bluuebunny/crossref_metadata_2025 huggingface dataset:
All-Inside Bicruciate Ligament and Open Posterolateral Corner Reconstruction With Suture Augmentation
Authors: Gwilt Matthew S. , Groothoff Jonathan D. , Puckett Caleb D. , van der List Jelle P. , Fiegen Anthony P. , Waterman Brian R.
Published: February 2025

Background:

Multiligamentous knee injuries (MLKIs) are complex, often highly traumatic injuries that require broad surgical techniques to restore joint stability. This study outlines novel surgical techniques for posterolateral corner (PLC) reconstruction with suture augmentation in the context of bicruciate reconstruction.

Indications:

Reconstruction is indicated in complete tears of the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and PLC due to joint instability. Allografts augmented with suture augmentation may be implemented at surgeon and patient discretion for enhanced long-term graft viability and have the benefits of lower donor morbidity with allografts along with suture augmentation to prevent stretching of allografts.

Technique Description:

The ACL was reconstructed with all-inside tunnels and allograft usage, and the same was performed for single-bundle allograft PCL reconstruction. The PLC reconstruction consisted of a modified open Arciero technique in which the lateral collateral ligament (LCL) and popliteus were reconstructed using 1 continuous allograft, and additional suture augmentation was performed for the LCL to prevent stretching. The PCL was fixed first, after which the ACL and the PLC were fixed.

Results:

At 6 weeks postoperatively, the patient continues to progress in restoring passive range of motion and tolerance of partial weightbearing. Barring any potential complications, a full recovery is expected in approximately 9 to 12 months, as is consistent with the MLKI recovery protocol.

Discussion/Conclusion:

This study describes the surgical management of a Schenck knee dislocation class III-L injury with concomitant Arciero open PLC reconstruction in a 65-year-old man. The ideal strategy for reconstruction of MLKIs is unclear and warrants further evidence to help guide treatment in the context of concomitant injuries.

Patient Consent Disclosure Statement:

The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
Quantifying the impact of wind shear coefficient on annual energy production of coastal wind farm in balochistan, Pakistan
Authors: Yasir Jan , Yong Wang , Mutale Sydney , Saeed Ahmed , Ishwor KC
Published: February 2025

This study examines the wind shear coefficient (WSC) values at three coastal wind sites in the southern region of Balochistan, Pakistan: Pasni, Ormara, and Jiwani. These WSC values were obtained using 10-min collected wind speed data at elevations of 20, 50, and 80 meters above ground level (AGL). Extrapolation techniques were employed to estimate wind speeds at higher altitudes since wind measurements are typically recorded at lower heights due to cost and resource constraints. However, using a constant WSC value for extrapolation may lead to significant errors between extrapolated and actual wind speed measurements, impacting the energy output of wind turbines. To evaluate the effect of WSC on energy yield, the study employed power curves and frequency distributions using the RETScreen Software for 2MW and 1.5MW wind turbines. Additionally, wind power density was calculated using air density covering two years from November 2016 to August 2018. The overall mean WSC and air densities values were 0.076 and 1.166 for Pasni, 0.094 and1.170 for Jiwani, and 0.053 and1.173 for Ormara. The study further investigated the seasonal, monthly, and daily variations of WSC. For assessing wind resources at a height of 80 m, the study utilized wind Roses, wind power density, and Weibull parameters. These findings will be essential for planning and financing new projects in the electric energy generation sector.
A Bateson-Inspired Model for the Generation of Semantic Concepts From Sensory Data
Authors: de Miguel Rodríguez Jaime , Sancho Caparrini Fernando
Published: February 2025

Although neural-symbolic techniques for symbol grounding in sensory data have shown significant effectiveness, they still require substantial training. This article revisits symbolic-only approaches by introducing a new algorithm for creating hierarchical concept structures from spatial sensory data. The method is based on Bateson’s idea of difference as the fundamental element of concept formation. By leveraging this principle, the algorithm extracts atomic features from raw data through basic sequential comparisons within a stream of multivariate numerical values. Experiments carried out on a set of common objects indicate that the method can successfully discriminate and assimilate categories as needed without training. The results show that the model improves on the neural networks it has been tested against, which required more than 400 training examples for the same task. The results also show that the model can generate rich conceptual structures and human-like representations, which (i) facilitate high composability, (ii) support formal reasoning, (iii) inherently enable generalisation, and (iv) possess potential for generative behaviour. Consequently, this approach offers a compelling contribution to symbol grounding and neural-symbolic research by providing a seamless algorithm to bridge perception and conceptual knowledge.
Clinical-genomic profiling of MDS to inform allo-HSCT:Recommendations from an international panel on behalf of the EBMT
Authors: Gurnari Carmelo , Robin Marie , Adès Lionel , Aljurf Mahmoud , Almeida Antonio M , Duarte Fernando Barroso , Bernard Elsa , Cutler Corey S. , Della Porta Matteo Giovanni , de Witte Theo M , DeZern Amy E. , Drozd-Sokolowska Joanna , Duncavage Eric J , Fenaux Pierre , Gagelmann Nico , Garcia-Manero Guillermo , Haferlach Claudia , Haferlach Torsten , Hasserjian Robert P. , Hellstrom-Lindberg Eva S , Jacoby Meagan A , Kulasekararaj Austin G , Lindsley R. Coleman , Maciejewski Jaroslaw P. , Makishima Hideki , Malcovati Luca , Mittelman Moshe , Myhre Anders Eivind , Ogawa Seishi , Onida Francesco , Papaemmanuil Elli , Passweg Jakob R , Platzbecker Uwe , Pleyer Lisa , Raj Kavita , Santini Valeria , Sureda Anna , Tobiasson Magnus , Voso Maria Teresa , Yakoub-Agha Ibrahim , Zeidan Amer M. , Walter Matthew J , Kröger Nicolaus , McLornan Donal P , Cazzola Mario
Published: February 2025

