bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study
Authors: Namayanja Cate , Eregu Egiru Emma Isaiah , Ongodia Paul , Okalebo Charles Benard , Okiror William , Okello Francis , Okibure Ambrose , Paasi George , Kakungulu Hellen , Grace Abongo , Muhindo Rita , Banks Duncan , Martin Chebet , Taylor-Robinson Simon , Olupot-Olupot Peter 
Published: June 2023

Abstract
Background
In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda.

Methods
This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the ‘Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda’ (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval.

Results
A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%).

Conclusion
During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.
Non-disclosure of developmental neurotoxicity studies obstructs the safety assessment of pesticides in the European Union
Authors: Mie Axel , Rudén Christina 
Published: June 2023

Abstract
Background
In the European Union (EU), the safety assessment of plant protection products relies to a large extent on toxicity studies commissioned by the companies producing them. By law, all performed studies must be included in the dossier submitted to authorities when applying for approval or renewal of the active substance.

Methods
For one type of toxicity, i.e. developmental neurotoxicity (DNT), we evaluated if studies submitted to the U.S. Environmental Protection Agency (EPA) had also been disclosed to EU authorities.

Results
We identified 35 DNT studies submitted to the U.S. EPA and with the corresponding EU dossiers available. Of these, 9 DNT studies (26%) were not disclosed by the pesticide company to EU authorities. For 7 of these studies, we have identified an actual or potential regulatory impact.

Conclusions
We conclude that (1) non-disclosure of DNT studies to EU authorities, in spite of clear legal requirements, seems to be a recurring phenomenon, (2) the non-disclosure may introduce a bias in the regulatory risk assessment, and (3) without full access to all performed toxicity studies, there can be no reliable safety evaluation of pesticides by EU authorities. We suggest that EU authorities should cross-check their data sets with their counterparts in other jurisdictions. In addition, applications for pesticide approval should be cross-checked against lists of studies performed at test facilities operating under Good Laboratory Practice (GLP), to ensure that all studies have been submitted to authorities. Furthermore, rules should be amended so that future studies should be commissioned by authorities rather than companies. This ensures the authorities’ knowledge of existing studies and prevents the economic interest of the company from influencing the design, performance, reporting and dissemination of studies. The rules or practices should also be revised to ensure that non-disclosure of toxicity studies carries a significant legal risk for pesticide companies.
Immunotherapy with Pru p 3 for food allergy to peach and non-specific lipid transfer protein: a systematic review
Authors: Rossi Carlo Maria , Lenti Marco Vincenzo , Merli Stefania , Licari Amelia , Marseglia Gian Luigi , Di Sabatino Antonio 
Published: May 2023

AbstractBackgroundNon-specific lipid-transfer protein (nsLTP) is a pan-allergen in the plant world, and a cause of significant concern as food allergen in the Mediterranean area, due to its general heat- and acid-resistance and hence the risk of severe allergic reactions.Pru p 3, the peach nsLTP, is considered the primary sensitizer to this allergen family and this allergy is usually persistent. Allergen-free diet and acute treatment of manifestations are the main recognized management goals in food allergy.Main textThe role of immunotherapy for treating food allergy in adult patients is controversial, but immunotherapy forPru p 3could potentially represent a relevant therapeutic strategy. We systematically searched databases for studies assessing the role of immunotherapyPru p 3in food allergy. Overall, nine studies were included. Immunotherapy withPru p 3appears to be effective and with a good safety profile in both peach and LTP allergy for some foods, such as peanut, in both RCT and real-life studies.ConclusionsImmunotherapy withPru p 3is a possible treatment option for food allergy to the peach LTP in the Mediterranean area, although at present have not reached routinary clinical practice. Larger studies are needed to confirm these findings and identify predictive biomarkers.
A bifunctional bortezomib-loaded porous nano-hydroxyapatite/alginate scaffold for simultaneous tumor inhibition and bone regeneration
Authors: Chen Jiafei , Wen Junru , Fu Yike , Li Xiang , Huang Jie , Guan Xiaoxu , Zhou Yi 
Published: June 2023

AbstractTreatments of osteolytic lesions due to malignant metastasis remain one of the major clinical challenges. The residual tumor cells after surgical resections and an acidic tumor microenvironment are unfavorable for osteogenic induction. Bortezomib (BTZ), a proteasome inhibitor used in chemotherapy, also has an osteogenic potential in concentration- and Ca2+-dependent manners. In this study, controlled delivery of BTZ in a novel bifunctional scaffold based on nano-hydroxyapatite (nHA) and sodium alginate (SA) nanocomposite, namely BTZ/nHA@SA, has been explored. By smartly adjusting microenvironments, a sustainable release of Ca2+ from nHA could be achieved, which was not only able to cross-link SA but also to regulate the switch between the dual functions of tumor inhibition and bone regeneration of BTZ to promote the osteogenic pathway. The freeze-dried BTZ/nHA@SA scaffold has excellent interconnectivity, is capable to promote the attachment and proliferation of mouse embryonic osteoblast precursor cells, as well as effectively induces breast cancer cell death in vitro. Furthermore, in vivo, studies using a mouse tumor model and a rabbit femoral defect model showed that the BTZ/nHA@SA scaffold could promote tumor ablation, and also enhance bone repair. Therefore, the BTZ/nHA@SA scaffold has unique dual functions of inhibiting tumor recurrence and promoting bone tissue regeneration simultaneously. This smart bi-functional scaffold offers a promising novel approach for oncological treatments by synchronously orchestrating tumor inhibition and tissue regeneration for the repair of neoplastic bone defects.
A qualitative exploration of barriers and facilitators to drug treatment services among people who inject drugs in West Virginia
Authors: Winiker Abigail K. , Schneider Kristin E. , Hamilton White Rebecca , O’Rourke Allison , Grieb Suzanne M. , Allen Sean T. 
Published: June 2023

