bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of the COVID-19 pandemic on patterns of attendance at emergency departments in two large London hospitals: an observational study
Authors: Vollmer Michaela A. C. , Radhakrishnan Sreejith , Kont Mara D. , Flaxman Seth , Bhatt Samir , Costelloe Ceire , Honeyford Kate , Aylin Paul , Cooke Graham , Redhead Julian , Sanders Alison , Mangan Helen , White Peter J. , Ferguson Neil , Hauck Katharina , Nayagam Shevanthi , Perez-Guzman Pablo N. 
Published: September 2021

Abstract
Background
Hospitals in England have undergone considerable change to address the surge in demand imposed by the COVID-19 pandemic. The impact of this on emergency department (ED) attendances is unknown, especially for non-COVID-19 related emergencies.

Methods
This analysis is an observational study of ED attendances at the Imperial College Healthcare NHS Trust (ICHNT). We calibrated auto-regressive integrated moving average time-series models of ED attendances using historic (2015–2019) data. Forecasted trends were compared to present year ICHNT data for the period between March 12, 2020 (when England implemented the first COVID-19 public health measure) and May 31, 2020. We compared ICHTN trends with publicly available regional and national data. Lastly, we compared hospital admissions made via the ED and in-hospital mortality at ICHNT during the present year to the historic 5-year average.

Results
ED attendances at ICHNT decreased by 35% during the period after the first lockdown was imposed on March 12, 2020 and before May 31, 2020, reflecting broader trends seen for ED attendances across all England regions, which fell by approximately 50% for the same time frame. For ICHNT, the decrease in attendances was mainly amongst those aged < 65 years and those arriving by their own means (e.g. personal or public transport) and not correlated with any of the spatial dependencies analysed such as increasing distance from postcode of residence to the hospital. Emergency admissions of patients without COVID-19 after March 12, 2020 fell by 48%; we did not observe a significant change to the crude mortality risk in patients without COVID-19 (RR 1.13, 95%CI 0.94–1.37, p = 0.19).

Conclusions
Our study findings reflect broader trends seen across England and give an indication how emergency healthcare seeking has drastically changed. At ICHNT, we find that a larger proportion arrived by ambulance and that hospitalisation outcomes of patients without COVID-19 did not differ from previous years. The extent to which these findings relate to ED avoidance behaviours compared to having sought alternative emergency health services outside of hospital remains unknown. National analyses and strategies to streamline emergency services in England going forward are urgently needed.
Duration and determinants of delayed tuberculosis diagnosis and treatment in high-burden countries: a mixed-methods systematic review and meta-analysis
Authors: Teo Alvin Kuo Jing , Singh Shweta R. , Prem Kiesha , Hsu Li Yang , Yi Siyan 
Published: September 2021

Abstract
Background
Thirty countries with the highest tuberculosis (TB) burden bear 87% of the world’s TB cases. Delayed diagnosis and treatment are detrimental to TB prognosis and sustain TB transmission in the community, making TB elimination a great challenge, especially in these countries. Our objective was to elucidate the duration and determinants of delayed diagnosis and treatment of pulmonary TB in high TB-burden countries.

Methods
We conducted a systematic review and meta-analysis of quantitative and qualitative studies by searching four databases for literature published between 2008 and 2018 following PRISMA guidelines. We performed a narrative synthesis of the covariates significantly associated with patient, health system, treatment, and total delays. The pooled median duration of delay and effect sizes of covariates were estimated using random-effects meta-analyses. We identified key qualitative themes using thematic analysis.

Results
This review included 124 articles from 14 low- and lower-middle-income countries (LIC and LMIC) and five upper-middle-income countries (UMIC). The pooled median duration of delays (in days) were—patient delay (LIC/LMIC: 28 (95% CI 20–30); UMIC: 10 (95% CI 10–20), health system delay (LIC/LMIC: 14 (95% CI 2–28); UMIC: 4 (95% CI 2–4), and treatment delay (LIC/LMIC: 14 (95% CI 3–84); UMIC: 0 (95% CI 0–1). There was consistent evidence that being female and rural residence was associated with longer patient delay. Patient delay was also associated with other individual, interpersonal, and community risk factors such as poor TB knowledge, long chains of care-seeking through private/multiple providers, perceived stigma, financial insecurities, and poor access to healthcare. Organizational and policy factors mediated health system and treatment delays. These factors included the lack of resources and complex administrative procedures and systems at the health facilities. We identified data gaps in 11 high-burden countries.