For patients with myelodysplastic neoplasm/syndrome (MDS), allogeneic hematopoietic cell transplantation (allo-HCT) represents the only potentially curative treatment, capable of eradicating disease-related mutant hematopoietic cells and establishing normal donor hematopoiesis. Biologic-assignment clinical trials have indicated that in eligible patients, allo-HCT is associated with superior clinical outcomes compared to non-transplant therapy. However, this therapeutic option is only available to a subset of patients, and the outcome is influenced by multiple factors inherent to the patient, the MDS subtype, and the allo-HCT procedure itself. In 2017, the EBMT published recommendations for allo-HCT in MDS to guide practical decision-making. In the contemporary era, genomic profiling has become routine clinical practice in many centers, and the most recent classification systems include MDS entities that are defined by genetic abnormalities. In particular, the Molecular International Prognostic Scoring System (IPSS-M) offers more precise prognostication across all clinical endpoints and currently represents the standard tool for estimating patient survival in the absence of disease-modifying treatment. Evidence from multiple sources increasingly indicates that allo-HCT should be considered at the time of diagnosis in all eligible MDS patients. Therefore, genomic profiling for somatic mutations and testing for germline predisposition variants are integral to determining a patient's eligibility for transplantation. While all patients with higher-risk MDS are potential candidates for immediate transplantation, a subset of those with lower-risk MDS may also derive benefit from this procedure at an earlier disease stage. Comprehensive recommendations on behalf of an expert international panel for clinical practice and future clinical studies of relevance are presented.
Sex and gender differences during the lung lifespan: unveiling a pivotal impact
Authors: Tondo Pasquale , Meschi Claudia , Mantero Marco , Scioscia Giulia , Siciliano Matteo , Bradicich Matteo , Stella Giulia M.
Published: February 2025

Sex and gender differences significantly influence lung parenchyma development, beginning as early as the embryonic stages of human life. Although this association is well known in the clinical manifestations of some relevant pulmonary diseases, there is less data available regarding their effects on cell biological programmes across different stages of body development. A deep understanding of these mechanisms could help in defining preventive strategies tailored to a fully personalised approach to respiratory medicine. From this perspective, this review aims to analyse the influence of sex and gender on bronchoalveolar and vascular compartments from embryonic and neonatal stages through to adolescence, adulthood and elder age.
Electro-oxidation of synthetic lignin with linoleic acid and co-catalyst
Authors: Xie Bing , Tobimatsu Yuki , Takano Toshiyuki
Published: February 2025

Linoleic acid (LA) was investigated as an electron transfer catalyst in biomimetic lignin degradation with an electrolytic mediator system (EMS). Initial attempts of electro-oxidations of synthetic lignin, guaiacyl (G)-type dehydrogenation polymer (G-DHP), with LA alone at 0.8 V and 1.8 V, resulted in limited G-DHP conversion, suggesting that LA-mediated EMS is not effective when LA was used alone. Next, electro-oxidations of G-DHP with LA with O2-sparging as well as in the presence of co-catalysts, such as p-coumaric acid (PCA), tris(2,2′-bipyridine) iron(II) [Fe(bpy)3], and 1-hydroxybenzotriazole (HBT) were performed. The combined use of oxygen and co-catalysts appeared to be effective to promote G-DHP conversion. In particular, G-DHP conversion proceeded effectively in the electro-oxidation with LA/HBT at 0.6 V, as demonstrated by structural analysis of the electrolysis residues using nuclear magnetic resonance. HBT was also found to be a vital mediator when used alone in the present system. Overall, the combined use of oxygen and co-catalysts was essential for the EMS oxidation with LA, as reported in laccase mediator system (LMS) oxidation with LA.
Out-of-hospital cardiac arrest event after cancer diagnosis: a korean metropolitan cohort study
Authors: Lee Sun Young , Park Jeong Ho , Kim Yoonjic , Lee Jungah , Ro Young Sun , Song Kyoung Jun , Do Shin Sang
Published: February 2025

Background

The importance of assessing out-of-hospital cardiac arrest (OHCA) risk in cancer patients is increasing as cancer incidence rises in aging populations.

Objective

This study aimed to investigate the association between newly diagnosed cancer and OHCA risk using a metropolitan cohort from South Korea.

Methods

A population-based retrospective cohort study was conducted, linking the nationwide OHCA registry with the National Health Information Database. The study included adults aged 40 years or older, residing in Seoul between 2015 and 2018, with no history of cancer or OHCA. The main exposure was cancer development. The primary outcome was the occurrence of OHCA with medical cause. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated using a cause-specific hazard model considering death as a competing risk. Analyses stratified by age group and cancer type were also conducted.

