bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the dental care queries in the “Mouth-Nose” discussion forum of the French association of patients with Gougerot-Sjögren’s syndromes and dryness
Authors: Danvers P. , Saide J. , Decup F. , Seror R. , Belkhir R. , Gosset M.
Published: September 2022

Background

Primary Sjögren Syndrome is a rare autoimmune systemic disease characterized by impaired secretory functions of the exocrine gland. One of the main clinical features is dry mouth and subsequent oral diseases, which are also found in patients with Sicca. This leads to a marked deterioration in the quality of life and the patient’s search for information and solutions. Many patients turn to patients’ associations that offer moments of sharing to their members, especially through online discussion forums. Today, these forums represent quality material for a sociological or biomedical analysis of patients' concerns, as close as possible to their daily lives. Our objective is to analyze the concerns of patients with SS or Sicca regarding their dry mouth especially dental care.

Methods

In this cross-sectional observation study, a quantitative analysis of the Mouth-Nose online forum discussion of the French Association of Patients with Gougerot-Sjögren’s Syndromes and Dryness have been performed. After reading and re-reading, initial request themes, topics, and subtopics were established and coding was performed. Then, the 885 threads were classified depending the initial request, pragma-linguistic indices and the main topic discussed in the thread. After identifying the threads dealing with dental care, we looked at which types of care were most discussed and classified the discussions according to whether or not the patient was satisfied with their care at the dentist.

Results

The majority of the initial requests are posts for experiences sharing and/or advice. The topic of “dental care” is one of the main concerns of the forum users. Among the threads that concern dental care, requests to share experience with implants are in the majority. Finally, the majority of the posts on dental care relate to care in private dental practice, deals with dental implants and prevention and resulted mainly in patient satisfaction.

Conclusions

Analysis of the forum reveals importance of patient concerns about prevention, and care costs due to implant treatment, which add to disease burden. Most of messages relate favorable experiences with their dentists, which is in line with the approach of sharing experiences and support characteristic of a forum.
Perceptions and attitudes of dental practitioners towards impacts of Covid 19 pandemic on clinical dentistry: a cross-sectional study
Authors: Zhou Xiaoyan , Gao Jinlong , Holden Alexander C. L. , Nanayakkara Shanika
Published: September 2022

Background

The COVID-19 pandemic challenged all healthcare providers including dental practitioners. This cross-sectional study aimed to investigate the dental practitioners’ perceptions and attitudes towards the impacts of COVID-19 on their professional practice, career decision and patient care.

Methods

Data was collected from dental practitioners registered in New South Wales (NSW), Australia using an online survey.

Results and conclusion

Responses received from 206 dental practitioners revealed their perceptions and attitudes towards COVID-19 infection risk, clinical guidelines, and measures adopted to deliver patient care. Majority of participants perceived the risk of infection in dentistry was higher compared with other health professionals. Most dental practices have followed guidelines received from professional associations and adopted multiple measures such as providing hand sanitizer, social distancing, and risk screen, to ensure safe delivery of oral health care. Over 80% of dental practitioners raised concerns on patients’ accessibility to dental care during the pandemic. Despite tele-dentistry was introduced, almost half of the participants did not recognize tele-dentistry as an effective alternative. Moreover, negative impacts of COVID-19 pandemic on dental practitioner’s professional career have been reported, including lower practice safety, reduction in working hours and income. Noteworthy, one quarter of participants even considered changing their practice environment, moving sectors or even leaving their career in dentistry. However, majority of the dental practitioners are willing to stay in their current practice environment and continue their career in dentistry. Our observations demonstrate the systematic disruption to dental practice faced in Australia due to the COVID-19 pandemic. Providing dental practitioners with timely educational training and support is important to minimise negative impacts of the challenges and to optimise dental care.
The experiences of clinical nurses coping with patient death in the context of rising hospital deaths in China: a qualitative study
Authors: Zhang Jinxin , Cao Yingjuan , Su Mingzhu , Cheng Joyce , Yao Nengliang
Published: September 2022

Background

Chinese clinical nurses are increasingly confronting patient death, as the proportion of hospital deaths is growing. Witnessing patient suffering and death is stressful, and failure to cope with this challenge may result in decreased well-being of nurses and impediment of the provision of “good death” care for patients and their families. To our knowledge, few studies have specifically explored clinical nurses’ experiences coping with patient death in mainland China. 

Objective

We aimed to explore nurses’ experiences coping with patient death in China in order to support frontline clinical nurses effectively and guide the government in improving hospice care policy.

