bluuebunny/crossref_metadata_2025 huggingface dataset:
Convolutional neural network for colorimetric glucose detection using a smartphone and novel multilayer polyvinyl film microfluidic device
Authors: Kanchan Mithun , Tambe Prasad Kisan , Bharati Sanjay , Powar Omkar S
Published: November 2024

Detecting glucose levels is crucial for diabetes patients as it enables timely and effective management, preventing complications and promoting overall health. In this endeavor, we have designed a novel, affordable point-of-care diagnostic device utilizing microfluidic principles, a smartphone camera, and established laboratory colorimetric methods for accurate glucose estimation. Our proposed microfluidic device comprises layers of adhesive poly-vinyl films stacked on a poly methyl methacrylate (PMMA) base sheet, with micro-channel contours precision-cut using a cutting printer. Employing the gold standard glucose-oxidase/peroxidase reaction on this microfluidic platform, we achieve enzymatic glucose determination. The resulting colored complex, formed by phenol and 4-aminoantipyrine in the presence of hydrogen peroxide generated during glucose oxidation, is captured at various glucose concentrations using a smartphone camera. Raw images are processed and utilized as input data for a 2-D convolutional neural network (CNN) deep learning classifier, demonstrating an impressive 95% overall accuracy against new images. The glucose predictions done by CNN are compared with ISO 15197:2013/2015 gold standard norms. Furthermore, the classifier exhibits outstanding precision, recall, and F1 score of 94%, 93%, and 93%, respectively, as validated through our study, showcasing its exceptional predictive capability. Next, a user-friendly smartphone application named “GLUCOLENS AI” was developed to capture images, perform image processing, and communicate with cloud server containing the CNN classifier. The developed CNN model can be successfully used as a pre-trained model for future glucose concentration predictions.
A sustainable HPTLC approach for green assessment of Tyrosine to phenylalanine ratio in chronic kidney disease
Authors: Kamel Rania M. , Abdel-aal Fatma A. M. , Osman Mostafa M. , Mohamed Fardous A. , Mohamed Abdel-Maaboud I.
Published: November 2024

The kidney is considered the main site for the net release of Tyrosine (Tyr) to the circulation through hydroxylation of Phenylalanine (Phe) using phenylalanine hydroxylase enzyme. In chronic kidney disease (CKD) patients the enzyme activity is impaired, therefore the serum concentration ratio of Tyr/Phe is reduced compared to healthy individuals. This motivates us to develop a cost effective, green, simple, sensitive, and selective HPTLC method to measure the levels of Tyr and Phe in serum samples. The analysis was carried out using acetonitrile: ethanol: 25% ammonia solution: ethyl acetate (6.5: 1.5: 1: 0.5) as a mobile phase. Rf values were 0.55 ± 0.05 for Phe and 0.39 ± 0.05 for Tyr. Densitometry scanning was performed using UV detector and dual wavelengths of 210 and 225 nm were obtained. A linear correlation was observed between the levels of Phe and Tyr, ranging from 50 to 700 ng band− 1 and 50 to 600 ng band− 1, respectively, under the optimum conditions. The method selectivity, linearity, precision, accuracy, and robustness were all confirmed in accordance with ICH recommendations. Calculations of the separation and resolution factors, number of theoretical plates, and height equivalent to theoretical plates prove to the chromatographic system accuracy and high separation efficiency. The developed method exhibits an acceptable eco-scale when measuring the method greenness using AGREE and GAPI softwares. It was applied for the determination of Phe and Tyr concentrations in human serum samples.
Cost-effectiveness analysis of mHealth applications for depression in Germany using a Markov cohort simulation
Authors: Freitag Bettina , Uncovska Marie , Meister Sven , Prinz Christian , Fehring Leonard
Published: November 2024

Regulated mobile health applications are called digital health applications (“DiGA”) in Germany. To qualify for reimbursement by statutory health insurance companies, DiGA have to prove positive care effects in scientific studies. Since the empirical exploration of DiGA cost-effectiveness remains largely uncharted, this study pioneers the methodology of cohort-based state-transition Markov models to evaluate DiGA for depression. As health states, we define mild, moderate, severe depression, remission and death. Comparing a future scenario where 50% of patients receive supplementary DiGA access with the current standard of care reveals a gain of 0.02 quality-adjusted life years (QALYs) per patient, which comes at additional direct costs of ~1536 EUR per patient over a five-year timeframe. Influencing factors determining DiGA cost-effectiveness are the DiGA cost structure and individual DiGA effectiveness. Under Germany’s existing cost structure, DiGA for depression are yet to demonstrate the ability to generate overall savings in healthcare expenditures.
Multiomics biomarkers were not superior to clinical variables for pan-cancer screening
Authors: Smelik Martin , Zhao Yelin , Mansour Aly Dina , Mahmud AKM Firoj , Sysoev Oleg , Li Xinxiu , Benson Mikael
Published: November 2024

Background

Cancer screening tests are considered pivotal for early diagnosis and survival. However, the efficacy of these tests for improving survival has recently been questioned. This study aims to test if cancer screening could be improved by biomarkers in peripheral blood based on multi-omics data.