Results

During a follow-up period of up to 4 years for 5,450,438 individuals, 174,785 participants developed cancer. The incidence rates of OHCA per 100,000 person-years were 54.0 in non-cancer and 145.0 in cancer groups, respectively. The aHR (95% CI) for OHCA associated with cancer development was 3.18 (2.97–3.41). The aHR (95% CI) for OHCA was highest in the 40–49 years of age group (7.52 [5.52–10.25]), followed by 50–59 years old (6.66 [5.56–7.97]) compared to older age groups. By cancer type, pancreatic, lung, biliary tract, and liver cancer were associated with a significantly increased risk of OHCA.

Conclusion

We found an association between newly diagnosed cancer and the occurrence of OHCA. Our findings underscore the importance of tailored risk assessments and proactive care planning for patients with cancer.
Mental health conditions of young ethiopians who use substances: a cross-sectional study in West Arsi zone
Authors: Shifa Jemal Ebrahim , Adams Jon , Demant Daniel
Published: February 2025

Background

Mental health conditions among young Ethiopians present a pressing public health concern, posing risks to their well-being and productivity. However, there is a limited understanding of the prevalence and associated factors among young people who use substances in the West Arsi Zone, Ethiopia. This study investigated the prevalence of mental health conditions and associated factors among young people who use substances in the West Arsi Zone, Ethiopia.

Methods

A community-based cross-sectional survey was conducted among 427 randomly selected young people aged 14–29 years in the West Arsi Zone of the Oromia region, Ethiopia from May 18, 2023, to September 22, 2023. Data were collected through structured interviewer-administered questionnaires. Logistic regression analysis was performed to determine the associations between the outcome and independent variables. Ethical approval was obtained from the University of Technology Sydney, Australia, and Madda Walabu University, Ethiopia.

Results

A total of 424 participants were included in the analysis, giving a response rate of 99.3%. The prevalence of mental health conditions was 47% (95% CI: 40.1%, 54.2%) among substance users and 26% (95% CI: 20.3%, 32.2%) among nonusers. In the final model, among substance users, participant sex, education level, family history of substance use, and family history of mental illness remained significantly associated with mental health conditions. Among nonusers, participant sex, perceived social support, and family history of mental illness remained significant predictors of mental health conditions.

Conclusions

Approximately half of the participants who used substances reported experiencing mental health conditions. This result highlights the need for appropriately focused interventions to address the growing challenges of mental health conditions and substance use among young people in Ethiopia.
Misconceptions, prejudice and social distance towards people with alcohol use disorders in China
Authors: Yang Qingyan , Rüsch Nicolas , Yang Kebing , Niu Yajuan , Xiao Yanxia , Zhou Yanfang , Tan Yunlong , Zhang Yi , Corrigan Patrick W. , Xu Ziyan
Published: February 2025

Purpose

Research from Western societies indicates pervasive public stigma against people with alcohol use disorders (AUDs). However, there is a lack of knowledge about the interactions between different components of stigma and their contribution to discriminatory behaviour towards individuals with AUDs within the Chinese cultural context. The aim of the present study was therefore to investigate the relationships of (mis-)conceptions, stereotypes, emotional reactions, perceived public stigma and their contribution to the desire for social distance among the Chinese adults.

Methods

(Mis-)conceptions, stereotypes, emotional responses, willingness to help and avoid, perceived stigma, and the desire for social distance from individuals with AUDs were assessed via a cross-sectional online survey with a sample of 1,100 adults from the Chinese population.

Results

Three-fourth of the participants recognised AUDs as mental illnesses, though 70% of the sample did not support health insurance coverage for the treatment of AUDs. A stronger desire for social distance was associated with greater recognition of alcohol use disorders as mental illnesses, heightened perceptions of dangerousness and personal responsibility, increased fear, and more willingness to avoid and withhold help, controlling for age, gender, education, employment, mental health service utilisation, and alcohol consumption. Fear fully mediated the effects of perceptions of dangerousness and responsibility on the desire for social distance.

Conclusions

To improve social integration for individuals with AUDs in China, culturally tailored anti-stigma programmes are needed to reduce negative attitudes and discriminatory behaviours among the Chinese population.
Effect of individual preventive practices on COVID-19 infection: an analysis of big data collected at PCR testing centers in Hiroshima, Japan
Authors: Nagata Tatsuhiro , Chimed-Ochir Odgerel , Yumiya Yui , Tanaka Junko , Kuwabara Masao , Kitahara Kanako , Ohge Hiroki , Kubo Tatsuhiko
Published: February 2025

Background

By May 7, 2023, COVID-19 had significantly impacted Japan, with 33,728,909 infections and 74,663 deaths reported. Hiroshima Prefecture alone recorded 816,354 cases and 1,373 deaths. The World Health Organization emphasized the importance of non-pharmaceutical interventions (NPIs) for preventing infectious disease transmission. Individual NPIs, such as hand hygiene, mask wearing, and avoiding crowded places, comprise simple everyday measures that individuals can personally undertake to protect themselves and others from contracting and transmitting respiratory infections. Japan’s Cabinet Secretariat also recommended these measures. Previous studies investigated the effectiveness of NPIs but often used relatively short data-collection periods. Starting in May 2020, Hiroshima Prefecture adopted a unique COVID-19 public health surveillance policy that used standardized data-collection forms. The present analysis examines the association between individual NPIs and COVID-19 infections.

