bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term comprehensive cardiopulmonary phenotyping of COVID-19
Authors: Kimmig Lucas M. , Rako Zvonimir A. , Ziegler Stefanie , Richter Manuel J. , G.S. Ashkan Tolou , Roller Fritz , Grimminger Friedrich , Vadász István , Seeger Werner , Herold Susanne , Tello Khodr , Matt Ulrich 
Published: September 2022

Abstract
Background
Persistent symptoms after initial COVID-19 infection are common and are frequently referred to by the umbrella terms “post-COVID syndrome” and “long COVID”. The sheer number of affected patients pose an increasing challenge to healthcare systems worldwide. To date, our understanding of the pathophysiology of the post-COVID syndrome remains poor and the extent to which persistent cardiopulmonary abnormalities contribute to the symptom complex is unclear. We sought to determine the presence and impact of cardiopulmonary sequelae after COVID-19 in longitudinal assessment.

Methods
We report on 71 patients who underwent comprehensive, longitudinal testing in regular intervals for up to 12 months after their initial COVID-19 diagnosis. Testing included pulmonary function testing, cardiopulmonary exercise testing, dedicated left and right heart echocardiography, lung ultrasonography, and cardiac MRI.

Results
Our results demonstrate that subjective quality of life after COVID-19 (EQ-5D visual acuity scale, VAS, 67.4 for patients treated as outpatient, 79.2 for patients admitted to the general floor, 71.8 for patients treated in an ICU) is not related to the severity of the initial infection. Maximal exercise capacity is also reduced (VO2max 79% predicted, SD ± 19%); however, this is driven in large parts by patients who had initially required ICU-level of care. The degree of objective reduction in exertion did not correlate with quality of life scores. Pulmonary function testing revealed mild and persistent reduction in DLCO over the first 12 months without significant restrictive or obstructive lung disease. Left and right heart function was intact with good RV function and intact RV/PA coupling, imaging findings suggestive of myocarditis were uncommon (7% of patients).

Conclusion
A reduction in exercise capacity after COVID-19 is common, but is most prominent in patients previously treated in the ICU and more likely related to deconditioning or fatigue than to cardiopulmonary impairment. Subjective quality of life scores are independent of the severity of initial infection and do not correlate with objective measures of cardiopulmonary function. In our cohort, persistent cardiopulmonary impairment after COVID-19 was uncommon. The post-COVID syndrome is unlikely to be the result of cardiopulmonary sequalae and may reflect a post-ICU syndrome in some.
Trial registration Registered on clinicaltrials.gov (NCT04442789), Date: June 23, 2020
Heroin pipe distribution to reduce high-risk drug consumption behaviors among people who use heroin: a pilot quasi-experimental study
Authors: Fitzpatrick Thomas , McMahan Vanessa M. , Frank Noah D. , Glick Sara N. , Violette Lauren R. , Davis Shantel , Jama Shilo 
Published: September 2022

Abstract
Background
Heroin pipe distribution may encourage people who use heroin (PWUH) to transition from injecting to smoking heroin, reducing harms associated with injection drug use. A syringe services program (SSP) in Seattle, Washington, led by people who use drugs developed a heroin pipe distribution program.

Methods
We conducted a pretest–posttest quasi-experimental study to evaluate the impact of heroin pipe distribution on drug consumption behaviors among PWUH between March and December 2019. SSP clients were surveyed during three weeklong timepoints before and four weeklong timepoints after heroin pipe distribution. Primary outcomes were change in proportion of SSP clients who exclusively injected heroin, exclusively smoked heroin, and both injected and smoked heroin in the past seven days comparing the pre- and post-intervention periods.

Results
Across the seven observation timepoints, 694 unique respondents completed 957 surveys. Multiple responses from a single respondent in a given period were collapsed, resulting in 360 pre-intervention and 430 post-intervention records. Heroin use was reported in over half of pre-intervention (56%, 201/360) and post-intervention records (58%, 251/430). Compared to pre-intervention behaviors, the proportion of respondents who exclusively injected heroin was lower after the start of heroin pipe distribution (32%, 80/251 vs 43%, 86/201, p = 0.02), while the proportion of respondents who both injected and smoked heroin was higher (45%, 113/251 vs 36%, 72/201, p = 0.048). Just under half (44%, 110/251) of respondents who used heroin during the post-intervention period used a heroin pipe obtained from the SSP, of which 34% (37/110) reported heroin pipe distribution had reduced their heroin injection frequency. Self-reported hospitalization for a pulmonary cause was not associated with using a heroin pipe.

