary degeneration on MRI.
Predictors of the severity of the course of COVID-19: demographic factors, clinical signs and laboratory markers
Authors: Bartoszewicz Klaudia , Bartoszewicz Mateusz , Stróż Samuel , Stasiak-Barmuta Anna , Kosiorek Piotr
Published: October 2024

Introduction. The Coronavirus Disease 2019 (COVID-19) pandemic has had a significant impact on global healthcare, with high mortality and severe complications remaining a major concern. Understanding the predictors of COVID-19 severity may improve patient management and outcomes. While considerable research has focused on the pathogenesis of the virus and vaccine development, the identification of reliable demographic, clinical and laboratory predictors of severe disease remains critical.

Hypothesis. Specific demographic factors, clinical signs and laboratory markers can reliably predict the severity of COVID-19. A comprehensive analysis integrating these predictors could provide a more accurate prognosis and guide timely interventions.

Aim. The aim of this study is to identify and evaluate the demographic, clinical and laboratory factors that can serve as reliable predictors of severe COVID-19, thereby aiding in the prediction and prevention of adverse outcomes.

Methodology. The methods of analysis, synthesis, generalization and descriptive statistics were used to achieve this objective.

Results. The analysis showed that demographic factors such as age over 60 and male sex are significant predictors of severe COVID-19. Clinical predictors include respiratory symptoms, especially dyspnoea, and comorbidities such as hypertension, coronary artery disease, chronic obstructive pulmonary disease, respiratory failure, asthma, diabetes mellitus and obesity. Laboratory markers with high prognostic value include elevated levels of C-reactive protein, interleukin-6, ferritin, neutrophil/lymphocyte ratio, d-dimer, aspartate aminotransferase enzyme and decreased lymphocyte count.

Conclusion. The study concludes that a holistic approach incorporating demographic, clinical and laboratory data is essential to accurately predict the severity of COVID-19. This integrated model may significantly improve patient prognosis by facilitating early identification of high-risk individuals and allowing timely, targeted interventions. The results highlight the importance of comprehensive patient assessment in managing and mitigating the impact of COVID-19.
Finite Element Modeling of Electrical Activity in Human Uterine Tissue: Advances in Simulation Techniques
Authors: Zahran Saeed
Published: October 2024

Simulating the electrical activity of the human uterus has become a crucial tool for understanding the underlying biophysical phenomena, such as uterine contractions during pregnancy. Finite element models (FEM) offer valuable insights into these dynamics by providing a scalable framework to explore the propagation of electrical signals at the cellular and tissue levels. This study presents a finite element-based bidomain model to simulate the excitation propagation across the human uterus. Our model integrates cellular-level electrophysiological properties with tissue-level electrical propagation using the FEniCS Python library. A three-dimensional, realistic representation of uterine tissue is employed to simulate excitation patterns, contributing to a deeper understanding of uterine electrophysiology. The model can also be adapted to investigate pathological conditions such as preterm labor and test potential interventions. The developed simulation framework provides a scalable solution for the numerical challenges posed by solving complex, non-linear ordinary differential equations (ODEs) associated with uterine electrical activity. These simulations could offer a foundation for future research on uterine function and its related disorders.
Bioinformatics Analysis Suggests That SE_1780 protein from Staphylococcus epidermidis may be a member of the Fph Family of Lipases
Authors: Qaddourah Maya , Jayasinghe Sajith
Published: October 2024

The Protein Databank entry for protein SE_1780 from Staphylococcus epidermidis lists the function as unknown. We leveraged the framework outlined in the Biochemistry Authentic Scientific Inquiry Laboratory and used bioinformatics tools to ascertain the function of the protein. Based on our analysis we posit that SE_1780 is a lipase of theα/βhydrolase family with a proposed active site catalytic triad composed of Ser144, Asp235, and His269. Further we identified the lipase FphD as having significant sequence identity to protein SE 1780, and suggest that the protein is a member of the Fph family of lipases from S. epidermidis.
Identifying barriers to care and child mortality in urban and rural areas: a mixed method study in Sierra Leone
Authors: Elston James W.T. , Danis Kostas , Gray Nell , West Kim , Lokuge Kamalini , Black Benjamin , Stringer Beverley , Jimmisa Augustine S. , Biankoe Aiah , Sanko Mohammed O. , Kazungu Donald S. , Sang Sibylle , Baker Holly , Caleo Grazia
Published: October 2024

Background

Reducing mortality of children <5 years in Sierra Leone is a priority. Despite an enabling policy environment, health indicators have remained poor. Evidence on barriers to care is limited.