Methods

Data were collected at 14 PCR centers from April 1, 2021, to August 3, 2022 in Hiroshima Prefecture. Participants filled out the J-SPEED-style COVID-19 form, which included items on demographic information, job type, symptoms, and NPIs. The data were analyzed for demographic information, NPI compliance rates, infection rates in relation to NPI adoption, and adjusted risk ratios, which were obtained using a multivariate log-binomial regression model.

Results

A total of 1,125,188 tested cases from 4th to 7th waves were analyzed. Among the study population, the infection rate increased through the various waves, with the highest rate (8.3%) seen in the 7th wave. Adults aged 40–49 were most commonly tested, while those aged 60–69 had the lowest infection rates. Wearing masks/washing hands was the most commonly followed NPI. Compliance with NPIs decreased through the waves. Individuals adhering to NPIs had lower infection rates. The number of preventive measures adopted was correlated with a reduced infection risk.

Conclusion

This analysis provides evidence to guide COVID-19 prevention policies. Simultaneous adherence to multiple NPIs proved more effective in preventing COVID-19. Despite changes in viral strains and the number of infected cases, hand washing/mask wearing, refraining from travel, and refraining from dining out significantly associated with a reduction of COVID-19 infection. Our findings are likely to be applicable in future infectious disease outbreaks.
Is there a difference between the incidence of subtypes of tibial plateau fractures between six different level 1, level 2 and level 3 trauma centers in the Netherlands?
Authors: van der Gaast N. , Jaarsma R. L. , Edwards M. J. R. , Doornberg J. N. , Hermans E. ,   the Trauma Platform Collaboration, Huitema Jellina , Assink Nick , IJpma Frank , Meijs Claartje , Duijff Jan , Hekma Edo , Moerbeek Patrick , de Bruin Marcel , Beetz Ivo , van Wijk Bart , Peperkamp Kirsten , Smeeing Diederik
Published: February 2025

Purposes

Tibial plateau fractures can present as different subtypes due to variation in patient characteristics and trauma mechanisms. Insight in the fracture pattern and classification is critical for adequate treatment.This study aims to assess the incidence of tibial plateau fracture subtypes among various levels of trauma centers in the Netherlands, to explore potential variations in fracture patterns and fracture classifications between these centers.

Methods

Over a one-year period data was collected from six Dutch trauma centers representing different levels of trauma care. Fractures were classified using both Schatzker and Luo’s systems. Interobserver agreement was calculated to evaluate the consistency of fracture classification among surgeons.

Results

We included 115 patients treated for a tibial plateau fracture across six different hospitals. The mean patient age was 54 years, ranging from 17 to 85 years. Differences in fracture incidence and mechanisms of injury across trauma centers were revealed; Level 1 trauma centers treated a higher proportion of high-energy trauma cases, predominantly Schatzker 6 fractures, while level 2 and 3 centers dealt with more low-energy traumas, particularly Schatzker 2 fractures. Interobserver agreement for both classification systems was moderate, indicating challenges in classifying tibial plateau fractures accurately.

Conclusion

This study sheds light on the diverse distribution of subtypes of tibial plateau fractures in Dutch trauma centers. Level 1 centers are treating younger, high-energy trauma patients, whereas level 2 and 3 centers handle more low-energy traumas, predominantly Schatzker 2 fractures.

Trial registration

METC Oost-Nederland: 2021–13,184.
Effect of holmium laser prostatectomy on surgical outcomes of primary bladder neck obstruction
Authors: Lee Hyomyoung , Jeong Hyun Ju , Choo Min Soo , Cho Sung Yong , Jeong Seong Jin , Oh Seung-June
Published: February 2025

Background

The purpose of this study is to evaluate the efficacy and safety of holmium laser prostatectomy in patients diagnosed with primary bladder neck obstruction (PBNO), compared with patients with benign prostatic hyperplasia (BPH).

Methods

We analyzed the databases of patients who underwent a holmium laser prostatectomy or enucleation of the prostate for PBNO and BPH between January 2018 and August 2022. PBNO was diagnosed primarily based on cystourethroscopic findings. Patients were followed up according to a regular protocol at 2 weeks, 3 mo, and 6 mo postoperatively.

Results

In total, 28 and 447 patients with PBNO and BPH, respectively, were identified. Preoperative urodynamic studies showed that detrusor underactivity was significantly more prevalent in the PBNO group (78.6%) than in the BPH group (57.5%) (p < 0.01). Both PBNO and BPH groups showed significant improvements in the total International Prostate Symptom Score, Overactive Bladder Symptom Score, and maximum flow rate at 6 mo postoperatively compared with the preoperative values (p < 0.01). Subjective satisfaction 6 mo after operation was not significantly different between the PBNO and BPH groups (p > 0.05). Complications in the PBNO group included recatheterization (n = 1, 3.5%), with no patients requiring blood transfusion or transurethral coagulation.