Methods

Clinical nurses were recruited using purposive and snowball sampling between June 2020 and August 2020. We gathered experiences of clinical nurses who have coped with patient death using face-to-face, semi-structured, in-depth interviews. Audio recordings were transcribed verbatim and analyzed using thematic analysis.

Results

Three thematic categories were generated from data analysis. The first was “negative emotions from contextual challenges.” This category involved grief over deaths of younger persons, pity for deaths without family, and dread related to coping with patient death on night duty. The second category was “awareness of mortality on its own.” Subthemes included the ideas that death means that everything stops being and good living is important because we all die and disappear. The third category was “coping style.” This category included focusing on treating dying patients, recording the signs and symptoms, and responding to changes in the patient’s condition. It also involved subthemes such as avoiding talk about death due to the grief associated with dying and death, and seeking help from colleagues.

Conclusions

Clinical nurses’ emotional experiences are shaped by intense Chinese filial love, charity, and cultural attitudes towards death. Reasonable nurse scheduling to ensure patient and staff safety is a major priority. “Good death” decisions based on Chinese ethical and moral beliefs must be embedded throughout hospital care.
Cost-effectiveness of a whole-area testing pilot of asymptomatic SARS-CoV-2 infections with lateral flow devices: a modelling and economic analysis study
Authors: Drakesmith Mark , Collins Brendan , Jones Angela , Nnoaham Kelechi , Thomas Daniel Rhys
Published: September 2022

Background

Mass community testing for SARS-CoV-2 by lateral flow devices (LFDs) aims to reduce prevalence in the community. However its effectiveness as a public heath intervention is disputed.

Method

Data from a mass testing pilot in the Borough of Merthyr Tydfil in late 2020 was used to model cases, hospitalisations, ICU admissions and deaths prevented. Further economic analysis with a healthcare perspective assessed cost-effectiveness in terms of healthcare costs avoided and QALYs gained.

Results

An initial conservative estimate of 360 (95% CI: 311–418) cases were prevented by the mass testing, representing a would-be reduction of 11% of all cases diagnosed in Merthyr Tydfil residents during the same period. Modelling healthcare burden estimates that 24 (16—36) hospitalizations, 5 (3–6) ICU admissions and 15 (11–20) deaths were prevented, representing 6.37%, 11.1% and 8.2%, respectively of the actual counts during the same period. A less conservative, best-case scenario predicts 2333 (1764–3115) cases prevented, representing 80% reduction in would-be cases. Cost -effectiveness analysis indicates 108 (80–143) QALYs gained, an incremental cost-effectiveness ratio of £2,143 (£860-£4,175) per QALY gained and net monetary benefit of £6.2 m (£4.5 m-£8.4 m). In the best-case scenario, this increases to £15.9 m (£12.3 m-£20.5 m).

Conclusions

A non-negligible number of cases, hospitalisations and deaths were prevented by the mass testing pilot. Considering QALYs gained and healthcare costs avoided, the pilot was cost-effective. These findings suggest mass testing with LFDs in areas of high prevalence (> 2%) is likely to provide significant public health benefit. It is not yet clear whether similar benefits will be obtained in low prevalence settings or with vaccination rollout.
Guidelines and clinical priority setting during the COVID-19 pandemic – Norwegian doctors’ experiences
Authors: Bringedal Berit H. , Rø Karin Isaksson , Bååthe Fredrik , Miljeteig Ingrid , Magelssen Morten
Published: September 2022

Background

In the first phase of the COVID-19 pandemic, strong measures were taken to avoid anticipated pressure on health care, and this involved new priorities between patient groups and changing working conditions for clinical personnel. We studied how doctors experienced this situation. Our focus was their knowledge about and adherence to general and COVID-19 specific guidelines and regulations on priority setting, and whether actual priorities were considered acceptable.

Methods

In December 2020, 2 316 members of a representative panel of doctors practicing in Norway received a questionnaire. The questions were designed to consider a set of hypotheses about priority setting and guidelines. The focus was on the period between March and December 2020. Responses were analyzed with descriptive statistics and regression analyses.

Results

In total, 1 617 (70%) responded. A majority were familiar with the priority criteria, though not the legislation on priority setting. A majority had not used guidelines for priority setting in the first period of the pandemic. 60.5% reported that some of their patients were deprioritized for treatment. Of these, 47.5% considered it medically indefensible to some/a large extent. Although general practitioners (GPs) and hospital doctors experienced deprioritizations equally often, more GPs considered it medically indefensible. More doctors in managerial positions were familiar with the guidelines.