Methods

We utilize multi-omics data from 500,000 participants in the UK Biobank. Machine learning is applied to search for proteins, metabolites, genetic variants, or clinical variables to diagnose cancers collectively and individually.

Results

Here we show that the overall performance of the potential blood biomarkers do not outperform clinical variables for collective diagnosis. However, we observe promising results for individual cancers in close proximity to peripheral blood, with an Area Under the Curve (AUC) greater than 0.8.

Conclusions

Our findings suggest that the identification of blood biomarkers for cancer might be complicated by variable overlap between molecular changes in tumor tissues and peripheral blood. This explanation is supported by local proteomics analyses of different tumors, which all show high AUCs, greater than 0.9. Thus, multi-omics biomarkers for the diagnosis of individual cancers may potentially be effective, but not for groups of cancers.
Determination of metal–biomolecule interactions by relative mobility shift partial filling affinity capillary electrophoresis
Authors: Huang Tao , Xu Jinxiang , Liang Chunsu , Gong Liyu , Ling Xiaomei
Published: November 2024

Metal ions and their interactions with biomolecules play an important role in human health.
Effects of memory on inventory control and pricing policy for imperfect production with rework process
Authors: Jain Madhu , Indoria Harsh , Chaudhary Aditya , Singh Praveendra
Published: November 2024

Fractional calculus is a pertinent way to study the memory effect in an inventory model for investigating its dynamical behavior. Since inventory management is a memory-dependent process, fractional calculus approach may be employed to discover some fruitful insights and can help to gain more profit. In realistic scenarios, the manufacturing process cannot be perfect, and it delivers some faulty units due to many inevitable reasons. In literature, an imperfect production inventory problem under the memory effect has not been studied. Our study aims to investigate the memory effect on a production inventory system. In this article, a fractional order inventory control problem is formulated by considering an imperfect manufacturing process and price-sensitive demand. The faulty units are repaired through a rework process. Caputo fractional derivatives and integrals are used to consider the memory effect. Due to the nonlinear cost elements in the formulated problem, optimal pricing and production policies are investigated by using a quasi-Newton optimization algorithm and particle swarm optimization approach. The managerial implications of the proposed study are discussed with the help of numerical illustrations. The numerical outcomes suggest that consideration of memory in the inventory system boosts the profitability of the firm.
Caregiver policies in the United States: a systematic review
Authors: Green Makenna R. , Hughes M. Courtney , Afrin Sadia , Vernon Erin
Published: November 2024

In the United States, there are nearly 53 million informal or unpaid caregivers, many of whom experience mental and physical stress related to their caregiving duties and increased financial responsibility. We identified federal and state informal caregiver support policies authorized by specific legislation along with their key provisions and conducted a systematic review of the academic literature related to quantitative evaluations of these policies. Twenty policies, eight academic studies, and four gray literature reports were included in the study, with half of the policies introduced since 2000. Our study criteria yielded few academic valuations tied to caregiver policies and few policies including research provisions. Of the provision areas identified in policies, respite services, caregiver training, and workplace protections appeared the most. Future policies and the studies examining them should incorporate cost outcomes and equity as focus areas and disaggregate data by vulnerable groups to ensure value and equity in caregiver support legislation.

Key messages

Increased legislation to support informal caregivers may be warranted. The limited academic research examining existing caregiver policies identifies mixed outcomes for caregivers.

Prioritizing vulnerable populations in such policy research examining outcomes could help improve caregiver support efforts.

The included studies investigated the outcomes of three policies and identified more negative than positive outcomes for caregivers.
How much time, effort and money is spent caring for wombats?
Authors: Old Julie M. , Lago Isabella , Wills Jessica , Stannard Hayley J.
Published: November 2024

Wildlife care and rehabilitation are undertaken by thousands of volunteers throughout Australia every year. Bare-nosed (Vombatus ursinus) and southern hairy-nosed wombats (Lasiorhinus latifrons) regularly come into care, with the demands on wombat carers and the numbers of wombats increasing. Understanding the burdens placed on wombat carers and rehabilitators will provide information to wildlife managers to assess the risks to wombats and document the concerns of wildlife carers. Data were collected via an online quantitative and qualitative survey using Qualtrics. The survey was distributed through Facebook groups to wombat carers and rehabilitators and received 22 responses. The survey confirmed that caring for wombats is time-consuming and expensive, particularly when raising wombat joeys. Both adult and juvenile wombats were brought into care; the most common reasons were vehicle collisions, sarcoptic mange, and injuries resulting from dog or wombat attacks. Despite the significant financial and mental health costs to wombat carers, in most cases, carers thought young wombats that came into care were successfully rehabilitated and re-introduced into their natural habitat. Our study provides insights into the issues facing wombats, the people that care for wombats, and the wider carer sector.
Performance analysis of position sensorless control of antagonistic shape memory alloy actuators
Authors: Bai Fengqiang , Zhang Xiangjun , Xu Dianguo
Published: November 2024