Conclusions

Holmium laser prostatectomy was effective and safe for patients with PBNO, with elevated subjective patient satisfaction.
Intratumoral microbiome: implications for immune modulation and innovative therapeutic strategies in cancer
Authors: Wang Na , Wu Si , Huang Lanxiang , Hu Yue , He Xin , He Jourong , Hu Ben , Xu Yaqi , Rong Yuan , Yuan Chunhui , Zeng Xiantao , Wang Fubing
Published: February 2025

Recent advancements have revealed the presence of a microbiome within tumor tissues, underscoring the crucial role of the tumor microbiome in the tumor ecosystem. This review delves into the characteristics of the intratumoral microbiome, underscoring its dual role in modulating immune responses and its potential to both suppress and promote tumor growth. We examine state-of-the-art techniques for detecting and analyzing intratumoral bacteria, with a particular focus on their interactions with the immune system and the resulting implications for cancer prognosis and treatment. By elucidating the intricate crosstalk between the intratumoral microbiome and the host immune system, we aim to uncover novel therapeutic strategies that enhance the efficacy of cancer treatments. Additionally, this review addresses the existing challenges and future prospects within this burgeoning field, advocating for the integration of microbiome research into comprehensive cancer therapy frameworks.

Graphical Abstract
EGF receptor in organ development, tissue homeostasis and regeneration
Authors: Tito Claudia , Masciarelli Silvia , Colotti Gianni , Fazi Francesco
Published: February 2025

The epidermal growth factor receptor (EGFR) is a protein embedded in the outer membrane of epithelial and mesenchymal cells, bone cells, blood and immune cells, heart cells, glia and stem neural cells. It belongs to the ErbB family, which includes three other related proteins: HER2/ErbB2/c-neu, HER3/ErbB3, and HER4/ErbB4. EGFR binds to seven known signaling molecules, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). This binding triggers the formation of receptor pairs (dimers), self-phosphorylation of EGFR, and the activation of several signaling pathways within the cell. These pathways influence various cellular processes like proliferation, differentiation, migration, and survival. EGFR plays a critical role in both development and tissue homeostasis, including tissue repair and adult organ regeneration. Altered expression of EGFR is linked to disruption of tissue homeostasis and various diseases, among which cancer. This review focuses on how EGFR contributes to the development of different organs like the placenta, gut, liver, bone, skin, brain, T cell regulation, pancreas, kidneys, mammary glands and lungs along with their associated pathologies. The involvement of EGFR in organ-specific branching morphogenesis process is also discussed. The level of EGFR activity and its impact vary across different organs. Factors as the affinity of its ligands, recycling or degradation processes, and transactivation by other proteins or environmental factors (such as heat stress and smoking) play a role in regulating EGFR activity. Understanding EGFR’s role and regulatory mechanisms holds promise for developing targeted therapeutic strategies.
Comprehensive molecular analysis of 26 newly established human pancreatic ductal adenocarcinoma cell lines reveals two clusters with variating drug sensitivities
Authors: Maeng Ju Eun , Kim Jae-Hyeon , Kim Soon-Chan , Yun Won-Gun , Kwon Wooil , Han Youngmin , Oh Do-Youn , Lee Sang Hyub , Jang Jin-Young , Ku Ja-Lok
Published: February 2025

Background

Pancreatic ductal adenocarcinoma (PDAC) is a malignant form of cancer with the worst survival rate and an extremely low rate of response to treatments. The development and molecular characterization of pancreatic cancer cell lines (PCCLs) are essential for studying the biology of highly aggressive pancreatic adenocarcinoma.

Methods

We applied whole exome sequencing (WES) and RNA-seq to identify molecular characteristics of 26 newly established PCCLs. Eighteen clinically relevant anti-cancer drugs were used to assess highly heterogeneous drug responses across the 26 cell lines.

Results

We confirmed that common driver mutations of PDAC were well retained in our cell lines through WES analysis. Transcriptomic analysis identified two representative clusters that correlated with responses to certain drugs. By using Moffitt’s classification method, the two clusters, C1 and C2, showed comparable expression patterns to “Basal-like” and “Classical” types, respectively. Drug screening results showed varying responses among different cell lines. In our cohort, C2 displayed greater sensitivity to anti-cancer drugs compared to C1. Furthermore, drugs targeting similar molecular pathways exhibited corresponding reactions among cell lines.

Conclusions

Our results underscored that transcriptomic features of pancreatic cancer correlate with drug sensitivity rather than with the effects of targeted drugs. Cell lines are useful in vitro model systems for studying the molecular mechanisms of PDAC.

Graphical Abstract
Making intersectoral stakeholder engagement in medicine quality research work: lessons from the STARmeds study in Indonesia
Authors: Hasnida Amalia , Bal Roland , Manninda Reise , Saputra Stanley , Nugrahani Yunita , Faradiba Faradiba , Kok Maarten Olivier
Published: February 2025

Background

Tackling falsified and substandard medicines requires intersectoral collaboration, impact-oriented research and the effective application of research findings. However, the best way to organize research and involve stakeholders from different sectors to ensure that results are used, remains unclear. We aimed to assess how intersectoral stakeholder engagement in research on medicine quality in Indonesia evolved, influenced the research processes and participants, and affected the uptake of the results.

