bluuebunny/crossref_metadata_2025 huggingface dataset:
TOP2A deficiency leads to human recurrent spontaneous abortion and growth retardation of mouse pre-implantation embryos
Authors: Duan Yuhan , Fu Huijia , Huang Jiayu , Yin Nanlin , Liu Linhong , Liu Xiru
Published: December 2022

Background

Recurrent spontaneous abortion (RSA), is a dangerous pregnancy-related condition and is a subject of debate in the gynaecology and obstetrics communities. The objective of this study was to determine the function of DNA Topoisomerase II Alpha (TOP2A) in RSA and elucidate the underlying molecular mechanisms.

Methods

In vitro models of TOP2A-knockdown and -overexpression were generated by transfecting specific sh-RNA lentivirus and overexpression plasmid, respectively. An in vitro TOP2A inhibition model was established by culturing mouse embryos at the two-cell stage in a medium containing PluriSIn2, a TOP2A inhibitor. Immunohistochemical staining was used to analyse expression of TOP2A in villi tissues of patients with RSA. Western blotting and qRT-PCR were used to analyse the expression of TOP2A and proteins involved in trophoblast functions, the FOXO signalling pathway, and the development of pre-implantation embryos. 5-Ethynyl-2′-deoxyuridine staining, TUNEL assay and flow cytometry were used to further evaluate the effect of TOP2A on cell proliferation and apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. Moreover, the effect of TOP2A inhibitor on embryos was determined by immunofluorescence and mitochondrial-related dyes.

Results

Evaluation of clinical samples revealed that the villi tissues of patients that have experienced RSA had lower TOP2A expression compared with that from women who have experienced normal pregnancy (P < 0.01). In vitro, TOP2A knockdown decreased the proliferation, migration, and invasion of trophoblast cell lines, and increased apoptosis and activation of the FOXO signalling pathway (P < 0.05). Conversely, TOP2A overexpression reversed these effects. Moreover, in vivo experiments confirmed that inhibition of TOP2A impairs trophectoderm differentiation, embryonic mitochondrial function as well as the developmental rate; however, no differences were noted in the expression of zygotic genome activation-related genes.

Conclusions

Collectively, our data suggest that lower TOP2A expression is related to RSA as it inhibits trophoblast cell proliferation, migration, and invasion by activation of the FOXO signalling pathway. Additionally, TOP2A inhibition resulted in impaired development of pre-implantation embryos in mice, which could be attributed to excessive oxidative stress.

Graphical Abstract
PrEP risk perception and adherence among men who have sex with men: a prospective cohort study based on growth mixture model
Authors: Lin Bing , Liu Jiaxiu , Zhong Xiaoni
Published: December 2022

Background

It can be considered that pre-exposure prophylaxis (PrEP) risk perception is the negative experiences or concerns about taking PrEP. The aim of this study is to explore the longitudinal trajectory of PrEP risk perception among men who have sex with men (MSM) and its impact on adherence.

Methods

Data related to PrEP risk perception and adherence were derived from a prospective cohort study in Western China from 2013 to 2015. Subjects were categorized into the time-driven, event-driven and blank control groups. Tenofovir disoproxil fumarate (TDF) was administered to subjects in the time-driven and event-driven groups, and all subjects were followed up every 12 weeks. The PrEP risk perception scale was constructed, and the growth mixture model (GMM) was used to classify longitudinal PrEP risk perception. The effect of different levels of PrEP risk perception on drug adherence was explored using generalized estimating equations (GEE) with relative risk (RR) and 95% confidence interval (CI).

Results

The PrEP risk perception scale consists of 4 dimensions and 16 items with Cronbach's alpha = 0.828 and a good model fit. According to the GMM analysis, the subjects' PrEP risk perceptions were separated into two groups: a "high-risk perception group" (n = 133) and a "low-risk perception group" (n = 493), where the proportion of high levels of drug adherence were 57.89% and 68.35%, respectively (p = 0.024). High levels of PrEP risk perception in the MSM population hinder drug adherence (RR = 0.71, 95% CI 0.50 to 0.99, p = 0.046). The results of this study were validated in the subsequent PrEP projects conducted in 2019 to 2021.