Conclusions
This review presented the duration of delays and detailed the determinants of delayed TB diagnosis and treatment in high-burden countries. The gaps identified could be addressed through tailored approaches, education, and at a higher level, through health system strengthening and provision of universal health coverage to reduce delays and improve access to TB diagnosis and care.
PROSPERO registration: CRD42018107237.
USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4
Authors: Pan Tingzheng , Li Xuetao , Li Yanyan , Tao Zhennan , Yao Hui , Wu Yue , Chen Guangliang , Zhang Kai , Zhou Youxin , Huang Yulun 
Published: September 2021

Abstract
Background
Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM.

Methods
Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7.

Results
Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes.

Conclusions
Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM.
Extended classifier system with continuous real-coded variables for feature extraction of instantaneous pulse-rate variability and respiration of individuals with gaming disorder
Authors: Chi Hung-Ming , Hsiao Tzu-Chien 
Published: September 2021

Abstract
Background
Individuals with gaming disorder (GD) exhibit autonomic nervous system responses that indicate dysfunctional emotion regulation. Pulse rate variability (PRV) is a valuable biomarker for investigating the autonomic function of patients with mental disorders. Because individuals with GD dynamically regulate emotions during gaming, the PRV response relating to GD is not well understood. To investigate the dynamic PRV responses of individuals with GD, this study proposed the indexes of instantaneous PRV (iPRV) and instantaneous respiratory frequency (IFresp) of arterial blood pressure signals using empirical mode decomposition and normalized direct-quadrature algorithms. iPRV consists of low-frequency (LF), high-frequency (HF), and very high-frequency (VHF) bands. Moreover, a novel method of extended classifier system with continuous real-coded variables (XCSR) was used to detect GD and extract GD-related iPRV features using iPRV and IFresp as input data.

Results
A total of 32 college students without depressive and anxiety symptoms or cardiovascular diseases were recruited in this study. Participants were grouped into the high-risk GD and low-risk GD using both Chen Internet Addiction Scale and Internet Gaming Disorder Questionnaire. Their arterial blood pressures signals were measured while they watched gameplay videos with negative or positive emotional stimuli. Seven participants with high-risk GD exhibited significantly increased normalized VHF (nVHF) PRV and IFresp readings and significantly decreased normalized LF (nLF) PRV readings and LF/HF PRV ratios (from baseline) during negative or positive gameplay videos stimuli. These participants also exhibited higher nVHF PRV and lower nLF PRV readings and LF/HF PRV ratios when they experienced negative gameplay video stimuli relative to 17 participants with low-risk GD. The classification accuracy of the XCSR reached 90% for both negative and positive video stimuli, and nVHF PRV was most frequently used to detect GD risk.

Conclusions
iPRV and IFresp can be used to detect GD and analyze the autonomic mechanism of individuals with GD.
‘It was hell in the community’: a qualitative study of maternal and child health care during health care worker strikes in Kenya
Authors: Scanlon Michael L. , Maldonado Lauren Y. , Ikemeri Justus E. , Jumah Anjellah , Anusu Getrude , Chelagat Sheilah , Keter Joann Chebet , Songok Julia , Ruhl Laura J. , Christoffersen-Deb Astrid 
Published: September 2021

Abstract
Background
Health care workers in Kenya have launched major strikes in the public health sector in the past decade but the impact of strikes on health systems is under-explored. We conducted a qualitative study to investigate maternal and child health care and services during nationwide strikes by health care workers in 2017 from the perspective of pregnant women, community health volunteers (CHVs), and health facility managers.

Methods
We conducted in-depth interviews and focus group discussions (FGDs) with three populations: women who were pregnant in 2017, CHVs, and health facility managers. Women who were pregnant in 2017 were part of a previous study. All participants were recruited using convenience sampling from a single County in western Kenya. Interviews and FGDs were conducted in English or Kiswahili using semi-structured guides that probed women’s pregnancy experiences and maternal and child health services in 2017. Interviews and FGDs were audio-recorded, translated, and transcribed. Content analysis followed a thematic framework approach using deductive and inductive approaches.

Results
Forty-three women and 22 CHVs participated in 4 FGDs and 3 FGDs, respectively, and 8 health facility managers participated in interviews. CHVs and health facility managers were majority female (80%). Participants reported that strikes by health care workers significantly impacted the availability and quality of maternal and child health services in 2017 and had indirect economic effects due to households paying for services in the private sector. Participants felt it was the poor, particularly poor women, who were most affected since they were more likely to rely on public services, while CHVs highlighted their own poor working conditions in response to strikes by physicians and nurses. Strikes strained relationships and trust between communities and the health system that were identified as essential to maternal and child health care.