Objectives

This study describes barriers to care, health-seeking behaviour, and health outcomes of children <5 years.

Methods

From October 2016 to January 2017, we conducted a sequential mixed-methods study in urban and rural areas of Tonkolili District comprising: household survey targeting carers of children <5 years; and in-depth interviews (IDIs) targeting community leaders and healthcare workers (HCWs). We chose 30 clusters in urban and 30 clusters in rural areas. Topics that were identified during the survey were examined further through IDIs.

Results

We surveyed 643 carers of 1092 children <5 years and conducted 72 IDIs. Of children <5 years, 62% had experienced febrile illness in the 2 weeks prior, and mortality was higher rurally (1.55/10,000/day vs urban 0.26/10,000/day). Barriers, including costs and physical inaccessibility of healthcare facilities, delayed or prevented 90% (287/318; 95%CI: 80-96) rural and 48% (155/325; 95%CI: 37-58) urban carers from accessing care for a febrile child. Mistrust of HCWs was frequent, primarily due to their requests for payment. HCWs described lack of pay and holistic support precluding provision of quality care.

Conclusions

Children <5 faced important barriers to healthcare, particularly in rural areas, contributing to high preventable mortality near to the emergency threshold. Access to healthcare was important to carers, however available services were costly and unreachable. Equally, HCWs experienced structural barriers to provide quality care.

Key messages

Child <5years mortality near to the humanitarian emergency threshold and substantially high among rural children.

Inequity in healthcare access and inequality in health between urban and rural areas.

Barriers, including costs of healthcare and physical inaccessibility of healthcare facilities, delayed or prevented 90% of rural and 48% of urban carers from accessing care for a febrile child.

Just 8% of rural children <5 years used Long-Lasting Insecticide-Treated bednets.

Mistrust of healthcare workers was widely expressed primarily due to payment demanded for “free” healthcare. Healthcare workers described lack of pay and poor conditions precluding provision of quality care.
Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5’UTRs
Authors: Meguerditchian Caroline , Baux David , Ludwig Thomas E , Genin Emmanuelle , Trégouët David-Alexandre , Soukarieh Omar
Published: October 2024

Non-canonical small Open Reading Frames (sORFs) are among main regulators of gene expression. The most studied ones are upstream ORFs (upORFs) located in the 5’UTR of coding genes. Internal ORFs (intORFs) in the coding sequence and downstream ORFs (dORFs) in the 3’UTR have received less attention. Different bioinformatics tools permit to predict single nucleotide variants (SNVs) altering upORFs, mainly those creating AUGs or deleting stop codons, but no tool predict variants altering non-canonical translation initiation sites and those altering intORFs or dORFs.

We propose an upgrade of our MORFEE bioinformatics tool to identify SNVs that may alter all types of sORFs in coding transcripts from a VCF file. Moreover, we generate an exhaustive catalog, named MORFEEdb, reporting all possible SNVs altering existing upORFs or creating new ones in human transcripts and provide an R script for visualizing the results. MORFEEdb has been implemented in the public platform Mobidetails. Finally, the annotation of ClinVar variants with MORFEE reveals that more than 45% of UTR-SNVs can alter upORFs or dORFs.