Conclusion

This study demonstrates that high levels of PrEP risk perception in the MSM population are an obstacle to drug adherence, emphasizing the necessity of focusing on PrEP risk perception in this population and the value of its application in the current context.
Cardiovascular events and mortality in chronic kidney disease in primary care patients with previous type 2 diabetes and/or hypertension. A population-based epidemiological study (KIDNEES)
Authors: Cunillera-Puértolas Oriol , Vizcaya David , Cerain-Herrero M. Jesús , Gil-Terrón Neus , Cobo-Guerrero Silvia , Salvador-González Betlem
Published: December 2022

Background

Chronic Kidney Disease (CKD), Type 2 Diabetes (T2D) and Hypertension (HTN) are frequently associated with adverse outcomes. We aimed to estimate the impact of a prior diagnosis of T2D and/or HTN on clinical characteristics, cardiovascular events (CVE) and all-cause mortality (ACM) of patients with CKD.

Methods

We conducted a retrospective cohort study based on primary care electronic health records of people without atherosclerotic cardiovascular disease, aged 18–90 years with incident CKD between January 1, 2007, and December 31, 2017. The association between CKD groups classified according to prior diagnosis of T2D and/or HTN and risk of ACM and CVE at follow-up was evaluated with Cox and Fine-Gray regression models, respectively.

Results

398,477 patients were included. Median age was 74 years and 55.2% were women. Individuals were classified as CKD with HTN (51.9%), CKD with T2D (3.87%), CKD with HTN/T2D (31.4%) and CKD without HTN/T2D (12.9%). In the multivariate analysis, with the CKD without HTN/T2D group as reference, the ACM Hazard Ratio (HR) was 0.74 (95%CI 0.72–0.75) for the CKD with HTN group, 0.81 (95%CI 0.79–0.83) for CKD with HTN/T2D and 1.14 (95%CI 1.10–1.19) for the CKD with T2D group. The sub distribution HRs for CVE were 1.40 (95%CI 1.34–1.47), 1.70 (95%CI 1.61–1.80) and 1.37 (95%CI 1.26–1.48), respectively.

Conclusion

In patients with CKD, the risk of ACM and CVE differed in patients with previous HTN and/or T2D. These comorbidities can help identify individuals at higher risk of adverse outcomes and improve the management of patients with CKD in primary care.
Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial
Authors: Borgers J. S. W. , Burgers F. H. , Terveer E. M. , van Leerdam M. E. , Korse C. M. , Kessels R. , Flohil C. C. , Blank C. U. , Schumacher T. N. , van Dijk M. , Henderickx J. G. E. , Keller J. J. , Verspaget H. W. , Kuijper E. J. , Haanen J. B. A. G.
Published: December 2022

Background

The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT.

Methods

In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells.

Discussion

Transplanting fecal microbiota to restore the patients’ perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness.

Trial registration

ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08–02-2022).
SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer
Authors: Gao Wen , Liu Dongli , Sun Haiyan , Shao Zhuyan , Shi Peipei , Li Tingting , Yin Sheng , Zhu Tao
Published: December 2022

Background

Secreted phosphoprotein 1 (SPP1) plays a vital role in tumor progression of multiple cancer types However, it still awaits further exploration whether SPP1 is a bystander or an actual player in the modulation of immune infiltration in ovarian cancer.

Methods

In this study, the expression level of SPP1 was identified by Oncomine, GEPIA and TIMER databases, and the result of SPP1 immumohistochemical staining was acquired by The HPA database. The impact of SPP1 expression level on the clinical outcome of ovarian cancer patients were evaluated via Kaplan–Meier Plotter and PrognoScan dataset. Immune infiltration analyses were conducted using TIMER and TISIDB dataset. In addition, Functional enrichment analyses were performed with Metascape and GeneMANIA database. To verify these findings from the public database, the results were validated in a cohort of ovarian cancer patients.

Results

SPP1 was found to be overexpressed in ovarian tumor tissues and high SPP1 expression was correlated with shorter survivals. Notably, SPP1 expression was positively correlated with infiltrating levels of CD4 + T cells, CD8 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression level showed strong correlation with diverse immune cells in ovarian cancer. Of note, functional enrichment analysis suggested that SPP1 was strongly correlated with immune response.

Conclusions

These findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in ovarian cancer.