This paper presents a comprehensive performance analysis of position sensorless control of antagonistic shape memory alloy actuators (ASMAA), focusing on enhancing the sensorless position sensing capabilities and servo performance. The mechanisms and influencing factors of ASMAA self-sensing characteristics are comprehensively analyzed. A self-sensing model framework based on the constitutive model of ASMAA is proposed, and a self-sensing model based on differential resistance feedback is developed. An experimental platform based on the ASMAA motion mechanism is established to test and analyze SMA wires of two different materials under various pretension force conditions. The experimental results show that the antagonistic configuration mitigates hysteresis and improves linearity. A simple polynomial fitting is employed to establish the resistance-displacement relationship, achieving good accuracy with minimal residuals. The system identification is employed to avoid the parameter complexity and time-varying in the constitutive model. Based on the identified transfer function, a traditional PID controller is designed for position sensorless servo control. However, the inherent nonlinear hysteresis of ASMAA is difficult to suppress using a linear PID controller. Furthermore, a compound control strategy based on the Duhem model and PID controller is proposed, which utilizes the particle swarm optimization algorithm to identify the Duhem inverse model controller. Experimental results demonstrate that the compound controller significantly enhances position tracking accuracy and response speed compared to a standalone PID controller.
All-in-one, flexible, diversified self-powered sensors through embedded 3D printing
Authors: Xian Shuai , Wu Zhenfeng , Li Yixin , Wu Zhigang , Zhong Yong
Published: November 2024

Triboelectric nanogenerators are characterized by zero power consumption and are often employed as self-powered sensors. However, the complex manufacturing process and expensive equipment limit the further promotion and application of self-powered sensors, which have become urgent challenges in this field. Here, a simple strategy using embedded three-dimensional (EMB 3D) printing is proposed to enable the fabrication of diverse self-powered sensors in one-step, reducing production costs while increasing design flexibility. Specifically, the designed sensors composed of the silicone as the triboelectric layer and silicone/multi-walled carbon nanotubes as flexible electrodes with excellent all-in-one structures. Meanwhile, diversified self-powered sensors with different complex structures (e.g. planar array sensors and gyroid-structures sensors) were developed to meet the diverse needs of different applications, verifying the capability of the proposed embedded 3D printing method to design and customize sensors with various shapes and structures. In addition, the applications of these functionalized self-powered sensors in cryptographic simulation, pressure position detection, and impact force recognition have been successfully demonstrated. Therefore, this self-powered sensor based on EMB 3D printing has a promising future in human-computer interaction, collision detection and other fields.
Prototyping sutureless shape memory valve stent via integrated 3D printing
Authors: Yang Meng , Yuan Chao , Chen Xi , Jiang Xiaochun , Wang Tiejun
Published: November 2024

Transcatheter aortic valve replacement (TAVR) has increasingly emerged as a forefront option for treating aortic valve diseases. However, the currently prevalent valve prostheses used in TAVR typically involve stitching biologic leaflets onto metallic stents, which introduces challenges in the durability of leaflets and the biocompatibility of metallic stents. This work proposes an integrated additive manufacturing method for prototyping sutureless prosthetic aortic valves that combine shape memory polymer (SMP) stents and hydrogel valve leaflets. The SMP stent exhibits sufficient toughness to maintain structural integrity upon shape memory programming, while the Fe3+-treated hydrogel leaflets possess sufficient swelling resistance to ensure dimensional stability. Finally, the proof-of-concept valve stent is successfully fabricated by integrated 3D printing and validated via an in vitro hemodynamic experiment. Overall, our approach holds promise for prototyping sutureless polymeric valve stents for future generations.
Electromechanical characteristics analysis of L-shaped pipelines with enhanced active constrained damping treatment
Authors: Zhang Zihan , Li Pengfei , Wang Wenzeng , He Tong , Yu Tao , Gao Peixin
Published: November 2024

Fluid-conveying pipelines are widely employed in various engineering fields, such as aerospace, nuclear, and marine fields. These pipelines work in serious vibration environments, which can quickly damage the pipeline system. The vibration control of pipelines is a prominent challenge in the engineering field. This paper is aimed to investigate the electromechanical analysis characteristics of L-shaped pipelines with the enhanced active constrained layer damping (EACLD) structure. A finite element model of the L-shaped pipeline with EACLD is established. The dynamic behavior of an L-shaped pipeline with an EACLD structure was analyzed in both the time and frequency domains. The influence of the voltage and the position, the length and the elastic modulus, the thickness and the edge element parameters are all considered. Additionally, the influence of the EACLD patch orientation on static displacement and stress are considered. Simulation results indicate that reasonable selection of the parameters for the EACLD patch and edge element can enhance vibration damping effectiveness, which can provide effective design guidance for active vibration control of the pipeline system.
An image too many: the contemporary biopic, the historical body, and the documentary footage trope
Authors: Wilder Seth A
Published: November 2024