Conclusions

Most doctors did not use priority guidelines in this period. They experienced, however, that some of their patients were deprioritized, which was considered medically indefensible by many. This might be explained by a negative reaction to the externally imposed requirements for rationing, while observing that vulnerable patients were deprioritized. Another interpretation is that they judged the rationing to have gone too far, or that they found it hard to accept rationing of care in general. Priority guidelines can be useful measures for securing fair and reasonable priorities. However, if the priority setting in clinical practice is to proceed in accordance with priority-setting principles and guidelines, the guidelines must be translated into a clinically relevant context and doctors’ familiarity with them must improve.
LncRNA MRF drives the regulatory function on monocyte recruitment and polarization through HNRNPD-MCP1 axis in mesenchymal stem cells
Authors: Lin Jiajie , Xie Zhongyu , Zhang Zhaoqiang , Li Ming , Ye Guiwen , Yu Wenhui , Li Jinteng , Ye Feng , Su Zepeng , Che Yunshu , Xu Peitao , Zeng Chenying , Wang Peng , Wu Yanfeng , Shen Huiyong
Published: September 2022

Background

Mesenchymal stem cells (MSCs) exhibit two bidirectional immunomodulatory abilities: proinflammatory and anti-inflammatory regulatory effects. Long noncoding RNAs (lncRNAs) have important functions in the immune system. Previously, we performed high-throughput sequencing comparing lncRNA expression profiles between MSCs cocultured with or without CD14+ monocytes and screened out a new lncRNA termed lncRNA MCP1 regulatory factor (MRF). However, the mechanism of MRF in MSCs is still unknown.

Methods

MRF expression was quantified via qRT–PCR. RNA interference and lentiviruses were used to regulate MRF expression. The immunomodulatory effects of MSCs on monocytes were evaluated via monocyte migration and macrophage polarization assays. RNA pull-down and mass spectrometry were utilized to identify downstream factors of MRF. A dual-luciferase reporter assay was applied to analyze the transcription factors regulating MRF. qRT–PCR, western blotting and ELISAs were used to assess MCP1 expression. A human monocyte adoptive transfer mouse model was applied to verify the function of MRF in vivo.

Results

MRF was upregulated in MSCs during coculture with CD14+ monocytes. MRF increased monocyte recruitment by upregulating the expression of monocyte chemotactic protein (MCP1). Knockdown of MRF enhanced the regulatory effect of MSCs on restraining M1 polarization and facilitating M2 polarization. Mechanistically, MRF bound to the downstream protein heterogeneous nuclear ribonucleoprotein D (HNRNPD) to upregulate MCP1 expression, and the transcription factor interferon regulatory factor 1 (IRF1) activated MRF transcription early during coculture. The human monocyte adoptive transfer model showed that MRF downregulation in MSCs inhibited monocyte chemotaxis and enhanced the effects of MSCs to inhibit M1 macrophage polarization and promote M2 polarization in vivo.

Conclusion

We identified the new lncRNA MRF, which exhibits proinflammatory characteristics. MRF regulates the ability of MSCs to accelerate monocyte recruitment and modulate macrophage polarization through the HNRNPD-MCP1 axis and initiates the proinflammatory regulatory process in MSCs, suggesting that MRF is a potential target to improve the clinical effect of MSC-based therapy or correct MSC-related immunomodulatory dysfunction under pathological conditions.
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

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

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

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

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

Background

Fibrodysplasia 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.

Results

We 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.

Conclusion

These 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

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

Background

Alzheimer’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.

Methods

We 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.

Results

We 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.

Conclusions

The 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

Background

Circular 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).

Methods

High-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.

Results

CircPAK1, 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.

Conclusion

CircPAK1 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

Background

Genomic 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.

Results

Here, 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.

Conclusions

Our 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

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.
Interventions pathways to reduce tuberculosis-related stigma: a literature review and conceptual framework
Authors: Nuttall Charlotte , Fuady Ahmad , Nuttall Holly , Dixit Kritika , Mansyur Muchtaruddin , Wingfield Tom
Published: September 2022

Background

Prevention of tuberculosis (TB)-related stigma is vital to achieving the World Health Organisation’s End TB Strategy target of eliminating TB. However, the process and impact evaluation of interventions to reduce TB-stigma are limited. This literature review aimed to examine the quality, design, implementation challenges, and successes of TB-stigma intervention studies and create a novel conceptual framework of pathways to TB-stigma reduction.