Trial registration

Not applicable.
Infant in extremis: respiratory failure secondary to lower airway infantile hemangioma
Authors: MacDougall Matthew S. , Afzal Sarah Y. , Freedman Michael S. , Han Peggy
Published: December 2022

Background

Infantile hemangiomas (IHs) are vascular tumors that commonly affect infants and usually regress spontaneously or can be easily treated as an outpatient with topical beta-blockers. However, IHs that present in the airway may cause life-threatening symptoms due to airway obstruction or risk of bleeding. Here we present the first documented case of an infant with rapid deterioration and acute respiratory failure secondary to a lower airway hemangioma.

Case presentation

This 3-month-old male initially presented in respiratory distress with symptoms consistent with a viral respiratory infection, however showed no clinical improvement with standard therapies. An urgent CT scan revealed a mass occluding the right mainstem bronchus. Upon transfer to a tertiary care facility, he developed acute respiratory failure requiring emergent intubation and single lung ventilation. The availability of multiple subspecialists allowed for stabilization of a critically ill child, expedited diagnosis, and ultimately initiation of life-saving treatment with beta blockers. After 17 total hospital days, he was extubated successfully and discharged home in good condition.

Conclusions

While IH is a rare cause of infantile respiratory distress, we present multiple pearls for the general pediatrician for management of IHs of the airway.
ARIMA model for predicting chronic kidney disease and estimating its economic burden in China
Authors: Jian Yining , Zhu Di , Zhou Dongnan , Li Nana , Du Han , Dong Xue , Fu Xuemeng , Tao Dong , Han Bing
Published: December 2022

Background

Chronic kidney disease (CKD) is an important global public health issue. In China, CKD affects a large number of patients and causes a huge economic burden. This study provided a new way to predict the number of patients with CKD and estimate its economic burden in China based on the autoregressive integrated moving average (ARIMA) model.

Methods

Data of the number of patients with CKD in China from 2000 to 2019 were obtained from the Global Burden of Disease. The ARIMA model was used to fit and predict the number of patients with CKD. The direct and indirect economic burden of CKD were estimated by the bottom-up approach and the human capital approach respectively.

Results

The results of coefficient of determination (0.99), mean absolute percentage error (0.26%), mean absolute error (343,193.8) and root mean squared error (628,230.3) showed that the ARIMA (1,1,1) model fitted well. Akaike information criterion (543.13) and Bayesian information criterion (546.69) indicated the ARIMA (1,1,1) model was reliable when analyzing our data. The result of relative error of prediction (0.23%) also suggested that the model predicted well. The number of patients with CKD in 2020 to 2025 was predicted to be about 153 million, 155 million, 157 million, 160 million, 163 million and 165 million respectively, accounting for more than 10% of the Chinese population. The total economic burden of CKD from 2019 to 2025 was estimated to be $179 billion, $182 billion, $185 billion, $188 billion, $191 billion, $194 billion and $198 billion respectively.

Conclusion

The number of patients with CKD and the economic burden of CKD will continue to rise in China. The number of patients with CKD in China would increase by 2.6 million (1.6%) per year on average from 2020 to 2025. Meanwhile, the total economic burden of CKD in China would increase by an average of $3.1 billion per year. The ARIMA model is applicable to predict the number of patients with CKD. This study provides a new perspective for more comprehensive understanding of the future risk of CKD.
Comparison of periodontal status and salivary IL-15 and -18 levels in cigarette-smokers and individuals using electronic nicotine delivery systems
Authors: Ali Dena , Kuyunov Isaac , Baskaradoss Jagan Kumar , Mikami Toshinari
Published: December 2022

Background

It is hypothesized that periodontal status is compromised and whole salivary (WS) interleukin (IL)-15 and IL-18 levels are higher among cigarette-smokers and electronic-nicotine-delivery-systems (ENDS)-users than never-smokers. The aim of the present case–control study was to compare the periodontal status and WS IL-15 and -18 levels among cigarette-smokers, ENDS-users and controls (never-smokers).

Methods

Participants were divided into 4 groups as follows: Group-1:Current cigarette-smokers; Group-2:ENDS-users; Group-3:Never-smokers with periodontitis; and Group-4: Never-smokers without periodontitis. Demographic data was collected and plaque index (PI), gingival index (GI), probing-depth (PD), clinical attachment-loss (AL), and marginal bone loss (MBL) were measured. Number of missing teeth were recorded and WS IL-15 and IL-18 levels were determined. Group-comparisons were done and P < 0.01 was selected as an indicator of statistical analysis.