Conclusions
The proportion of SSP clients who exclusively injected heroin was lower after implementation of heroin pipe distribution. Randomized studies with longer follow-up are needed to investigate whether heroin pipe distribution reduces heroin injection and improves health outcomes associated with drug use. Limited intervention exposure, loss to follow-up, and pipe availability from other sources pose methodological challenges to evaluations of route transition interventions in community settings. This pilot highlights the potential for organizations led by people who use drugs to develop, implement, and evaluate novel public health programming.
Lung recovery from DNA damage induced by graphene oxide is dependent on size, dose and inflammation profile
Authors: de Luna Luis Augusto Visani , Loret Thomas , Fordham Alexander , Arshad Atta , Drummond Matthew , Dodd Abbie , Lozano Neus , Kostarelos Kostas , Bussy Cyrill 
Published: September 2022

Abstract
Background
A key aspect of any new material safety assessment is the evaluation of their in vivo genotoxicity. Graphene oxide (GO) has been studied for many promising applications, but there are remaining concerns about its safety profile, especially after inhalation. Herein we tested whether GO lateral dimension, comparing micrometric (LGO) and nanometric (USGO) GO sheets, has a role in the formation of DNA double strand breaks in mouse lungs. We used spatial resolution and differential cell type analysis to measure DNA damages in both epithelial and immune cells, after either single or repeated exposure.

Results
GO induced DNA damages were size and dose dependent, in both exposure scenario. After single exposure to a high dose, both USGO and LGO induced significant DNA damage in the lung parenchyma, but only during the acute phase response (p < 0.05 for USGO; p < 0.01 for LGO). This was followed by a fast lung recovery at day 7 and 28 for both GOs. When evaluating the chronic impact of GO after repeated exposure, only a high dose of LGO induced long-term DNA damages in lung alveolar epithelia (at 84 days, p < 0.05). Regardless of size, low dose GO did not induce any significant DNA damage after repeated exposure. A multiparametric correlation analysis of our repeated exposure data revealed that transient or persistent inflammation and oxidative stress were associated to either recovery or persistent DNA damages. For USGO, recovery from DNA damage was correlated to efficient recovery from acute inflammation (i.e., significant secretion of SAA3, p < 0.001; infiltration of neutrophils, p < 0.01). In contrast, the persistence of LGO in lungs was associated to a long-lasting presence of multinucleated macrophages (up to 84 days, p < 0.05), an underlying inflammation (IL-1α secretion up to 28 days, p < 0.05) and the presence of persistent DNA damages at 84 days.

Conclusions
Overall these results highlight the importance of the exposure scenario used. We showed that LGO was more genotoxic after repeated exposure than single exposure due to persistent lung inflammation. These findings are important in the context of human health risk assessment and toward establishing recommendations for a safe use of graphene based materials in the workplace.
Against ‘instantaneous’ expertise
Authors: Mebius Alexander 
Published: September 2022

Abstract
Background
Healthcare is predicated on the use of biotechnology and medical technology, both of which are indispensable in diagnosis, treatment, and most aspects of patient care. It is therefore imperative that justifications for use of new technologies are appropriate, with the technologies working as advertised. In this paper, I consider philosophical accounts of how such justifications are made.

Methods
Critical philosophical reflection and analysis.

Results
I propose that justification in many prominent accounts is based on the designer’s professional experience and on expert testimony. I argue, however, that professional designers are not in a position to justify a new biotechnology or medical device if the justification is based on testimony or past experience of presumably similar technologies. I argue (1) that similarity judgments offered by instantaneous experts cannot be viewed as contributing (epistemically) to evidential justification of new and unproven technologies; and (2) that designers and manufacturers cannot endorse a technology’s effective function in a patient-care context until it has been successfully used in that context.