Abstract
Background
The opioid overdose crisis in the USA has called for expanding access to evidence-based substance use treatment programs, yet many barriers limit the ability of people who inject drugs (PWID) to engage in these programs. Predominantly rural states have been disproportionately affected by the opioid overdose crisis while simultaneously facing diminished access to drug treatment services. The purpose of this study is to explore barriers and facilitators to engagement in drug treatment among PWID residing in a rural county in West Virginia.

Methods
From June to July 2018, in-depth interviews (n = 21) that explored drug treatment experiences among PWID were conducted in Cabell County, West Virginia. Participants were recruited from locations frequented by PWID such as local service providers and public parks. An iterative, modified constant comparison approach was used to code and synthesize interview data.

Results
Participants reported experiencing a variety of barriers to engaging in drug treatment, including low thresholds for dismissal, a lack of comprehensive support services, financial barriers, and inadequate management of withdrawal symptoms. However, participants also described several facilitators of treatment engagement and sustained recovery. These included the use of medications for opioid use disorder and supportive health care workers/program staff.

Conclusions
Our findings suggest that a range of barriers exist that may limit the abilities of rural PWID to successfully access and remain engaged in drug treatment in West Virginia. Improving the public health of rural PWID populations will require expanding access to evidence-based drug treatment programs that are tailored to participants’ individual needs.
A multi-phase approach for developing a conceptual model for human resources for health observatory (HRHO) toward integrating data and evidence: a case study of Iran
Authors: Najafpour Zhila , Arab Mohammad , Shayanfard Kamran 
Published: June 2023

Abstract
Background
Evidence-informed policymaking on human resources for health (HRH) has been directly linked with health system productivity, accessibility, equity, quality, and efficiency. The lack of reliable HRH data has made the task of planning the HRH more difficult in all settings.

Aim
This study aimed to develop a conceptual model to integrate HRH data and evidence.

Methods
The current study is a mixed-method study conducted in three phases: a rapid literature review, a qualitative phase, and an expert panel. Firstly, the electronic databases were searched up to 2018. Then, in the qualitative phase, semi-structured interviews with 50 experts were conducted. Data analysis was performed using the content analysis approach. After several expert panels, the draft of the model was validated with 15 key informants via two Delphi rounds.

Results
Our proposed model embraces all dominant elements on the demand and supply side of the HRH in Iran. The conceptual model consists of several components, including input (regulatory system, structure, functions), educational system (pre-service and in-service education), health labor market structure, process (technical infrastructure), and output (productions, policymaking process). We considered networking toward sustainable interaction among stakeholders, and also the existence of capacity to integrate HRH information and produce evidence for actions.

Conclusion
The proposed model can be considered a platform for developing a harmonized system based on the HRH data flow to evidence-informed decision-making via networking. We proposed a step-by-step approach for the sustainability of establishing a national human resources for health observatory (HRHO). The proposed HRHO model can be replicable and flexible enough to be used in different context domains.
Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer
Authors: Jin Juan , Li Bin , Cao Jianing , Li Ting , Zhang Jian , Cao Jun , Zhao Mingchuan , Wang Leiping , Wang Biyun , Tao Zhonghua , Hu Xichun 
Published: June 2023

Abstract
Background
Novel human epidermal growth factor receptor 2 (HER2)-directed antibody–drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear.

Methods
Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed.

Findings
First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer.

Conclusions
After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.
Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK–Sirt3 pathway in stress-induced hypertension
Authors: Wang Linping , Liu Tianfeng , Wang Xueping , Tong Lei , Chen Gaojun , Zhou Shumin , Zhang Haili , Liu Haisheng , Lu Wen , Wang Guohua , Zhang Shuai , Du Dongshu 
Published: June 2023

Abstract
Background
Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown.

Methods
The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor‐α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050.

Results
The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF‐α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α–treated N2a cells. AMPK activator A769662 upregulated AMPK–Sirt3 signaling pathway and consequently reversed TNF-α–induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p‐AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP.