Results

Nineteen, 18, 19 and 19 individuals were enrolled in groups 1, 2, 3 and 4, respectively. Scores of PI, clinical AL, PD, and number of missing-teeth were elevated in groups 1(P < 0.001), 2 (P < 0.001) and 3 (P < 0.001) than -4. Scores of PI, clinical AL, PD, MBL and missing teeth were comparable among patients in groups 1, 2 and 3. Levels of IL-15 and IL-18 were elevated in groups 1 (P < 0.001) and 2 (P < 0.001) than groups 3 and 4. The levels of IL-15 and -18 were higher in Group-3 than in Group-4 (P < 0.001).

Conclusion

Clinically, cigarette-smokers and never-smokers demonstrate similar periodontal statuses; however, WS immunoinflammatory biomarkers (IL-15 and -18) are elevated in these individuals than non-smokers.
Evaluation of antenatal point-of-care ultrasound training workshops for rural/remote healthcare clinicians: a prospective single cohort study
Authors: Bidner Amber , Bezak Eva , Parange Nayana
Published: December 2022

Background

There is limited access to life-saving antenatal ultrasound in low-resource rural and remote settings worldwide, including Australia, mainly due to shortages in skilled staff. Point-of-care ultrasound (PoCUS) offers a viable solution to this service deficit, however, rural clinicians face many barriers accessing training and professional development critical to advancing their clinical practice. Standards for PoCUS training and competency assessment are unclear. Regulation is lacking globally, allowing untrained and inexperienced clinicians to practice PoCUS clinically.

Methods

This prospective single cohort study aimed to evaluate antenatal PoCUS training workshops for General Practitioners (GPs) and Midwives/Nurses (M/Ns) from rural/remote Australia, assessing the impact of the training on trainees’ knowledge, confidence and translation of PoCUS into clinical practice. Two-day antenatal ultrasound workshops were delivered at the University of South Australia (UniSA) in 2018 and 2019 to 41 rural/remote clinicians . The training was designed and evaluated using the New world Kirkpatrick Evaluation Framework. Sixteen GPs and 25 M/Ns with mixed prior ultrasound experience were funded to attend. The course consisted of lectures interspaced with hands-on training sessions using high-fidelity simulators and live pregnant models. Pre- and post-knowledge assessments were performed. Post-workshop evaluation and follow-up surveys (3- and 6-month post-training) assessed the workshops and changes to trainees’ clinical practice. A 2-day follow-up training session was conducted 12 months after the workshops for 9 trainees.

Results

Pre/post knowledge testing demonstrated a 22% mean score improvement (95% CI 17.1 to 27.8,P < 0.0001). At 6 months, 62% of trainees were performing PoCUS that had assisted in patient management and clinical diagnosis, and 46% reported earlier diagnosis and changes to patient management. 74% of trainees had increased scanning frequency and 93% reported improved scanning confidence.

Conclusion

This study demonstrated intensive 2-day workshops can equip clinicians with valuable antenatal PoCUS skills, offering a viable solution to assist in the assessment and management of pregnant women in the rural/resource-poor setting where access to ultrasound services is limited or non-existent. Geographical isolation and lack of onsite specialist supervision poses an ongoing challenge to the continuing professional development of remote trainees and the implementation of PoCUS.
Perceptions of portfolio assessment in family medicine graduates: a qualitative interview study
Authors: AlRadini Faten A.
Published: December 2022

Background

The use of the portfolio methodology in medical education can serve as a tool for learning, assessment, and reflection on practice. This study concentrates on perceptions of the portfolio assessment methodology among participants in the Saudi Diploma of Family Medicine program.

Methods

In this qualitative interview study, data were collected and analysed using a grounded theory approach.

Results

Nine codes emerged: (1) Importance of understanding the definition, objectives, and process of portfolio assessment, (2) Impact of different understandings on the part of various trainers, (3) Role of the type of assessment, (4) Workload and stress of portfolio assessment, (5) Effectiveness of the portfolio contents, (6) Role of the mentor’s feedback, (7) Role in the learning process, (8) Role in practice, (9) Suggestions for portfolio improvement. Open codes were then regrouped into three axial codes: context, strategy, and outcome of portfolio assessment.