Conclusion
I show that an expert’s past professional experiences can never predict or justify the impact of a novel technology on human health. This is because any new technology leads to the introduction of new mechanisms with unprecedented functions. The new technology therefore needs to be studied in situ and justified as a newly created mechanism within the relevant healthcare setting. Ultimately, justifications of this type rely on the scientific community and society engaging in repeated experimentation and observation of the technology, and confirming its successful use.
Recapitulation of pro-inflammatory signature of monocytes with ACVR1A mutation using FOP patient-derived iPSCs
Authors: Maekawa Hirotsugu , Jin Yonghui , Nishio Megumi , Kawai Shunsuke , Nagata Sanae , Kamakura Takeshi , Yoshitomi Hiroyuki , Niwa Akira , Saito Megumu K. , Matsuda Shuichi , Toguchida Junya 
Published: September 2022

AbstractBackgroundFibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated.ResultsWe generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutantACVR1Agene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation ofINHBAgene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such asCD16andCCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML includingLYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments.ConclusionThese results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.
Limited efficacy of tocilizumab in adult patients with secondary hemophagocytic lymphohistiocytosis: a retrospective cohort study
Authors: Kim Ju Yeon , Kim Miso , Park Jin Kyun , Lee Eun Bong , Park Jun Won , Hong Junshik 
Published: September 2022

Abstract
Background
Interleukin (IL)-6 is one of the key cytokines in the pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH); however, the efficacy and safety of tocilizumab (TCZ), a monoclonal IL-6 receptor antibody, in patients with sHLH is uncertain.

Methods/Results
This study included 64 adult patients who were diagnosed with sHLH based on the HLH-2004 criteria. Patients were classified into two groups based on treatment regimen at baseline: tocilizumab (TCZ group, n = 8) versus other treatments (control group), including HLH-2004 protocol (n = 35), chemotherapy (n = 7), glucocorticoid alone (n = 8), and with other immunosuppressants (n = 6). Primary outcome was overall 8-week survival. Baseline characteristics between the two groups were comparable. At day 56, one patient (12.5%) in the TCZ group and twenty-eight patients (51.9%) in the control group survived. Univariable and multivariable Cox proportional hazard analysis showed that TCZ significantly increased the risk of death (adjusted hazard ratio 5.55; 95% CI 2.13–14.49). The complete or partial response rate at day 14 was 44.6% in the control group, and nil in the TCZ group. In contrast, infectious complications occurred more frequently in the TCZ group than in the control group (14.3% vs. 50.0%).

Conclusion
Our results suggest that tocilizumab has limited efficacy in treating adult patients with sHLH and could increase the risk of infectious complications compared to the conventional treatments.
Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity
Authors: Hsieh Yi-Chen , Negri Joseph , He Amy , Pearse Richard V. , Liu Lei , Duong Duc M. , Chibnik Lori B. , Bennett David A. , Seyfried Nicholas T. , Young-Pearse Tracy L. 
Published: September 2022

AbstractBackgroundAlzheimer’s Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies.MethodsWe expose cultured neurons to aqueous-soluble human brain extract from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts.ResultsWe observe associations between spontaneous activity and Aβ42:40 levels, between neurite integrity and oligomeric Aβ, and between neurite integrity and tau levels present in the brain extracts. However, these associations with Aβ and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing.ConclusionsThe techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.
CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3ζ
Authors: Hao Xiaopei , Zhang Yao , Shi Xiaoli , Liu Hanyuan , Zheng Zhiying , Han Guoyong , Rong Dawei , Zhang Chuanyong , Tang Weiwei , Wang Xuehao 
Published: September 2022