This article explores the inclusion of historical footage at the end of biopics. The impact of such footage, commonly appended to recent films, varies depending on the specific film. By drawing on theories of viewership, historical film, ontology, and epistemology, this investigation attempts to shed light on why this footage is sometimes, but not inevitably, troubling. Its analysis of the use of such footage in Bohemian Rhapsody and I’m Not There delves into the viewer’s relationship with images and the complexities arising from the intersection of reality and fiction. By exploring the shifting modes of engagement that influence the viewer’s experience, the analysis suggests that this choice may imply a claim to historical authenticity or truth. In questioning the reasons for the increasing prevalence of this trope in contemporary biopics, this article considers the implications of blurring the boundaries between the real and the imaginary.
Medical Risk, Patient Hope, and Hospital Chaplaincy: Cautionary Tales
Authors: Cherry Mark J
Published: November 2024

Secular bioethics fails to grasp the central moral and spiritual realities of medicine. As the authors in this issue of Christian Bioethics argue, contemporary healthcare practice is often based on the false premise that medical science can secure the safety of human life. Yet, the standard “biopsychosocial model” of medicine fails to grasp the theological dimensions of healthcare often harming patients and their families in the process. Indeed, as the articles explore, all too often secular bioethics manipulates medicine to achieve immoral purposes, such as active euthanasia of the sick or elderly. Such spiritual decay is acutely manifested in the pressure put on patients to accept an economically efficient and medically expedient assisted death as well as in how society often treats the human body as mere res—a thing unimportant in itself apart from animation as a living person. Together the articles illustrate that without careful religiously grounded advice modern medicine is often spiritually disorienting for both patients and practitioners.
Risk factors for readmission following esophagectomy and gastrectomy for cancer
Authors: Geerts J F M , van den Berg I , van Nistelrooij A M J , Lagarde S M , Wijnhoven B P L
Published: November 2024

Introduction

Hospital readmission after surgery is a key quality indicator. This nationwide cohort study aimed to assess readmission rates following esophagectomy and gastrectomy for cancer and identify associated risk factors.

Methods

Data were extracted from the Dutch Upper GI Cancer Audit (DUCA) for patients with esophagogastric cancer who underwent esophagectomy or gastrectomy with curative intent between January 2011 and June 2016. Logistic regression analysis identified risk factors for 30-day readmission.

Results

In total, 5566 patients were included. Readmission within 30 days occurred in 483 of 3488 (13.8%) patients after esophagectomy and 243 of 2078 patients (11.7%) after gastrectomy. Both minor (Clavien Dindo 1–2) and major (Clavien Dindo ≥3) postoperative complications were independent predictors of readmission after esophagectomy (OR 2.99; 95%CI 2.23–4.02; p < 0.001 and OR 5.20; 95%CI 3.82–7.09; p < 0.001). Specific complications included pulmonary (OR 1.49; 95%CI 1.20–1.85; p < 0.001), gastrointestinal (OR 2.43; 95%CI 1.94–3.05; p < 0.001), and infectious (OR 2.27; 95%CI 1.60–3.22; p < 0.001). Prolonged length of stay (pLOS) was associated with higher readmission rates in patients without complications following esophagectomy (OR 1.91 95% CI 1.19–3.07; p = 0.008), but lower rates in those with complications (OR 0.65 95% CI 0.51–0.83; p < 0.001). For gastrectomy, postoperative complications were also linked to readmission (OR 3.18; 95%CI 2.30–4.40; p < 0.001), particularly gastrointestinal (OR 2.16; 95%CI 1.40–3.32; p < 0.001), and infectious (OR 3.80; 95%CI 2.53–5.71; p < 0.001).

Conclusion

Readmission after esophagogastric resection is common, particularly among patients with both minor and major postoperative complications. Prolonged stay after esophagectomy impacts readmission risk differently based on the presence of complications.
Carbon capture and recycling technology of carbon resources under the target of carbon neutrality
Authors: Tao William Li Wei
Published: November 2024

Carbon capture and recycling (CCR) offers a promising solution to mitigate CO2 emissions. Unlike traditional carbon capture and storage, CCR uses green hydrogen and natural gas infrastructure to enhance process efficiency, capturing over 90% of CO2. By converting CO2 and hydrogen into methane, the system provides a low-carbon alternative to natural gas. CCR is cost-effective and scalable, with reduced risks of long-term CO2 storage. However, challenges like hydrogen production and economic viability remain, requiring further research. CCR could be key in achieving carbon neutrality and addressing future energy demands.
Knowledge, attitudes, and practices of community pharmacists providing over-the-counter emergency hormonal contraception: a scoping review
Authors: Nona Ruth A , Ray Robin A , Taylor Selina M , Glass Beverley D
Published: November 2024

Objectives

Reducing the rate and impact of unintended pregnancy through effective contraception is a public health goal. Since deregulation, globally, ease of access to community pharmacists has enabled them to play a key role in the provision of emergency hormonal contraceptive pills (ECP). The aim of this scoping review is to explore pharmacists’ overall knowledge of and attitudes and practices towards the provision of emergency contraception.