Conclusion
We found that the impacts of strikes by health care workers in 2017 extended beyond negative health and economic effects and exacerbated fundamental inequities in the health system. While this study was conducted in one County, our findings suggest several potential avenues for strengthening maternal and child health care in Kenya that were highlighted by nationwide strikes in 2017.
Valuing child and adolescent health: a qualitative study on different perspectives and priorities taken by the adult general public
Authors: Powell Philip A. , Rowen Donna , Rivero-Arias Oliver , Tsuchiya Aki , Brazier John E. 
Published: September 2021

AbstractBackgroundQuantitative health preference research has shown that different “perspectives”, defined here as who is imagined to be experiencing particular health states, impact stated preferences. This qualitative project aimed to elucidate this phenomenon, within the context of adults’ valuation of child and adolescent health states.MethodsSix focus groups with 30 members of the UK adult public were conducted between December 2019 and February 2020 and analysed using framework analysis. Each focus group had two stages. First, participants individually completed time trade-off tasks and a pairwise task (mirroring a discrete choice experiment without duration) for two EQ-5D-Y health states, assuming a series of perspectives: (a) themselves at current age; (b) another adult; (c) 10-year old child; (d) themselves as a 10-year old child. Second, a semi-structured discussion explored their responses.ResultsParticipants’ views were often heterogeneous, with some common themes. Qualitatively, participants expressed a different willingness to trade-off life years for a 10-year old child versus themselves or another adult, and this differed by the health profile and child imagined. The same health states were often viewed as having a different impact on utility for a 10-year old child than adults. Imagining a 10-year old child is difficult and there is variation in who is imagined. Participants found answering based on their own—adult perspective most acceptable. There were no strong preferences for prioritising child health over working-age adults’ health.ConclusionsIf an adult sample is used to value child- and adolescent-specific health states it is important to consider the perspective employed. Members of the adult public provide different responses when different perspectives are used due to differences in the perceived impact of the same health states. If adults are asked to imagine a child, we recommend that sampling is representative for parental status, since this can affect preferences.
Cytometric analysis of patients with COVID-19: what is changed in the second wave?
Authors: Scalia Giulia , Raia Maddalena , Gelzo Monica , Cacciapuoti Sara , De Rosa Annunziata , Pinchera Biagio , Scotto Riccardo , Giaccone Agnese , Mormile Mauro , Fabbrocini Gabriella , Gentile Ivan , Parrella Roberto , Castaldo Giuseppe 
Published: September 2021

Abstract
Background
Coronavirus disease 2019 (COVID-19) pandemic had a 1st wave in Europe from March to May 2020 and a 2nd wave since September 2020. We previously studied 35 hospitalized COVID-19 patients of the 1st wave demonstrating a cytokine storm and the exhaustion of most lymphocyte subpopulations. Herein, we describe the results obtained from COVID-19 patients of the 2nd wave.

Methods
We analyzed interleukin (IL)-6 by human-specific enzyme-linked immunosorbent assay and a large set of lymphocyte subpopulations by flow cytometry in 274 COVID-19 patients hospitalized from September 2020 to May 2021.

Results
Patients of 2nd wave compared with those of 1st wave showed lower serum IL-6 levels and a higher number of B and most T lymphocyte subpopulations in advanced stages, in relation with the age and the gender. On the other hand, we observed in 2nd wave patients: (i) a reduction of most lymphocyte subpopulations at mild and moderate stages; (ii) a reduction of natural killer cells and T regulatory cells together with a higher number of activated T helper (TH) 17 lymphocytes in all stages, which were mainly related to steroid and azithromycin therapies before hospitalization.

Conclusions
COVID-19 had a less severe impact in patients of the 2nd wave in advanced stages, while the impact appeared more severe in patients of mild and moderate stages, as compared with 1st wave patients. This finding suggests that in COVID-19 patients with milder expression at diagnosis, steroid and azithromycin therapies appear to worsen the immune response against the virus. Furthermore, the cytometric profile may help to drive targeted therapies by monoclonal antibodies to modulate specific IL/lymphocyte inhibition or activation in COVID-19 patients.
Rapid generation of conditional knockout mice using the CRISPR-Cas9 system and electroporation for neuroscience research
Authors: Nishizono Hirofumi , Hayano Yuki , Nakahata Yoshihisa , Ishigaki Yasuhito , Yasuda Ryohei 
Published: September 2021