Method

We searched relevant articles recorded in four scientific databases from 1999 to 2022, using pre-defined inclusion and exclusion criteria, supplemented by the snowball method and complementary grey literature searches. We assessed the quality of studies using the Crowe Critical Appraisal Tool, then reviewed study characteristics, data on stigma measurement tools used, and interventions implemented, and designed a conceptual framework to illustrate the pathways to TB-stigma reduction in the interventions identified.

Results

Of 14,259 articles identified, eleven met inclusion criteria, of which three were high quality. TB-stigma reduction interventions consisted mainly of education and psychosocial support targeted predominantly toward three key populations: people with TB, healthcare workers, and the public. No psychosocial interventions for people with TB set TB-stigma reduction as their primary or co-primary aim. Eight studies on healthcare workers and the public reported a decrease in TB-stigma attributed to the interventions. Despite the benefits, the interventions were limited by a dearth of validated stigma measurement tools. Three of eight studies with quantitative stigma measurement questionnaires had not been previously validated among people with TB. No qualitative studies used previously validated methods or tools to qualitatively evaluate stigma. On the basis of these findings, we generated a conceptual framework that mapped the population targeted, interventions delivered, and their potential effects on reducing TB-stigma towards and experienced by people with TB and healthcare workers involved in TB care.

Conclusions

Interpretation of the limited evidence on interventions to reduce TB-stigma is hampered by the heterogeneity of stigma measurement tools, intervention design, and outcome measures. Our novel conceptual framework will support mapping of the pathways to impacts of TB-stigma reduction interventions.

Graphical Abstract
Predictors for the duration of breastfeeding among ethiopia women of childbearing age with babies; application of accelerate failure time and parametric shared frailty models
Authors: Mulugeta Getahun , Tesfaye Dagne , Tegegne Awoke Seyoum
Published: September 2022

Introduction

Duration of breastfeeding is the length of the time that infants who were initially breastfed continue to receive breast milk until weaning. The duration of breastfeeding is important for a child's health, growth, and development. However, the duration of breastfeeding decreases from time to time and further leads children to be exposed to malnutrition (stunting, wasting, and weight loss). Children who did not get enough breastfeeding are also exposed to different diseases. Previous studies used a simple survival model and didn’t see the shared frailty model on the variable of interest. Therefore, the current study aimed to investigate the factors affecting the duration of breastfeeding among Ethiopian women of reproductive age with babies.

Methods

A cross-sectional study design was conducted on 15,400 women of childbearing age with babies in nine regional states and two city administrations. The data source for the analysis was the 2016 EDHS data. The Cox-proportional hazard model, AFT, and parametric shared frailty models were conducted for the current investigation. Weibull-gamma shared frailty model was in favor of others for current data analysis.

Results

Among the covariates, women living in urban area (Φ = 0.96; 95% CI; (0.94,0.97); p-value = 0.001), non-educated women(Φ = 1.03; 95% CI; (1.00,1.06); p-value = 0.039), primary educated women (Φ = 1.13; 95% CI; (1.11,1.15); p-value < 0.001), age of a child (Φ = 0.99; 95% CI; (0.76.0.99); p-value < 0.001) and non-smoker mothers (Φ = 1.60; 95% CI; (1.57, 1.63); p-value < 0.001),birth interval between 2–3 years(Φ = 1.02; 95% CI;(1.09, 1.25, p-value = 0.027), birth interval, > 3 years(Φ = 1.28; 95% CI; (1.06, 1.43); p-value < 0.01 significantly affected the duration of breastfeeding. The median survival time of breastfeeding of women of reproductive age with babies considered under study was 23.4 months. Clustering had a significant effect on the variable of interest.

Conclusion

Residence area, level of education, age of the child, smoking status of women, and birth interval of successive birth significantly affected the duration of breastfeeding in the current investigation. Hence, the health staff should conduct health-related education for young women, educated women, urban women, smoker women, and women with a shorter interval of birth to increase the women's attitude and awareness towards the use of long-duration of breastfeeding.
A Novel Oncodental Collaborative Team: Integrating Expertise for Central Line–Associated Bloodstream Infection Prevention in Pediatric Oncology Patients
Authors: Bledsaw Kandice , Prudowsky Zachary D. , Yang Esther , Harriehausen Claudia X. , Robins Jenell , DeJean Janet , Staton Sharon , Campbell Judith R. , Davis Andrea L. , George Anil , Steffin David , Stevens Alexandra M.
Published: September 2022

PURPOSE:

Pediatric oncology and bone marrow transplant patients are at high risk of infection, and limitations to dental expertise among medical providers render patients vulnerable to central line–associated bloodstream infections from oral pathogens. Traditionally, oral health maintenance relied on patients and bedside nurses; however, routine methods are often suboptimal to prevent central line–associated bloodstream infection in high-risk patients. Limited overlap of medical and dental expertise, and limited dental resources in typical oncology units, prevent optimal oral care for children with cancer, requiring novel solutions to better integrate specialties.