Methods

A systematic literature search for the period from 1999 to 2023 was conducted using Scopus, Medline (Ovid), CINAHL, Emcare, Web of Science, and Google Scholar. Keywords such as emergency contraception, emergency contraceptive, morning after pill, plan B, pharmacist, community pharmacist, and pharmacy were applied. Articles published only in English that described the knowledge, attitudes, and practices of community pharmacists providing emergency contraception were included in this review.

Key findings

Twenty studies met the inclusion criteria. Despite positive attitudes towards the provision of ECP, there is a clear deficit in both the knowledge and counselling practices of pharmacists, with some pharmacists lacking an open attitude towards the supply of ECP to adolescents and third parties. Usage of a private counselling area ranged from 0% to 90% highlighting privacy for patients seeking ECPs is lacking during consultations. In countries where practice guidelines are available, these are often not being optimally utilized.

Conclusions

This review has highlighted gaps in pharmacists’ knowledge and counselling practices, demonstrating shortcomings in pharmacists’ education, training, and application of professional practice guidelines. Future research on ECP guidelines is recommended to improve implementation and usability in practice.
Capitalist and anti-capitalist placemaking through street art
Authors: Kukla Quill R
Published: November 2024

Street art can function as a tool of placemaking. It shapes how we experience, move through, and attach meaning to space, as well as how space is territorialized and bounded. Street art can be a restructuring force that changes how a space is legible or interpretable to its users, how it is used, how it is experienced, and how it forms a territory with insiders and outsiders. But how street art does this along with what kinds of impact it has varies dramatically from neighborhood to neighborhood. More specifically, the relationship between street art, placemaking, and capitalism is remarkably different in different neighborhoods. Street art can support capitalist placemarketing, or it can work toward secession from the capitalist landscape, either by preserving or by creating alternative place identities. I use three different neighborhoods in New York City—The Bowery, El Barrio, and the South Bronx—as case studies for each of the three phenomena, respectively. I end by examining a paradox that street art faces: explicitly anti-capitalist street art is easily coopted by capitalist forces that seek to commodify its aesthetic, so attempts to use street art to combat capitalist appropriations of space often (though not always) backfire.
Seasonal drought drives sugarcane borer outbreaks
Authors: Wang Leyun , Zhao Zihua
Published: November 2024

Sugarcane borers (SCB) pose a major threat to sugarcane production. Effective pest management requires detailed knowledge of SCB phenology and population dynamics in responses to environmental changes. This study tested the hypothesis that drought drives SCB outbreaks and identified season-specific effects by investigating large-scale field data of these pests in 4 key sugarcane-growing provinces in south subtropical and tropical China (Guangxi, Guangdong, Yunnan, and Hainan) from 1987 to 2018. The standardized precipitation evapotranspiration index was used as a drought indicator at various time scales. We found that drought during a specific month can result in significant changes in the annual SCB outbreak status, such as November in Guangxi, June in Yunnan, and September in Hainan. By summarizing seasonal effects of drought across study locations, we found a general pattern that SCB outbreaks increased with drier conditions in summer, whereas they were promoted by wetter conditions in fall. This research provides crucial knowledge for predicting SCB outbreaks under seasonal and climate changes. This information is also highly critical for increasing the efficiency and accuracy of integrated pest management strategies.
Ascorbic acid and glucose can cause significant interference on quantitative measurement of biochemistry analytes in urine
Authors: Mašković Sara , Nikolac Gabaj Nora
Published: November 2024

Background and aims

Preanalytical errors due to interferences can lead to inaccurate results, necessitating an understanding of potential interferences for each test. This study explores the impact of elevated concentrations of ascorbic acid and glucose on urine analysis, a pivotal diagnostic tool.

Methods

Conducted at the Clinical Institute of Chemistry, KBC Sestre milosrdnice, the research utilized a 24-hour urine sample. Parameters assessed included total proteins, albumin, amylase, sodium, potassium, chlorides, calcium, phosphates, magnesium, creatinine, urea, and uric acid. Various concentrations of added interferents were prepared for duplicate measurements using statistical analysis in Microsoft Excel.

Results

No statistically significant interferences were found in albumin, amylase, sodium, potassium, or phosphate concentrations. However, ascorbic acid interfered with chloride, calcium, and magnesium determinations. Conversely, elevated glucose affected total protein, calcium, magnesium, creatinine, urea, and uric acid determinations. Interference of ascorbic acid with chloride and interference of glucose with total proteins and uric acid displayed a linear relationship.