In conclusion, MORFEE and MORFEEdb have the potential to improve the molecular diagnosis of rare human diseases and to facilitate the identification of functional variants from genome-wide association studies of complex traits.
Engineering liposomes with cell membrane proteins to disrupt melanosome transfer
Authors: Liu Chunhuan , Liu Yuchun , Xue Changhu , Yang Cheng , Weitz David A. , Jahnke Kevin
Published: October 2024

Cells communicate by transporting vesicles and organelles, essential for maintaining cellular homeostasis. However, excessive vesicle transfer can cause several diseases and medical conditions like hyperpigmentation due to an unregulated intercellular transfer of melanosomes. Current treatments often focus on eliminating the compartment contents with drugs but can cause significant side effects. Here, we engineer liposomes with cell membrane proteins to directly disrupt intercellular transport without specialized therapeutics. We demonstrate this approach by reducing melanosome transfer from melanocytes to keratinocytes. To achieve this, we incorporate keratinocyte cell membrane proteins into liposomes using microfluidics, which can enhance uptake by melanocytes while reducing uptake by keratinocytes. We also show that these engineered liposomes reduce melanosome transfer because they attach to the surface of pigment globules, impeding pigment globule uptake by keratinocytes. Our findings provide an effective strategy for reducing melanosome transfer to treat hyperpigmentation and introduce a drug-free approach for regulating cellular communication via extracellular vesicles and organelles.
Schizandrin A suppressed pancreatic cancer proliferation and cancer associated fibroblast activation via inhibiting the COX-2/ALOX5 shunting
Authors: Zeng Zhirui , Lei Shan , Wang Jingya , Li Dahuan , Yang Yushi , Tian Qianting , Hao Xiaojiang , Chen Tengxiang
Published: October 2024

Background

Schizandrin A is major components extracted fromSchisandra chinenzis-Turcz. BaillandSchisandra sphenanthear Rend. etWils. Schizandrin A exhibits remarkable hepatoprotective, antiviral and anti-inflammatory effects. However, the anti-tumor effects and its molecular mechanism were still known limited.

Methods

The affinity between Schizandrin A and COX-2/ALOX5 protein was analyzed using network pharmacology, computer molecular docking, and surface plasmon resonance experiments. Bioinformatic analysis and review of clinical characteristics were conducted to assess the necessity of simultaneous blocking of COX-2 and ALOX5 in pancreatic cancer (PC). LC/MS metabolomics and RNA-sequencing were utilized to investigate the effects of schizandrin A on the activation and expression of COX-2/ALOX5 in PC cells. Biological function experiments were conducted to investigate the inhibitory effects of Schizandrin A on PC cell proliferation and cancer-associated fibroblast activationin vitroandin vivo.

Results

Schizandrin A demonstrated a high affinity for binding directly with COX-2 and ALOX5, with kinetic association constants of 14.8 μM and 21.8 μM, respectively. PC exhibited a significant COX-2/ALOX5 signature, while PC cases with a high COX-2/ALOX5 signature showed lower overall survival and disease-free survival rates. Treatment of PC cells with schizandrin A resulted in decreased COX-2/ALOX5 activity and expression, leading to inhibition of leukotriene and prostaglandin production, as well as suppression of the downstream pathway NF-kappaB signaling. Schizandrin A demonstrated significant inhibitory effects on the proliferation and sphericity of PC cellsin vitro, as well as on cell proliferationin vivo, while exhibiting low toxicity to normal tissues. Treatment of conditioned medium from PC cells with schizandrin A resulted in reduced induction of normal fibroblasts into cancer-associated fibroblasts. Furthermore, mutations in the binding sites of ALXO5 (Arg246) and COX-2 proteins (Ile124 and Ser126) resulted in a significant decrease in affinity to Schizandrin A, and blocking the inhibitory effects of schizandrin A.

Conclusions

Taken together, schizandrin A directly bound with COX-2 and ALOX5, reduced their activation and leukotrienes and prostaglandins production, thus exhibiting distinguished effects on suppressing PC proliferation and inhibiting the ability of PC cell to induce normal fibroblasts to transform into tumor-associated fibroblasts. Therefore, schizandrin A represents a potentially novel therapeutic approach for PC.