bluuebunny/crossref_metadata_2025_split huggingface dataset:
Launch sequencing of pharmaceuticals with multiple therapeutic indications: evidence from seven countries
Authors: Mills Mackenzie , Michaeli Daniel , Miracolo Aurelio , Kanavos Panos 
Published: February 2023

Abstract
Background
New medicines are increasingly being identified as efficacious across multiple indications. The impact of current pricing and reimbursement policies on launch decisions across these indications remains unclear.

Objective
This paper, first, maps marketing authorisation and HTA coverage recommendation sequences of multi-indication medicines across Germany, France, England, Scotland, Canada, Australia, and the USA, and, second, evaluates the clinical characteristics, clinical development time and coverage recommendation time of multi-indication medicines, drawing comparisons between the first and subsequent indications of an approved molecule.

Methods
Medicine approvals by the Food and Drug Administration between 2009–2019 were screened to identify multi-indication products with approved oncology indications. Data on clinical trial characteristics, clinical performance and HTA outcomes were extracted from publicly available regulatory approval and HTA reports.

Results
Relative to subsequent indications, first indications were more likely to receive conditional marketing authorisation, have an orphan designation, have a single arm phase II pivotal trial and lower MCBS score. Subsequent indications had faster HTA coverage recommendation times in England and Canada. While the majority of first indications received HTA coverage recommendations across all settings, the proportion of subsequent indications with HTA coverage recommendations was lower and uptake varied considerably across settings.

Conclusions
Discordance in the value of first versus subsequent indications can pose major challenges in systems that define price based on the initial indication. Current pricing and reimbursement systems generate significant fragmentation in the approval and availability of multi-indication products across settings.
Heart failure with preserved ejection fraction and atrial fibrillation: recent advances and open questions
Authors: Fauchier Laurent , Bisson Arnaud , Bodin Alexandre 
Published: February 2023

AbstractAtrial fibrillation (AF) and heart failure (HF) are frequently associated and can be caused or exacerbated by each other through different mechanisms. AF is particularly common in patients with heart failure with preserved ejection fraction (HFpEF) defined as left ventricular ejection fraction (LVEF) ≥ 50%, with a prevalence ranging around 40–60%.In two recent trials, treatment with SGLT2 inhibitors resulted in a lower risk of worsening heart failure or cardiovascular death than placebo in patients with HFpEF, and SGLT2 inhibitors similarly improved prognosis whether patients had AF or not at enrolment. Analyses for subgroups of interest of patients with HFpEF likely to be at higher risk of AF (particularly those with older age or obesity) similarly indicated a consistent benefit with SGLT2 inhibitors. That subgroup in patients with HFpEF is those with a history of previous HF with LVEF ≤ 40%. The EAST-AFNET 4 trial indicated that early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with recent AF and cardiovascular conditions, including those with HF. In patients with AF and HF included in the CABANA trial, catheter ablation produced marked improvements in survival, freedom from AF recurrence, and quality of life compared to drug therapy. When strategies aiming at rhythm control eventually fail in patients with AF and HFpEF, a strategy of rate control with atrioventricular junction ablation and cardiac resynchronisation should be discussed since it may also reduce all-cause mortality.Finally, and in conclusion, considering that patients with AF and HFpEF may have a variety of cardiovascular and non-cardiovascular additional comorbidities, they are among those likely to have the highest clinical benefit being adherent to a holistic and integrated care management of AF following the ABC (Atrial Fibrillation Better Care) pathway.
Understanding work-related travel and its relation to malaria occurrence in Thailand using geospatial maximum entropy modelling
Authors: Memarsadeghi Natalie , Stewart Kathleen , Li Yao , Sornsakrin Siriporn , Uthaimongkol Nichaphat , Kuntawunginn Worachet , Pidtana Kingkan , Raseebut Chatree , Wojnarski Mariusz , Jongsakul Krisada , Jearakul Danai , Waters Norman , Spring Michele , Takala-Harrison Shannon 
Published: February 2023

Abstract
Background
Estimating malaria risk associated with work locations and travel across a region provides local health officials with information useful to mitigate possible transmission paths of malaria as well as understand the risk of exposure for local populations. This study investigates malaria exposure risk by analysing the spatial pattern of malaria cases (primarily Plasmodium vivax) in Ubon Ratchathani and Sisaket provinces of Thailand, using an ecological niche model and machine learning to estimate the species distribution of P. vivax malaria and compare the resulting niche areas with occupation type, work locations, and work-related travel routes.

Methods
A maximum entropy model was trained to estimate the distribution of P. vivax malaria for a period between January 2019 and April 2020, capturing estimated malaria occurrence for these provinces. A random simulation workflow was developed to make region-based case data usable for the machine learning approach. This workflow was used to generate a probability surface for the ecological niche regions. The resulting niche regions were analysed by occupation type, home and work locations, and work-related travel routes to determine the relationship between these variables and malaria occurrence. A one-way analysis of variance (ANOVA) test was used to understand the relationship between predicted malaria occurrence and occupation type.

