bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis identifies CXCL11 as an immune-related prognostic biomarker correlated with cell proliferation and immune infiltration in multiple myeloma microenvironment
Authors: Wang Huizhong , Shao Ruonan , Liu Wenjian , Peng Shumei , Bai Shenrui , Fu Bibo , Zhao Congling , Lu Yue 
Published: May 2022

Abstract
Purpose
The interaction between tumor cells and tumor microenvironment (TME) has an important impact on progression and prognosis of multiple myeloma (MM), and has been proven to be promising therapeutic targets. This study intended to explore the relationship between TME and prognosis and identify valuable biomarkers of MM.

Methods
The transcriptomic and clinical information of MM retrieved from the Gene Expression Omnibus (GEO) were used to establish the model. The curve of Kaplan–Meier survival and the time-dependent receiver operating characteristic (ROC) were used to appraise the predictive ability. A nomogram was established for clinical application. Furthermore, the CIBERSORT algorithm was used to investigate the relation between IRGPI with the infiltration of immune cells. We also used histology, as well as in vitro and in vivo experiments to validate these findings.

Results
The results demonstrated an immune-related gene-based prognostic index (IRGPI) combined with clinical information. Patients were separated into high- and low-risk groups based on risk score, which had significantly difference in survival status and immune infiltrations. Furthermore, we identified CXCL11 as a key factor, which positively promotes the progression of MM and correlate with macrophage M2-like polarization and tumor immune cells infiltration.

Conclusion
Our findings suggest the IRGPI significantly demonstrate the differential prognosis and prediction of immune cells infiltration. It provides some insights into the complex interaction between myeloma tumor cells and the TME, as well as in the development of a novel biomarker target for anti-MM therapy.
Impact of the COVID-19 pandemic on malaria cases in health facilities in northern Ghana: a retrospective analysis of routine surveillance data
Authors: Heuschen Anna-Katharina , Abdul-Mumin Alhassan , Adokiya Martin , Lu Guangyu , Jahn Albrecht , Razum Oliver , Winkler Volker , Müller Olaf 
Published: May 2022

Abstract
Background
The COVID-19 pandemic and its collateral damage severely impact health systems globally and risk to worsen the malaria situation in endemic countries. Malaria is a leading cause of morbidity and mortality in Ghana. This study aims to describe the potential effects of the COVID-19 pandemic on malaria cases observed in health facilities in the Northern Region of Ghana.

Methods
Monthly routine data from the District Health Information Management System II (DHIMS2) of the Northern Region of Ghana were analysed. Overall outpatient department visits (OPD) and malaria case rates from the years 2015–2019 were compared to the corresponding data of the year 2020.

Results
Compared to the corresponding periods of the years 2015–2019, overall visits and malaria cases in paediatric and adult OPDs in northern Ghana decreased in March and April 2020, when major movement and social restrictions were implemented in response to the pandemic. Cases slightly rebounded afterwards in 2020, but stayed below the average of the previous years. Malaria data from inpatient departments showed a similar but more pronounced trend when compared to OPDs. In pregnant women, however, malaria cases in OPDs increased after the first COVID-19 wave.

Conclusions
The findings from this study show that the COVID-19 pandemic affects the malaria burden in health facilities of northern Ghana, with declines in inpatient and outpatient rates except for pregnant women. They may have experienced reduced access to insecticide-treated nets and intermittent preventive malaria treatment in pregnancy, resulting in subsequent higher malaria morbidity. Further data, particularly from community-based studies and ideally complemented by qualitative research, are needed to fully determine the impact of the pandemic on the malaria situation in Africa.
A cost analysis of the diagnosis and treatment of malaria at public health facilities and communities in three districts in Rwanda
Authors: Masimbi Ornella , Schurer Janna M. , Rafferty Ellen , Ndahimana Jean D’ Amour , Amuguni J. Hellen 
Published: May 2022

Abstract
Background
Malaria is a potentially fatal disease spread by the bites of Plasmodium-infected Anopheles mosquitoes. Despite long-term efforts to control malaria in Rwanda, malaria incidence increased from 48 to 403 cases/1000 individuals between 2012 and 2016. The diagnosis and treatment of malaria occurs at multiple levels, but the costs of these activities are not well understood. This research was conducted to estimate the direct medical costs incurred by the Ministry of Health in diagnosing and treating malaria in three districts of Rwanda in 2018.