Methods

For this prospective case study, we adopted an abductive approach inspired by contribution mapping and collaborative governance. We conducted 37 interviews with key informants, observed 24 meetings and analysed 121 documents to systematically map the engagement of stakeholders in a study on medicine quality, focusing on processes, influences and research-related contributions.

Results

From the outset, it proved feasible, but challenging, to effectively engage stakeholders in research into falsified and substandard medicines in Indonesia. After a cautious start and persistent efforts, stakeholders, such as the national medicine regulatory authority, became increasingly involved and developed a shared understanding of the need for intersectoral collaboration to tackle problems with medicine quality. While the research findings did not lead to a different estimate of the magnitude of the problem, the involvement of stakeholders was beneficial. After formalizing the collaboration, stakeholders provided data needed to study potential risk factors, product varieties and sales volumes, and contributed to decisions during the research and interpretation of the findings. Owing to frequent personnel changes and diverging priorities, stakeholder engagement required more effort than anticipated, and necessitated a strategic and adaptive approach. This approach had to account for the varying priorities and interests of stakeholders, the evolving framing of the problem, the implications of the findings and the nature of the field, where regulators must operate cautiously, balance interests and respond to critical incidents.

Conclusions

Intersectoral stakeholder engagement in medicine quality research is challenging but beneficial. Engagement contributed to building trust and relationships between researchers and stakeholders, helped forge an intersectoral network focused on medicine quality, exposed the medicine regulator to new methods, inspired stakeholders to take on new roles and make better use of existing data and furthered a research–policy partnership forum on pharmaceutical topics.
Helping the medicine go down: the role of the healthcare professional in a young person’s experience of achalasia, a rare oesophageal motility disorder
Authors: Capps Geena
Published: February 2025

Young patients can be uniquely vulnerable to the impacts of a rare disease, diagnosed in their critical years of identity formation, social development, and planning for the future. Drawing from my journey as both a rare disease patient and a medical student, this essay explores how the rare disease achalasia has shaped my life, alongside the experiences of another young patient, Isobel. Most importantly, this essay highlights the critical role that individual healthcare professionals play in shaping young patients’ experiences of their condition. Although diagnosing and managing rare diseases can be challenging due to limited research and awareness, my own experiences demonstrate that individual, intentional changes can have profound impacts. By engaging with and believing young patients, individual healthcare providers can reduce misdiagnoses, alleviate isolation and uncertainty, and ultimately, improve healthcare outcomes for young people with rare diseases.
An index of the initial blood pressure response to angiotensin II treatment and its association with clinical outcomes in vasodilatory shock
Authors: Leisman Daniel E. , Wieruszewski Patrick M. , Busse Laurence W. , Chawla Lakhmir S. , Hibbert Kathryn A. , Handisides Damian R. , Khanna Ashish K. , Ostermann Marlies , McCurdy Michael T. , Adams Christopher D. , Hodges Tony N. , Bellomo Rinaldo ,   the ATHOS-3 Investigators
Published: February 2025

Background

No standardized index exists to assess cardiovascular responsiveness to angiotensin-II. We hypothesized that a standardized index of initial blood pressure response to angiotensin-II treatment would be associated with clinical outcomes.

Methods

Using data from the Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we developed an Angiotensin-II Initial MAP Response Index of Treatment Effect (AIMRITE) defined as (MAP at hr1 – MAP at baseline)/study drug dose. We assessed AIMRITE continuously and, based on observed distributions, we additionally categorized patients as “responsive” or “resistant”, with responsiveness defined by an AIMRITE ≥ 0.90 mmHg/ng/kg/min. The primary clinical outcome was 28-day mortality. Secondary outcomes included days alive and vasopressor- or ventilator- or renal replacement therapy-free at day-7. Biological outcomes included baseline renin, angiotensin-II, and renin/angiotensin-II ratio, and their change at hr3.

Results

Of 158 placebo patients, as expected, 157 (99%) had AIMRITE < 0.90 mmHg/ng/kg/min (median AIMRITE 0.02; IQR − 0.03–0.10). In contrast, 163 patients assigned to angiotensin-II had a median AIMRITE of 1.43 mmHg/ng/kg/min (IQR 0.35–2.83). Of these, 97 (60%) were responsive (median AIMRITE 2.55; IQR 1.66–4.12) and 66 (40%) were resistant (median AIMRITE 0.24; IQR 0.10–0.52). Each 1.0-unit increase in AIMRITE was associated with a 16% lower hazard of death (HR: 0.84 per-mmHg/ng/kg/min [95% CI 0.74–0.95], p = 0.0062). Responsive patients had half the mortality hazard than resistant patients (HR: 0.50 [95% CI 0.32–0.78], p = 0.0026) and placebo patients (HR 0.58 [95% CI 0.40–0.86], p = 0.0064). Resistant patients had a similar mortality hazard to placebo (HR 1.17 [95% CI 0.80–1.72], p = 0.41). Compared to resistant patients, responsive patients had lower baseline renin and renin/angiotensin-II ratio, but a greater decrease in both at hr3. When stratified by baseline renin level, mortality was highest in placebo patients with high renin (69%) and angiotensin-II resistant patients with low renin (61%).