Conclusions
This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK–Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.
Relevance of hazards in exoskeleton applications: a survey-based enquiry
Authors: Massardi Stefano , Pinto-Fernandez David , Babič Jan , Dežman Miha , Trošt Andrej , Grosu Victor , Lefeber Dirk , Rodriguez Carlos , Bessler Jule , Schaake Leendert , Prange-Lasonder Gerdienke , Veneman Jan F. , Torricelli Diego 
Published: May 2023

AbstractExoskeletons are becoming the reference technology for assistance and augmentation of human motor functions in a wide range of application domains. Unfortunately, the exponential growth of this sector has not been accompanied by a rigorous risk assessment (RA) process, which is necessary to identify the major aspects concerning the safety and impact of this new technology on humans. This situation may seriously hamper the market uptake of new products. This paper presents the results of a survey that was circulated to understand how hazards are considered by exoskeleton users, from research and industry perspectives. Our analysis aimed to identify the perceived occurrence and the impact of a sample of generic hazards, as well as to collect suggestions and general opinions from the respondents that can serve as a reference for more targeted RA. Our results identified a list of relevant hazards for exoskeletons. Among them, misalignments and unintended device motion were perceived as key aspects for exoskeletons’ safety. This survey aims to represent a first attempt in recording overall feedback from the community and contribute to future RAs and the identification of better mitigation strategies in the field.
Prevalence of udder pathogens in milk samples from Norwegian dairy cows recorded in a national database in 2019 and 2020
Authors: Smistad Marit , Bakka Haakon Christopher , Sølverød Liv , Jørgensen Hannah Joan , Wolff Cecilia 
Published: June 2023

Abstract
Background
Identification of aetiological agents of mastitis in dairy cattle is important for herd management of udder health. In Norway, results from mastitis diagnostics are systematically recorded in a central database, so that the dairy industry can follow trends in the recorded frequency of udder pathogens and antimicrobial resistance patterns at national level. However, bacteriological testing of milk samples is based on voluntary sampling, and data are therefore subject to some bias. The aim of this study was to examine the prevalence of udder pathogens in Norwegian dairy cows by analysing data from the national routine mastitis diagnostics and to explore how routines for sampling and diagnostic interpretations may affect the apparent prevalence of different bacterial pathogens. We also assessed associations between udder pathogen findings and the barn- and milking systems of the herds.

Results
The most frequently detected major udder pathogens among all milk samples submitted for bacterial culture (n = 36,431) were Staphylococcus aureus (24.5%), Streptococcus dysgalactiae (13.3%) and Streptococcus uberis (9.0%). In the subset of samples from clinical mastitis (n = 7598); Escherichia coli (14.5%) was the second most frequently detected pathogen following S. aureus (27.1%). Staphylococcus epidermidis (10.0%), Corynebacterium bovis (9.4%), and Staphylococcus chromogenes (6.0%) dominated among the minor udder pathogens. Non-aureus staphylococci as a group, identified in 39% of the sampling events, was the most frequently identified udder pathogen in Norway. By using different definitions of cow-level bacterial diagnoses, the distribution of minor udder pathogens changed.
Several udder pathogens were associated with the barn- and milking system but the associations were reduced in strength when data were analysed from farms with a comparable herd size. S. aureus was associated with tiestall housing, E. coli and S. dysgalactiae were associated with freestall housing, and S. epidermidis was associated with automatic milking systems.
Only 2.5% of the 10,675 tested S. aureus isolates were resistant to benzylpenicillin. Among the 2153 tested non-aureus staphylococci, altogether 34% were resistant to benzylpenicillin.

Conclusions
This study presents the recorded prevalence of udder pathogens in Norway over a two-year period and assesses the possible impact of the sampling strategies, diagnostic methods and diagnostic criteria utilized in Norway, as well as associations with different housing and milking systems. The national database with records of results from routine mastitis diagnostics in Norway provides valuable information about the aetiology of bovine mastitis at population level and can reveal shifts in the distribution and occurrence of udder pathogens.
Culture of vibrating microtome tissue slices as a 3D model in biomedical research
Authors: Siwczak Fatina , Hiller Charlotte , Pfannkuche Helga , Schneider Marlon R. 
Published: June 2023

AbstractThe basic idea behind the use of 3-dimensional (3D) tools in biomedical research is the assumption that the structures under study will perform at the best in vitro if cultivated in an environment that is as similar as possible to their natural in vivo embedding. Tissue slicing fulfills this premise optimally: it is an accessible, unexpensive, imaging-friendly, and technically rather simple procedure which largely preserves the extracellular matrix and includes all or at least most supportive cell types in the correct tissue architecture with little cellular damage. Vibrating microtomes (vibratomes) can further improve the quality of the generated slices because of the lateral, saw-like movement of the blade, which significantly reduces tissue pulling or tearing compared to a straight cut. In spite of its obvious advantages, vibrating microtome slices are rather underrepresented in the current discussion on 3D tools, which is dominated by methods as organoids, organ-on-chip and bioprinting. Here, we review the development of vibrating microtome tissue slices, the major technical features underlying its application, as well as its current use and potential advances, such as a combination with novel microfluidic culture chambers. Once fully integrated into the 3D toolbox, tissue slices may significantly contribute to decrease the use of laboratory animals and is likely to have a strong impact on basic and translational research as well as drug screening.