Methods
A cross-sectional and retrospective costing analysis was conducted in three districts that represented low (5–200 cases per 1000 individuals), moderate (> 200–400 cases per 1000 individuals), and high (> 400 cases per 1000 individuals) endemicity regions. Data on malaria cases managed at three healthcare levels (community, health centre, district hospital) was obtained from national databases. The direct medical costs of cases per malaria severity (‘simple malaria’, ‘simple malaria with minor digestive symptoms’, and ‘severe malaria’) were calculated based on the minimum package of health services provided. Total costs for each of the three districts were also calculated.

Results
A total of 298,381 malaria cases were recorded in Burera, Kirehe, and Southern Kayonza districts in 2018. The average unit cost per case ranged from USD 1.36 (for simple malaria at the community level) to USD 92.80 (for severe malaria with cerebral complications at district hospitals). Simple malaria cases managed at health centres and district hospitals were more than two-fold (USD 2.99–USD 3.00) and more than eight-fold (USD 12.10–USD 12.12) higher, respectively, than those managed in the community (USD 1.36). Overall, the Ministry of Health incurred USD 645,647.68 in direct medical costs related to malaria management across the three districts in 2018. Changes in disease rates from different endemicity regions and costs of anti-malarial oral medications significantly impacted the study results.

Conclusion
In Rwanda, severe malaria results in much higher expenses compared to other malaria types. Prompt diagnosis and appropriate treatment are crucial to prevent the progression of simple malaria to severe malaria, to reduce Ministry of Health malaria expenditures, and to reduce community transmission.
Exo-erythrocytic development of Plasmodium matutinum (lineage pLINN1) in a naturally infected roadkill fieldfare Turdus pilaris
Authors: Pendl Helene , Hernández-Lara Carolina , Kubacki Jakub , Borel Nicole , Albini Sarah , Valkiūnas Gediminas 
Published: May 2022

AbstractBackgroundSpecies ofPlasmodium(Haemosporida, Plasmodiidae) are remarkably diverse haemoparasites. Information on genetic diversity of avian malaria pathogens has been accumulating rapidly, however exo-erythrocytic development of these organisms remains insufficiently addressed. This is unfortunate because, contrary toPlasmodiumspecies parasitizing mammals, the avian malaria parasites undergo several cycles of exo-erythrocytic development, often resulting in damage of various organs. Insufficient knowledge on the exo-erythrocytic development in most describedPlasmodiumspecies precludes the understanding of mechanisms of virulence during avian malaria. This study extends information on the exo-erythrocytic development of bird malaria parasites.MethodsA roadkill fieldfare (Turdus pilaris) was sampled in Switzerland and examined using pathologic, cytologic, histologic, molecular and microbiologic methods. Avian malaria was diagnosed, and erythrocytic and exo-erythrocytic stages of the parasite were identified using morphologic characteristics and barcode DNA sequences of the cytochromebgene. The species-specific characteristics were described, illustrated, and pathologic changes were reported.ResultsAn infection withPlasmodium matutinumlineage pLINN1 was detected. Parasitaemia was relatively low (0.3%), with all erythrocytic stages (trophozoites, meronts and gametocytes) present in blood films. Most growing erythrocytic meronts were markedly vacuolated, which is a species-specific feature of this parasite’s development. Phanerozoites at different stages of maturation were seen in leukocytes, macrophages, and capillary endothelial cells in most organs examined; they were particularly numerous in the brain. Like the erythrocytic meronts, growing phanerozoites were markedly vacuolated. Conspicuous exo-erythrocytic development and maturation in leucocytes suggests that this fieldfare was not adapted to the infection and the parasite was capable to escape from cellular immunity.ConclusionsThis is the first report of exo-erythrocytic development of the malaria parasite lineage pLINN1 during single infection and the first report of this lineage in the fieldfare. The findings of multiple phanerozoites in brain, skeletal muscle, and eye tissue in combination with signs of vascular blockage and thrombus formation strongly suggest an impaired vision and neuromuscular responsiveness as cause of the unexpected collision with a slowly moving car. Further studies on exo-erythrocytic stages of haemosporidian parasites are pivotal to understand the true level of populational damage of avian malaria in wild birds.
Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside
Authors: Khandelwal Akash , Arez Francisca , Alves Paula M. , Badolo Lassina , Brito Catarina , Fischli Christoph , Fontinha Diana , Oeuvray Claude , Prudêncio Miguel , Rottmann Matthias , Wilkins Justin , Yalkinoglu Özkan , Bagchus Wilhelmina M. , Spangenberg Thomas 
Published: May 2022