Conclusions

Results suggest cautious analysis interpretation from certain parameters in patients with elevated glucose and/or ascorbic acid in urine. Whereas ascorbic acid interference may go unnoticed due to its infrequent measurement, routine determination of glucose in urine is crucial, especially for diabetes patients.
Three-year survival follow-up of patients with gastrointestinal cancer treated during the COVID-19 pandemic in Spain: data from the PANDORA-TTD20 study
Authors: García-Alfonso Pilar , Jimenez-Fonseca Paula , Soto-Alsar Javier , Baraibar Iosune , Santos Cristina , La Casta Adelaida , Ghanem Ismael , Pulido Cortijo Gema , Mariño Méndez Axel , Pazo-Cid Roberto , Vera Ruth , Melián Marcos , Alcaide Julia , Graña Begoña , Páez David , Gallego Inmaculada , Lobo Miriam , Borregón Miguel , Fernández Montes Ana , Martínez de Castro Eva , Carmona-Bayonas Alberto , Aranda Enrique
Published: November 2024

Introduction

The initial SARS-CoV-2 pandemic wave in Spain in 2020 precipitated significant paradigm shifts in gastrointestinal oncology patient management. This study captures the “Zeitgeist” of this period by analyzing adaptive strategies, treatment modifications, and survival outcomes, leveraging a 3-year follow-up perspective to extract insights from this unprecedented experience.

Methods

We conducted a multicenter, retrospective cohort study utilizing the RETUD-TTD registry, encompassing 703 patients across 19 Spanish centers in April 2020. We evaluated alterations in clinical practice, therapeutic approaches, coronavirus disease 2019 (COVID-19)-related impacts, and patient survival. A Bayesian hierarchical model was employed to identify potential regional-specific frailties.

Results

The peak of the pandemic in April 2020 catalyzed substantial shifts in oncological care delivery. Outpatient consultations decreased by 13%, with a notable selection bias toward cases with more favorable prognostic indicators. Multidisciplinary tumor board discussions were significantly curtailed (eg, mean monthly colorectal cancer cases discussed was reduced from 40 to 23), compromising qualitative care measures. This occurred concurrently with an average of over 3 oncologists per center on medical leave. Contrary to initial concerns, the healthcare system demonstrated remarkable resilience. The majority of patients received standard-of-care therapies with regulatory approval, albeit with regimen modifications in 15% of cases. These adaptations included extended dosing intervals, dose intensity modulations, and transitions to oral formulations while maintaining unexpectedly stable long-term survival outcomes. The Bayesian frailty model detected minimal unmeasured prognostic factors related to geographic location, and the type of pandemic-induced adaptation did not significantly impact survival. The model revealed that coronavirus disease 2019’s impact was less pronounced than other core prognostic variables.

Conclusions

The decentralized Spanish healthcare system exhibited substantial robustness in managing pre-pandemic diagnosed gastrointestinal malignancies, despite asymmetrical, and occasionally severe organizational disruptions. The insights gleaned from this experience could inform future crisis preparedness strategies and optimize care provision during subsequent public health emergencies.
Real-world application of disitamab vedotin (RC48-ADC) in patients with breast cancer with different HER2 expression levels: efficacy and safety analysis
Authors: Wang Ke , Xu Ting , Wu Jing , Yuan Yuan , Guan Xiaoxiang , Zhu Chengjun
Published: November 2024

Background

Disitamab vedotin (RC48-ADC), an antibody-drug conjugate (ADC), combines specific antibody disitamab with cytotoxicity monomethyl auristatin E to effectively target the human epidermal growth factor receptor 2 (HER2) protein on tumor cells for precise elimination. Recent studies have demonstrated that RC48-ADC offers therapeutic benefits for patients with HER2-positive and HER2-low-expression breast cancer (BC). However, a thorough exploration of its efficacy and safety in real-world settings for patients with metastatic breast cancer (mBC) is currently lacking.

Methods

This retrospective, multicenter, real-world study included patients with mBC who received RC48-ADC from September 2021 to March 2024. These patients include HER2-positive BC and HER2-low-expression BC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), restricted mean survival time, objective response rate (ORR), and disease control rate (DCR). Factors affecting efficacy and the occurrence of treatment-related adverse events (TRAE) were evaluated.

Results

The study included a cohort of 89 patients with mBC, with 48 of those being identified as HER2-positive. As of March 2024, 22 deaths were recorded, with an immature median OS. Total PFS varied from 1.0 to 31.2 months, with a median of 5.5 months (95% CI, 4.368-6.632). HER2-positive patients exhibited prolonged PFS compared with HER2-low-expression patients (6.6 months vs 4.1 months, P = .023). The overall ORR stood at 25.8% (95% CI, 0.178-0.358), with higher rates observed in HER2-positive patients compared with HER2-low-expression patients (31.3% vs 19.5%). Similarly, the overall DCR was 78.7% (95% CI, 0.691-0.859), with HER2-positive patients demonstrating superior DCR compared with HER2-low-expression patients (83.3% vs 73.2%). Notably, HER2 expression emerged as the primary determinant of RC48-ADC efficacy. The most prevalent TRAE among all patients included leukopenia (21.3%) and alopecia (20.2%).

Conclusion

RC48-ADC showcases promising efficacy and manageable safety in patients with both HER2-positive and HER2-low-expression mBC.
Coping Power at the REACH School Network: A pilot feasibility study
Authors: Rasiah Saisujani , Andrade Brendan F , Cohen-Silver Justine , Suri Anjali , Rasiah Shajitha , Huber Joelene , Freeman Sloane J
Published: November 2024

Objectives

School-based health centres (SBHCs) provide developmental and mental health care to children with socioeconomic disparities. We piloted a validated behavioural intervention called Coping Power (CP) for children with disruptive behaviour through our SBHC program. The objective of this pilot study was to examine the feasibility of CP in the SBHC setting.