Conclusions

Among patients with catecholamine-refractory vasodilatory shock treated with angiotensin-II, the AIMRITE was associated with mortality at day-28. Responsive angiotensin-II patients had higher survival versus both angiotensin-II resistant patients and those treated with placebo plus standard vasopressors. This index may serve as a prognostic indicator and early identifier of patients most likely to benefit from angiotensin-II.
Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): statistical analysis plan for a randomised controlled trial
Authors: Ahmed Norin , Dehbi Hakim-Moulay , Freemantle Nick , Best Jonathan , Nash Philip S. , Ruffle James K. , Doig David , Werring David J.
Published: February 2025

Background

Atrial fibrillation causes one-fifth of ischaemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke can be delayed by concerns over intracranial haemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial haemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of ischaemic stroke recurrence, but the safety and efficacy of this approach has not been established. This article describes the statistical analysis plan for the OPTIMAS trial as an update to the published protocol. It was written prior to the end of patient follow-up, before database lock and thus while the outcome of the trial is still unknown.

Aim

The optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS) trial will investigate whether early treatment with a direct oral anticoagulant within 4 days of stroke onset is as effective as, or better than, delayed initiation at 7 to 14 days from onset.

Methods and design

OPTIMAS is a multicentre randomised controlled trial with blinded outcome adjudication. Participants with acute ischaemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomised 1:1 to early or delayed initiation. Here, we describe in detail the statistical aspects of OPTIMAS, including outcome measures, sample size calculation, general analysis principles, descriptive statistics, statistical models, and planned subgroup analyses.

Study outcomes

The primary outcome is a composite of recurrent stroke (ischaemic stroke or symptomatic intracranial haemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include each individual component of the composite outcome, major bleeding, functional status assessed by the modified Rankin Scale, ongoing anticoagulation, quality of life, health and social care resource use, and length of hospital stay.

Discussion

OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated acute ischaemic stroke.

Trial registrations

ISRCTN: 17,896,007; ClinicalTrials.gov: NCT03759938. Registered on November 30 2018.
Comparative effects of selenium-enriched lactobacilli and selenium-enriched yeast on performance, egg selenium enrichment, antioxidant capacity, and ileal microbiota in laying hens
Authors: Zhou Jianmin , Obianwuna Uchechukwu Edna , Zhang Longfei , Liu Yongli , Zhang Haijun , Qiu Kai , Wang Jing , Qi Guanghai , Wu Shugeng
Published: February 2025

Background

Organic selenium (Se) has gained recognition in poultry nutrition as a feed additive to boost production and Se deposition in eggs and tissues, owing to its high bioavailability, efficient tissue accumulation and minimal toxicity. Selenium-enriched yeast (SeY) is a well-established source, while selenium-enriched lactobacilli (SeL), a newer alternative, offers the added benefits of probiotics. This study examined the effects of SeY and SeL on egg quality, antioxidant capacity, Se deposition, and gut health in laying hens. After a two-week pre-treatment with a Se-deficient diet (SeD), 450 Hy-Line Brown laying hens (30-week-old) were assigned into five dietary groups with six replicates of 15 hens each. The groups included a SeD, SeD supplemented with 1.5 mg Se/kg from SeY (SeY15), or 1.5, 3.0, and 6.0 mg Se/kg from SeL (SeL15, SeL30, SeL60). The feeding trial lasted for 12 weeks.

Results

SeY15 and SeL15 improved the feed-to-egg ratio (P < 0.05) in the latter stages. Haugh units were significantly increased (P < 0.05) in the SeY15 and SeL30 groups, while darker yolk color (P < 0.05) was observed in the SeY15, SeL15, and SeL60 groups. All Se-supplemented diets increased Se content in whole eggs, albumen, and yolk (P < 0.05), while SeL groups showed a dose-dependent effect. Antioxidant enzyme activities increased, and MDA content decreased in the serum (P < 0.05), with SeY15 showing the highest GSH-Px levels (P < 0.05). SeL60 increased serum alkaline phosphatase and aspartate transaminase, and distorted the liver architecture (P < 0.05). Se-diets reduced concentrations of reactive oxygen species (ROS) in the ileum and liver (P < 0.05). SeL15 improved the ileal villus height-to-crypt depth ratio (P < 0.05). SeY15 and/or SeL15 up-regulated TXNRD1 and SEPHS1 mRNA while down-regulating SCLY expression in the liver. SeY15 altered ileal microbiota by increasing both beneficial and pathogenic bacteria, whereas SeL15 predominantly boosted beneficial bacteria.

Conclusion

SeL integrates the antioxidant properties of organic Se with the probiotic benefits on gut health, resulting in a performance-enhancing effect comparable to that of SeY. However, high SeL level (6.0 mg Se/kg) compromised productivity and metabolic functions while enhancing Se deposition.
The use of AI in epilepsy and its applications for people with intellectual disabilities: commentary
Authors: Milne-Ives Madison , Brownson-Smith Rosiered , Ananthakrishnan Ananya , Wang Yihan , Cong Cen , Winston Gavin P. , Meinert Edward
Published: February 2025