Abstract
Background
Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.

Methods
M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.

Results
Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively.

Conclusions
This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.

Graphical Abstract
Association of LDL:HDL ratio with prediabetes risk: a longitudinal observational study based on Chinese adults
Authors: Kuang Maobin , Peng Nan , Qiu Jiajun , Zhong Yanjia , Zou Yang , Sheng Guotai 
Published: May 2022

Abstract
Background
Low-density lipoprotein:high-density lipoprotein cholesterol ratio (LDL:HDL ratio) has a good performance in identifying diabetes mellitus (DM) and insulin resistance. However, it is not yet clear whether the LDL:HDL ratio is associated with a high-risk state of prediabetes.

Methods
This cohort study retrospectively analyzed the data of 100,309 Chinese adults with normoglycemia at baseline. The outcome event of interest was new-onset prediabetes. Using multivariate Cox regression and smoothing splines to assess the association of LDL:HDL ratio with prediabetes.

Results
During an average observation period of 37.4 months, 12,352 (12.31%) subjects were newly diagnosed with prediabetes. After adequate adjustment for important risk factors, the LDL:HDL ratio was positively correlated with the prediabetes risk, and the sensitivity analysis further suggested the robustness of the results. Additionally, in stratified analysis, we discovered significant interactions between LDL:HDL ratio and family history of DM, sex, body mass index and age (all P-interaction < 0.05); among them, the LDL:HDL ratio-related prediabetes risk decreased with the growth of body mass index and age, and increased significantly in women and people with a family history of DM.

Conclusions
The increased LDL:HDL ratio in the Chinese population indicates an increased risk of developing prediabetes, especially in women, those with a family history of DM, younger adults, and non-obese individuals.
Comparison of immune response to human rhinovirus C and respiratory syncytial virus in highly differentiated human airway epithelial cells
Authors: Yuan Xin-hui , Pang Li-li , Yang Jing , Jin Yu 
Published: May 2022

Abstract
Background
Human rhinovirus C (HRV-C) accounts for a large proportion of HRV-related illnesses, but the immune response to HRV-C infection has not been elucidated. Our objective was to assess the effect of HRV-C on cytokine secretion in human bronchial epithelial (HBE) cells grown at air–liquid interface (ALI) and compare it with that of respiratory syncytial virus (RSV).

Methods
HBE cells were differentiated at ALI culture and the full-length cDNA clones of HRV-C651 and HRV-C15, clinical isolates of HRV-C79 and HRV-C101, and two RSV isolates were inoculated in the HBE cells. The effect of HRV-C on cytokine secretion was assessed and compared with that of RSV.

Results
HRV-Cs infect and propagate in fully differentiated HBE cells and significantly increase the secretion of IFN-λ1, CCL5, IP10, IL-6, IL-8, and MCP-1. The virus loads positively correlated with the levels of the cytokines. HRV-C induced lower secretion of CCL5 (P = 0.048), IL-6 (P = 0.016), MCP-1 (P = 0.008), and IL-8 (P = 0.032), and similar secretion of IP10 (P = 0.214) and IFN-λ1 (P = 0.214) when compared with RSV.