Methods

All parent/caregiver and child dyads enrolled in CP from 2018 to 2019 and 2021 to 2022 were invited to participate in the study. Demographic information and behaviour rating scales were collected at baseline. Feasibility metrics included attendance and satisfaction survey responses.

Results

A total of 31 parent/caregiver-child dyads were included. Approximately 40% of families had an annual income of <$49,999. Regarding attendance, 22/31 children/parent/caregiver dyads (70.9%) missed ≤2 sessions. Thirteen parents/caregivers completed the CP satisfaction survey and indicated that they were either ‘somewhat’ (n = 4) or ‘very satisfied’ (n = 9) with the program. Of the 18 children who completed the satisfaction survey, 13 (72.2%) shared that either the ‘sort of’ or ‘for sure’ group helped them cope with their anger better.

Conclusions

This pilot study found that CP delivered within the SBHCs was feasible. Improving access to CP for disadvantaged children may improve mental health outcomes.
Exploring mesenchymal stem cells homing mechanisms and improvement strategies
Authors: Sajjad Umar , Ahmed Muhammad , Iqbal M Zohaib , Riaz Mahrukh , Mustafa Muhammad , Biedermann Thomas , Klar Agnes S
Published: November 2024

Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.
AACDB: Antigen-Antibody Complex Database — a Comprehensive Database Unlocking Insights into Interaction Interface
Authors: Zhou Yuwei , Liu Wenwen , Huang Ziru , Gou Yushu , Liu Siqi , Jiang Lixu , Yang Yue , Huang Jian
Published: November 2024

Antibodies play a crucial role in the vertebrate immune system and have diverse biomedical applications. Understanding the intricate interactions between antibodies and antigens is an important step in drug development. However, the complex and vast nature of the data presents significant challenges in accurately identifying and comprehending these interactions. To address these challenges and enhance our understanding of the antibody-antigen interface, the Antigen-Antibody Complex Database (AACDB) has been established. The current version provides a comprehensive collection of 7,498 manually processed antigen-antibody complexes, ensuring accuracy and detail. This database not only provides rich metadata but also corrects annotation errors observed in the PDB database. Furthermore, it integrates data on antibody developability and antigen-drug target relationships, making it valuable for assisting new antibody therapies development. Notably, the database includes comprehensive paratope and epitope annotation information, thereby serving as a valuable benchmark for immunoinformatics research. The AACDB interface is designed to be user-friendly, providing researchers with powerful search and visualization tools that enable effortless querying, manipulation, and visualization of complex data. Researchers can access AACDB completely online athttp://i.uestc.edu.cn/AACDB. Regular updates are promised to ensure the timely provision of scientific and valuable information.
SAM transmethylation pathway and adenosine recycling to ATP are essential for systemic regulation and immune response
Authors: Nedbalova Pavla , Kaislerova Nikola , Chodakova Lenka , Moos Martin , Dolezal Tomas
Published: November 2024

During parasitoid wasp infection, activated immune cells ofDrosophila melanogasterlarvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delayDrosophilalarval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.
Sugar phosphate-mediated inhibition of peptidoglycan precursor synthesis
Authors: Keller Megan R. , Soni Vijay , Brown Megan , Rosch Kelly M. , Saleh Anas , Rhee Kyu , Doerr Tobias
Published: November 2024

Antibiotic tolerance, the widespread ability of diverse pathogenic bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied steppingstone towards antibiotic resistance. The Gram-negative pathogenVibrio cholerae, the causative agent of cholera, is highly tolerant to β-lactam antibiotics. We previously found that the disruption of glycolysis, via deletion ofpgi(vc0374, glucose-6-phosphate isomerase), resulted in significant cell wall damage and increased sensitivity towards β-lactam antibiotics. Here, we uncover the mechanism of this resulting damage. We find that glucose causes growth inhibition, partial lysis, and a damaged cell envelope in Δpgi. Supplementation with N-acetylglucosamine, but not other carbon sources (either from upper glycolysis, TCA cycle intermediates, or cell wall precursors) restored growth, re-established antibiotic resistance towards β-lactams, and recovered cellular morphology of apgimutant exposed to glucose. Targeted metabolomics revealed the cell wall precursor synthetase enzyme GlmU (vc2762, coding for the bifunctional enzyme that converts glucosamine-1P to UDP-GlcNAc) as a critical bottleneck and mediator of glucose toxicity in Δpgi.In vitroassays of GlmU revealed that sugar phosphates (primarily glucose-1-phosphate) inhibit the acetyltransferase activity of GlmU (likely competitively), resulting in compromised PG and LPS biosynthesis. These findings identify GlmU as a critical branchpoint enzyme between central metabolism and cell envelope integrity and reveal the molecular mechanism of Δpgiglucose toxicity inVibrio cholerae.