Epilepsy is one of the most common neurological disorders, affecting more than 50 million people worldwide. Management is particularly complex in individuals with intellectual disabilities, who are at a much higher risk of having severe seizures compared to the general population. People with intellectual disabilities are regularly excluded from epilepsy research, despite having significantly higher risks of negative health outcomes and early mortality. Recent advances in artificial intelligence (AI) have shown great potential in improving the diagnosis, monitoring, and management of epilepsy. Machine learning techniques have been used in analysing electroencephalography data for efficient seizure detection and prediction, as well as individualised treatment, which facilitates timely and customised intervention for individuals with epilepsy. Research and implementation of AI-based solutions for people with intellectual disabilities and epilepsy still remains limited due to a lack of accessible long-term clinical data for model training, difficulties in communicating with people with intellectual disabilities, and ethical challenges in ensuring the safety of the AI systems for this population. This paper presents an overview of recent AI applications in epilepsy and for people with intellectual disabilities, highlighting key challenges and the necessity of including people with intellectual disabilities in research on AI and epilepsy, and potential strategies to promote the development and use of AI applications for this vulnerable population. Given the prevalence and consequences associated with epilepsy in people with intellectual disabilities, the application of AI in epilepsy care has the potential to have a significant positive impact. To achieve this impact and to avoid increasing existing health inequity, there is an urgent need for greater inclusion of people with intellectual disabilities in research around the application of AI to epilepsy care and management.
Harnessing synergy: a holistic review of hybrid renewable energy systems and unified power quality conditioner integration
Authors: Samala Nagaraju , Bethi Chandramouli
Published: February 2025

This comprehensive review explores the growing importance of sustainable energy solutions, with a particular focus on the integration of solar and wind technologies within hybrid renewable energy systems. As the demand for clean energy increases, hybrid systems offer a promising solution to address energy security and environmental concerns. However, these systems face significant challenges, including intermittency issues and the complexity of integration into existing power grids. This paper examines the role of hybrid systems in mitigating these challenges and improving grid stability. Additionally, it highlights the role of the unified power quality conditioner in managing power quality and facilitating the integration of renewable sources into distribution networks. Drawing from over 395 research papers, the review offers valuable insights into the current state of the field and presents key directions for future research and practical applications.
Parametric modeling in cold extrusion of Al 2014 alloy using Taguchi method–based GRA
Authors: K. Anupama Francy , S. Venkata Sai Sudheer , N. Naga Krishna , Ch. Naveen Kumar , M. Venu
Published: February 2025

Cold extrusion is a fundamental metal forming technique and involves subjecting a block of material to high pressure as it passes over a die orifice of exact profile. The method remains influenced by numerous parameters including die angle, ram speed, lubricant type, extrusion ratio, die land height, workpiece geometry and material properties. Accurate estimation of extrusion force is critical, as it significantly impacts product quality. The current study explores the effects of die angle (15°, 25° and 35°), ram speed (1.5 mm/min, 3 mm/min and 4.5 mm/min) and lubricant (coconut oil, petroleum jelly and grease) on extrusion force, compressive strength, time and displacement. L27 orthogonal array design is used to conduct the tests, and aluminium 2014 alloys are chosen as the workpiece material. Analysis of variance (ANOVA) is employed to assess the significance of extrusion process parameters. Results depict that die angle has a greater impact on extrusion force compared to ram speed and lubricant. Multi-parameter optimization using Grey relation analysis with equal weighting for extrusion force, compressive strength, time and displacement have been considered. The optimal conditions for minimizing extrusion force, compressive strength and time, while maximizing displacement, are obtained at a die angle of 15°, ram speed of 3 mm/min and lubricant grease.
ADHD symptom trajectories across childhood and early adolescence and risk for hypomanic symptoms in young adulthood
Authors: Durdurak Buse Beril , Morales-Muñoz Isabel , Hosang Georgina Mayling , Marwaha Steven
Published: February 2025

Background

There is increasing evidence that childhood Attention-Deficit Hyperactivity Disorder (ADHD) elevates the risk of later Bipolar Spectrum Disorder (BD). However, it remains unclear whether different trajectories of ADHD symptoms confer differential risk for BD.

Methods

Data from the Avon Longitudinal Study of Parents and Children were available from 7811 children at age 8 years, 7435 at 10, 6798 at 13, and 1217 at 21–23 years. ADHD symptoms were assessed at 8, 10, and 13 years with the Development and Well-Being Assessment. Clinically significant hypomanic symptoms (CSHS) at 21–23 years were assessed using the Hypomania Symptom Checklist (HCL-32). Group trajectories of ADHD and its subtypes were estimated using latent class growth analysis. The prospective associations between different ADHD trajectories and CSHS were tested using logistic regression analysis.

Results

Persistently high, increasing, remitting, and persistently low ADHD symptom trajectories were identified for the three ADHD-related categories. Individuals with persistently high and increasing levels of ADHD symptoms had increased odds of CSHS compared to persistently low class. Sensitivity analyses validated these results. In separate analyses, persistently high levels of hyperactivity and inattentive, and increasing levels of inattentive symptoms were also independently associated with CSHS.

Conclusions

Young people with a longitudinal pattern of high and increasing ADHD symptoms are at higher risk for developing CSHS in young adulthood compared to individuals with low symptom patterns. These two trajectories in childhood and adolescence may represent distinct phenotypic risk profiles for subsequently developing BD and be clinically significant targets for prevention and treatment of BD.