Results
The MaxEnt (full name) model indicated a higher occurrence of P. vivax malaria in forested areas especially along the Thailand–Cambodia border. The ANOVA results showed a statistically significant difference between average malaria risk values predicted from the ecological niche model for rubber plantation workers and farmers, the two main occupation groups in the study. The rubber plantation workers were found to be at higher risk of exposure to malaria than farmers in Ubon Ratchathani and Sisaket provinces of Thailand.

Conclusion
The results from this study point to occupation-related factors such as work location and the routes travelled to work, being risk factors in malaria occurrence and possible contributors to transmission among local populations.
Pre-exposure prophylaxis (PrEP) for HIV prevention among people who inject drugs: a global mapping of service delivery
Authors: Shaw Graham , Schaefer Robin , Schmidt Heather-Marie A , Madden Annie , Chang Judy , Mozalevskis Antons , Msimanga-Radebe Busisiwe , Mangadan Konath Nabeel , Verster Annette , Baggaley Rachel , Rodolph Michelle , Macdonald Virginia 
Published: February 2023

Abstract
Background
The World Health Organization (WHO) recommends oral pre-exposure prophylaxis (PrEP) for all people at substantial risk of HIV as part of combination prevention. The extent to which this recommendation has been implemented globally for people who inject drugs is unclear. This study mapped global service delivery of PrEP for people who inject drugs.

Methods
Between October and December 2021, a desk review was conducted to obtain information on PrEP services for people who inject drugs from drug user-led networks and HIV, harm reduction, and human rights stakeholders. Websites of organizations involved in HIV prevention or services for people who inject drugs were searched. Models of service delivery were described in terms of service location, provider, and package.

Results
PrEP services were identified in 27 countries (15 high-income). PrEP delivery models varied within and across countries. In most services, PrEP services were implemented in healthcare clinics without direct links to other harm reduction services. In three countries, PrEP services were also provided at methadone clinics. In 14 countries, PrEP services were provided through community-based models (outside of clinic settings) that commonly involved peer-led outreach activities and integration with harm reduction services.

Conclusions
This study indicates limited PrEP availability for people who inject drugs. There is potential to expand PrEP services for people who inject drugs within harm reduction programs, notably through community-based and peer-led services. PrEP should never be offered instead of evidence-based harm reduction programs for people who inject drugs; however, it could be offered as an additional HIV prevention choice as part of a comprehensive harm reduction program.
Changes in cognitive function, synaptic structure and protein expression after long-term exposure to 2.856 and 9.375 GHz microwaves
Authors: Wang Hui , Liu Yu , Sun Yunbo , Dong Ji , Xu Xinping , Wang Haoyu , Zhao Xuelong , Zhang Jing , Yao Binwei , Zhao Li , Liu Shuchen , Peng Ruiyun 
Published: February 2023

AbstractHealth hazards from long-term exposure to microwaves, especially the potential for changes in cognitive function, are attracting increasing attention. The purpose of this study was to explore changes in spatial learning and memory and synaptic structure and to identify differentially expressed proteins in hippocampal and serum exosomes after long-term exposure to 2.856 and 9.375 GHz microwaves. The spatial reference learning and memory abilities and the structure of the DG area were impaired after long-term exposure to 2.856 and 9.375 GHz microwaves. We also found a decrease in SNARE-associated protein Snapin and an increase in charged multivesicular body protein 3 in the hippocampus, indicating that synaptic vesicle recycling was inhibited and consistent with the large increase in presynaptic vesicles. Moreover, we investigated changes in serum exosomes after 2.856 and 9.375 GHz microwave exposure. The results showed that long-term 2.856 GHz microwave exposure could induce a decrease in calcineurin subunit B type 1 and cytochrome b-245 heavy chain in serum exosomes. While the 9.375 GHz long-term microwave exposure induced a decrease in proteins (synaptophysin-like 1, ankyrin repeat and rabankyrin-5, protein phosphatase 3 catalytic subunit alpha and sodium-dependent phosphate transporter 1) in serum exosomes. In summary, long-term microwave exposure could lead to different degrees of spatial learning and memory impairment, EEG disturbance, structural damage to the hippocampus, and differential expression of hippocampal tissue and serum exosomes.
A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology
Authors: Gomes Patrícia A. , Bodo Cristian , Nogueras-Ortiz Carlos , Samiotaki Martina , Chen Minghao , Soares-Cunha Carina , Silva Joana M. , Coimbra Bárbara , Stamatakis George , Santos Liliana , Panayotou George , Tzouanou Foteini , Waites Clarissa L. , Gatsogiannis Christos , Sousa Nuno , Kapogiannis Dimitrios , Costa-Silva Bruno , Sotiropoulos Ioannis 
Published: February 2023

Abstract
Background
Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles.