Importance

Sugar-phosphate toxicity is a well characterized phenomenon that is seen within diverse bacterial species, and yet the molecular underpinnings remain elusive. We previously discovered that disruptingVibrio cholerae’sability to eat glucose (by disrupting thepgigene), also resulted in a damaged cell envelope. Upon deletion ofpgi, glucose-phosphate levels rapidly build and inhibit the enzymatic activity of GlmU, a key step of bacterial peptidoglycan precursor synthesis. GlmU inhibition causes enhanced killing by antibiotics and a pronounced cell envelope defect. Thus, GlmU serves as a prime target for novel drug development. This research opens new routes through which central metabolism and sugar-phosphate toxicity modulate antibiotic susceptibility.
Novel Library Assembly Technique for Developing Nanobodies Targeting IPNv VP2 Protein
Authors: Pino-Belmar Camila , Himelreichs Johanna , Deride Camila , Matute Tamara , Nuñez Isaac , Cazaux Severine , Federici Fernan , Moreno Karen , Rauch Genaro Soto , Munizaga Jose , Haussmann Denise , Rojas-Fernandez Alejandro , Jaime Figueroa V , Valenzuela-Nieto Guillermo
Published: November 2024

Infectious pancreatic necrosis virus (IPNv) poses a significant threat to the global salmon farming industry, causing high mortality and economic losses. Given the limitations of traditional antibody therapies in aquaculture, we explored the development of nanobodies targeting the VP2 protein of IPNv. We developed a novel nanobody library generation method using a streamlined assembly protocol based on Type IIS restriction enzymes. This method enabled quick and efficient bacterial display library generation, and concatenated, multi-level cloning through an ingenious design in which the ligation of the first level generates a new restriction site that can be utilized in the subsequent cloning level, allowing for rapid transfer to other vectors. By combining this assembly approach with density gradient-based enrichment and high-throughput screening, we identified nanobodies that specifically recognize IPNv’s VP2 protein. Notably, the P9 clone demonstrated high specificity for IPNv in immunofluorescence assays, highlighting its diagnostic potential. Our method not only accelerates nanobody library generation but also enhances its quality and adaptability, marking a significant advancement in enhancing the responsiveness of nanobody development platforms against emerging pathogen outbreaks.
Trans-Translation inhibitors and copper synergize for enhanced antibiotic activity
Authors: Vázquez-Hernández Melissa , Uzun Huriye Deniz , Otte Mona , Schipp Lea , Senges Christoph H. R. , Heinrich Sascha , Alumasa John N. , Stepien Jennifer , Demirbas Fatih , Cignoni Paolo , Marcus-Alic Katrin , Tschulik Kristina , Krämer Ute , Günther Pomorski Thomas , Keiler Kenneth C. , Bandow Julia E.
Published: November 2024

Trans-Translation is the most effective ribosome rescue mechanism and a compelling target for new antimicrobial agents. A recent proteomic study revealed similarities between the responses ofBacillus subtilisto the inhibitors small-molecule inhibitors oxadiazole KKL-40 and tetrazole KKL-55 and divalent cation ionophores, indicating the disturbance of metal homeostasis as potential secondary mechanism of action. Here, we report increased copper levels in KKL-40 and KKL-55-treatedB. subtilis. Both inhibitors form copper complexes that enter large unilamellar vesicles. Copper supplementation enhanced the antibacterial activity againstB. subtilisby simultaneously increasing inhibitor and copper uptake. The co-treatment ofB. subtiliswithtrans-translation inhibitors and copper concentrations normally benign fortrans-translation-competent cells, caused an immediate stalling of growth and translation, as observed at higher KKL-40 and KKL-55 concentrations without copper supplementation. Proteome analysis showed that during translation stalling cells were unable to mount an effective copper toxicity response. Taken together, the synergetic uptake of KKL-40 and KKL-55 with copper leads to a quick-onset translation stalling, preventingB. subtilisfrom counteracting the toxic effects of rapid copper influx.

Significance statement

The challenge of antimicrobial resistance is growing, necessitating an exploration of novel antibiotic targets. Among these,trans-translation has attracted considerable attention due to its ubiquitous presence in bacteria as well as its role in virulence and pathogenesis. Several inhibitors oftrans-translation have been identified in a target-based screening using a whole-cell assay. However, recent proteomic profiling studies suggested that the testedtrans-translation inhibitors might have an additional mode of action. In this work, we shed light on their previously undiscovered copper ionophore activity and explore the consequences of co-treatingB. subtiliswith KKL-40 or KKL-55 and CuCl2. This co-treatment results in a rapid antibiotic influx, and, consequently to the stalling of ribosomes, translation, and bacterial growth. Simultaneously, massive amounts of copper accumulate in the cells, the toxic effects of which require a copper stress response to mitigate. However, such a response is averted by the stalled translation. Dual mechanism antibacterial agents are attractive because they are typically associated with slow emergence of resistance. A deep understanding of the complex interplay of KKL-40 and KKL-55 with metal ions will help to fully exploittrans-translation as an antibacterial target and to develop KKL-40 and KKL-55-based antibiotics into novel treatments for bacterial infections.