Conclusion

This study explored a general explanation of portfolio assessment shaped by the postgraduate students. It identifies the importance of portfolio understanding in student acceptability of the portfolio assessment methodology. Thus, proper implementation is vital for the success of assessing the student by the portfolio methodology. The students perceived reflection as the most valuable part of the process, which facilitated their learning, confidence, and self-assessment. Mentor feedback is a good strategy for coping with portfolio challenges. Our findings provide some evidence of positive outcomes of portfolio assessment in practice and professional development.
Exploring sustainable care pathways - a scoping review
Authors: Sather Eva Walderhaug , Iversen Valentina Cabral , Svindseth Marit Folsvik , Crawford Paul , Vasset Frøydis
Published: December 2022

Background

Patients with mental health problems experience numerous transitions into and out of hospital.

Aim

The review studies assessing clinical care pathways between psychiatric hospitalization and community health services.

Methods

We used publications between 2009–2020 to allow a broad scoping review of the published research. Sixteen review-articles were identified, 12 primary studies were chosen, both on care pathways in the transition between psychiatric hospital and community.

Results

Organizational issues: Systems and procedures to ensure clear responsibilities and transparency at each stage of the pathways of care. Resources: Information-technology in objectively improving patient outcome. Information/documentation: Providing patients with adequate structured information and documented plans at the appropriate time. Patient/families: Continuous collaborative decision-making. Clinical care and teamwork: Collaboration between mental health and other professionals to guarantee that planned activities meet patient need. Ethical issues: Respectful communication and patient-centred, non-humiliating care.

Conclusions

System and procedures ensure clear responsibilities and transparency. Information technology support decision-making and referral and objectively improve patient outcomes in care pathways. Collaboration between mental health and other professionals guarantee that planned activities meet patients’ needs along with regular meetings sharing key information. Around-the-clock ambulant-teams important to transition success. Informed-shared decision-making between parties, support patient participation and respectful communication.
How a point-of-care dashboard facilitates co-production of health care and health for and with individuals with psychotic disorders: a mixed-methods case study
Authors: Gremyr Andreas , Holmberg Christopher , Thor Johan , Malm Ulf , Gäre Boel Andersson , Andersson Ann-Christine
Published: December 2022

Background

Individuals with psychotic disorders experience widespread treatment failures and risk early death. Sweden’s largest department specializing in psychotic disorders sought to improve patients’ health by developing a point-of-care dashboard to support joint planning and co-production of care. The dashboard was tested for 18 months and included more than 400 patients at two outpatient clinics.

Methods

This study evaluates the dashboard by addressing two questions:

Can differences in health-related outcome measures be attributed to the use of the dashboard?

How did the case managers experience the accessibility, use, and usefulness of the dashboard for co-producing care with individuals with psychotic disorders?

This mixed-method case study used both Patient-Reported Outcome Measures (PROM) and data from a focus group interview with case managers. Data collection and analysis were framed by the Clinical Adoption Meta Model (CAMM) phases: i) accessibility, ii) system use, iii) behavior, and iv) clinical outcomes. The PROM used was the 12-item World Health Organization Disability Assessment Schedule (WHODAS 2.0), which assesses functional impairment and disability. Patients at clinics using the dashboard were matched with patients at clinics not using the dashboard. PROM data were compared using non-parametric statistics due to skewness in distribution. The focus group included five case managers who had experience using the dashboard with patients.

Results

Compared to patients from clinics that did not use the dashboard, patients from clinics that did use the dashboard improved significantly overall (p = 0.045) and in the domain self-care (p = 0.041). Focus group participants reported that the dashboard supported data feedback-informed care and a proactive stance related to changes in patients’ health. The dashboard helped users identify critical changes and enabled joint planning and evaluation.

Conclusion

Dashboard use was related to better patient health (WHODAS scores) when compared with matched patients from clinics that did not use the dashboard. In addition, case managers had a positive experience using the dashboard. Dashboard use might have lowered the risk for missing critical changes in patients’ health while increasing the ability to proactively address needs. Future studies should investigate how to enhance patient co-production through use of supportive technologies.
Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders
Authors: Auvinen P. , Vehviläinen J. , Marjonen H. , Modhukur V. , Sokka J. , Wallén E. , Rämö K. , Ahola L. , Salumets A. , Otonkoski T. , Skottman H. , Ollikainen M. , Trokovic R. , Kahila H. , Kaminen-Ahola N.
Published: December 2022

Background

Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth.

Methods

We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro.

Results

DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered—particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development.