AbstractBackgroundCircular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development of many diseases, including tumors. This study aimed to investigate the potential roles of circPAK1 in hepatocellular carcinoma (HCC).MethodsHigh-throughput sequencing was performed on 3 pairs of HCC and matched normal tissues to determine the upregulated circRNAs. The expression level of circPAK1 was detected by qRT-PCR in HCC and paired with normal liver tissue samples. The effects of circPAK1 on proliferation, invasion, metastasis and apoptosis of HCC cells were evaluated by in vitro and in vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material to evaluate its in vivo therapeutic effect on HCC. High-throughput sequencing, RNA-sequencing, RNA probe pull-down, RNA immunoprecipitation and Co-Immunoprecipitation assays were performed to explore the relationship between circPAK1, 14–3-3ζ, p-LATS1 and YAP. Exosomes isolated from lenvatinib-resistant HCC cell lines were used to evaluate the relationship between exosomal circPAK1 and lenvatinib resistance.ResultsCircPAK1, a novel circRNA, is highly expressed in HCC tumor tissues and cell lines as well as correlated with poor outcomes in HCC patients. Functionally, circPAK1 knockdown inhibited HCC cell proliferation, migration, invasion and angiogenesis while circPAK1 overexpression promoted HCC progression. The tumor-promoting phenotypes of circPAK1 on HCC were also confirmed by animal experiments. Importantly, the application of CS/si-circPAK1 nanocomplexes showed a better therapeutic effect on tumor growth and metastasis. Mechanistically, circPAK1 enhanced HCC progression by inactivating the Hippo signaling pathway, and this kind of inactivation is based on its competitively binding of 14–3-3 ζ with YAP, which weakens the recruitment and cytoplasmic fixation of 14–3-3 ζ to YAP, thus promoting YAP nucleus localization. Additionally, circPAK1 could be transported by exosomes from lenvatinib-resistant cells to sensitive cells and induce lenvatinib resistance of receipt cells.ConclusionCircPAK1 exerts its oncogenic function by competitively binding 14–3-3 ζ with YAP, thus promoting YAP nucleus localization, leading to the inactivation of a Hippo signaling pathway. Exosomal circPAK1 may drive resistance to lenvatinib, providing a potential therapeutic target for HCC patients.
Genomics and epigenetics guided identification of tissue-specific genomic safe harbors
Authors: Shrestha Dewan , Bag Aishee , Wu Ruiqiong , Zhang Yeting , Tang Xing , Qi Qian , Xing Jinchuan , Cheng Yong 
Published: September 2022

AbstractBackgroundGenomic safe harbors are regions of the genome that can maintain transgene expression without disrupting the function of host cells. Genomic safe harbors play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited safe harbors have been identified.ResultsHere, we develop a framework to facilitate searches for genomic safe harbors by integrating information from polymorphic mobile element insertions that naturally occur in human populations, epigenomic signatures, and 3D chromatin organization. By applying our framework to polymorphic mobile element insertions identified in the 1000 Genomes project and the Genotype-Tissue Expression (GTEx) project, we identify 19 candidate safe harbors in blood cells and 5 in brain cells. For three candidate sites in blood, we demonstrate the stable expression of transgene without disrupting nearby genes in host erythroid cells. We also develop a computer program, Genomics and Epigenetic Guided Safe Harbor mapper (GEG-SH mapper), for knowledge-based tissue-specific genomic safe harbor selection.ConclusionsOur study provides a new knowledge-based framework to identify tissue-specific genomic safe harbors. In combination with the fast-growing genome engineering technologies, our approach has the potential to improve the overall safety and efficiency of gene and cell-based therapy in the near future.
Creating concise and readable patient information sheets for interventional studies in Australia: are we there yet?
Authors: Symons Tanya , Davis Joshua S. 
Published: September 2022

Abstract
Background
Participant information sheets and consent forms (PICFs) used in interventional studies are often criticised for being hard to read and understand. We assessed the readability and its correlates of a broad range of Australian PICFs.

Methods
We analysed the participant information sheet portion of 248 PICFs. Readability scores were measured using three formulae: the Flesch Reading Ease, the Flesch-Kincaid Grade Level, and the Simple Measure of Gobbledygook (SMOG). We investigated how various features (including sponsor type and PICF type) correlated with PICF length and readability and examined compliance with other measures known to improve readability.

Results
For a sample of 248 PICFs, the mean (standard deviation) Flesch Reading Ease score was 49.3 (5.7) and for the Flesch-Kincaid Grade Level 11.4 (1.1). The mean (SD) SMOG score was 13.2 (0.9). The median document length was 3848 words (8 pages). Commercial PICFs were more than twice as long as non-commercial, but statistically more readable (p = 0.03) when analysed using the SMOG formula. Subgroup analyses indicated that PICFs for self-consenters were statistically more readable than those for proxy consenters. The use of tables, but not the use of illustrations was associated with better readability scores.

Conclusions
The PICFs in our sample are long and complex, and only 3 of the 248 achieved the recommended readability score of grade 8 or below. The broader use of best practice principles for writing health information for consumers and the development of more context-sensitive templates could improve their utility.