METHODS:

Here, we outline the creation of a novel Pediatric oncodental team to address oral-systemic infection prevention strategies for high-risk patients.

RESULTS:

Our oncology and dental teams created a systematic approach for increasing oral surveillance and treatment in select high-risk patients. Supervised pediatric dental residents participated in scheduled oncology rounds, and a permanent oral health educator with a background in dental hygiene was also hired as a dedicated dental professional within our oncology department.

CONCLUSION:

Our pediatric oncodental team aims to sustain optimal oral complication prevention strategies to reduce the risk of infection, provide education on the significance of the oral-systemic link in cancer care, and improve access and continuity of care.
How Does Mortality Contribute to Lifetime Pension Inequality? Evidence From Five Decades of Swedish Taxation Data
Authors: Shi Jiaxin , Kolk Martin
Published: September 2022

As with many social transfer schemes, pension systems around the world are often progressive: individuals with lower incomes receive a higher percentage of their income as a subsequent pension. On the other hand, those with lower earnings have higher mortality and thus accumulate fewer years of pension income. Both of these opposing factors influence the progressiveness of pension systems. Empirical efforts to disentangle the effects of mortality inequality on lifetime pension inequality have been scarce. Using Swedish taxation data linked with death registers for 1970–2018, we study how education and preretirement earnings relate to lifetime pensions from age 60 onward and how mortality inequalities contribute to overall inequalities in lifetime pensions. The results show that a progressive replacement structure and mortality differences contribute to the overall distribution of pension payments over the life course. Up to one quarter of lifetime pension inequality is attributable to the greater longevity of socially advantaged groups—particularly among men. Hence, mortality inequalities are an important determinant of the overall degree of between-group income transfers in a pension system, but they are not as important as inequalities in prior earnings.
The Oxidative–Glycolytic Balance Influenced by Sprint Duration Is Key during Repeated Sprint in Hypoxia
Authors: RABERIN ANTOINE , ELMER JOAKIM , WILLIS SARAH J. , RICHARD THOMAS , VERNILLO GIANLUCA , IAIA F. MARCELLO , GIRARD OLIVIER , MALATESTA DAVIDE , MILLET GRÉGOIRE P.
Published: September 2022

Purpose

This study investigates the effects of normobaric hypoxia on repeated sprint exercise (RSE) with different balance between oxidative (phosphocreatine and oxidative pathway) and glycolytic contributions. Therefore, performance and psychophysiological responses were compared during RSE to exhaustion with the same exercise-to-rest ratio (1:2) but different sprint durations (5, 10, or 20 s) either in normoxic (RSN) or hypoxic (RSH; Fio
2 = 0.13) conditions.

Methods

On separate visits, 10 active participants completed in random order three cycling RSN (5:10; 10:20 and 20:40) and three similar RSH sessions to exhaustion. Vastus lateralis muscle oxygenation was recorded by near-infrared spectroscopy. Blood lactate concentration, limb and breathing discomfort, and ratings of perceived exertion were measured.

Results

Total sprint number was smaller in hypoxia than in normoxia for 5:10 (20.8 ± 8.6 vs 14.7 ± 3.4; P = 0.014) and 10:20 (13.7 ± 6.3 vs 8.8 ± 2.5; P = 0.018) but not 20:40 (5.6 ± 1.9 vs 5.6 ± 2.5). The fatigue index was larger in hypoxia only for 5:10 (−43.5%, P < 0.001). Irrespective of condition, blood lactate concentration increased with the sprint duration with higher values for 20:40 than 5:10 (13.1 ± 2.7 vs 11.5 ± 2.2 mmoL·L−1; P = 0.027). Limb and breathing discomfort and ratings of perceived exertion did not differ in all RSE. Muscle oxygenation was mainly impacted by sprint duration (i.e., main effect of sprint duration on [HHb] min, [tHb] max, Δ[HHb], and Δ[tHb]) but not by hypoxia. The normoxia-to-hypoxia percentage decrease for total sprint number for 5:10 was correlated with the highest power output over 5 s (R
2 = 0.55; P = 0.013) and 10 s (R
2 = 0.53; P = 0.016).

Conclusions

Hypoxia impairs repeated sprint ability when the oxidative but not the glycolytic contribution is substantial. The oxidative–glycolytic balance, influenced partly by sprint duration, is key during repeated sprint in hypoxia.