Conclusions

Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.
Improved natural melanin production by Aspergillus nidulans after optimization of factors involved in the pigment biosynthesis pathway
Authors: Medeiros William Bartolomeu , Medina Kelly Johana Dussán , Sponchiado Sandra Regina Pombeiro
Published: December 2022

Background

Melanin is a natural pigment that can be applied in different fields such as medicine, environment, pharmaceutical, and nanotechnology. Studies carried out previously showed that the melanin produced by the mel1 mutant from Aspergillus nidulans exhibits antioxidant, anti-inflammatory, and antimicrobial activities, without any cytotoxic or mutagenic effect. These results taken together suggest the potential application of melanin from A. nidulans in the pharmaceutical industry. In this context, this study aimed to evaluate the effect of factors L-tyrosine, glucose, glutamic acid, l-DOPA, and copper on melanin production by the mel1 mutant and to establish the optimal concentration of these factors to maximize melanin production.

Results

The results showed that l-DOPA, glucose, and copper sulfate significantly affected melanin production, where l-DOPA was the only factor that exerted a positive effect on melanin yield. Besides, the tyrosinase activity was higher in the presence of l-DOPA, considered a substrate required for enzyme activation, this would explain the increased production of melanin in this condition. After establishing the optimal concentrations of the analyzed factors, the melanin synthesis was increased by 640% compared to the previous studies.

Conclusions

This study contributed to elucidating the mechanisms involved in melanin synthesis in A. nidulans as well as to determining the optimal composition of the culture medium for greater melanin production that will make it possible to scale the process for a future biotechnological application.
The whole-of-society approach of mass COVID-19 vaccination in China: a qualitative study
Authors: Wang Qian , Qu Zhiqiang , Tu Shiyi , Chen Xi , Hou Zhiyuan
Published: December 2022

Background

Many countries have an inefficient vaccination system, which hinders global exit from the COVID-19 pandemic. It is vital to summarize COVID-19 vaccination practices in countries with high vaccination coverage and provide implications for other countries. This study aimed to investigate China’s COVID-19 vaccination system and to summarize its implementation experience from a health system perspective.

Methods

We conducted key informant interviews in five representative cities of China in late 2021. Guided by the health systems framework proposed by WHO, we developed our interview guidelines which included seven building blocks—leadership and governance, health workforce, vaccination service delivery, vaccination mobilization and communication, financing, access to vaccines, and information systems. Semi-structured interviews and COVID-19 vaccination policy documents were collected and coded using a thematic analysis approach.

Results

A total of 61 participants (nine vaccination programme directors of the local Center for Disease Control and Prevention, four government staff and 48 vaccination service workers) were interviewed. We found that China adopted a whole-of-society approach with adequate government engagement and linked health and non-health sectors to promote COVID-19 vaccination. Key measures included the collaboration of multiple systems and departments from a governance perspective, allocating sufficient health workers and resources, large-scale vaccination mobilization and communication, expansion of vaccine financing channels, localized production and digital information systems. With the vaccination system strengthening, the two-doses vaccination coverage reached 89.5% for the total population but relatively lower coverage for older adults as of July 2022.

Conclusions

Our study highlights the importance of a government-led whole-of-society approach to promote mass vaccination. The low vaccination coverage among older adults should be paid the greatest attention to. The experiences and lessons from China may serve as a reference for other countries.
Modular hip exoskeleton improves walking function and reduces sedentary time in community-dwelling older adults
Authors: Jayaraman Chandrasekaran , Embry Kyle R. , Mummidisetty Chaithanya K. , Moon Yaejin , Giffhorn Matt , Prokup Sara , Lim Bokman , Lee Jusuk , Lee Younbaek , Lee Minhyung , Jayaraman Arun
Published: December 2022

Background

Despite the benefits of physical activity for healthy physical and cognitive aging, 35% of adults over the age of 75 in the United States are inactive. Robotic exoskeleton-based exercise studies have shown benefits in improving walking function, but most are conducted in clinical settings with a neurologically impaired population. Emerging technology is starting to enable easy-to-use, lightweight, wearable robots, but their impact in the otherwise healthy older adult population remains mostly unknown. For the first time, this study investigates the feasibility and efficacy of using a lightweight, modular hip exoskeleton for in-community gait training in the older adult population to improve walking function.

Methods

Twelve adults over the age of 65 were enrolled in a gait training intervention involving twelve 30-min sessions using the Gait Enhancing and Motivating System for Hip in their own senior living community.