AbstractThe Cre/LoxP-based conditional knockout technology is a powerful tool for gene function analysis that allows region- and time-specific gene manipulation. However, inserting a pair of LoxP cassettes to generate conditional knockout can be technically challenging and thus time- and resource-consuming. This study proposes an efficient, low-cost method to generate floxed mice using in vitro fertilization and the CRISPR-Cas9 system over two consecutive generations. This method allowed us to produce floxed mice targeting exons 5 and 6 of CaMK1 in a short period of 125 days, using only 16 mice. In addition, we directly edited the genome of fertilized eggs of mice with our target genetic background, C57BL/6 N, to eliminate additional backcrossing steps. We confirmed that the genome of the generated floxed mice was responsive to the Cre protein. This low-cost, time-saving method for generating conditional knockout will facilitate comprehensive, tissue-specific genome analyses.
Targeting the DNA damage response enhances CD70 CAR-T cell therapy for renal carcinoma by activating the cGAS-STING pathway
Authors: Ji Feng , Zhang Fan , Zhang Miaomiao , Long Kaili , Xia Mingyue , Lu Fei , Li Enjie , Chen Jiannan , Li Jun , Chen Zhengliang , Jing Li , Jia Shaochang , Yang Rong , Hu Zhigang , Guo Zhigang 
Published: September 2021

AbstractChimeric antigen receptor T-cell (CAR-T) therapy has shown tremendous success in eradicating hematologic malignancies. However, this success has not yet been extrapolated to solid tumors due to the limited infiltration and persistence of CAR-T cells in the tumor microenvironment (TME). In this study, we screened a novel anti-CD70 scFv and generated CD70 CAR-T cells that showed effective antitumor functions against CD70+ renal carcinoma cells (RCCs) both in vitro and in vivo. We further evaluated the effect and explored the molecular mechanism of a PARP inhibitor (PARPi) in CAR-T cell immunotherapy by administering the PARPi to mouse xenografts model derived from human RCC cells. Treatment with the PARPi promoted CAR-T cell infiltration by stimulating a chemokine milieu that promoted CAR-T cell recruitment and the modulation of immunosuppression in the TME. Moreover, our data demonstrate that PARPi modulates the TME by activating the cGAS-STING pathway, thereby altering the balance of immunostimulatory signaling and enabling low-dose CAR-T cell treatment to induce effective tumor regression. These data demonstrate the application of CD70 CAR-T cell therapeutic strategies for RCC and the cross-talk between targeting DNA damage responses and antitumor CAR-T cell therapy. These findings provide insight into the mechanisms of PARPis in CAR-T cell therapy for RCC and suggest a promising adjuvant therapeutic strategy for CAR-T cell therapy in solid tumors.
The pattern of health insurance economic resilience in the Covid 19 pandemic shock
Authors: Kharazmi Erfan , Bordbar Shima , Gholampoor Hanie 
Published: September 2021

Abstract
Objective
Health insurance is based on people’s significant risks in receiving health services that they cannot afford alone. Since the outbreak of the corona epidemic, the health insurance system has suffered many economic problems. Designing a model of a health insurance system based on the requirements of a resilient economy can improve the functions of this system in the corona crisis.

Results
In this research 12, structural components were obtained in the form of 4 conceptual components. The 4 main conceptual components are Knowledge-based economy, Economic stability, Economic resilience, and justice. The knowledge-based economy is the basis for the formation of economic resilience in the health insurance systems. Health insurance systems will achieve two crucial intermediate results, namely economic resilience, and economic stability, by building the basic infrastructure of a knowledge-based economy. In the long run, maintaining such intermediate results is the foundation of justice in the health insurance system.
Evaluating context and interest in training in evidence-based mental health care: a qualitative investigation among healthcare providers in Kyiv, Ukraine
Authors: Hook Kimberly , Kozishkurt Julia , Kovalchuk Olga , Goncharenko Evelina , Kodovbetskyi Vitalii , Opanasenko Milana , Kopytko Andrii , Girnyk Andriy , Kliuzko Kateryna , Drainoni Mari-Lynn , Bogdanov Sergiy 
Published: September 2021

Abstract
Objective
Increasing access to quality, evidence-based mental health treatments, including psychotherapy, is a global priority. Knowledge of factors associated with delivery settings is critical to ensure that new practices are appropriate and effectively adapted for novel settings. Understanding perceived needs for training and interest in ongoing education is one key factor. This qualitative study aimed to identify perspectives on contemporary evidence-based psychotherapies, perceived needs for mental health training, and existing barriers and facilitators to provision of mental health services in community clinics in Ukraine. Purposive and snowball sampling was used to recruit 18 physicians and psychologists employed in community clinics in Kyiv. A combination of free-listing and semi-structured interviews was used to collect data, which were thematically coded using emergent coding.

Results
Findings from this study indicated that participants recognize a need for improved mental health knowledge and training, as well as suggested interest and openness to learning short-term, structured psychological interventions. Additional barriers and existing strengths described by participants provide insight into possible factors that may impact future trainings in and implementation of modern mental health approaches.