Conclusion
HBE ALI culture system supported HRV-C infection and propagation and HRV-C induced relatively weaker cytokine expression than RSV.
Identification and genome characterization of novel parechovirus sequences from Hipposideros armiger in China
Authors: Zeng Jian , Yang Zijun , Guo Wentao , Wang Xiaochun , Yang Shixing , Shen Quan , Wang Hao , Zhang Wen 
Published: May 2022

Abstract
Background
Bats were identified as a natural reservoir of emerging and re-emerging infectious pathogens threatening human health and life.

Methods
This study collected 21 fecal samples of Hipposideros armiger in Mengla County of Xishuangbanna Prefecture Yunnan Province to combine one pool for viral metagenomic sequencing.

Results
Two nearly complete genomes of parechoviruses, BPeV11 and BPeV20, were sequenced. Genome analysis revealed that BPeV11 and BPeV20 follow a 3-3-4 genome layout: 5′ UTR-VP0-VP3-VP1-2A-2B-2C-3A-3B-3C-3D-3′ UTR. The prevalence of BPev11 and BPev20 by Nested-PCR showed that 1 of 21 fecal samples was positive. Based on amino acid identity comparison and phylogenetic analysis of P1, 2C, and 3D, BPeV11 and BPeV20 were closely related to but distinct from FPeVs.

Conclusion
It was probably proposed to be a novel species in the genus Parechovirus of the family Picornaviridae. The isolation of BPev11 and BPev20 from H. armiger in China is the first complete genome of parechovirus isolations from bat feces of the genus Hipposideros.
Identification of the first C1 subgenotype of enterovirus 71 in the Chinese mainland in a retrospective study
Authors: Si Fenfen , Wang Dongyan , Ji Tianjiao , Zhang Yong , Zhu Shuangli , Li Junhan , Xu Wenbo , Tao Zexin , Yan Dongmei 
Published: May 2022

AbstractThe C4 sub-genotype of Enterovirus 71 (EV71) has been identified as the most dominant sub-genotype circulating in the Chinese mainland since 1998. The circulation situation of EV71 before 1998 is not well established due to insufficient experimental data. The C1 subgenotype of EV71 has not yet been reported in the Chinese mainland by now. Based on the AFP surveillance system of the mainland of China, this study conducted a retrospective study of AFP cases for 1985–1999: a strain of EV-A71 C1 subgenotype was found. To our knowledge, this strain (SD92-41) is the first C1 sub-genotype reported in the Chinese mainland. This study demonstrates that the C1 gene subtype also appeared in the Chinese mainland, but it is unknown whether it is an imported or a local epidemic strain. With sufficient information known from retrospective studies, the source of the SD92-41 strain will be identified and the prevalence of EV-A71 in the Chinese mainland before 1998 will be clearer.
NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study
Authors: Reese Justin T. , Coleman Ben , Chan Lauren , Blau Hannah , Callahan Tiffany J. , Cappelletti Luca , Fontana Tommaso , Bradwell Katie R. , Harris Nomi L. , Casiraghi Elena , Valentini Giorgio , Karlebach Guy , Deer Rachel , McMurry Julie A. , Haendel Melissa A. , Chute Christopher G. , Pfaff Emily , Moffitt Richard , Spratt Heidi , Singh Jasvinder A. , Mungall Christopher J. , Williams Andrew E. , Robinson Peter N. 
Published: May 2022

Abstract
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use.

Methods
A 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. The primary outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at any time following COVID-19 diagnosis.

Results
Logistic regression showed that NSAID use was not associated with increased COVID-19 severity (OR: 0.57 95% CI: 0.53–0.61). Analysis of secondary outcomes using logistic regression showed that NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: 0.47–0.56), invasive ventilation (OR: 0.59 95% CI: 0.55–0.64), AKI (OR: 0.67 95% CI: 0.63–0.72), or ECMO (OR: 0.51 95% CI: 0.36–0.7). In contrast, the odds ratios indicate reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between 1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder associations could explain away the observed associations.