Results

Performance-based outcome measures suggest clinically significant improvements in balance, gait speed, and endurance following the exoskeleton training, and the device was safe and well tolerated. Gait speed below 1.0 m/s is an indicator of fall risk, and two out of the four participants below this threshold increased their self-selected gait speed over 1.0 m/s after intervention. Time spent in sedentary behavior also decreased significantly.

Conclusions

This intervention resulted in greater improvements in speed and endurance than traditional exercise programs, in significantly less time. Together, our results demonstrated that exoskeleton-based gait training is an effective intervention and novel approach to encouraging older adults to exercise and reduce sedentary time, while improving walking function. Future work will focus on whether the device can be used independently long-term by older adults as an everyday exercise and community-use personal mobility device.

Trial registration This study was retrospectively registered with ClinicalTrials.gov (ID: NCT05197127).
Inhibition of NUCB2 suppresses the proliferation, migration, and invasion of rheumatoid arthritis synovial fibroblasts from patients with rheumatoid arthritis in vitro
Authors: Zhang Shuo , Zhang Tao , Xu Yayun , Rong Genxiang , Jing Juehua
Published: December 2022

Rheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SF) play a major role in cartilage and bone destruction through tumorlike proliferation, migration, and invasion. Nesfatin-1, an 82-amino-acid-long peptide discovered by Oh-I in 2006, is derived from the precursor protein nucleobindin-2 (NUCB2). NUCB2/nesfatin-1 promotes cell proliferation, migration, and invasion in various tumors. We have previously shown that increased nesfatin-1 levels in the synovium may be associated with disease severity in patients with RA. However, the effect of NUCB2 on the tumorlike transformation of RASF has not yet been reported. The expression of NUCB2 mRNA in the synovium of RA and non-RA patients was further confirmed using three individual datasets from the NCBI GEO database. Gene set enrichment analysis (GSEA) was employed to explore the association between NUCB2 mRNA and RA-related gene signatures or signaling pathways in the GSE77298 dataset. Cell proliferation, migration, and invasion abilities were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays, respectively. The results showed that the levels of NUCB2 mRNA in the synovium were significantly elevated in patients with RA. Moreover, GSEA showed that high expression of NUCB2 mRNA was related to gene signatures, including those involved in the cell cycle, DNA replication, extracellular matrix–receptor interaction, and focal adhesion. Furthermore, the results of CCK-8 and EdU assays indicated that inhibition of NUCB2 markedly repressed RASF proliferation. Additionally, the results of wound healing and transwell assays demonstrated that inhibition of NUCB2 significantly suppressed the migratory and invasive abilities of RASFs. Our findings are the first to demonstrate that the inhibition of NUCB2 suppresses the proliferation, migration, and invasion of RASFs in vitro.
Relation of dietary insulin index and dietary insulin load to metabolic syndrome depending on the lifestyle factors: Tehran lipid and glucose study
Authors: Khoshnoudi-Rad Bayyeneh , Hosseinpour-Niazi Somayeh , Javadi Maryam , Mirmiran Parvin , Azizi Fereidoun
Published: December 2022

Aim

The hypothesis of the effect of the insulinogenic effects of diet on the development of cardiovascular diseases has been proposed, but the findings of previous studies are very contradictory. We investigated the association between dietary insulin index (DII) and dietary insulin load (DIL), and metabolic syndrome (MetS) risk. Another objective was to examine the extent to which lifestyle (physical activity, smoking status, and weight change) and sex influence the relationship between DII, DIL, and MetS risk.

Materials and methods

We followed 1915 participants in the Tehran Lipid and Glucose Study. DIL and DII were calculated based on a validated food frequency questionnaire. Weight change was measured, and participants were categorized into > 3% weight loss, weight stable (± 3%), and > 3% weight gain. By joint classification, the association between DII and DIL (< median and ≥ median) and risk of MetS was assessed according to weight change, sex, physical activity levels, and smoking status. Cox proportional hazards models were used to estimate the HRs (95% CI), adjusting for potential confounders.