Methods
Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles.

Results
We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals’ exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer’s disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology.

Conclusions
Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology.
Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity
Authors: Tassan Mazzocco Margherita , Murtaj Valentina , Martins Daniel , Schellino Roberta , Coliva Angela , Toninelli Elisa , Vercelli Alessandro , Turkheimer Federico , Belloli Sara , Moresco Rosa Maria 
Published: February 2023

Abstract
Background
One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.

Methods
The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.

Results
MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK—compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.

Conclusions
Overall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.
Pediatric combined hepatocellular-cholangiocarcinoma (cHCC-CC) with neuroendocrine features: distinguishing genetic alterations detected by chromosomal microarray
Authors: Wilhelm Alyeesha B. , Cunningham Arwyn G. , Kassab Cynthia , Fitz Eric C. , Dong Jianli , Radhakrishnan Ravi S. , Ranganathan Sarangarajan , Tan Dongfeng , Stevenson Heather L. 
Published: February 2023

Abstract
Background
Liver tumors exhibiting hepatocellular, cholangiocarcinoma, and neuroendocrine features are extremely rare, with only five cases reported in the literature.

Case presentation
We present an unusual case of a combined hepatocellular-cholangiocarcinoma (cHCC-CC) with neuroendocrine features in a pediatric patient. A 16-year-old presented with abdominal pain and a 21.0 cm mass in the right hepatic lobe with extension into the left lobe. Histology showed a poorly differentiated tumor with a solid, tubuloglandular, and microcystic architecture. Immunohistochemistry results were negative for hepatic markers, positive for markers of biliary differentiation, and positive for neuroendocrine differentiation. The neoplasm was reviewed at several institutions with differing diagnoses. Single nucleotide polymorphism (SNP) chromosomal microarray (CMA) showed large deletions within chromosomes 6q and 13q in both the hepatocellular-like areas and the cholangiocarcinoma-like areas, with additional large deletions in the cholangiocarcinoma-like areas, supporting origin from hepatocellular carcinoma. The final diagnosis was a cHCC-CC with neuroendocrine features.

Conclusions
Diagnosis of cHCC-CCs relies predominately on histomorphology, as per the 2018 International Consensus Group on the nomenclature of cHCC-CC. These findings in this case support that the pathological classification of these lesions be based on molecular data, which could better direct treatment. Further classification of cHCC-CCs and determination of their clinicopathological relevance will require more interobserver consistency and continued molecular profiling of these lesions.
Traditional Chinese medicine for colorectal cancer treatment: potential targets and mechanisms of action
Authors: Chen Jin-Fang , Wu Shi-Wei , Shi Zi-Man , Hu Bing 
Published: February 2023

AbstractColorectal cancer (CRC) is a disease with complex pathogenesis, it is prone to metastasis, and its development involves abnormalities in multiple signaling pathways. Surgery, chemotherapy, radiotherapy, target therapy, and immunotherapy remain the main treatments for CRC, but improvement in the overall survival rate and quality of life is urgently needed. Traditional Chinese medicine (TCM) has a long history of preventing and treating CRC. It could affect CRC cell proliferation, apoptosis, cell cycle, migration, invasion, autophagy, epithelial–mesenchymal transition, angiogenesis, and chemoresistance by regulating multiple signaling pathways, such as PI3K/Akt, NF-κB, MAPK, Wnt/β-catenin, epidermal growth factor receptors, p53, TGF-β, mTOR, Hedgehog, and immunomodulatory signaling pathways. In this paper, the main signaling pathways and potential targets of TCM and its active ingredients in the treatment of CRC were systematically summarized, providing a theoretical basis for treating CRC with TCM and new ideas for further exploring the pathogenesis of CRC and developing new anti-CRC drugs.
Prophylactic treatment with oral azithromycin in cancer patients during the COVID-19 pandemic (OnCoVID): a randomized, single-blinded, placebo-controlled phase 2 trial
Authors: Mair Maximilian J. , Maj-Hes Agnieszka , Nussbaumer-Pröll Alina , Puhr Rainer , Christenheit Agnieszka , Troch Marlene , Puhr Hannah C. , Starzer Angelika M. , Steindl Ariane , Eberl Sabine , Haslacher Helmuth , Perkmann Thomas , Minichsdorfer Christoph , Prager Gerald W. , Lamm Wolfgang W. , Berghoff Anna S. , Kiesewetter Barbara , Zeitlinger Markus , Preusser Matthias , Raderer Markus 
Published: February 2023

Abstract
Background
Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial.

Methods
This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation.

Results
In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios.

Conclusion
Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients.
ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.