Conclusions
Study interpretation is limited by the observational design. Recording of NSAID use may have been incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A conservative interpretation in light of the quantitative bias analysis is that there is no evidence that NSAID use is associated with risk of increased severity or the other measured outcomes. Our results confirm and extend analogous findings in previous observational studies using a large cohort of patients drawn from 38 centers in a nationally representative multicenter database.
Arterial vasodilation drives convective fluid flow in the brain: a poroelastic model
Authors: Kedarasetti Ravi Teja , Drew Patrick J. , Costanzo Francesco 
Published: May 2022

AbstractThe movement of fluid into, through, and out of the brain plays an important role in clearing metabolic waste. However, there is controversy regarding the mechanisms driving fluid movement in the fluid-filled paravascular spaces (PVS), and whether the movement of metabolic waste in the brain extracellular space (ECS) is primarily driven by diffusion or convection. The dilation of penetrating arterioles in the brain in response to increases in neural activity (neurovascular coupling) is an attractive candidate for driving fluid circulation, as it drives deformation of the brain tissue and of the PVS around arteries, resulting in fluid movement. We simulated the effects of vasodilation on fluid movement into and out of the brain ECS using a novel poroelastic model of brain tissue. We found that arteriolar dilations could drive convective flow through the ECS radially outward from the arteriole, and that this flow is sensitive to the dynamics of the dilation. Simulations of sleep-like conditions, with larger vasodilations and increased extracellular volume in the brain showed enhanced movement of fluid from the PVS into the ECS. Our simulations suggest that both sensory-evoked and sleep-related arteriolar dilations can drive convective flow of cerebrospinal fluid not just in the PVS, but also into the ECS through the PVS around arterioles.
Exposure to lead-free frangible firing emissions containing copper and ultrafine particulates leads to increased oxidative stress in firing range instructors
Authors: McNeilly Ryan J. , Schwanekamp Jennifer A. , Hyder Logan S. , Hatch John P. , Edwards Brett T. , Kirsh Jacob A. , Jackson Jerimiah M. , Jaworek Thomas , Methner Mark M. , Duran Christin M. 
Published: May 2022

AbstractBackgroundSince the introduction of copper based, lead-free frangible (LFF) ammunition to Air Force small arms firing ranges, instructors have reported symptoms including chest tightness, respiratory irritation, and metallic taste. These symptoms have been reported despite measurements determining that instructor exposure does not exceed established occupational exposure limits (OELs). The disconnect between reported symptoms and exposure limits may be due to a limited understanding of LFF firing byproducts and subsequent health effects. A comprehensive characterization of exposure to instructors was completed, including ventilation system evaluation, personal monitoring, symptom tracking, and biomarker analysis, at both a partially enclosed and fully enclosed range.ResultsInstructors reported symptoms more frequently after M4 rifle classes compared to classes firing only the M9 pistol. Ventilation measurements demonstrated that airflow velocities at the firing line were highly variable and often outside established standards at both ranges. Personal breathing zone air monitoring showed exposure to carbon monoxide, ultrafine particulate, and metals. In general, exposure to instructors was higher at the partially enclosed range compared to the fully enclosed range. Copper measured in the breathing zone of instructors, on rare occasions, approached OELs for copper fume (0.1 mg/m3). Peak carbon monoxide concentrations were 4–5 times higher at the partially enclosed range compared to the enclosed range and occasionally exceeded the ceiling limit (125 ppm). Biological monitoring showed that lung function was maintained in instructors despite respiratory symptoms. However, urinary oxidative stress biomarkers and urinary copper measurements were increased in instructors compared to control groups.ConclusionsConsistent with prior work, this study demonstrates that symptoms still occurred despite exposures below OELs. Routine monitoring of symptoms, urinary metals, and oxidative stress biomarkers can help identify instructors who are particularly affected by exposures. These results can assist in guiding protective measures to reduce exposure and protect instructor health. Further, a longitudinal study is needed to determine the long-term health consequences of LFF firing emissions exposure.