Results

During 8.9 years of follow-up, among 1915 participants, we documented 591 new cases of MetS. DII and DIL were not associated with MetS risk in the crude and adjusted models. However, DIL and DII were associated with weight gain (≥ 3%). In the crude model, DIL and DII were associated with a higher risk of weight gain [HR: 1.74: 95% CI 1.50–2.03, and 1.70 (1.46–1.98), respectively]. These associations remained significant after further adjustment for confounders. The HRs were 1.61 (1.35–1.92) for DIL and 1.64 (1.39–1.93) for DII. Among men, women, participants with low physical activity levels, and smokers, the risk of MetS, independent of DIL and DII, only increased in a participant with weight gain. In women with weight stability, DIL and DII, higher than the median, were positively associated with MetS risk.

Conclusion

Our findings suggest that the association between MetS risk and a hyperinsulinemic diet depended on weight change.
Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity
Authors: Campagna Maria Pia , Xavier Alexandre , Lea Rodney A. , Stankovich Jim , Maltby Vicki E. , Butzkueven Helmut , Lechner-Scott Jeannette , Scott Rodney J. , Jokubaitis Vilija G.
Published: December 2022

Background

The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene–environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker.

Methods

We conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis usingToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance.

Results

Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity.

Conclusion

RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.
Brucellosis with rare complications and review of diagnostic tests: a case report
Authors: Altunçekiç Yildirim Arzu , Kurt Celali , Çetinkol Yeliz
Published: December 2022

Background

Brucellosis is one of the most common zoonotic diseases in the world. Osteoarticular complications, especially vertebral system involvement, are most commonly reported. However, reports and coreports of pulmonary complications and thoracal spondylodiscitis and epidural abscess are rare.

Case presentation

Spondylodiscitis was detected at the T11–12 vertebral level, followed by epidural and paravertebral abscess, and then empyema was detected in a 17-year-old Asian female patient without any additional disease. The patient had used various antibiotics and the disease could not be proven bacteriologically. Also, the Rose Bengal test was negative. However, serologically high titer Brucella positivity was detected in the blood and pleural fluid sample. Drainage was required for bilateral empyema. Disease duration prolonged due to multiple complications. The patient was cured with combined long-term treatment for brucellosis.

Conclusions

Although some are rare, brucellosis is a zoonotic disease that can cause many complications. The gold standard for diagnosis is the growth of bacteria in blood culture or tissue culture. However, isolation of the microorganism can be very difficult. Clinical suspicion and serological tests are important guides.
Pediatric sigmoid colonic perforation with Campylobacter enterocolitis: a case report and review of the literature
Authors: Chu Yung-Yu , Lin Cheng-Yi , Kuo Tien-Lin , Mu Shu-Chi , Lau Beng-Huat , Chou Yuh-Yu
Published: December 2022

Background

Campylobacter-related infectious gastroenteritis is common and usually self-limited. Intestinal perforation is a rare complication of the infectious colitis caused by Campylobacter, and only handful of cases have been reported. This is the first published case report of pediatric Campylobacter intestinal perforation located in the sigmoid colon.

Case presentation

A 15-year-old previously Taiwanese healthy boy presented with 5 days of fever up to 39.8 °C, with right lower quadrant abdominal pain and watery diarrhea. Although he received antimotility agents and antipyretics at a local clinic to relieve symptoms, he came to the emergency department with signs of shock manifesting as hypothermia to 35.2 °C, tachycardia, and low blood pressure. Laboratory testing demonstrated leukocytosis with left shift and significant elevation of C-reactive protein. Stool and blood cultures were obtained, and he was admitted for fluid challenge and antibiotic treatment. On the second day of admission, he suffered from sudden onset of severe, diffuse abdominal pain. Physical examination revealed muscle guarding, rebounding tenderness, and silent bowel sound. Abdominal X-ray showed subdiaphragmatic free air at standing view. The patient underwent emergent exploratory laparotomy, which revealed sigmoid colon perforation about 0.5 cm. Enterolysis and repair of sigmoid colon were performed. Intraoperative stool specimen nucleic acid amplification testing had turned positive for Campylobacter spp. with negative results for other bacterial pathogens. His symptoms improved and he tolerated food well, and was discharged 15 days after admission.

Conclusions

We present this case because of the rarity of Campylobacter-induced sigmoid colon perforation in the pediatric population. It is important to keep in mind that sigmoid colon perforation can be due to an infectious cause, and one of the culprits can be Campylobacter. Infectious colitis caused by Campylobacter spp. should be managed cautiously and the use of antimotility agents in such conditions should be considered judiciously.